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in vitro activity of expanded-spectrum pyridazinyl oxime ethers related to pirodavir: novel capsid-binding inhibitors with potent antipicornavirus activity.picornaviruses (pv) include human rhinovirus (hrv), the primary cause of the common cold, and the enteroviruses (ev), which cause serious diseases such as poliomyelitis, meningoencephalitis, and systemic neonatal disease. although no compounds for pv infections have been approved in the united states, pirodavir was one of the most promising capsid-binding compounds to show efficacy in human clinical trials for chemoprophylaxis of the common cold. susceptibility to hydrolysis precluded its use as ...200415105133
synergistic drug combinations against the in vitro replication of coxsackie b1 virus.the existence of synergistic drug combinations against the in vitro replication of poliovirus type 1 (mahoney) (pv-1) had been established in our previous work. the objective of the present study was to test the combined effects of the different drugs against another representative of the enterovirus genus, i.e. coxsackievirus b1 (cbv-1). dual combinations of enviroxime, disoxaril, arildone, ptu-23, hbb and s-7 were evaluated. the susceptibility of cbv-1 to the individual effects of the inhibito ...200415026197
the structure of echovirus type 12 bound to a two-domain fragment of its cellular attachment protein decay-accelerating factor (cd 55).echovirus type 12 (ev12), an enterovirus of the picornaviridae family, uses the complement regulator decay-accelerating factor (daf, cd55) as a cellular receptor. we have calculated a three-dimensional reconstruction of ev12 bound to a fragment of daf consisting of short consensus repeat domains 3 and 4 from cryo-negative stain electron microscopy data (emd code 1057). this shows that, as for an earlier reconstruction of the related echovirus type 7 bound to daf, attachment is not within the vir ...200414634014
the interferon inducer ampligen [poly(i)-poly(c12u)] markedly protects mice against coxsackie b3 virus-induced myocarditis.viral replication, as well as an immunopathological component, is assumed to be involved in coxsackie b virus-induced myocarditis. we evaluated the efficacy of the interferon inducer ampligen on coxsackie b3 virus-induced myocarditis in c3h/henhsd mice. the efficacy of ampligen was compared with that of the interferon inducer poly(inosinic acid)-poly(cytidylic acid) [poly(ic)], alpha interferon 2b (intron a), and pegylated alpha interferon 2b (peg-intron-alpha-2b). ampligen at 20 mg/kg of body w ...200414693549
evidence for frequent recombination within species human enterovirus b based on complete genomic sequences of all thirty-seven serotypes.the species human enterovirus b (hev-b) in the family picornaviridae consists of coxsackievirus a9; coxsackieviruses b1 to b6; echoviruses 1 to 7, 9, 11 to 21, 24 to 27, and 29 to 33; and enteroviruses 69 and 73. we have determined complete genome sequences for the remaining 22 hev-b serotypes whose sequences were not represented in public databases and analyzed these in conjunction with previously available complete sequences in genbank. members of hev-b were monophyletic relative to all other ...200414694117
inhibition of coxsackie b3 virus induced myocarditis in mice by 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile.myocarditis is a common cause of dilated cardiomyopathy, one of the most important single causes of heart transplantation. coxsackie b viruses (cbv) are considered to be the principal etiological agents of viral myocarditis and direct virus-induced damage to the heart tissue has been suggested to be the main mechanism underlying myocarditis in the murine model [horwitz et al. 2000 nat med 6:693-697]. we demonstrate that 2-(3,4-dichloro-phenoxy)-5-nitrobenzonitrile (dnb), a compound that was earl ...200414695668
molecular characterization of coxsackievirus b5 isolates.coxsackie b viruses of serotype 5 are associated frequently with sporadic cases of neurological diseases, epidemics of meningitis, and chronic diseases such as cardiomyopathy and diabetes. in this article, 15 strains of coxsackievirus b5 isolated from patients with neurological disorders and healthy people were investigated by partial sequencing in the 5' half of the vp1 region and compared to other published sequences of coxsackievirus b5, in the same genomic region. all coxsackievirus b5 seque ...200414695669
structural and functional analysis of integrin alpha2i domain interaction with echovirus 1.integrins are cell surface receptors for several microbial pathogens including echovirus 1 (ev1), a picornavirus. cryo-electron microscopy revealed that the functional domain (alpha(2)i) of human alpha(2)beta(1) integrin binds to a surface depression on the ev1 capsid. this three-dimensional structure of ev1 bound to alpha(2)i domain provides the first structural details of an integrin interacting with a picornavirus. the model indicates that alpha(2)beta(1) integrin cannot simultaneously bind b ...200414701832
acute transverse myelitis caused by coxsackie virus b5 infection.a 6-year-old boy developed symptoms of rapidly progressive paraplegia, associated with bowel and urinary dysfunction, but without sensory loss. magnetic resonance imaging (mri) examination showed diffuse swelling of the lower spinal cord on t1-weighted images. based on the clinical presentation and mri findings, a diagnosis of acute transverse myelitis was made. the serum titer of neutralizing antibody against coxsackie virus b5 rose from 1/4 on admission to 1/256 1 month later and coxsackie vir ...200414718010
enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells.it is thought that enterovirus infections cause beta-cell damage and contribute to the development of type 1 diabetes by replicating in the pancreatic islets. we sought evidence for this through autopsy studies and by investigating known enterovirus receptors in cultured human islets.200414727023
induction of chemokines in human astrocytes by picornavirus infection requires activation of both ap-1 and nf-kappa b.infection with different picornaviruses can cause meningitis/encephalitis in humans and experimental animals. to investigate the mechanisms of such inflammatory diseases, potential chemokine gene activation in human astrocytes was investigated following infection with theiler's murine encephalomyelitis virus (tmev), coxsackievirus b3 (cvb3), or coxsackievirus b4 (cvb4). we report that all these viruses are potent inducers for the expression of interleukin-8 (il-8) and monocyte chemoattractant pr ...200414730702
evaluation of real-time reverse transcription polymerase chain reaction assays for the detection of swine vesicular disease virus.differential detection of swine vesicular disease virus (svdv) from the other vesicular disease viruses of foot-and-mouth disease (fmd), vesicular stomatitis (vs) and vesivirus is important as the vesicular lesions produced by these viruses are indistinguishable in pigs. two independent sets of primers and probe, designed from nucleotide sequences within the 5' untranslated region (utr) of the svdv genome, were evaluated in a real-time (5' nuclease probe-based or fluorogenic) pcr format. althoug ...200414738984
mechanisms of beta cell death during restricted and unrestricted enterovirus infection.coxsackie b virus (cvb-5) infections potentially trigger and accelerate pancreatic beta cell damage leading to type 1 diabetes. in vivo, all viruses face natural resistance mediated by various host factors which restrict the progression of infection. thus, the aims of this study were to generate a tissue culture model of restricted coxsackie b virus infection in primary islet cells by preventing the production of viral progeny with a selective inhibitor of viral rna replication and to investigat ...200414748069
isolation and identification of an enterovirus 77 recovered from a refugee child from kosovo, and characterization of the complete virus genome.the complete nucleotide sequence of an enterovirus 77 isolate is reported. the virus designated fr/cf496-99 (france/clermont-ferrand 496-1999) was recovered from the feces of a 4-year-old child hospitalized for salmonella gastroenteritis. the virus was identified by a molecular typing assay based on the genomic sequence encoding the vp1 capsid protein. the phylogenetic analysis based on the vp1 sequence demonstrated that the enterovirus isolated in the child clustered with viruses included in th ...200414749180
the humoral immune response in viral heart disease: characterization and pathophysiological significance of antibodies.several lines of evidence suggest a viral infection as the initiating event for the development of myocarditis (mc). especially enteroviruses like coxsackie b3 virus have been shown to induce mc in humans and strains of mc-prone mice after an infection. the further course of the disease is, however, determined not only by the viral infection but also by the host's immune system. both the humoral and the cellular immune system can modify the extent of the damage caused by the disease. the humoral ...200414760530
solution structure of the coxsackievirus and adenovirus receptor domain 1.the coxsackievirus and adenovirus receptor (car) mediates entry of coxsackievirus b (cvb) and adenovirus (ad). the normal cellular function of car, which is expressed in a wide variety of tissue types, is thought to involve homophilic cell adhesion in the developing brain. the extracellular domain of car consists of two immunoglobulin (ig) domains termed car-d1 and car-d2. car-d1 is shown by sedimentation velocity to be monomeric at ph 3.0. the solution structure and the dynamic properties of mo ...200414967025
alternatively spliced soluble coxsackie-adenovirus receptors inhibit coxsackievirus infection.the coxsackie-adenovirus receptor (car) is a transmembrane receptor of the immunoglobulin superfamily whose expression is altered in myocardial and malignant diseases. soluble isoforms of other adhesion molecules and cytokine receptors have been proven to have significant agonist and antagonist effects on their full-length receptors; however, little is known about soluble car receptors. using reverse transcription-pcr, we identified three car isoforms that lack the transmembrane domain and are t ...200414978041
mechanisms of coxsackievirus b5 mediated beta-cell death depend on the multiplicity of infection.coxsackievirus infections may trigger and accelerate pancreatic beta-cell death, leading to type i diabetes. unrestricted coxsackievirus b5 replication in cultured beta-cells inoculated with high multiplicity leads to rapid lytic cell death. evidence from other virus-host cell systems indicates that host cell responses to infection may depend on the multiplicity of infection (moi). thus, the aim of this study was to compare the mechanisms of beta-cell death during high versus low multiplicity of ...200414981761
