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virus adsorption of water-stable quaternized chitosan nanofibers.the burden of unsafe drinking water is responsible for millions of deaths each year. to relieve this burden, we are in search of an inexpensive material that can adsorb pathogens from drinking water. in this pursuit, we have studied the natural carbohydrate, chitosan. to impart virus removal features, chitosan has been functionalized with a quaternary amine to form quaternized chitosan n-[(2-hydroxyl-3-trimethylammonium) propyl] chitosan (htcc). htcc can be electrospun into nanofibers with the n ...201424561959
human cases of sindbis fever in south africa, 2006-2010.sindbis virus (sinv), the prototype positive-sense rna alphavirus, causes febrile arthritis and is present throughout afro-eurasia. little is known of the epidemiology of sindbis fever due to insufficient surveillance in most endemic countries. the epidemiological features of sindbis fever in humans in south africa are described here based on a retrospective study of suspected arbovirus cases submitted for laboratory investigation from 2006 to 2010. cases were detected annually mostly during the ...201423611492
neuronal network imaging in acute slices using ca2+ sensitive bioluminescent reporter.genetically encoded indicators are valuable tools to study intracellular signaling cascades in real time using fluorescent or bioluminescent imaging techniques. imaging of ca(2+) indicators is widely used to record transient intracellular ca(2+) increases associated with bioelectrical activity. the natural bioluminescent ca(2+) sensor aequorin has been historically the first ca(2+) indicator used to address biological questions. aequorin imaging offers several advantages over fluorescent reporte ...201424166366
seroprevalence of sindbis virus and associated risk factors in northern sweden.mosquito-borne sindbis virus (sinv) cause disease characterized by rash, fever and arthritis which often leads to long-lasting arthralgia. to determine the seroprevalence of sinv and associated risk factors in northern sweden, a randomly selected population aged between 25 and 74 years were invited to join the monica study. serum from 1611 samples were analysed for specific igg antibodies. overall, 2·9% had igg against sinv. more men (3·7%) than women (2·0%) were sinv seropositive (p = 0·047) an ...201424029159
parp13 regulates cellular mrna post-transcriptionally and functions as a pro-apoptotic factor by destabilizing trailr4 transcript.poly(adp-ribose) polymerase-13 (parp13/zap/zc3hav1) is an antiviral factor, active against specific rna viruses such as murine leukaemia virus, sindbis virus and human immunodeficiency virus. during infection, parp13 binds viral rna via its four ccch-type zinc-finger domains and targets it for degradation by recruiting cellular messenger rna (mrna) decay factors such as the exosome complex and xrn1. here we show that parp13 binds to and regulates cellular mrnas in the absence of viral infection. ...201425382312
il-1r1 signaling regulates cxcl12-mediated t cell localization and fate within the central nervous system during west nile virus encephalitis.immune cell entry into the virally infected cns is vital for promoting viral clearance yet may contribute to neuropathology if not rigorously regulated. we previously showed that signaling through il-1r1 is critical for effector t cell reactivation and virologic control within the cns during murine west nile virus (wnv) encephalitis. wnv-infected il-1r1(-/-) mice also display increased parenchymal penetration of cd8(+) t cells despite lack of cd4-mediated full activation, suggesting dysregulatio ...201425200953
intracellular sensing of complement c3 activates cell autonomous immunity.pathogens traverse multiple barriers during infection, including cell membranes. we found that during this transition, pathogens carried covalently attached complement c3 into the cell, triggering immediate signaling and effector responses. sensing of c3 in the cytosol activated mitochondrial antiviral signaling (mavs)-dependent signaling cascades and induced proinflammatory cytokine secretion. c3 also flagged viruses for rapid proteasomal degradation, preventing their replication. this system c ...201425190799
viral rnas are unusually compact.a majority of viruses are composed of long single-stranded genomic rna molecules encapsulated by protein shells with diameters of just a few tens of nanometers. we examine the extent to which these viral rnas have evolved to be physically compact molecules to facilitate encapsulation. measurements of equal-length viral, non-viral, coding and non-coding rnas show viral rnas to have among the smallest sizes in solution, i.e., the highest gel-electrophoretic mobilities and the smallest hydrodynamic ...201425188030
current strategic thinking for the development of a trivalent alphavirus vaccine for human use.vaccinations against the encephalitic alphaviruses (western, eastern, and venezuelan equine encephalitis virus) are of significant interest to biological defense, public health, and agricultural communities alike. although vaccines licensed for veterinary applications are used in the western hemisphere and attenuated or inactivated viruses have been used under investigational new drug status to protect at-risk personnel, there are currently no licensed vaccines for use in humans. here, we will d ...201424842880
nup98 promotes antiviral gene expression to restrict rna viral infection in drosophila.in response to infection, the innate immune system rapidly activates an elaborate and tightly orchestrated gene expression program to induce critical antimicrobial genes. while many key players in this program have been identified in disparate biological systems, it is clear that there are additional uncharacterized mechanisms at play. our previous studies revealed that a rapidly-induced antiviral gene expression program is active against disparate human arthropod-borne viruses in drosophila. mo ...201425197089
inhibition of west nile virus by calbindin-d28k.evidence indicates that west nile virus (wnv) employs ca(2+) influx for its replication. moreover, calcium buffer proteins, such as calbindin d28k (cb-d28k), may play an important role mitigating cellular destruction due to disease processes, and more specifically, in some neurological diseases. we addressed the hypothesis that cb-d28k inhibits wnv replication in cell culture and infected rodents. wnv envelope immunoreactivity (ir) was not readily co-localized with cb-d28k ir in wnv-infected ver ...201425180779
host factors that interact with the pestivirus n-terminal protease, npro, are components of the ribonucleoprotein complex.the viral n-terminal protease n(pro) of pestiviruses counteracts cellular antiviral defenses through inhibition of irf3. here we used mass spectrometry to identify a new role for n(pro) through its interaction with over 55 associated proteins, mainly ribosomal proteins and ribonucleoproteins, including rna helicase a (dhx9), y-box binding protein (ybx1), ddx3, ddx5, eif3, igf2bp1, multiple myeloma tumor protein 2, interleukin enhancer binding factor 3 (iebp3), guanine nucleotide binding protein ...201424965446
