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climate, environmental and socio-economic change: weighing up the balance in vector-borne disease transmission.arguably one of the most important effects of climate change is the potential impact on human health. while this is likely to take many forms, the implications for future transmission of vector-borne diseases (vbds), given their ongoing contribution to global disease burden, are both extremely important and highly uncertain. in part, this is owing not only to data limitations and methodological challenges when integrating climate-driven vbd models and climate change projections, but also, perhap ...025688012
sindbis virus interferes with dengue 4 virus replication and its potential transmission by aedes albopictus.mosquitoes transmit a number of arboviruses associated with disease outbreaks in humans and other animals. the majority of medically important arboviruses belong to three families: togaviridae, flaviviridae and bunyaviridae. several members of these families have overlapping distributions and share common vectors, increasing the potential for arboviral coinfections. this study examined how two model viruses: sindbis virus (sinv, togaviridae: alphavirus) and dengue-4 virus (denv-4, flaviviridae: ...201525633862
eilat virus host range restriction is present at multiple levels of the virus life cycle.most alphaviruses are mosquito-borne and exhibit a broad host range, infecting many different vertebrates, including birds, rodents, equids, humans, and nonhuman primates. this ability of most alphaviruses to infect arthropods and vertebrates is essential for their maintenance in nature. recently, a new alphavirus, eilat virus (eilv), was described, and in contrast to all other mosquito-borne viruses, it is unable to replicate in vertebrate cell lines. investigations into the nature of its host ...201425392227
chemokine receptors as important regulators of pathogenesis during arboviral encephalitis.the central nervous system (cns) is a highly complex network comprising long-lived neurons and glial cells. accordingly, numerous mechanisms have evolved to tightly regulate the initiation of inflammatory responses within the brain. under neuroinflammatory conditions, as in the case of viral encephalitides, the infiltration of leukocytes is often required for efficient viral clearance and recovery. the orchestration of leukocyte migration into the inflamed cns is largely coordinated by a large f ...201425324719
mosquito cell lines: history, isolation, availability and application to assess the threat of arboviral transmission in the united kingdom.mosquitoes are highly effective vectors for transmission of human and animal pathogens. understanding the relationship between pathogen and vector is vital in developing strategies to predict and prevent transmission. cell lines derived from appropriate mosquito hosts provide a relatively simple tool for investigating the interaction between the host and viruses transmitted by mosquitoes. this review provides a brief overview of the development of mosquito cell lines, methods of isolation, their ...201425141888
second generation inactivated eastern equine encephalitis virus vaccine candidates protect mice against a lethal aerosol challenge.currently, there are no fda-licensed vaccines or therapeutics for eastern equine encephalitis virus (eeev) for human use. we recently developed several methods to inactivate cvev1219, a chimeric live-attenuated eastern equine encephalitis virus (eeev). dosage and schedule studies were conducted to evaluate the immunogenicity and protective efficacy of three potential second-generation inactivated eeev (ieeev) vaccine candidates in mice: formalin-inactivated cvev1219 (fcvev1219), ina-inactivated ...201425116127
human trophoblasts confer resistance to viruses implicated in perinatal infection.primary human trophoblasts were previously shown to be resistant to viral infection, and able to confer this resistance to nontrophoblast cells. can trophoblasts protect nontrophoblastic cells from infection by viruses or other intracellular pathogens that are implicated in perinatal infection?201425108145
replication of many human viruses is refractory to inhibition by endogenous cellular micrornas.the issue of whether viruses are subject to restriction by endogenous micrornas (mirnas) and/or by virus-induced small interfering rnas (sirnas) in infected human somatic cells has been controversial. here, we address this question in two ways. first, using deep sequencing, we demonstrate that infection of human cells by the rna virus dengue virus (denv) or west nile virus (wnv) does not result in the production of any virus-derived sirnas or viral mirnas. second, to more globally assess the pot ...201424807715
discovery of a novel compound with anti-venezuelan equine encephalitis virus activity that targets the nonstructural protein 2.alphaviruses present serious health threats as emerging and re-emerging viruses. venezuelan equine encephalitis virus (veev), a new world alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. to date, compounds reported as anti-veev or anti-alphavirus inhibitors have shown moderate activity. to discover new classes of anti-veev inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from liv ...201424967809
human-like antibodies neutralizing western equine encephalitis virus.this study describes the development of the first neutralizing antibodies against western equine encephalitis virus (weev), a member of the genus alphavirus. weev is transmitted by mosquitoes and can spread to the human central nervous system, causing symptoms ranging from mild febrile reactions to life-threatening encephalitis. weev has been classified as a biological warfare agent by the us centers for disease control and prevention. no anti-weev drugs are currently commercially available. neu ...201424518197
genome-wide rnai screen identifies novel host proteins required for alphavirus entry.the enveloped alphaviruses include important and emerging human pathogens such as chikungunya virus and eastern equine encephalitis virus. alphaviruses enter cells by clathrin-mediated endocytosis, and exit by budding from the plasma membrane. while there has been considerable progress in defining the structure and function of the viral proteins, relatively little is known about the host factors involved in alphavirus infection. we used a genome-wide sirna screen to identify host factors that pr ...201324367265
approaches to the treatment of disease induced by chikungunya virus.chikungunya virus, a re-emerging mosquito-borne alphavirus, causes fever, rash and persistent arthralgia/arthritis in humans. severe outbreaks have occurred resulting in infections of millions of people in southeast asia and africa. currently there are no antiviral drugs or vaccines for prevention and treatment of chikungunya infections. herein we report the current status of research on antiviral drugs and vaccines for chikungunya virus infections.024434329
comprehensive mapping of common immunodominant epitopes in the eastern equine encephalitis virus e2 protein recognized by avian antibody responses.eastern equine encephalitis virus (eeev) is a mosquito-borne virus that can cause both human and equine encephalitis with high case fatality rates. eeev can also be widespread among birds, including pheasants, ostriches, emu, turkeys, whooping cranes and chickens. the e2 protein of eeev and other alphaviruses is an important immunogenic protein that elicits antibodies of diagnostic value. while many therapeutic and diagnostic applications of e2 protein-specific antibodies have been reported, the ...201323922704