heparan sulphate mediates swine vesicular disease virus attachment to the host cell.heparan sulphate (hs) has been found to serve as receptor for initial cell binding of numerous viruses. different glycosaminoglycans (gags), including heparin and hs, were analysed for their ability to bind swine vesicular disease virus (svdv), a picornavirus with close homology to human coxsackie b5 virus. binding of svdv was established by heparin-affinity chromatography. in addition, infection of ib-rs-2 epithelial porcine cells was inhibited by treating the virus with soluble hs, heparin, an ...200414993651
coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of beta cells.epidemiological studies have associated coxsackie b virus (cbv) with the development of insulin-dependent diabetes mellitus (iddm) in humans. infections of genetically susceptible mice with cbv strain 4 (cb4) induce autoimmune diabetes. herein, we demonstrate that in mice, cb4 infection of insulin-producing pancreatic beta cells does not directly cause beta cell death. instead, we observed the phagocytosis of beta cells by macrophages following infection. further, antigen-presenting cells isolat ...200415003810
analysis of the serotype and genotype correlation of vp1 and the 5' noncoding region in an epidemiological survey of the human enterovirus b species.the sequence identity of the enterovirus vp1 gene has been shown to correlate with the serotype concept. enterovirus molecular typing methods are therefore often based on sequencing of the vp1 genomic region and monophyletic clustering of vp1 sequences of a homologous serotype. for epidemiological surveillance, 342 enterovirus samples obtained from patients with aseptic meningitis in belgium from 1999 to 2002 were first diagnosed as being enterovirus positive by amplification of the 5' noncoding ...200415004039
[outbreak of enteroviral infection in vitebsk during pollution of water supply by enteroviruses].the conducted virologic, serological and molecular-and-biological investigations showed that virus coxsakie b4, isolated from cerebrospinal fluid and rhinopharyngeal lavages of patients, was the main etiological agent, which caused mainly an outbreak of enterovirus infection in the city of vitebsk in 2001. coxsakie b4 viruses were found in 30% of samples by using the cultural method and in 76.9% of samples--by polymerase chain reaction (pcr) while carrying out the sanitary-and-virologic investig ...200415017851
immunopathological basis of virus-induced myocarditis.heart diseases are an important cause of morbidity and mortality in industrialized countries. dilated cardiomyopathy (dcm), one of the most common heart diseases, may be the consequence of infection-associated myocardits. coxsackievirus b3 (cvb3) can be frequently detected in the inflamed heart muscle. cvb3-induced acute myocarditis is most likely the consequence of direct virus-induced myocyte damage, whereas chronic cvb3 infection-associated heart disease is dominated by its immunopathological ...200415154605
coxsackie b virus serology and type 1 diabetes mellitus: a systematic review of published case-control studies.enteroviruses, in particular coxsackie b4, have been implicated in the aetiology of type 1 diabetes mellitus, but the epidemiological evidence has not been systematically evaluated.200415154932
susceptibility of mouse primary cortical neuronal cells to coxsackievirus b.coxsackievirus b (cvb) is often associated with aseptic meningitis and encephalitis, but the six serotypes of cvb vary in their relative disease severity. to elucidate the detailed mechanisms of cvb-induced cytopathological effects, the morphological and biochemical characteristics caused by the cvb serotypes in mouse primary cortical neuronal cells were investigated. by 24 h post-infection, all cvb serotypes except cvb2 induced severe cytotoxic alterations, including a loss of neurites. both fl ...200415166439
unexpected hazard of illegal immigration: outbreak of viral myocarditis exacerbated by confinement and deprivation in a shipboard cargo container.we present a group of 18 illegal immigrant stowaways who arrived in a shipboard cargo container suffering from gastroenteritis, dehydration, and malnutrition and showing evidence of viral myocarditis in 3 of 4 fatalities. our investigation included an evaluation of the 2-week ocean voyage, analysis of medical records and laboratory results of the survivors, autopsies on the decedents, and viral studies on their heart tissue. of 3 stowaways who died shipboard, 2 showed lymphocytic myocarditis and ...200415166761
application of universal primers for identification of foot-and-mouth disease virus and swine vesicular disease virus by pcr and pcr-elisa.two approaches for simultaneous identification of both foot-and-mouth disease virus (fmdv) and swine vesicular disease virus (svdv) are described: (1) a single-step reverse transcription-pcr with three primers and (2) a pcr-elisa assay with two universal primers for genome amplification and two virus-specific probes for identification. these methods are based on the use of 3d gene universal pcr primers, the structure of which was optimized and refined due to the close relationship between the tw ...200415168202
isolation and molecular identification of echovirus 13 isolated from patients of aseptic meningitis in korea, 2002.during 2002, several epidemics of aseptic meningitis were attributed to echovirus 13 in korea. the causative agents of these outbreaks were isolated and identified using rhabdosarcoma cells, hep-2 and buffalo green monkey kidney cells, and a neutralization test using monospecific antiserum. fifty-four echovirus 13 isolates were isolated from patients with aseptic meningitis in the provinces, seoul, kyonggi, gwangju, jeonju, busan, and ulsan. symptoms associated with aseptic meningitis infection ...200415170640