virus-host interactomics: new insights and opportunities for antiviral drug discovery.the current therapeutic arsenal against viral infections remains limited, with often poor efficacy and incomplete coverage, and appears inadequate to face the emergence of drug resistance. our understanding of viral biology and pathophysiology and our ability to develop a more effective antiviral arsenal would greatly benefit from a more comprehensive picture of the events that lead to viral replication and associated symptoms. towards this goal, the construction of virus-host interactomes is in ...201425593595
interferon-stimulated gene 15 (isg15) and isg15-linked proteins can associate with members of the selective autophagic process, histone deacetylase 6 (hdac6) and sqstm1/p62.the ubiquitin-like interferon (ifn)-stimulated gene 15 (isg15) and its specific e1, e2, and e3 enzymes are transcriptionally induced by type i ifns. isg15 conjugates newly synthesized proteins. isg15 linkage to proteins appears to be an important downstream ifn signaling event that discriminates cellular and pathogenic proteins synthesized during ifn stimulation from existing proteins. this eliminates potentially pathogenic proteins as the cell attempts to return to normal homeostasis after ifn ...201425429107
interferon-induced ifit proteins: their role in viral pathogenesis.a major component of the protective antiviral host defense is contributed by the intracellular actions of the proteins encoded by interferon-stimulated genes (isgs); among these are the interferon-induced proteins with tetratricopeptide repeats (ifits), consisting of four members in human and three in mouse. ifit proteins do not have any known enzyme activity. instead, they inhibit virus replication by binding and regulating the functions of cellular and viral proteins and rnas. although all ifi ...201425428874
the nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis.all coronaviruses encode a macrodomain containing adp-ribose-1"-phosphatase (adrp) activity within the n terminus of nonstructural protein 3 (nsp3). previous work showed that mouse hepatitis virus strain a59 (mhv-a59) with a mutated catalytic site (n1348a) replicated similarly to wild-type virus but was unable to cause acute hepatitis in mice. to determine whether this attenuated phenotype is applicable to multiple disease models, we mutated the catalytic residue in the jhm strain of mhv (jhmv), ...201425428866
going viral and the fatal vulnerability of neurons from immunity, not from infection. 201425422437
detection of chikungunya virus antigen by a novel rapid immunochromatographic test.chikungunya fever is a mosquito-borne disease of key public health importance in tropical and subtropical countries. although severe joint pain is the most distinguishing feature of chikungunya fever, diagnosis remains difficult because the symptoms of chikungunya fever are shared by many pathogens, including dengue fever. the present study aimed to develop a new immunochromatographic diagnosis test for the detection of chikungunya virus antigen in serum. mice were immunized with isolates from p ...201425411170
mosquito immunity against arboviruses.arthropod-borne viruses (arboviruses) pose a significant threat to global health, causing human disease with increasing geographic range and severity. the recent availability of the genome sequences of medically important mosquito species has kick-started investigations into the molecular basis of how mosquito vectors control arbovirus infection. here, we discuss recent findings concerning the role of the mosquito immune system in antiviral defense, interactions between arboviruses and fundament ...201425415198
emerging biomedical applications of nano-chitins and nano-chitosans obtained via advanced eco-friendly technologies from marine resources.the present review article is intended to direct attention to the technological advances made in the 2010-2014 quinquennium for the isolation and manufacture of nanofibrillar chitin and chitosan. otherwise called nanocrystals or whiskers, n-chitin and n-chitosan are obtained either by mechanical chitin disassembly and fibrillation optionally assisted by sonication, or by e-spinning of solutions of polysaccharides often accompanied by poly(ethylene oxide) or poly(caprolactone). the biomedical are ...201425415349
enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication.redox homeostasis is an important host factor determining the outcome of infectious disease. enterovirus 71 (ev71) infection has become an important endemic disease in southeast asia and china. we have previously shown that oxidative stress promotes viral replication, and progeny virus induces oxidative stress in host cells. the detailed mechanism for reactive oxygen species (ros) generation in infected cells remains elusive. in the current study, we demonstrate that mitochondria were a major ro ...201425401329
immune responses to non-tumor antigens in the central nervous system.the central nervous system (cns), once viewed as an immune-privileged site protected by the blood-brain barrier (bbb), is now known to be a dynamic immunological environment through which immune cells migrate to prevent and respond to events such as localized infection. during these responses, endogenous glial cells, including astrocytes and microglia, become highly reactive and may secrete inflammatory mediators that regulate bbb permeability and recruit additional circulating immune cells. her ...201425431758
a drosophila toolkit for the visualization and quantification of viral replication launched from transgenic genomes.arthropod rna viruses pose a serious threat to human health, yet many aspects of their replication cycle remain incompletely understood. here we describe a versatile drosophila toolkit of transgenic, self-replicating genomes ('replicons') from sindbis virus that allow rapid visualization and quantification of viral replication in vivo. we generated replicons expressing luciferase for the quantification of viral replication, serving as useful new tools for large-scale genetic screens for identify ...201425386852
mechanism and treatment for learning and memory deficits in mouse models of noonan syndrome.in noonan syndrome (ns) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. here, we report that knock-in mice expressing either of two ns-associated mutations in ptpn11, which encodes the nonreceptor protein tyrosine phosphatase shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (ltp). in addition, viral overexpression of an ns-associated allele ptpn11(d61g) in adult mouse hippocampus result ...201425383899
macroautophagy proteins assist epstein barr virus production and get incorporated into the virus particles.epstein barr virus (ebv) persists as a latent herpes virus infection in the majority of the adult human population. the virus can reactivate from this latent infection into lytic replication for virus particle production. here, we report that autophagic membranes, which engulf cytoplasmic constituents during macroautophagy and transport them to lysosomal degradation, are stabilized by lytic ebv replication in infected epithelial and b cells. inhibition of autophagic membrane formation compromise ...201426137519
organ-specific protective role of nkt cells in virus-induced inflammatory demyelination and myocarditis depends on mouse strain.theiler's murine encephalomyelitis virus (tmev) can induce demyelination or myocarditis in susceptible mouse strains. a deficiency of nkt cells exacerbated tmev-induced demyelinating disease (tmev-idd) in sjl/j and balb/c mice. in c57bl/6 background, however, nkt-cell-deficient jα18 ko mice remained as resistant to tmev-idd as wild-type mice. echocardiography and histology showed that jα18 ko mice developed more severe myocarditis (greater t cell infiltration and fibrosis) than wild-type mice, s ...201425434008