antiviral type i and type iii interferon responses in the central nervous system.the central nervous system (cns) harbors highly differentiated cells, such as neurons that are essential to coordinate the functions of complex organisms. this organ is partly protected by the blood-brain barrier (bbb) from toxic substances and pathogens carried in the bloodstream. yet, neurotropic viruses can reach the cns either by crossing the bbb after viremia, or by exploiting motile infected cells as trojan horses, or by using axonal transport. type i and type iii interferons (ifns) are cy ...201323503326
a chimeric sindbis-based vaccine protects cynomolgus macaques against a lethal aerosol challenge of eastern equine encephalitis virus.eastern equine encephalitis virus (eeev) is a mosquito-borne alphavirus that causes sporadic, often fatal disease outbreaks in humans and equids, and is also a biological threat agent. two chimeric vaccine candidates were constructed using a cdna clone with a sindbis virus (sinv) backbone and structural protein genes from either a north (sin/naeeev) or south american (sin/saeeev) strain of eeev. the vaccine candidates were tested in a nonhuman primate (nhp) model of eastern equine encephalitis ( ...201323333212
the alphavirus e3 glycoprotein functions in a clade-specific manner.the 80 trimeric, glycoprotein spikes that cover the surface of alphavirus particles are required for mediating viral entry into a host cell. spike assembly is a regulated process that requires interactions between five structural proteins, e3, e2, 6k and its translational frameshift product tf, and e1. e3 is a small, ∼65-amino-acid glycoprotein that has two known functions: e3 serves as the signal sequence for translocation of the e3-e2-6k-e1 polyprotein into the endoplasmic reticulum (er), and ...201223035234
dephosphorylation of hur protein during alphavirus infection is associated with hur relocalization to the cytoplasm.we have demonstrated previously that the cellular hur protein binds u-rich elements in the 3' untranslated region (utr) of sindbis virus rna and relocalizes from the nucleus to the cytoplasm upon sindbis virus infection in 293t cells. in this study, we show that two alphaviruses, ross river virus and chikungunya virus, lack the conserved high-affinity u-rich hur binding element in their 3' utrs but still maintain the ability to interact with hur with nanomolar affinities through alternative bind ...201222915590
isolation and characterisation of a human-like antibody fragment (scfv) that inactivates veev in vitro and in vivo.venezuelan equine encephalitis virus (veev) belongs to the alphavirus genus and several species of this family are pathogenic to humans. the viruses are classified as potential agents of biological warfare and terrorism and sensitive detection as well as effective prophylaxis and antiviral therapies are required.in this work, we describe the isolation of the anti-veev single chain fragment variable (scfv), tor67-3b4, from a non-human primate (nhp) antibody gene library. we report its recloning i ...201222666347
alphaviruses: population genetics and determinants of emergence.alphaviruses are responsible for several medically important emerging diseases and are also significant veterinary pathogens. due to the aerosol infectivity of some alphaviruses and their ability to cause severe, sometimes fatal neurologic diseases, they are also of biodefense importance. this review discusses the ecology, epidemiology and molecular virology of the alphaviruses, then focuses on three of the most important members of the genus: venezuelan and eastern equine encephalitis and chiku ...201222522323
proteomic analysis of chikungunya virus infected microgial cells.chikungunya virus (chikv) is a recently re-emerged public health problem in many countries bordering the indian ocean and elsewhere. chikungunya fever is a relatively self limiting febrile disease, but the consequences of chikungunya fever can include a long lasting, debilitating arthralgia, and occasional neurological involvement has been reported. macrophages have been implicated as an important cell target of chikv with regards to both their role as an immune mediator, as well evidence pointi ...201222514668
the adaptive immune system in diseases of the central nervous system.tissues of the cns, such as the brain, optic nerves, and spinal cord, may be affected by a range of insults including genetic, autoimmune, infectious, or neurodegenerative diseases and cancer. the immune system is involved in the pathogenesis of many of these, either by causing tissue damage or alternatively by responding to disease and contributing to repair. it is clearly vital that cells of the immune system patrol the cns and protect against infection. however, in contrast to other tissues, ...201222466659
rapid, specific detection of alphaviruses from tissue cultures using a replicon-defective reporter gene assay.we established a rapid, specific technique for detecting alphaviruses using a replicon-defective reporter gene assay derived from the sindbis virus xj-160. the pvaxj expression vector containing the xj-160 genome was engineered to form the expression vectors pvaxj-egfp expressing enhanced green fluorescence protein (egfp) or pvaxj-gluc expressing gaussia luciferase (gluc). the replicon-defective reporter plasmids pvaxj-egfpδnsp4 and pvaxj-glucδnsp4 were constructed by deleting 1139 bp in the non ...201222427930
endogenous rna viruses of plants in insect genomes.endogenous viral elements (eves) derived from rna viruses with no dna stage are rare, especially those where the parental viruses possess single-strand positive-sense (ssrna+) genomes. here we provide evidence that eves that share a sequence similarity to ssrna+viruses of plants are integrated into the genomes of a number of insects, including mosquito, fruit flies, bees, ant, silkworm, pea aphid, monarch butterfly, and wasps. a preliminary phylogenetic analysis places these eves as divergent re ...201222410578
development of an elisa-array for simultaneous detection of five encephalitis viruses.japanese encephalitis virus(jev), tick-borne encephalitis virus(tbev), and eastern equine encephalitis virus (eeev) can cause symptoms of encephalitis. establishment of accurate and easy methods by which to detect these viruses is essential for the prevention and treatment of associated infectious diseases. currently, there are still no multiple antigen detection methods available clinically. an elisa-array, which detects multiple antigens, is easy to handle, and inexpensive, has enormous potent ...201222369052
specific and nonspecific host adaptation during arboviral experimental evolution.during the past decade or so, there has been a substantial body of work to dissect arboviral evolution and to develop models of adaptation during host switching. regardless of what species serve as host or vectors, and of the geographic distribution and the mechanisms of replication, arboviruses tend to have slow evolutionary rates in nature. the hypothesis that this is the result of replication in the disparate environments provided by host and vector did not receive solid experimental support ...201222248544