integrin alpha v beta 6 is an rgd-dependent receptor for coxsackievirus a9.coxsackievirus a9 (cav9), a member of the enterovirus genus of picornaviridae, is a common human pathogen and is one of a significant number of viruses containing a functional arginine-glycine-aspartic acid (rgd) motif in one of their capsid proteins. previous studies identified the rgd-recognizing integrin alpha(v)beta(3) as its cellular receptor. however, integrin alpha(v)beta(6) has been shown to be an efficient receptor for another rgd-containing picornavirus, foot-and-mouth disease virus (f ...200415194773
detection of enteroviruses in treated drinking water.this study deals with the routine monitoring of drinking water for the presence of enteroviruses, over a period of 1 year. a rapid and simple method was employed for the simultaneous detection and typing of enteroviruses in large-volume water samples. this included an integrated cell culture/nested pcr approach, followed by restriction enzyme analysis. the two drinking water supplies studied were derived from acceptable quality surface water sources using treatment processes, which conform to in ...200415207600
progression or resolution of coxsackievirus b4-induced pancreatitis: a genomic analysis.group b coxsackieviruses are associated with chronic inflammatory diseases of the pancreas, heart, and central nervous system. chronic pancreatitis, which can develop from acute pancreatitis, is considered a premalignant disorder because it is a major risk factor for pancreatic cancer. to explore the genetic events underlying the progression of acute to chronic disease, a comparative analysis of global gene expression during coxsackievirus b4-induced acute and chronic pancreatitis was undertaken ...200415254194
in vitro anti-coxsackievirus b(3) effect of ethyl acetate extract of tian-hua-fen.to investigation the anti-coxsackievirus b(3) (cvb(3m)) effect of the ethyl acetate extract of tian-hua-fen on hela cells infected with cvb(3m).200415259078
lipid-raft-dependent coxsackievirus b4 internalization and rapid targeting to the golgi.coxsackievirus b4 (cbv4), a member of the picornavirus genus, has long been implicated in the development of insulin-dependent diabetes mellitus (iddm), by viral-induced pancreatic cell damage. although the pancreotropic nature of this virus is well documented, the early stages of cbv4 viral infection that involve the attachment of virions to the cell surface by binding to their cellular receptors followed by entry into the cell, are poorly understood. in this study, we show that the entry of cb ...200415262490
t cells in coxsackievirus-induced myocarditis.myocarditis is a complex disease in which distinct immunopathogenic mechanisms cause tissue injury. in some but not all cases, autoimmunity is a major pathogenic factor. cross-reactivity between viral and myosin epitopes underlies both cellular and humoral autoimmunity in myocarditis. thus, the genetics of the host as well as the virus determine disease pathogenicity. innate immunity, as represented by gammadelta+ t cells, is important in determining disease susceptibility. the innate effectors ...200415279696
peroxynitrite inhibition of coxsackievirus infection by prevention of viral rna entry.although peroxynitrite is harmful to the host, the beneficial effects of peroxynitrite are less well understood. we explored the role of peroxynitrite in the host immune response to coxsackievirus infection. peroxynitrite inhibits viral replication in vitro, in part by inhibiting viral rna entry into the host cell. nitrotyrosine, a marker for peroxynitrite production, is colocalized with viral antigens in the hearts of infected mice but not control mice. nitrotyrosine coprecipitates with the vir ...200415286280
animal models for autoimmune myocarditis and autoimmune thyroiditis.this chapter describes four murine models of autoimmune diseases: two related to autoimmune myocarditis and two related to autoimmune thyroiditis. the first model, coxsackie virus b3 (cb3)-induced myocarditis, results in the development of acute myocarditis in susceptible as well as resistant mouse strains, whereas chronic myocarditis develops only in genetically susceptible mice. cb3-induced myocarditis closely resembles the course of human myocarditis, which is believed to be initiated by vira ...200415286386
detection of economically important viruses in boar semen by quantitative realtime pcr technology.the objective of this study was to develop quantitative real-time polymerase chain reaction (reti-pcr) tests for the detection of five economically important viruses in swine semen namely, pseudorabies virus (prv), classical swine fever virus (csfv), foot-and-mouth disease virus (fmdv), swine vesicular disease virus (svdv), and porcine reproductive and respiratory syndrome virus (prrsv). each reti-pcr test was validated for specificity, analytical sensitivity (detection limits), and experimental ...200415288957
development of a simple restriction fragment length polymorphism assay for subtyping of coxsackie b viruses.coxsackie b viruses (genus, enterovirus; family, picornaviridae) can cause aseptic meningitis, encephalitis, pleurodynia, myocarditis and are implicated in the pathogenesis of dilated cardiomyopathy. the differentiation of the group b coxsackieviruses into their subtypes has potential clinical and epidemiological implications. in the present study, a simple restriction fragment length polymorphism (rflp) assay was developed for typing of group b coxsackieviruses into subtypes 1-6. it is a two st ...200415288959