viruses and rna interference: issues and controversies.the question of whether any mammalian cells are able to mount an effective rna interference-mediated antiviral innate immune response has remained highly controversial. in this gem, i review recent data addressing this important issue and propose a testable hypothesis that can explain many of the apparently contradictory results published in this area of research.201425210170
interleukin 10 modulation of pathogenic th17 cells during fatal alphavirus encephalomyelitis.mosquito-borne alphaviruses are important causes of epidemic encephalomyelitis. neuronal cell death during fatal alphavirus encephalomyelitis is immune-mediated; however, the types of cells involved and their regulation have not been determined. we show that the virus-induced inflammatory response was accompanied by production of the regulatory cytokine il-10, and in the absence of il-10, paralytic disease occurred earlier and mice died faster. to determine the reason for accelerated disease in ...201425362048
a cytoplasmic rna virus generates functional viral small rnas and regulates viral ires activity in mammalian cells.the roles of virus-derived small rnas (vsrnas) have been studied in plants and insects. however, the generation and function of small rnas from cytoplasmic rna viruses in mammalian cells remain unexplored. this study describes four vsrnas that were detected in enterovirus 71-infected cells using next-generation sequencing and northern blots. viral infection produced substantial levels (>10(5) copy numbers per cell) of vsrna1, one of the four vsrnas. we also demonstrated that dicer is involved in ...201425352551
cellular responses to sindbis virus infection of neural progenitors derived from human embryonic stem cells.sindbis virus (sinv) causes age-dependent encephalitis in mice, and therefore serves as a model to study viral encephalitis. sinv is used as a vector for the delivery of genes into selected neural stem cell lines; however, the toxicity and side effects of this vector have rarely been discussed. in this context, we investigated the cellular responses of human embryonic stem cell (hescs) derived neural progenitors (hnpcs) to sinv infection by assessing susceptibility of the cells to sinv infection ...201425343994
putative novel lineage of west nile virus in uranotaenia unguiculata mosquito, hungary.west nile virus (wnv) is an increasing public health concern in europe with numerous human cases. a total of 23,029 female mosquitoes were tested for a variety of mosquito-borne flaviviruses and orthobunyaviruses supposedly endemic in southern transdanubia, hungary, in the frames of a large-scale surveillance between 2011 and 2013. wnv nucleic acid was detected in a single pool containing uranotaenia unguiculata mosquitoes. sequence- and phylogenetic analyses for two different regions (ns5 and e ...201425674630
arboviral bottlenecks and challenges to maintaining diversity and fitness during mosquito transmission.the term arbovirus denotes viruses that are transmitted by arthropods, such as ticks, mosquitoes, and other biting arthropods. the infection of these vectors produces a certain set of evolutionary pressures on the virus; involving migration from the midgut, where the blood meal containing the virus is processed, to the salivary glands, in order to transmit the virus to the next host. during this process the virus is subject to numerous bottlenecks, stochastic events that significantly reduce the ...201425341663
ribosomal readthrough at a short uga stop codon context triggers dual localization of metabolic enzymes in fungi and animals.translation of mrna into a polypeptide chain is a highly accurate process. many prokaryotic and eukaryotic viruses, however, use leaky termination of translation to optimize their coding capacity. although growing evidence indicates the occurrence of ribosomal readthrough also in higher organisms, a biological function for the resulting extended proteins has been elucidated only in very few cases. here, we report that in human cells programmed stop codon readthrough is used to generate peroxisom ...201425340584
autophagy restricts hiv-1 infection by selectively degrading tat in cd4+ t lymphocytes.autophagy is a ubiquitous mechanism involved in the lysosomal-mediated degradation of cellular components when they are engulfed in vacuoles called autophagosomes. autophagy is also recognized as an important regulator of the innate and adaptive immune responses against numerous pathogens, which have, therefore, developed strategies to block or use the autophagy machinery to their own benefit. upon human immunodeficiency virus type 1 (hiv-1) infection, viral envelope (env) glycoproteins induce a ...201425339774
the ubiquitin c-terminal hydrolase l1 (uch-l1) c terminus plays a key role in protein stability, but its farnesylation is not required for membrane association in primary neurons.ubiquitin c-terminal hydrolase l1 (uch-l1) is a deubiquitinating enzyme that is highly expressed in neurons. a possible role for uch-l1 in neurodegeneration has been highlighted because of its presence in lewy bodies associated with parkinson disease and neurofibrillary tangles observed in alzheimer disease. uch-l1 exists in two forms in neurons, a soluble cytoplasmic form (uch-l1(c)) and a membrane-associated form (uch-l1(m)). alzheimer brains show reduced levels of soluble uch-l1(c) correlatin ...201425326379
venezuelan equine encephalitis virus variants lacking transcription inhibitory functions demonstrate highly attenuated phenotype.alphaviruses represent a significant public health threat worldwide. they are transmitted by mosquitoes and cause a variety of human diseases ranging from severe meningoencephalitis to polyarthritis. to date, no efficient and safe vaccines have been developed against any alphavirus infection. however, in recent years, significant progress has been made in understanding the mechanism of alphavirus replication and virus-host interactions. these data have provided the possibility for the developmen ...201425320296
differentiation of neurons restricts arbovirus replication and increases expression of the alpha isoform of irf-7.susceptibility to alphavirus infection is age dependent, and host maturation is associated with decreased virus replication and less severe encephalitis. to identify factors associated with maturation-dependent restriction of virus replication, we studied ap-7 rat olfactory bulb neuronal cells, which can differentiate in vitro. differentiation was associated with a 150- to 1,000-fold decrease in replication of the alphaviruses sindbis virus and venezuelan equine encephalitis virus, as well as la ...201425320290
variations in ph sensitivity, acid stability, and fusogenicity of three influenza virus h3 subtypes.influenza a virus strains adapt to achieve successful entry into host species. entry is mediated by the viral membrane protein hemagglutinin (ha), which triggers membrane fusion and genome release under acidic conditions in the endosome. in addition to changes in the receptor binding domain, the acid stability of ha has been linked to the successful transmission of virus between avian and human hosts. however, to fully understand the connection between changes in ha and host tropism, additional ...201425320308