the evolution of viruses in multi-host fitness landscapes.provided that generalist viruses will have access to potentially unlimited hosts, the question is why most viruses specialize in few hosts. it has been suggested that selection should favor specialists because there are tradeoffs limiting the fitness of generalists in any of the alternative hosts or because evolution proceeds faster with narrower niches. here we review experiments showing that virus adaptation to a specific host is often coupled with fitness losses in alternative ones. in most i ...200919572052
biological transmission of arboviruses: reexamination of and new insights into components, mechanisms, and unique traits as well as their evolutionary trends.among animal viruses, arboviruses are unique in that they depend on arthropod vectors for transmission. field research and laboratory investigations related to the three components of this unique mode of transmission, virus, vector, and vertebrate host, have produced an enormous amount of valuable information that may be found in numerous publications. however, despite many reviews on specific viruses, diseases, or interests, a systematic approach to organizing the available information on all f ...016223950
an updated checklist of mosquito species (diptera: culicidae) from madagascar.an updated checklist of 235 mosquito species from madagascar is presented. the number of species has increased considerably compared to previous checklists, particularly the last published in 2003 (178 species). this annotated checklist provides concise information on endemism, taxonomic position, developmental stages, larval habitats, distribution, behavior, and vector-borne diseases potentially transmitted. the 235 species belong to 14 genera: aedeomyia (3 species), aedes (35 species), anophel ...201627101839
an rna trapping mechanism in alphavirus mrna promotes ribosome stalling and translation initiation.during translation initiation, eukaryotic initiation factor 2 (eif2) delivers the met-trna to the 40s ribosomal subunit to locate the initiation codon (augi) of mrna during the scanning process. stress-induced eif2 phosphorylation leads to a general blockade of translation initiation and represents a key antiviral pathway in mammals. however, some viral mrnas can initiate translation in the presence of phosphorylated eif2 via stable rna stem-loop structures (dlp; downstream loop) located in thei ...201626984530
experimental piscine alphavirus rna recombination in vivo yields both viable virus and defective viral rna.rna recombination in non-segmented rna viruses is important for viral evolution and documented for several virus species through in vitro studies. here we confirm viral rna recombination in vivo using an alphavirus, the sav3 subtype of salmon pancreas disease virus. the virus causes pancreas disease in atlantic salmon and heavy losses in european salmonid aquaculture. atlantic salmon were injected with a sav3 6k-gene deleted cdna plasmid, encoding a non-viable variant of sav3, together with a he ...201627805034
molecular evolutionary and epidemiological dynamics of genotypes 1g and 2b of rubella virus.rubella virus (rv), which causes measles-like rashes in children, puts millions of infants at risk of congenital defects across the globe. employing phylogenetic approaches to the whole genome sequence data and e1 glycoprotein sequence data, the present study reports the substitution rates and dates of emergence of all thirteen previously described rubella genotypes, and gains important insights into the epidemiological dynamics of two geographically widely distributed genotypes 1g and 2b. the o ...201425329480
mannose binding lectin is required for alphavirus-induced arthritis/myositis.mosquito-borne alphaviruses such as chikungunya virus and ross river virus (rrv) are emerging pathogens capable of causing large-scale epidemics of virus-induced arthritis and myositis. the pathology of rrv-induced disease in both humans and mice is associated with induction of the host inflammatory response within the muscle and joints, and prior studies have demonstrated that the host complement system contributes to development of disease. in this study, we have used a mouse model of rrv-indu ...201222457620
mutating conserved cysteines in the alphavirus e2 glycoprotein causes virus-specific assembly defects.there are 80 trimeric, glycoprotein spikes that cover the surface of an alphavirus particle. the spikes, which are composed of three e2 and e1 glycoprotein heterodimers, are responsible for receptor binding and mediating fusion between the viral and host-cell membranes during entry. in addition, the cytoplasmic domain of e2 interacts with the nucleocapsid core during the last stages of particle assembly, possibly to aid in particle stability. during assembly, the spikes are nonfusogenic until th ...201222238319
receptors and tropisms of envelope viruses.envelope virus replication begins with receptor binding, followed by fusion of the viral envelope with the cell membrane. the binding and fusion steps are usually mediated by envelope proteins. the ability of envelope proteins of a particular virus to bind and fuse with target cells defines the host range of the virus, known as 'viral tropism'. the mechanism(s) of fusion by the viral envelope is largely categorized as either ph-dependent or ph-independent. by redirecting the binding specificitie ...021804908
development of 2, 7-diamino-1, 8-naphthyridine (danp) anchored hairpin primers for rt-pcr detection of chikungunya virus infection.a molecular diagnostic platform with danp-anchored hairpin primer was developed and evaluated for the rapid and cost-effective detection of chikungunya virus (chikv) with high sensitivity and specificity. the molecule 2, 7-diamino-1, 8-naphthyridine (danp) binds to a cytosine-bulge and emits fluorescence at 450 nm when it is excited by 400 nm light. thus, by measuring the decline in fluorescence emitted from danp-primer complexes after pcr reaction, we could monitor the pcr progress. by adapting ...201627571201
detection of sindbis and inkoo virus rna in genetically typed mosquito larvae sampled in northern sweden.mosquito-borne viruses have a widespread distribution across the globe and are known to pose serious threats to human and animal health. the maintenance and dissemination of these viruses in nature are driven through horizontal and vertical transmission. in the temperate climate of northern sweden, there is a dearth of knowledge on whether mosquito-borne viruses that occur are transmitted transovarially. to gain a better understanding of mosquito-borne virus circulation and maintenance, mosquito ...201627159120
development and validation of a quantitative, one-step, multiplex, real-time reverse transcriptase pcr assay for detection of dengue and chikungunya viruses.dengue virus (denv) and chikungunya virus (chikv) are important human pathogens with common transmission vectors and similar clinical presentations. patient care may be impacted by the misdiagnosis of denv and chikv in areas where both viruses cocirculate. in this study, we have developed and validated a one-step multiplex reverse transcriptase pcr (rt-pcr) to simultaneously detect, quantify, and differentiate between four denv serotypes (pan-denv) and chikungunya virus. the assay uses taqman te ...201627098955