coxsackievirus b4 infection of human fetal thymus cells.the infection of human fetal thymus organ cultures (ftoc) with coxsackievirus b4 e2 (cvb4 e2) was investigated. both positive- and negative-strand viral rna were detected by real-time quantitative reverse transcription-pcr (rt-pcr) in cvb4 e2-infected ftoc, which supported high yields of virus production (approximately 10(6) 50% tissue culture infective doses/ml), and in flow-sorted thymocyte populations for 7 days after inoculation. cortical cd4+ cd8+ thymocytes were found to be the principal t ...200415331720
coxsackievirus b3 replication and persistence in intestinal cells from mice infected orally and in the human caco-2 cell line.although the transmission of coxsackievirus b3 occurs mainly via the oral route, little is known about the primary replication and persistence of this agent in the intestine. to address this question, balb/c mice were inoculated by gavage with coxsackievirus b3, nancy strain. the mice were killed from 1 hr to 90 days after infection. the viral markers were detected in the small intestine using rt-pcr, cell culture and detection of vp1 protein. coxsackievirus b3 was detected positive by the three ...200415332278
coxsackie b viruses use multiple receptors to infect human cardiac cells.viral myocarditis is an inflammatory disease of the heart muscle that can be fatal. the primary viruses that have been linked to myocarditis and dilated cardiomyopathy are the human enteroviruses. the most common viruses associated with this disease are the coxsackie b viruses and in particular coxsackievirus b3 and coxsackievirus b5. early events in viral infection include attachment of the virus onto cell surface receptors. even though, cd55 and coxsackievirus adenovirus receptor protein (car) ...200415332279
[clinical study on fufang sishen decoction in treating arrhythmia after virus myocarditis].to observe the effect of fufang sishen decoction (ffssd) on arrhythmia after virus myocarditis.200415339466
[antisense oligonucleotide inhibition of coxsackievirus b3 gene expression in hela cells and dose-response experiments].in this study, the authors investigated inhibition of coxsackievirus b (cvb) gene expression using antisense oligonucleotides complementary to the 5' ncr, translation initiation codon and structural protein coding sequences and also observed the dose-response of the sequence specific inhibition of cvb plaque formation by antisense oligonucleotides.200415340530
echovirus 1 endocytosis into caveosomes requires lipid rafts, dynamin ii, and signaling events.binding of echovirus 1 (ev1, a nonenveloped rna virus) to the alpha2beta1 integrin on the cell surface is followed by endocytic internalization of the virus together with the receptor. here, video-enhanced live microscopy revealed the rapid uptake of fluorescently labeled ev1 into mobile, intracellular structures, positive for green fluorescent protein-tagged caveolin-1. partial colocalization of ev1 with sv40 (sv40) and cholera toxin, known to traffic via caveosomes, demonstrated that the vesic ...200415356270
coxsackievirus-induced pancreatitis.in humans, infections with the group b coxsackieviruses (cvbs) range from asymptomatic infections to chronic, debilitating diseases. the cvbs are associated with chronic inflammatory diseases of the pancreas, heart, and central nervous system. a major focus in cvb pathogenesis is to understand the mechanisms by which these viruses cause acute diseases that resolve or acute diseases that progress to chronic diseases. the present review explores cvb infections in the development of acute and chron ...200415357902
dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis.matrix metalloproteinases (mmps) are the major regulators of collagen degradation involved in the pathogenesis of several diseases of the heart. the purpose of this study was to investigate the dynamic changes in myocardial mmp activity in mice with viral myocarditis (vm), the relationship between mmp activity and both cardiac function and the quantity of myocardial collagen, and the role mmps playing in the pathological lesions of vm.200415361294
microarray analysis of extracellular matrix genes expression in myocardium of mouse with coxsackie virus b3 myocarditis.extracellular matrix (ecm) orchestrates cell behaviour including growth, death, apoptosis, adhesion, migration, and invasion by activating several signalling pathways. certain components of ecm, such as integrins, may act as receptors or co-receptors of enterovirus. ecm-activated gene expressions in myocardium of viral heart disease including myocarditis and partial cardiomyopathy remain elusive. this study was to investigate the expression of ecm-activated genes in myocardium of mouse with vira ...200415361300
coxsackievirus b4-induced cytokine production in pancreatic cells is mediated through toll-like receptor 4.coxsackievirus b4 (cbv4), a member of the picornavirus genus, has long been implicated in the development of insulin-dependent diabetes mellitus (iddm) caused by virus-induced pancreatic cell damage. the progressive destruction of pancreatic beta cells is responsible for the development of iddm. it has recently been suggested that cbv4 infection can induce the production of proinflammatory cytokines, and these cytokines seem to be involved in the damage to the insulin-producing cells. in this st ...200415452251
coxsackie virus b 4 encephalitis in a 7 year old boy.enteroviruse belongs to the family of picornaviruses. they can be devided in 4 groups: polioviruses (typ 1-3) enteric cythopathogenic human orphan (echo)- viruses, unclassified enteroviruses 68-71 and coxsackie viruses. coxsackie virus type b can cause pharyngitis, myalgia, myocarditis and meningitis as well as severe neonatal infections.200415455298