novel mode of isg15-mediated protection against influenza a virus and sendai virus in mice.isg15 is a diubiquitin-like modifier and one of the most rapidly induced genes upon type i interferon stimulation. hundreds of host proteins and a number of viral proteins have been shown to be isgylated, and understanding how these modifications affect the interferon response and virus replication has been of considerable interest. isg15(-/-) mice exhibit increased susceptibility to viral infection, and in the case of influenza b virus and vaccinia virus, isg15 conjugation has been shown to res ...201425320315
alginate hydrogel protects encapsulated hepatic huh-7 cells against hepatitis c virus and other viral infections.cell microencapsulation in alginate hydrogel has shown interesting applications in regenerative medicine and the biomedical field through implantation of encapsulated tissue or for bioartificial organ development. although alginate solution is known to have low antiviral activity, the same property regarding alginate gel has not yet been studied. the aim of this work is to investigate the potential protective effect of alginate encapsulation against hepatitis c virus (hcv) infection for a hepati ...201425310111
age-dependent myeloid dendritic cell responses mediate resistance to la crosse virus-induced neurological disease.la crosse virus (lacv) is the major cause of pediatric viral encephalitis in the united states; however, the mechanisms responsible for age-related susceptibility in the pediatric population are not well understood. our current studies in a mouse model of lacv infection indicated that differences in myeloid dendritic cell (mdc) responses between weanling and adult mice accounted for susceptibility to lacv-induced neurological disease. we found that type i interferon (ifn) responses were signific ...201425008929
short self-interacting n-terminal region of rubella virus capsid protein is essential for cooperative actions of capsid and nonstructural p150 proteins.nucleocapsid formation is a primary function of the rubella virus capsid protein, which also promotes viral rna synthesis via an unknown mechanism. the present study demonstrates that in infected cells, the capsid protein is associated with the nonstructural p150 protein via the short self-interacting n-terminal region of the capsid protein. mutational analyses indicated that hydrophobic amino acids in this n-terminal region are essential for its n-terminal self-interaction, which is critical fo ...201425056903
regulation of autophagic activation by rta of epstein-barr virus via the extracellular signal-regulated kinase pathway.autophagy is an intracellular degradation pathway that provides a host defense mechanism against intracellular pathogens. however, many viruses exploit this mechanism to promote their replication. this study shows that lytic induction of epstein-barr virus (ebv) increases the membrane-bound form of lc3 (lc3-ii) and lc3-containing punctate structures in ebv-positive cells. transfecting 293t cells with a plasmid that expresses rta also induces autophagy, revealing that rta is responsible for autop ...201425122800
a chimeric virus-mouse model system for evaluating the function and inhibition of papain-like proteases of emerging coronaviruses.to combat emerging coronaviruses, developing safe and efficient platforms to evaluate viral protease activities and the efficacy of protease inhibitors is a high priority. here, we exploit a biosafety level 2 (bsl-2) chimeric sindbis virus system to evaluate protease activities and the efficacy of inhibitors directed against the papain-like protease (plpro) of severe acute respiratory syndrome coronavirus (sars-cov), a biosafety level 3 (bsl-3) pathogen. we engineered sindbis virus to coexpress ...201425100850
engineering recombinant orsay virus directly in the metazoan host caenorhabditis elegans.the recent identification of orsay virus, the first virus that is capable of naturally infecting caenorhabditis elegans, provides a unique opportunity to explore host-virus interaction studies in this invaluable model organism. a key feature of this system is the robust genetic tractability of the host, c. elegans, which would ideally be complemented by the ability to genetically manipulate orsay virus in parallel. to this end, we developed a plasmid-based reverse genetics system for orsay virus ...201425078701
phosphatidylserine receptors: enhancers of enveloped virus entry and infection.a variety of both rna and dna viruses envelop their capsids in a lipid bilayer. one of the more recently appreciated benefits this envelope is incorporation of phosphatidylserine (ptdser). surface exposure of ptdser disguises viruses as apoptotic bodies; tricking cells into engulfing virions. this mechanism is termed apoptotic mimicry. several ptdser receptors have been identified to enhance virus entry and we have termed this group of proteins ptdser-mediated virus entry enhancing receptors or ...201425277499
potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying rna vaccine expressing hiv type 1 envelope with a cationic nanoemulsion.self-amplifying messenger rna (mrna) of positive-strand rna viruses are effective vectors for in situ expression of vaccine antigens and have potential as a new vaccine technology platform well suited for global health applications. the sam vaccine platform is based on a synthetic, self-amplifying mrna delivered by a nonviral delivery system. the safety and immunogenicity of an hiv sam vaccine encoding a clade c envelope glycoprotein formulated with a cationic nanoemulsion (cne) delivery system ...201425234719
sponging of cellular proteins by viral rnas.viral rnas accumulate to high levels during infection and interact with a variety of cellular factors including mirnas and rna-binding proteins. although many of these interactions exist to directly modulate replication, translation and decay of viral transcripts, evidence is emerging that abundant viral rnas may in certain cases serve as a sponge to sequester host non-coding rnas and proteins. by effectively reducing the ability of cellular rna binding proteins to regulate host cell gene expres ...201425233339
virus-mediated compartmentalization of the host translational machinery.viruses require the host translational apparatus to synthesize viral proteins. host stress response mechanisms that suppress translation, therefore, represent a significant obstacle that viruses must overcome. here, we report a strategy whereby the mammalian orthoreoviruses compartmentalize the translational machinery within virus-induced inclusions known as viral factories (vf). vf are the sites of reovirus replication and assembly but were thought not to contain ribosomes. it was assumed viral ...201425227463
the toll-dorsal pathway is required for resistance to viral oral infection in drosophila.pathogen entry route can have a strong impact on the result of microbial infections in different hosts, including insects. drosophila melanogaster has been a successful model system to study the immune response to systemic viral infection. here we investigate the role of the toll pathway in resistance to oral viral infection in d. melanogaster. we show that several toll pathway components, including spätzle, toll, pelle and the nf-kb-like transcription factor dorsal, are required to resist oral ...201425473839