antagonism of the sodium-potassium atpase impairs chikungunya virus infection.chikungunya virus (chikv) is a reemerging alphavirus that has caused epidemics of fever, arthralgia, and rash worldwide. there are currently no licensed vaccines or antiviral therapies available for the prevention or treatment of chikv disease. we conducted a high-throughput, chemical compound screen that identified digoxin, a cardiac glycoside that blocks the sodium-potassium atpase, as a potent inhibitor of chikv infection. treatment of human cells with digoxin or a related cardiac glycoside, ...201627222471
identification of critical residues in hepatitis e virus macro domain involved in its interaction with viral methyltransferase and orf3 proteins.hepatitis e virus (hev) is a major cause of hepatitis in normal and organ transplant individuals. hev open reading frame-1 encodes a polypeptide comprising of the viral nonstructural proteins as well as domains of unknown function such as the macro domain (x-domain), v, duf3729 and y. the macro domain proteins are ubiquitously present from prokaryotes to human and in many positive-strand rna viruses, playing important roles in multiple cellular processes. towards understanding the function of th ...201627113483
vertical transmission of indian ocean lineage of chikungunya virus in aedes aegypti and aedes albopictus mosquitoes.the re-emergence of chikungunya (chik) fever in thailand has been caused by a novel lineage of chikungunya virus (chikv) termed the indian ocean lineage (iol). the aedes albopictus mosquito is thought to be a primary vector of chik fever in thailand, whereas ae. aegypti acts as a secondary vector of the virus. the vertical transmission is believed to be a primary means to maintain chikv in nature and may be associated with an increased risk of outbreak. therefore, the goal of this study was to a ...201627108077
dynamics of chikungunya virus cell entry unraveled by single-virus tracking in living cells.chikungunya virus (chikv) is a rapidly emerging mosquito-borne human pathogen causing major outbreaks in africa, asia, and the americas. the cell entry pathway hijacked by chikv to infect a cell has been studied previously using inhibitory compounds. there has been some debate on the mechanism by which chikv enters the cell: several studies suggest that chikv enters via clathrin-mediated endocytosis, while others show that it enters independently of clathrin. here we applied live-cell microscopy ...201626912616
dissecting the role of e2 protein domains in alphavirus pathogenicity.alphaviruses represent a diverse set of arboviruses, many of which are important pathogens. chikungunya virus (chikv), an arthritis-inducing alphavirus, is the cause of a massive ongoing outbreak in the caribbean and south america. in contrast to chikv, other related alphaviruses, such as venezuelan equine encephalitis virus (veev) and semliki forest virus (sfv), can cause encephalitic disease. e2, the receptor binding protein, has been implicated as a determinant in cell tropism, host range, pa ...201526676771
assessment of productivity of culex spp. larvae (diptera: culicidae) in urban storm water catch basin system in wrocław (sw poland).in urban environments, catch basins serve as major developmental and resting sites for anthropophilic and zoophilic mosquitoes. however, the use of this habitat is inconsistent, with abundance of larvae varying significantly across catch basins at a fine spatial scale. during seasonal summer investigations on mosquito species composition, their spatial and temporal distribution and the environmental characteristic of the breeding sites in the underground storm drain systems of the wrocław urban ...201626809340
rainbow trout (oncorhynchus mykiss) muscle satellite cells are targets of salmonid alphavirus infection.sleeping disease in rainbow trout is characterized by an abnormal swimming behaviour of the fish which stay on their side at the bottom of the tanks. this sign is due to extensive necrosis and atrophy of red skeletal muscle induced by the sleeping disease virus (sdv), also called salmonid alphavirus 2. infections of humans with arthritogenic alphaviruses, such as chikungunya virus (chikv), are global causes of debilitating musculoskeletal diseases. the mechanisms by which the virus causes these ...201626743565
cryo-em structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity.chikungunya virus (chikv) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. although highly inhibitory murine and human monoclonal antibodies (mabs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. here, we determined the cryo-em structures of chikungunya virus-like particles complexed with antibody fragments (fab) of two highly protective human mabs, 4j21 and 5m16, that block virus fusion with host ...201526504196
myeloid cell arg1 inhibits control of arthritogenic alphavirus infection by suppressing antiviral t cells.arthritogenic alphaviruses, including ross river virus (rrv) and chikungunya virus (chikv), are responsible for explosive epidemics involving millions of cases. these mosquito-transmitted viruses cause inflammation and injury in skeletal muscle and joint tissues that results in debilitating pain. we previously showed that arginase 1 (arg1) was highly expressed in myeloid cells in the infected and inflamed musculoskeletal tissues of rrv- and chikv-infected mice, and specific deletion of arg1 from ...201526436766
la crosse virus field detection and vector competence of culex mosquitoes.la crosse virus (lacv), a leading cause of arboviral pediatric encephalitis in the united states, is emerging in appalachia. here, we report field and laboratory evidence that suggest lacv may be using culex mosquitoes as additional vectors in this region. this bunyavirus was detected by reverse-transcriptase polymerase chain reaction in two pools of culex mosquitoes in southwestern virginia and in six pools in west virginia. to assess vector competence, we offered lacv blood meals to field-coll ...201526175029
viral polymerase-helicase complexes regulate replication fidelity to overcome intracellular nucleotide depletion.to date, the majority of work on rna virus replication fidelity has focused on the viral rna polymerase, while the potential role of other viral replicase proteins in this process is poorly understood. previous studies used resistance to broad-spectrum rna mutagens, such as ribavirin, to identify polymerases with increased fidelity that avoid misincorporation of such base analogues. we identified a novel variant in the alphavirus viral helicase/protease, nonstructural protein 2 (nsp2) that opera ...201526311883
a potent neutralizing igm mab targeting the n218 epitope on e2 protein protects against chikungunya virus pathogenesis.chikungunya virus (chikv) is a medically important human viral pathogen that causes chikungunya fever accompanied with debilitating and persistent joint pain. host-elicited or passively-transferred monoclonal antibodies (mab) are essential mediators of chikv clearance. therefore, this study aimed to generate and characterize a panel of mabs for their neutralization efficacy against chikv infection in a cell-based and murine model. to evaluate their antigenicity and neutralization profile, indire ...201526305993