evidence for coxsackievirus infection in primary sjögren's syndrome.primary sjögren's syndrome (ss) is an autoimmune disease characterized by activation of minor salivary gland (msg) epithelial cells and b and t lymphocytic infiltrates. these findings have long encouraged the hypothesis that a persistent viral infection of the msg epithelial cells may drive the autoimmune response; however, the identity of that virus has remained elusive. the aim of this study was to test this hypothesis.200415457458
prevalent human coxsackie b-5 virus infects porcine islet cells primarily using the coxsackie-adenovirus receptor.we have previously demonstrated that transplanting porcine encephalomyocarditis virus (emcv)-infected porcine islet cells (pics) results in transmission of the virus to recipient mice, which is manifested by acute fatal infection within 5 to 8 days. here, we determined pic susceptibility to a related and highly prevalent human picornavirus, coxsackie b-5 virus (cvb-5).200415479464
molecular identification and characterization of two proposed new enterovirus serotypes, ev74 and ev75.sequencing of the gene that encodes the capsid protein vp1 has been used as a surrogate for antigenic typing in order to distinguish enterovirus serotypes; three new serotypes were identified recently by this method. in this study, 14 enterovirus isolates from six countries were characterized as members of two new types within the species human enterovirus b, based on sequencing of the complete capsid-encoding (p1) region. isolates within each of these two types differed significantly from one a ...200415483233
co-expression of interleukin-2 to increase the efficacy of dna vaccine-mediated protection in coxsackievirus b3-infected mice.dna immunizations with the major structural protein vp1 of coxsackievirus b3 (cvb3) have been previously found to protect mice from a lethal challenge with cvb3. the function of this vaccination procedure is mainly based on accelerated antibody induction with an early cytokine expression and increased virus-specific cytotoxic activity of spleen cells causing decreased myocyte destruction and reduced viral replication. here, we report that the co-expression of the immune-stimulatory interleukin-2 ...200415498609
use of automated real-time reverse transcription-polymerase chain reaction (rt-pcr) to monitor experimental swine vesicular disease virus infection in pigs.automated real-time rt-pcr was evaluated as a diagnostic tool for swine vesicular disease virus (svdv) infection on a range of samples (vesicular epithelium, serum, nasal swabs, faeces) from four inoculated and three in-contact pigs over a period of 28 days. traditional diagnostic procedures (virus isolation, and elisas for antigen and antibody) were used in parallel. each inoculated pig developed a significant viraemia and clinical disease, and excreted virus, which was transmitted to the in-co ...200415511539
coxsackievirus b3 infection and type 1 diabetes development in nod mice: insulitis determines susceptibility of pancreatic islets to virus infection.group b coxsackieviruses (cvb) are believed to trigger some cases of human type 1 diabetes (t1d), although the mechanism by which this may occur has not been shown. we demonstrated previously that inoculation of young nonobese diabetic (nod) mice with any of several different cvb strains reduced t1d incidence. we also observed no evidence of cvb replication within islets of young nod mice, suggesting no role for cvb in t1d induction in the nod mouse model. the failure to observe cvb replication ...200415518817
generation and analysis of an rna vaccine that protects against coxsackievirus b3 challenge.coxsackievirus b3 (cvb3) is an important human pathogen that causes substantial morbidity and mortality but, to date, no vaccine is available. we have generated an rna-based vaccine against cvb3 and have evaluated it in the murine model of infection. the vaccine was designed to allow production of the viral polyprotein, which should be cleaved to generate most of the viral proteins in their mature form; but infectious virus should not be produced. in vitro translation studies indicated that the ...200415527846
identification of a naturally processed cytotoxic cd8 t-cell epitope of coxsackievirus b4, presented by hla-a2.1 and located in the pevkek region of the p2c nonstructural protein.the adaptive immune system generates cd8 cytotoxic t lymphocytes (ctls) as a major component of the protective response against viruses. knowledge regarding the nature of the peptide sequences presented by hla class i molecules and recognized by ctls is thus important for understanding host-pathogen interactions. in this study, we focused on identification of a ctl epitope generated from coxsackievirus b4 (cvb4), a member of the enterovirus group responsible for several inflammatory diseases in ...200415564450
coxsackievirus b3 infection induces cyr61 activation via jnk to mediate cell death.coxsackievirus b3 (cvb3), an enterovirus in the picornavirus family, is the most common human pathogen associated with myocarditis and idiopathic dilated cardiomyopathy. we found upregulation of the cysteine-rich protein gene (cyr61) after cvb3 infection in hela cells with a cdna microarray approach, which is confirmed by northern blot analysis. it is also revealed that the extracellular amount of cyr61 protein was increased after cvb3 infection in hela cells. cyr61 is an early-transcribed gene, ...200415564459