mosquitoes (diptera: culicidae) and their relevance as disease vectors in the city of vienna, austria.mosquitoes (diptera: culicidae) are important vectors for a wide range of pathogenic organisms. as large parts of the human population in developed countries live in cities, the occurrence of vector-borne diseases in urban areas is of particular interest for epidemiologists and public health authorities. in this study, we investigated the mosquito occurrence in the city of vienna, austria, in order to estimate the risk of transmission of mosquito-borne diseases. mosquitoes were captured using di ...201425468380
drosophila c virus systemic infection leads to intestinal obstruction.drosophila c virus (dcv) is a positive-sense rna virus belonging to the dicistroviridae family. this natural pathogen of the model organism drosophila melanogaster is commonly used to investigate antiviral host defense in flies, which involves both rna interference and inducible responses. although lethality is used routinely as a readout for the efficiency of the antiviral immune response in these studies, virus-induced pathologies in flies still are poorly understood. here, we characterize the ...201425253354
pick1 links ampa receptor stimulation to cdc42.rho-family gtpases control numerous cell biological processes via effects on actin dynamics, such as cell migration, cell adhesion, morphogenesis and vesicle traffic. in neurons, they are involved in dendritic spine morphogenesis and other aspects of neuronal morphology via regulation of the actin cytoskeleton. the rho-family member cdc42 regulates dendritic spine morphology via its effector n-wasp, which activates the actin-nucleating arp2/3 complex. excitatory synaptic transmission is known to ...201425475687
the combined use of alphavirus replicons and pseudoinfectious particles for the discovery of antivirals derived from natural products.alphaviruses are a prominent class of reemergent pathogens due to their globally expanding ranges, potential for lethality, and possible use as bioweapons. the absence of effective treatments for alphaviruses highlights the need for innovative strategies to identify antiviral agents. primary screens that use noninfectious self-replicating rnas, termed replicons, have been used to identify potential antiviral compounds for alphaviruses. only inhibitors of viral genome replication, however, will b ...201425550354
antiviral immunity of anopheles gambiae is highly compartmentalized, with distinct roles for rna interference and gut microbiota.arboviruses are transmitted by mosquitoes and other arthropods to humans and animals. the risk associated with these viruses is increasing worldwide, including new emergence in europe and the americas. anopheline mosquitoes are vectors of human malaria but are believed to transmit one known arbovirus, o'nyong-nyong virus, whereas aedes mosquitoes transmit many. anopheles interactions with viruses have been little studied, and the initial antiviral response in the midgut has not been examined. he ...201425548172
upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon beta producers that protect from lethal encephalitis.previously we found that following intranasal (i.n.) infection with neurotropic vesicular stomatitis virus (vsv) type i interferon receptor (ifnar) triggering of neuroectodermal cells was critically required to constrain intracerebral virus spread. to address whether locally active ifn-β was induced proximally, we studied spatiotemporal conditions of vsv-mediated ifn-β induction. to this end, we performed infection studies with ifn-β reporter mice. one day after intravenous (i.v.) vsv infection, ...201425540366
deficiency in either 4e-bp1 or 4e-bp2 augments innate antiviral immune responses.genetic deletion of both 4e-bp1 and 4e-bp2 was found to protect cells against viral infections. here we demonstrate that the individual loss of either 4e-bp1 or 4e-bp2 in mouse embryonic fibroblasts (mefs) is sufficient to confer viral resistance. shrna-mediated silencing of 4e-bp1 or 4e-bp2 renders mefs resistant to viruses, and compared to wild type cells, mefs knockout for either 4e-bp1 or 4e-bp2 exhibit enhanced translation of irf-7 and consequently increased innate immune response to viruse ...201425531441
enhancing and initiating phage-based therapies.drug development has typically been a primary foundation of strategy for systematic, long-range management of pathogenic cells. however, drug development is limited in speed and flexibility when response is needed to changes in pathogenic cells, especially changes that produce drug-resistance. the high replication speed and high diversity of phages are potentially useful for increasing both response speed and response flexibility when changes occur in either drug resistance or other aspects of p ...201426713220
capacity of mosquitoes to transmit malaria depends on larval environment.adult traits of holometabolous insects such as reproduction and survival can be shaped by conditions experienced during larval development. these "carry-over" effects influence not only individual life history and fitness, but can also impact interactions between insect hosts and parasites. despite this, the implications of larval conditions for the transmission of human, wildlife and plant diseases that are vectored by insects remain poorly understood.201425496502
oxidative stress influences positive strand rna virus genome synthesis and capping.flaviviruses are 5' capped positive-stranded rna viruses that replicate their genomes within endoplasmic reticulum-derived vesicles. flaviviruses are well known to induce oxidative stress late in infection but it is unknown if oxidative stress plays a positive role in the viral rna replication cycle. we therefore examined how oxidation affects flavivirus rna replication. we found that antioxidant treatment reduced virus production, reduced the viral positive-to-negative strand rna ratio, and res ...201425514423
murine herc6 plays a critical role in protein isgylation in vivo and has an isgylation-independent function in seminal vesicles.isg15 conjugation (isgylation) to proteins is a multistep process involving interferon (ifn)-inducible ube1l (e1), ubch8 (e2), and isg15 e3 ligases (e3s). studies performed over the past several years have shown that isgylation plays a pivotal role in the host antiviral response against certain viruses. recent in vitro studies revealed that human herc5 and mouse herc6 are major isg15 e3 ligases, respectively. however, the global function of herc5/6 proteins in vivo still remains unclear. here, w ...201425406959
recovery of recombinant crimean congo hemorrhagic fever virus reveals a function for non-structural glycoproteins cleavage by furin.crimean congo hemorrhagic fever virus (cchfv) is a negative-strand rna virus of the family bunyaviridae (genus: nairovirus). in humans, cchfv causes fever, hemorrhage, severe thrombocytopenia, and high fatality. a major impediment in precisely determining the basis of cchfv's high pathogenicity has been the lack of methodology to produce recombinant cchfv. we developed a reverse genetics system based on transfecting plasmids into bsr-t7/5 and huh7 cells. in our system, bacteriophage t7 rna polym ...201525933376