serial femtosecond x-ray diffraction of enveloped virus microcrystals.serial femtosecond crystallography (sfx) using x-ray free-electron lasers has produced high-resolution, room temperature, time-resolved protein structures. we report preliminary sfx of sindbis virus, an enveloped icosahedral rna virus with ∼700 å diameter. microcrystals delivered in viscous agarose medium diffracted to ∼40 å resolution. small-angle diffuse x-ray scattering overlaid bragg peaks and analysis suggests this results from molecular transforms of individual particles. viral proteins un ...201526798819
sec14l2 enables pan-genotype hcv replication in cell culture.since its discovery in 1989, efforts to grow clinical isolates of the hepatitis c virus (hcv) in cell culture have met with limited success. only the jfh-1 isolate has the capacity to replicate efficiently in cultured hepatoma cells without cell culture-adaptive mutations. we hypothesized that cultured cells lack one or more factors required for the replication of clinical isolates. to identify the missing factors, we transduced huh-7.5 human hepatoma cells with a pooled lentivirus-based human c ...201526266980
early events in chikungunya virus infection-from virus cell binding to membrane fusion.chikungunya virus (chikv) is a rapidly emerging mosquito-borne alphavirus causing millions of infections in the tropical and subtropical regions of the world. chikv infection often leads to an acute self-limited febrile illness with debilitating myalgia and arthralgia. a potential long-term complication of chikv infection is severe joint pain, which can last for months to years. there are no vaccines or specific therapeutics available to prevent or treat infection. this review describes the crit ...201526198242
the chikungunya virus capsid protein contains linear b cell epitopes in the n- and c-terminal regions that are dependent on an intact c-terminus for antibody recognition.chikungunya virus (chikv) is an arthropod-borne agent that causes severe arthritic disease in humans and is considered a serious health threat in areas where competent mosquito vectors are prevalent. chikv has recently been responsible for several millions of cases of disease, involving over 40 countries. the recent re-emergence of chikv and its potential threat to human health has stimulated interest in better understanding of the biology and pathogenesis of the virus, and requirement for impro ...201526061335
ability of the encephalitic arbovirus semliki forest virus to cross the blood-brain barrier is determined by the charge of the e2 glycoprotein.semliki forest virus (sfv) provides a well-characterized model system to study the pathogenesis of virus encephalitis. several studies have used virus derived from the molecular clone sfv4. sfv4 virus does not have the same phenotype as the closely related l10 or the prototype virus from which its molecular clone was derived. in mice, l10 generates a high-titer plasma viremia, is efficiently neuroinvasive, and produces a fatal panencephalitis, whereas low-dose sfv4 produces a low-titer viremia, ...201525972559
alphaviruses in gene therapy.alphavirus vectors present an attractive approach for gene therapy applications due to the rapid and simple recombinant virus particle production and their broad range of mammalian host cell transduction. mainly three types of alphavirus vectors, namely naked rna, recombinant particles and dna/rna layered vectors, have been subjected to preclinical studies with the goal of achieving prophylactic or therapeutic efficacy, particularly in oncology. in this context, immunization with alphavirus vect ...201525961488
native wolbachia from aedes albopictus blocks chikungunya virus infection in cellulo.wolbachia, a widespread endosymbiont of terrestrial arthropods, can protect its host against viral and parasitic infections, a phenotype called "pathogen blocking". however, in some cases wolbachia may have no effect or even enhance pathogen infection, depending on the host-wolbachia-pathogen combination. the tiger mosquito aedes albopictus is naturally infected by two strains of wolbachia, walba and walbb, and is a competent vector for different arboviruses such as dengue virus (denv) and chiku ...201525923352
noncapped alphavirus genomic rnas and their role during infection.alphaviruses are enveloped positive-sense rna viruses that exhibit a wide host range consisting of vertebrate and invertebrate species. previously we have reported that the infectivity of sindbis virus (sinv), the model alphavirus, was largely a function of the cell line producing the viral particles. mammalian-cell-derived sinv particles, on average, exhibit a higher particle-to-pfu ratio than mosquito cell-derived sinv particles. nevertheless, the outcome of nonproductive infection, the molecu ...201525833042
nuclear proteins hijacked by mammalian cytoplasmic plus strand rna viruses.plus strand rna viruses that replicate in the cytoplasm face challenges in supporting the numerous biosynthetic functions required for replication and propagation. most of these viruses are genetically simple and rely heavily on co-opting cellular proteins, particularly cellular rna-binding proteins, into new roles for support of virus infection at the level of virus-specific translation, and building rna replication complexes. in the course of infectious cycles many nuclear-cytoplasmic shuttlin ...201525818028
fighting arbovirus transmission: natural and engineered control of vector competence in aedes mosquitoes.control of aedine mosquito vectors, either by mosquito population reduction or replacement with refractory mosquitoes, may play an essential role in the fight against arboviral diseases. in this review, we will focus on the development and application of biological approaches, both natural or engineered, to limit mosquito vector competence for arboviruses. the study of mosquito antiviral immunity has led to the identification of a number of host response mechanisms and proteins that are required ...201526463078
viral rna intermediates as targets for detection and discovery of novel and emerging mosquito-borne viruses.mosquito-borne viruses encompass a range of virus families, comprising a number of significant human pathogens (e.g., dengue viruses, west nile virus, chikungunya virus). virulent strains of these viruses are continually evolving and expanding their geographic range, thus rapid and sensitive screening assays are required to detect emerging viruses and monitor their prevalence and spread in mosquito populations. double-stranded rna (dsrna) is produced during the replication of many of these virus ...201525799391
protective and pathogenic responses to chikungunya virus infection.chikungunya virus (chikv) is an arbovirus responsible for causing epidemic outbreaks of human disease characterized by painful and often debilitating arthralgia. recently chikv has moved into the caribbean and the americas resulting in massive outbreaks in naïve human populations. given the importance of chikv as an emerging disease, a significant amount of effort has gone into interpreting the virus-host interactions that contribute to protection or virus-induced pathology following chikv infec ...026366337
shp-1-dependent macrophage differentiation exacerbates virus-induced myositis.virus-induced myositis is an emerging global affliction that remains poorly characterized with few treatment options. moreover, muscle-tropic viruses often spread to the cns, causing dramatically increased morbidity. therefore, there is an urgent need to explore genetic factors involved in this class of human disease. this report investigates critical innate immune pathways affecting murine virus-induced myositis. of particular importance, the key immune regulator src homology region 2 domain-co ...201525681345