characterization of coxsackievirus b3-caused apoptosis under in vitro conditions.among several mechanisms of pathogenesis of the frequent and sometimes serious infections with coxsackievirus b3 (cvb3), one detail is apoptosis. recently, a new apoptotic mechanism involving the specific interaction between the capsid protein vp2 of the highly virulent variant cvb3h3 and the proapoptotic host protein siva was identified. the relevance of this observation for virus pathogenicity was shown in a balb/c mouse model using cvb3h3 and the interaction-deficient mutant virus cvb3h310a1. ...200413680215
dystrophin disruption in enterovirus-induced myocarditis and dilated cardiomyopathy: from bench to bedside.genetic defects of the dystrophin-glycoprotein complex (dgc) cause hereditary dilated cardiomyopathy. enteroviruses can also cause cardiomyopathy and we have previously described a mechanism involved in enterovirus-induced dilated cardiomyopathy: the enteroviral protease 2a directly cleaves dystrophin in the hinge 3 region, leading to functional dystrophin impairment. during infection of mice with coxsackievirus b3, the dgc in the heart is disrupted and the sarcolemmal integrity is lost in virus ...200412920582
virus-receptor interactions of coxsackie b viruses and their putative influence on cardiotropism.specific virus-receptor interactions are important determinants in the pathogenesis of viral infections, influencing the location and initiation of primary infection as well as the viral spread to other target organs in the postviremic phase. coxsackieviruses of group b (cvb) specifically interact with at least two receptor proteins, the coxsackievirus-adenovirus receptor (car) and the decay-accelerating factor (daf), and cause a broad spectrum of diseases, including acute and chronic myocarditi ...200412920584
coxsackievirus replication and the cell cycle: a potential regulatory mechanism for viral persistence/latency.coxsackieviruses (cv) are characterized by their ability to cause cytopathic effects in tissue culture and by their capacity to initiate acute disease by inducing apoptosis within targeted organs in vivo. these viruses are considered highly cytolytic, but can establish persistence/latency in susceptible cells, indicating that a regulatory mechanism may exist to shut off viral protein synthesis and replication under certain situations. the persistence of coxsackieviral rna is of particular medica ...200412925877
enteroviruses in tunisia: virological surveillance over 12 years (1992-2003).this report is an overview of enterovirus epidemiology in tunisia during a 12-year period from 1992 to 2003. a total of 4700 clinical samples were collected as part of the national poliovirus surveillance programme and the routine diagnostic programme for aseptic meningitis. enterovirus detection was performed by isolation on cell culture according to world health organization recommended protocols. serotype identification was performed by seroneutralization of the cytopathic effect using pools ...200515591257
importance of arginine 20 of the swine vesicular disease virus 2a protease for activity and virulence.a major virulence determinant of swine vesicular disease virus (svdv), an enterovirus that causes an acute vesicular disease, has been mapped to residue 20 of the 2a protease. the svdv 2a protease cleaves the 1d-2a junction in the viral polyprotein, induces cleavage of translation initiation factor eif4gi, and stimulates the activity of enterovirus internal ribosome entry sites (iress). the 2a protease from an attenuated strain of svdv (ile at residue 20) is significantly defective at inducing c ...200515596836
interaction with coxsackievirus and adenovirus receptor, but not with decay-accelerating factor (daf), induces a-particle formation in a daf-binding coxsackievirus b3 isolate.although many coxsackie b viruses interact with decay accelerating factor (daf), attachment to daf by itself is not sufficient to initiate infection. we examined the early events in infection that follow virus interaction with daf, and with the coxsackievirus and adenovirus receptor (car). interaction with soluble car in a cell-free system, or with car on the surfaces of transfected cells, induced the formation of a particles; interaction with soluble or cell surface daf did not. the results sug ...200515596863
all cvb serotypes and clinical isolates induce irreversible cytopathic effects in primary cardiomyocytes.coxsackievirus b3 (cvb3) has been identified as a major causative agent of acute and chronic myocarditis, but the involvement of other cvb serotypes in myocarditis has not been investigated. to dissect the pathological properties of different cvb serotypes toward primary cardiomyocytes, we tested their effects on primary cardiomyocyte cultures from neonatal rats. morphological abnormalities were examined by both light and fluorescence microscopy after hoechst 33342 staining, and loss of cell via ...200515602738
synthesis and antiviral activity against coxsackie virus b3 of some novel benzimidazole derivatives.some benzimidazole derivatives were synthesized and evaluated for their antiviral properties. compounds 20 and 21 showed potent selective activity against coxsackie virus b(3) in vero cells. some structure-activity relationships were discussed.200515603937
characterization of an infectious cdna copy of the genome of a naturally occurring, avirulent coxsackievirus b3 clinical isolate.group b coxsackieviruses (cvb) cause numerous diseases, including myocarditis, pancreatitis, aseptic meningitis and possibly type 1 diabetes. to date, infectious cdna copies of cvb type 3 (cvb3) genomes have all been derived from pathogenic virus strains. an infectious cdna copy of the well-characterized, non-pathogenic cvb3 strain ga genome was cloned in order to facilitate mapping of the cvb genes that influence expression of a virulence phenotype. comparison of the sequence of the parental cv ...200515604447