detection of persistent chikungunya virus rna but not infectious virus in experimental vertical transmission in aedes aegypti from malaysia.vertical transmission may contribute to the maintenance of arthropod-borne viruses, but its existence in chikungunya virus (chikv) is unclear. experimental vertical transmission of infectious clones of chikv in aedes aegypti mosquitoes from malaysia was investigated. eggs and adult progeny from the second gonotrophic cycles of infected parental mosquitoes were tested. using polymerase chain reaction (pcr), 56.3% of pooled eggs and 10% of adult progeny had detectable chikv rna, but no samples had ...201526598564
inhibition of cav3.2 t-type calcium channels by its intracellular i-ii loop.voltage-dependent calcium channels (cav) of the t-type family (cav3.1, cav3.2, and cav3.3) are activated by low threshold membrane depolarization and contribute greatly to neuronal network excitability. enhanced t-type channel activity, especially cav3.2, contributes to disease states, including absence epilepsy. interestingly, the intracellular loop connecting domains i and ii (i-ii loop) of cav3.2 channels is implicated in the control of both surface expression and channel gating, indicating t ...201525931121
comparison of α-glucosyl hesperidin of citrus fruits and epigallocatechin gallate of green tea on the loss of rotavirus infectivity in cell culture.a number of secondary plant metabolites (e.g., flavonoids) possess antiviral/antimicrobial activity. most flavonoids, however, are difficult to study, as they are immiscible in water-based systems. the relatively new semisynthetic α-glucosyl hesperitin (gh), and the natural plant product epigallocatechin gallate (egcg) are unique among most flavonoids, as these flavonoids are highly soluble. the antiviral activity of these plant metabolites were investigated using the rotavirus as a model enteri ...201525972850
a neuron-specific antiviral mechanism prevents lethal flaviviral infection of mosquitoes.mosquitoes are natural vectors for many etiologic agents of human viral diseases. mosquito-borne flaviviruses can persistently infect the mosquito central nervous system without causing dramatic pathology or influencing the mosquito behavior and lifespan. the mechanism by which the mosquito nervous system resists flaviviral infection is still largely unknown. here we report that an aedes aegypti homologue of the neural factor hikaru genki (aahig) efficiently restricts flavivirus infection of the ...201525915054
the hub protein loquacious connects the microrna and short interfering rna pathways in mosquitoes.aedes aegypti mosquitoes vector several arboviruses of global health significance, including dengue viruses and chikungunya virus. rna interference (rnai) plays an important role in antiviral immunity, gene regulation and protection from transposable elements. double-stranded rna binding proteins (dsrbps) are important for efficient rnai; in drosophila functional specialization of the mirna, endo-sirna and exo-sirna pathway is aided by the dsrbps loquacious (loqs-pb, loqs-pd) and r2d2, respectiv ...201525765650
simultaneous recording of fluorescence and electrical signals by photometric patch electrode in deep brain regions in vivo.despite its widespread use, high-resolution imaging with multiphoton microscopy to record neuronal signals in vivo is limited to the surface of brain tissue because of limited light penetration. moreover, most imaging studies do not simultaneously record electrical neural activity, which is, however, crucial to understanding brain function. accordingly, we developed a photometric patch electrode (pme) to overcome the depth limitation of optical measurements and also enable the simultaneous recor ...201525761950
activation of tomato bushy stunt virus rna-dependent rna polymerase by cellular heat shock protein 70 is enhanced by phospholipids in vitro.similar to other positive-strand rna viruses, tombusviruses are replicated by the membrane-bound viral replicase complex (vrc). the vrc consists of the p92 virus-coded rna-dependent rna polymerase (rdrp), the viral p33 rna chaperone, and several co-opted host proteins. in order to become a functional rdrp after its translation, the p92 replication protein should be incorporated into the vrc, followed by its activation. we have previously shown in a cell-free yeast extract-based assay that the ac ...201525762742
role of zinc-finger anti-viral protein in host defense against sindbis virus.accumulating evidence indicates that type i interferon (ifn) mediates the host protective response to rna viruses. however, the anti-viral effector molecules involved in this response have not been fully identified. here, we show that zinc-finger anti-viral protein (zap), an ifn-inducible gene, plays a critical role in the elimination of sindbis virus (sinv) in vitro and in vivo. the loss of zap greatly enhances the replication of sinv but does not inhibit type i ifn production in primary mouse ...201525758257
mechanisms of innate immune evasion in re-emerging rna viruses.recent outbreaks of ebola, west nile, chikungunya, middle eastern respiratory and other emerging/re-emerging rna viruses continue to highlight the need to further understand the virus-host interactions that govern disease severity and infection outcome. as part of the early host antiviral defense, the innate immune system mediates pathogen recognition and initiation of potent antiviral programs that serve to limit virus replication, limit virus spread and activate adaptive immune responses. conc ...201525765605
the role of misshapen nck-related kinase (mink), a novel ste20 family kinase, in the ires-mediated protein translation of human enterovirus 71.human enterovirus 71 (ev71) commonly causes hand, foot and mouth disease in young children, and occasional occurrences of neurological complications can be fatal. in this study, a high-throughput cell-based screening on the serine/threonine kinase sirna library was performed to identify potential antiviral agents against ev71 replication. among the hits, misshapen/niks-related kinase (mink) was selected for detailed analysis due to its strong inhibitory profile and novelty. in the investigation ...201525747578
xrn1 stalling in the 5' utr of hepatitis c virus and bovine viral diarrhea virus is associated with dysregulated host mrna stability.we demonstrate that both hepatitis c virus (hcv) and bovine viral diarrhea virus (bvdv) contain regions in their 5' utrs that stall and repress the enzymatic activity of the cellular 5'-3' exoribonuclease xrn1, resulting in dramatic changes in the stability of cellular mrnas. we used biochemical assays, virus infections, and transfection of the hcv and bvdv 5' untranslated regions in the absence of other viral gene products to directly demonstrate the existence and mechanism of this novel host-v ...201525747802
to translate, or not to translate: viral and host mrna regulation by interferon-stimulated genes.type i interferon (ifn) is one of the first lines of cellular defense against viral pathogens. as a result of ifn signaling, a wide array of ifn-stimulated gene (isg) products is upregulated to target different stages of the viral life cycle. we review recent findings implicating a subset of isgs in translational regulation of viral and host mrnas. translation inhibition is mediated either by binding to viral rna or by disrupting physiological interactions or levels of the translation complex co ...201525748385