the 5' and 3' ends of alphavirus rnas--non-coding is not non-functional.the non-coding regions found at the 5' and 3' ends of alphavirus genomes regulate viral gene expression, replication, translation and virus-host interactions, which have significant implications for viral evolution, host range, and pathogenesis. the functions of these non-coding regions are mediated by a combination of linear sequence and structural elements. the capped 5' untranslated region (utr) contains promoter elements, translational regulatory sequences that modulate dependence on cellula ...201525630058
cd8+ t cells control ross river virus infection in musculoskeletal tissues of infected mice.ross river virus (rrv), chikungunya virus, and related alphaviruses cause debilitating polyarthralgia and myalgia. mouse models of rrv and chikungunya virus have demonstrated a role for the adaptive immune response in the control of these infections. however, questions remain regarding the role for t cells in viral control, including the magnitude, location, and dynamics of cd8(+) t cell responses. to address these questions, we generated a recombinant rrv expressing the h-2(b)-restricted glycop ...201425488988
multiple immune factors are involved in controlling acute and chronic chikungunya virus infection.the recent epidemic of the arthritogenic alphavirus, chikungunya virus (chikv) has prompted a quest to understand the correlates of protection against virus and disease in order to inform development of new interventions. herein we highlight the propensity of chikv infections to persist long term, both as persistent, steady-state, viraemias in multiple b cell deficient mouse strains, and as persistent rna (including negative-strand rna) in wild-type mice. the knockout mouse studies provided evid ...201425474568
exposure of epitope residues on the outer face of the chikungunya virus envelope trimer determines antibody neutralizing efficacy.chikungunya virus (chikv) is a reemerging alphavirus that causes a debilitating arthritic disease and infects millions of people and for which no specific treatment is available. like many alphaviruses, the structural targets on chikv that elicit a protective humoral immune response in humans are poorly defined. here we used phage display against virus-like particles (vlps) to isolate seven human monoclonal antibodies (mabs) against the chikv envelope glycoproteins e2 and e1. one mab, im-ckv063, ...201425275138
manipulation of host factors optimizes the pathogenesis of western equine encephalitis virus infections in mice for antiviral drug development.while alphaviruses spread naturally via mosquito vectors, some can also be transmitted as aerosols making them potential bioterrorism agents. one such pathogen, western equine encephalitis virus (weev), causes fatal human encephalitis via multiple routes of infection and thus presumably via multiple mechanisms. although weev also produces acute encephalitis in non-human primates, a small animal model that recapitulates features of human disease would be useful for both pathogenesis studies and t ...201425361697
prime-boost immunization strategies against chikungunya virus.chikungunya virus (chikv) is a reemerging mosquito-borne alphavirus that causes debilitating arthralgia in humans. here we describe the development and testing of novel dna replicon and protein chikv vaccine candidates and evaluate their abilities to induce antigen-specific immune responses against chikv. we also describe homologous and heterologous prime-boost immunization strategies using novel and previously developed chikv vaccine candidates. immunogenicity and efficacy were studied in a mou ...201425210177
residue 82 of the chikungunya virus e2 attachment protein modulates viral dissemination and arthritis in mice.chikungunya virus (chikv) is a mosquito-borne alphavirus that has reemerged to cause profound epidemics of fever, rash, and arthralgia throughout sub-saharan africa, southeast asia, and the caribbean. like other arthritogenic alphaviruses, mechanisms of chikv pathogenesis are not well defined. using the attenuated chikv strain 181/25 and virulent strain af15561, we identified a residue in the e2 viral attachment protein that is a critical determinant of viral replication in cultured cells and pa ...201425142598
bindarit, an inhibitor of monocyte chemotactic protein synthesis, protects against bone loss induced by chikungunya virus infection.the recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (chikv), highlights an urgent need for the development of therapeutic intervention strategies. while there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in chikv-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. here, we used microcomputed tomog ...201425339772
structural differences observed in arboviruses of the alphavirus and flavivirus genera.arthropod borne viruses have developed a complex life cycle adapted to alternate between insect and vertebrate hosts. these arthropod-borne viruses belong mainly to the families togaviridae, flaviviridae, and bunyaviridae. this group of viruses contains many pathogens that cause febrile, hemorrhagic, and encephalitic disease or arthritic symptoms which can be persistent. it has been appreciated for many years that these viruses were evolutionarily adapted to function in the highly divergent cell ...201425309597
the role of myeloid cell activation and arginine metabolism in the pathogenesis of virus-induced diseases.when an antiviral immune response is generated, a balance must be reached between two opposing pathways: the production of proinflammatory and cytotoxic effectors that drive a robust antiviral immune response to control the infection and regulators that function to limit or blunt an excessive immune response to minimize immune-mediated pathology and repair tissue damage. myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activitie ...201425250029
evidence of experimental vertical transmission of emerging novel ecsa genotype of chikungunya virus in aedes aegypti.chikungunya virus (chikv) has emerged as one of the most important arboviruses of public health significance in the past decade. the virus is mainly maintained through human-mosquito-human cycle. other routes of transmission and the mechanism of maintenance of the virus in nature are not clearly known. vertical transmission may be a mechanism of sustaining the virus during inter-epidemic periods. laboratory experiments were conducted to determine whether aedes aegypti, a principal vector, is cap ...201425080107
regulation of the hepatitis c virus rna replicase by endogenous lipid peroxidation.oxidative tissue injury often accompanies viral infection, yet there is little understanding of how it influences virus replication. we show that multiple hepatitis c virus (hcv) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic rna viruses. lipid peroxidation, regulated in part through sphingosine kinase-2, severely restricts hcv replication in huh-7 cells and primary human hepatoblasts. endogenous oxidative membrane damage lo ...201425064127