impacts of the creation, expansion and management of english wetlands on mosquito presence and abundance - developing strategies for future disease mitigation.the incidence of mosquito-borne diseases is increasing in europe, partly due to the incursion of a number of invasive species known to be vectors of dengue and chikungunya viruses, but also due to the involvement of native species in the transmission of west nile virus and malaria. for some of these pathogens, there is a risk of the re-emergence of vector-borne diseases that were once widespread in europe, but declined partly due to large-scale land-drainage projects. some mosquito species explo ...201525889666
forced complementation between subgenomic rnas: does human immunodeficiency type 1 virus reverse transcription occur in viral core, cytoplasm, or early endosome?although the process of reverse transcription is well elucidated, it remains unclear if viral core disruption provides a more cellular or viral milieu for hiv-1 reverse transcription. we have devised a method to require mixing of viral cores or core constituents to produce infectious progeny virus by a bipartite subgenomic rna (sgrna) system, in which hiv-1 cplt_r/u5/gag/δpol and nfl sgrnas are complementary to each other and when together can complete viral reverse transcription. only the heter ...201527239643
a small antigenic determinant of the chikungunya virus e2 protein is sufficient to induce neutralizing antibodies which are partially protective in mice.the mosquito-borne chikungunya virus (chikv) causes high fever and severe joint pain in humans. it is expected to spread in the future to europe and has recently reached the usa due to globalization, climate change and vector switch. despite this, little is known about the virus life cycle and, so far, there is no specific treatment or vaccination against chikungunya infections. we aimed here to identify small antigenic determinants of the chikv e2 protein able to induce neutralizing immune resp ...201525905779
the brainstem oscillator for whisking and the case for breathing as the master clock for orofacial motor actions.whisking and sniffing are predominant aspects of exploratory behavior in rodents. we review evidence that these motor rhythms are coordinated by the respiratory patterning circuitry in the ventral medulla. a recently described region in the intermediate reticular zone of the medulla functions as an autonomous whisking oscillator, whose neuronal output is reset upon each breath by input from the pre-bötzinger complex. based on similarities between this neuronal circuit architecture and that of ot ...201525876629
endogenous sirnas and pirnas derived from transposable elements and genes in the malaria vector mosquito anopheles gambiae.the sirna and pirna pathways have been shown in insects to be essential for regulation of gene expression and defence against exogenous and endogenous genetic elements (viruses and transposable elements). the vast majority of endogenous small rnas produced by the sirna and pirna pathways originate from repetitive or transposable elements (te). in d. melanogaster, te-derived endogenous sirnas and pirnas are involved in genome surveillance and maintenance of genome integrity. in the medically rele ...201525879960
discovery of itraconazole with broad-spectrum in vitro antienterovirus activity that targets nonstructural protein 3a.there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections, which remain a substantial threat to public health. to discover inhibitors that can be immediately repurposed for treatment of enterovirus infections, we developed a high-throughput screening assay that measures the cytopathic effect induced by enterovirus 71 (ev71) to screen an fda-approved drug library. itraconazole (itz), a triazole antifungal agent, was identified as an effective inhi ...201525691649
understanding west nile virus ecology in europe: culex pipiens host feeding preference in a hotspot of virus emergence.understanding wildlife disease ecology is becoming an urgent need due to the continuous emergence and spread of several wildlife zoonotic diseases. west nile virus (wnv) is the most widespread arthropod-borne virus in the world, and in recent decades there has been an increase both in geographic range, and in the frequency of symptomatic infections in humans and wildlife. the principal vector for wnv in europe is the common house culex pipiens mosquito, which feeds on a wide variety of vertebrat ...201525888754
structural basis of arc binding to synaptic proteins: implications for cognitive disease.arc is a cellular immediate-early gene (ieg) that functions at excitatory synapses and is required for learning and memory. we report crystal structures of arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (hiv) gag protein. analysis indicates arc originated from the ty3/gypsy retrotransposon family and was "domesticated" in higher vertebrates for synaptic functions. the arc n-terminal lobe evolved a unique hydrophobic pocket ...201525864631
the transcription factor foxk participates with nup98 to regulate antiviral gene expression.upon infection, pathogen recognition leads to a rapidly activated gene expression program that induces antimicrobial effectors to clear the invader. we recently found that nup98 regulates the expression of a subset of rapidly activated antiviral genes to restrict disparate rna virus infections in drosophila by promoting rna polymerase occupancy at the promoters of these antiviral genes. how nup98 specifically targets these loci was unclear; however, it is known that nup98 participates with trans ...201525852164
generation of a safe and effective live viral vaccine by virus self-attenuation using species-specific artificial microrna.vaccination with live attenuated vaccines (lavs) is an effective way for prevention of infectious disease. while several methods are employed to create them, efficacy and safety are still a challenge. in this study, we evaluated the feasibility of creating a self-attenuated rna virus expressing a functional species-specific artificial microrna. using influenza virus as a model, we produced an attenuated virus carrying a mammalian-specific mir-93 expression cassette that expresses a viral nucleop ...201525858415
emerging role of natural killer cells in oncolytic virotherapy.natural killer (nk) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. the ability of nk cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. therapies with nk cells involve activation of endogenous nk cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. to exploit the diverse functional abil ...201527471713
virus-induced dormancy in the archaeon sulfolobus islandicus.we investigated the interaction between sulfolobus spindle-shaped virus (ssv9) and its native archaeal host sulfolobus islandicus. we show that upon exposure to ssv9, s. islandicus strain rjw002 has a significant growth delay where the majority of cells are dormant (viable but not growing) for 24 to 48 hours postinfection (hpi) compared to the growth of controls without virus. we demonstrate that in this system, dormancy (i) is induced by both active and inactive virus particles at a low multipl ...201525827422