a 6k-deletion variant of salmonid alphavirus is non-viable but can be rescued through rna recombination.pancreas disease (pd) of atlantic salmon is an emerging disease caused by salmonid alphavirus (sav) which mainly affects salmonid aquaculture in western europe. although genome structure of sav has been characterized and each individual viral protein has been identified, the role of 6k protein in viral replication and infectivity remains undefined. the 6k protein of alphaviruses is a small and hydrophobic protein which is involved in membrane permeabilization, protein processing and virus buddin ...201425009976
characterizing functional domains for tim-mediated enveloped virus entry.t-cell immunoglobulin and mucin domain 1 (tim-1) and other tim family members were recently identified as phosphatidylserine (ptdser)-mediated virus entry-enhancing receptors (pveers). these proteins enhance entry of ebola virus (ebov) and other viruses by binding ptdser on the viral envelope, concentrating virus on the cell surface, and promoting subsequent internalization. the ptdser-binding activity of the immunoglobulin-like variable (igv) domain is essential for both virus binding and inter ...201424696470
buggy creek virus (togaviridae: alphavirus) upregulates expression of pattern recognition receptors and interferons in house sparrows (passer domesticus).birds serve as reservoirs for at least 10 arthropod-borne viruses, yet specific immune responses of birds to arboviral infections are relatively unknown. here, adult house sparrows were inoculated with an arboviral alphavirus, buggy creek virus (bcrv), or saline, and euthanized between 1 and 3 days postinoculation. virological dynamics and gene expression dynamics were investigated. birds did not develop viremia postinoculation, but cytopathic virus was found in the skeletal muscle and spleen of ...201424866749
antiviral perspectives for chikungunya virus.chikungunya virus (chikv) is a mosquito-borne pathogen that has a major health impact in humans and causes acute febrile illness in humans accompanied by joint pains and, in many cases, persistent arthralgia lasting for weeks to years. chikv reemerged in 2005-2006 in several parts of the indian ocean islands and india after a gap of 32 years, causing millions of cases. the re-emergence of chikv has also resulted in numerous outbreaks in several countries in the eastern hemisphere, with a threat ...201424955364
role of phosphatidylserine receptors in enveloped virus infection.we recently demonstrated that a soluble protein, gas6, can facilitate viral entry by bridging viral envelope phosphatidylserine to axl, a receptor tyrosine kinase expressed on target cells. the interaction between phosphatidylserine, gas6, and axl was originally shown to be a molecular mechanism through which phagocytes recognize phosphatidylserine exposed on dead cells. since our initial report, several groups have confirmed that axl/gas6, as well as other phosphatidylserine receptors, facilita ...201424478428
attenuating mutations in nsp1 reveal tissue-specific mechanisms for control of ross river virus infection.ross river virus (rrv) is one of a group of mosquito-transmitted alphaviruses that cause debilitating, and often chronic, musculoskeletal disease in humans. previously, we reported that replacement of the nonstructural protein 1 (nsp1) gene of the mouse-virulent rrv strain t48 with that from the mouse-avirulent strain dc5692 generated a virus that was attenuated in a mouse model of disease. here we find that the six nsp1 nonsynonymous nucleotide differences between strains t48 and dc5692 are det ...201424429363
infection of myofibers contributes to increased pathogenicity during infection with an epidemic strain of chikungunya virus.chikungunya virus (chikv) is an alphavirus transmitted by mosquitoes that is known to cause severe arthritis and myositis in affected patients. the ongoing epidemic began in eastern africa in 2004 and then spread to islands of the indian ocean, india, and southeast asia, ultimately afflicting millions. during this outbreak, more severe disease manifestations, including fatalities, have been documented. the reasons for this change in pathogenesis are multifactorial but likely include mutations th ...201324335291
a single-amino-acid polymorphism in chikungunya virus e2 glycoprotein influences glycosaminoglycan utilization.chikungunya virus (chikv) is a reemerging arbovirus responsible for outbreaks of infection throughout asia and africa, causing an acute illness characterized by fever, rash, and polyarthralgia. although chikv infects a broad range of host cells, little is known about how chikv binds and gains access to the target cell interior. in this study, we tested whether glycosaminoglycan (gag) binding is required for efficient chikv replication using chikv vaccine strain 181/25 and clinical isolate sl1564 ...201324371059
evolution of bovine ephemeral fever virus in the australian episystem.bovine ephemeral fever virus (befv) is an arthropod-borne rhabdovirus that causes a debilitating disease of cattle in africa, asia, and australia; however, its global geodynamics are poorly understood. an evolutionary analysis of g gene (envelope glycoprotein) ectodomain sequences of 97 befv isolates collected from australia during 1956 to 2012 revealed that all have a single common ancestor and are phylogenetically distinct from befv sampled in other geographical regions. the age of the austral ...201324227855
functional cross-talk between distant domains of chikungunya virus non-structural protein 2 is decisive for its rna-modulating activity.chikungunya virus (chikv) non-structural protein 2 (nsp2) is a multifunctional protein that is considered a master regulator of the viral life cycle and a main viral factor responsible for cytopathic effects and subversion of antiviral defense. the c-terminal part of nsp2 possesses protease activity, whereas the n-terminal part exhibits ntpase and rna triphosphatase activity and is proposed to have helicase activity. bioinformatics analysis classified chikv nsp2 into helicase superfamily 1. howe ...201424407286
identical strength of the t cell responses against e2, nsp1 and capsid chikv proteins in recovered and chronic patients after the epidemics of 2005-2006 in la reunion island.to characterize the immunity developed by patients infected by chikungunya virus (chikv), we studied the intensity and specificity of chikv-specific t cells mediated responses in chronic and recovered patients at 12 to 24 months post-infection. t cells were challenged in vitro against chikv synthetic peptides covering the length of three viral proteins, capsid, e2 and nsp1 proteins as well as all inactivated virus particles. cytokine production was assessed by elispot and intracellular labeling. ...201324376836
rubella virus capsid protein structure and its role in virus assembly and infection.rubella virus (rv) is a leading cause of birth defects due to infectious agents. when contracted during pregnancy, rv infection leads to severe damage in fetuses. despite its medical importance, compared with the related alphaviruses, very little is known about the structure of rv. the rv capsid protein is an essential structural component of virions as well as a key factor in virus-host interactions. here we describe three crystal structures of the structural domain of the rv capsid protein. th ...201324282305