autophagy mediates tolerance to staphylococcus aureus alpha-toxin.resistance and tolerance are two defense strategies employed by the host against microbial threats. autophagy-mediated degradation of bacteria has been extensively described as a major resistance mechanism. here we find that the dominant function of autophagy proteins during infections with the epidemic community-associated methicillin-resistant staphylococcus aureus usa300 is to mediate tolerance rather than resistance. atg16l1 hypomorphic mice (atg16l1(hm)), which have reduced autophagy, were ...201525816775
parallel epigenomic and transcriptomic responses to viral infection in honey bees (apis mellifera).populations of honey bees are declining throughout the world, with us beekeepers losing 30% of their colonies each winter. though multiple factors are driving these colony losses, it is increasingly clear that viruses play a major role. however, information about the molecular mechanisms mediating antiviral immunity in honey bees is surprisingly limited. here, we examined the transcriptional and epigenetic (dna methylation) responses to viral infection in honey bee workers. one-day old worker ho ...201525811620
catch me if you can: the link between autophagy and viruses. 201525811485
dissection of amino-terminal functional domains of murine coronavirus nonstructural protein 3.coronaviruses, the largest rna viruses, have a complex program of rna synthesis that entails genome replication and transcription of subgenomic mrnas. rna synthesis by the prototype coronavirus mouse hepatitis virus (mhv) is carried out by a replicase-transcriptase composed of 16 nonstructural protein (nsp) subunits. among these, nsp3 is the largest and the first to be inserted into the endoplasmic reticulum. nsp3 comprises multiple structural domains, including two papain-like proteases (plps) ...201525810552
in vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin.we have described a novel antidepressant peptide, spadin, that acts by blocking the twik-related-potassium channel, type 1 (trek-1). here, we examined possible mechanisms of action of spadin at both molecular and cellular levels.201525598009
antiviral and immunoregulatory effects of indoleamine-2,3-dioxygenase in hepatitis c virus infection.in patients with hepatitis c virus (hcv) infection, enhanced activity of indoleamine-2,3-dioxygenase 1 (ido) has been reported. ido - a tryptophan-catabolizing enzyme - has been considered as both an innate defence mechanism and an important regulator of the immune response. the molecular mechanism of ido induction in hcv infection and its role in the antiviral immune response remain unknown. using primary human hepatocytes, we show that hcv infection stimulates ido expression. ido gene inductio ...201525792183
cross-species comparative analysis of dicer proteins during sindbis virus infection.in plants and invertebrates rna silencing is a major defense mechanism against virus infections. the first event in rna silencing is dicing of long double stranded rnas into small interfering rnas (sirnas). the dicer proteins involved in this process are phylogenetically conserved and have the same domain organization. accordingly, the production of viral derived sirnas has also been observed in the mouse, but only in restricted cell types. to gain insight on this restriction, we compare the dic ...201526024431
elevation of intraocular pressure in rodents using viral vectors targeting the trabecular meshwork.rodents are increasingly being used as glaucoma models to study ocular hypertension, optic neuropathy, and retinopathy. a number of different techniques are used to elevate intraocular pressure in rodent eyes by artificially obstructing the aqueous outflow pathway. another successful technique to induce ocular hypertension is to transduce the trabecular meshwork of rodent eyes with viral vectors expressing glaucoma associated transgenes to provide more relevant models of glaucomatous damage to t ...201526025608
the baculovirus antiapoptotic p35 protein functions as an inhibitor of the host rna interference antiviral response.rna interference (rnai) is considered an ancient antiviral defense in diverse organisms, including insects. virus infections generate double-strand rnas (dsrnas) that trigger the rnai machinery to process dsrnas into virus-derived short interfering rnas (vsirnas), which target virus genomes, mrnas, or replication intermediates. viruses, in turn, have evolved viral suppressors of rnai (vsrs) to counter host antiviral rnai. following recent discoveries that insects mount an rnai response against d ...201526018163
astaxanthin pretreatment attenuates hepatic ischemia reperfusion-induced apoptosis and autophagy via the ros/mapk pathway in mice.hepatic ischemia reperfusion (ir) is an important issue in complex liver resection and liver transplantation. the aim of the present study was to determine the protective effect of astaxanthin (asx), an antioxidant, on hepatic ir injury via the reactive oxygen species/mitogen-activated protein kinase (ros/mapk) pathway.201526023842
full length and protease domain activity of chikungunya virus nsp2 differ from other alphavirus nsp2 proteases in recognition of small peptide substrates.alphavirus nsp2 proteins are multifunctional and essential for viral replication. the protease role of nsp2 is critical for virus replication as only the virus protease activity is used for processing of the viral non-structural polypeptide. chikungunya virus is an emerging disease problem that is becoming a world-wide health issue. we have generated purified recombinant chikungunya virus nsp2 proteins, both full length and a truncated protease domain from the c-terminus of the nsp2 protein. enz ...201526182358
virus-induced translational arrest through 4ebp1/2-dependent decay of 5'-top mrnas restricts viral infection.the mosquito-transmitted bunyavirus, rift valley fever virus (rvfv), is a highly successful pathogen for which there are no vaccines or therapeutics. translational arrest is a common antiviral strategy used by hosts. in response, rvfv inhibits two well-known antiviral pathways that attenuate translation during infection, pkr and type i ifn signaling. despite this, translational arrest occurs during rvfv infection by unknown mechanisms. here, we find that rvfv infection triggers the decay of core ...201526038567
development of a replication-competent lentivirus assay for dendritic cell-targeting lentiviral vectors.it is a current regulatory requirement to demonstrate absence of detectable replication-competent lentivirus (rcl) in lentiviral vector products prior to use in clinical trials. immune design previously described an hiv-1-based integration-deficient lentiviral vector for use in cancer immunotherapy (vp02). vp02 is enveloped with e1001, a modified sindbis virus glycoprotein which targets dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (dc-sign) expressed on dendrit ...201526029728
x-ray structural and functional studies of the three tandemly linked domains of non-structural protein 3 (nsp3) from murine hepatitis virus reveal conserved functions.murine hepatitis virus (mhv) has long served as a model system for the study of coronaviruses. non-structural protein 3 (nsp3) is the largest nsp in the coronavirus genome, and it contains multiple functional domains that are required for coronavirus replication. despite the numerous functional studies on mhv and its nsp3 domain, the structure of only one domain in nsp3, the small ubiquitin-like domain 1 (ubl1), has been determined. we report here the x-ray structure of three tandemly linked dom ...201526296883
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