encapsidation of host-derived factors correlates with enhanced infectivity of sindbis virus.the genus alphavirus consists of a group of enveloped, single-stranded rna viruses, many of which are transmitted by arthropods to a wide range of vertebrate host species. here we report that sindbis virus (sinv) produced from a representative mammalian cell line consists of at least two unique particle subpopulations, separable on the basis of virion density. in contrast, mosquito-derived sinv consists of a homogeneous population of particles. our findings indicate that the denser particle subp ...201324006438
identification of novel compounds inhibiting chikungunya virus-induced cell death by high throughput screening of a kinase inhibitor library.chikungunya virus (chikv) is a mosquito-borne arthrogenic alphavirus that causes acute febrile illness in humans accompanied by joint pains and in many cases, persistent arthralgia lasting weeks to years. the re-emergence of chikv has resulted in numerous outbreaks in the eastern hemisphere, and threatens to expand in the foreseeable future. unfortunately, no effective treatment is currently available. the present study reports the use of resazurin in a cell-based high-throughput assay, and an i ...201324205414
insect antiviral innate immunity: pathways, effectors, and connections.insects are infected by a wide array of viruses some of which are insect restricted and pathogenic, and some of which are transmitted by biting insects to vertebrates. the medical and economic importance of these viruses heightens the need to understand the interaction between the infecting pathogen and the insect immune system in order to develop transmission interventions. the interaction of the virus with the insect host innate immune system plays a critical role in the outcome of infection. ...201324120681
the transmembrane domain and acidic lipid flip-flop regulates voltage-dependent fusion mediated by class ii and iii viral proteins.voltage dependence of fusion induced by class ii and class iii viral fusion proteins was investigated. class ii proteins from ross river and sindbus virus and a mutant class iii protein from epstein barr virus were found to induce cell-cell fusion that is voltage dependent. combined with previous studies, in all, four class ii and two class iii protein have now been shown to exhibit voltage-dependent fusion, demonstrating that this is probably a general phenomenon for these two classes of viral ...201324124539
the antiviral activities of isg15.post-translational protein modification is an important strategy for the regulation of the cell proteome independent of the need for new gene expression. ubiquitin and ubiquitin-like modifiers mediate the regulation of protein levels, signaling pathways, vesicular trafficking, and many other cellular processes through their covalent conjugation to proteins. interferon stimulated gene 15 (isg15) is a ubiquitin-like modifier induced by type i interferon. in addition to conjugating to potentially h ...201324095857
induction of cytopathogenicity in human glioblastoma cells by chikungunya virus.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) ...201324086645
the c-terminal domain of chikungunya virus nsp2 independently governs viral rna replication, cytopathicity, and inhibition of interferon signaling.alphavirus nonstructural protein 2 (nsp2) has pivotal roles in viral rna replication, host cell shutoff, and inhibition of antiviral responses. mutations that individually rendered other alphaviruses noncytopathic were introduced into chikungunya virus nsp2. results show that (i) nsp2 mutation p718s only in combination with kr649aa or adaptive mutation d711g allowed noncytopathic replicon rna replication, (ii) prohibiting nsp2 nuclear localization abrogates inhibition of antiviral interferon-ind ...201323864632
multi-gene detection and identification of mosquito-borne rna viruses using an oligonucleotide microarray.arthropod-borne viruses are important emerging pathogens world-wide. viruses transmitted by mosquitoes, such as dengue, yellow fever, and japanese encephalitis viruses, infect hundreds of millions of people and animals each year. global surveillance of these viruses in mosquito vectors using molecular based assays is critical for prevention and control of the associated diseases. here, we report an oligonucleotide dna microarray design, termed arbochip5.1, for multi-gene detection and identifica ...201323967358
bed bugs and infectious disease: a case for the arboviruses. 201323966852
methotrexate treatment causes early onset of disease in a mouse model of ross river virus-induced inflammatory disease through increased monocyte production.part of the togaviridae family, alphaviruses, including chikungunya virus (chikv), sindbis virus (sinv) and ross river virus (rrv), are able to cause significant inflammatory pathologies ranging from arthritis to encephalitis. following symptomatic infection with arthritis-associated alphaviruses, patients often experience severe joint pain, affecting distal and small joints, which can last six months or longer. recently, methotrexate (mtx), a disease modifying anti-rheumatic drug (dmard), was u ...201323951095
point mutations in the paramyxovirus f protein that enhance fusion activity shift the mechanism of complement-mediated virus neutralization.parainfluenza virus 5 (piv5) activates and is neutralized by the alternative pathway (ap) in normal human serum (nhs) but not by heat-inactivated (hi) serum. we have tested the relationship between the fusion activity within the piv5 f protein, the activation of complement pathways, and subsequent complement-mediated virus neutralization. recombinant piv5 viruses with enhanced fusion activity were generated by introducing point mutations in the f fusogenic peptide (g3a) or at a distal site near ...201323785199
role of the phosphatidylserine receptor tim-1 in enveloped-virus entry.the cell surface receptor t cell immunoglobulin mucin domain 1 (tim-1) dramatically enhances filovirus infection of epithelial cells. here, we showed that key phosphatidylserine (ptdser) binding residues of the tim-1 igv domain are critical for ebola virus (ebov) entry through direct interaction with ptdser on the viral envelope. ptdser liposomes but not phosphatidylcholine liposomes competed with tim-1 for ebov pseudovirion binding and transduction. further, annexin v (anxv) substituted for the ...201323698310
functional characterization of the alphavirus tf protein.alphavirus dogma has long dictated the production of a discrete set of structural proteins during infection of a cell: capsid, pe2, 6k, and e1. however, bioinformatic analyses of alphavirus genomes (a. e. firth, b. y. chung, m. n. fleeton, and j. f. atkins, virol. j. 5:108, 2008) suggested that a ribosomal frameshifting event occurs during translation of the alphavirus structural polyprotein. specifically, a frameshift event is suggested to occur during translation of the 6k gene, yielding produ ...201323720714
inhibition of hepatitis b virus replication by the host zinc finger antiviral protein.the zinc finger antiviral protein (zap) is a mammalian host restriction factor that inhibits the replication of a variety of rna viruses, including retroviruses, alphaviruses and filoviruses, through interaction with the zap-responsive elements (zre) in viral rna, and recruiting the exosome to degrade rna substrate. hepatitis b virus (hbv) is a pararetrovirus that replicates its genomic dna via reverse transcription of a viral pregenomic (pg) rna precursor. here, we demonstrate that the two isof ...201323853601
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