analysis of translational initiation in coxsackievirus b3 suggests an alternative explanation for the high frequency of r+4 in the eukaryotic consensus motif.translational initiation of most eukaryotic mrnas occurs when a preinitiation complex binds to the 5' cap, scans the mrna, and selects a particular aug codon as the initiation site. selection of the correct initiation codon relies, in part, on its flanking residues; in mammalian cells, the core of the "kozak" consensus is r-3ccaugg+4 (r=purine; the a residue is designated position +1). the r-3 is considered the most important flanking residue, followed by g+4. picornaviral mrnas differ from most ...200515613327
increased susceptibility of male balb/c mice to coxsackievirus b3-induced myocarditis: role for cd1d.balb/c male mice infected with the h3 variant of coxsackievirus b3 (cvb3) develop fulminant myocarditis. age-matched female mice show little myocarditis due to decreased virus receptor expression on cardiac cells. tnfalpha and il-1beta levels were increased in males by 3 days after infection. ifngamma levels increased more slowly throughout the 7-day observation period. cd4+, cd8+, macrophage (mac3+) and gammadelta+ cells all accumulated in male hearts, with gammadelta+ cells showing early (day ...200515107990
inhibition of coxsackievirus b3 replication by small interfering rnas requires perfect sequence match in the central region of the viral positive strand.coxsackievirus b3 (cvb3) is the most common causal agent of viral myocarditis, but existing drug therapies are of limited value. application of small interfering rna (sirna) in knockdown of gene expression is an emerging technology in antiviral gene therapy. to investigate whether rna interference (rnai) can protect against cvb3 infection, we evaluated the effects of rnai on viral replication in hela cells and murine cardiomyocytes by using five cvb3-specific sirnas targeting distinct regions of ...200515681418
oncolysis of human ovarian cancers by echovirus type 1.a small number of enteroviruses possess the capacity to induce rapid and marked lytic infections in cells of various human malignancies. during screening of representative human enteroviruses for their oncolytic capacity, we observed that echovirus type 1 (ev1) displayed a high level of tropism for human ovarian cancer cells. ev1 is an enterovirus which largely causes asymptomatic infections in humans and whose tissue tropism is primarily regulated via interactions with the i domain of the alpha ...200515688406
characterization of virus isolates by particle-associated nucleic acid pcr.diagnostic virus isolation is still frequently used, particularly from respiratory tract secretions. testing positive virus cultures for all possible viruses is time-consuming, and unexpected or unknown viruses may escape detection. therefore, a novel random pcr approach was developed that allows sequence-independent amplification of viral nucleic acids from virus isolation-positive cultures. selectivity for viral sequences is obtained by preferential isolation of nucleic acids that are particle ...200515695669
internalization and trafficking mechanisms of coxsackievirus b3 in hela cells.coxsackievirus b3 (cvb3) is nonenveloped and has a single-stranded positive-sense rna genome. cvb3 induces myocarditis and ultimately dilated cardiomyopathy. although there are mounting evidences of an interaction between cvb3 particles and the cellular receptors, coxsackievirus and adenovirus receptor (car) and decay-accelerating factor (daf), very little is known about the mechanisms of internalization and trafficking. in the present study, we used the cvb3 h3 strain, which is car-dependent bu ...200515708590
roles of tumor necrosis factor alpha (tnf-alpha) and the p55 tnf receptor in cd1d induction and coxsackievirus b3-induced myocarditis.giving c57bl/6 mice 10(4) pfu of coxsackievirus b3 (h3 variant) fails to induce myocarditis, but increasing the initial virus inoculum to 10(5) or 10(6) pfu causes significant cardiac disease. virus titers in the heart were equivalent at days 3 and 7 in mice given all three virus doses, but day 3 titers in the pancreases of mice inoculated with 10(4) pfu were reduced. tumor necrosis factor alpha (tnf-alpha) concentrations in the heart were increased in all infected mice, but cytokine levels were ...200515708985
phenotypic and genetic changes in coxsackievirus b5 following repeated passage in mouse pancreas in vivo.common enterovirus infections appear to initiate or facilitate the pathogenetic processes leading to type 1 diabetes, and also sometimes precipitate the clinical disease. in experimental infection of mice, coxsackieviruses have shown to have a strong affinity for the exocrine tissue, while even in lethal cases, the islets remain unaffected. the virus strain most intensively studied in this respect is the diabetogenic variant e2 of coxsackievirus b4. in addition, it is known that all six serotype ...200515714484
novel [(biphenyloxy)propyl]isoxazole derivatives for inhibition of human rhinovirus 2 and coxsackievirus b3 replication.during this study, novel biphenyl derivatives were synthesized and tested for antiviral activity.200515743897
coxsackievirus targets proliferating neuronal progenitor cells in the neonatal cns.type b coxsackieviruses (cvb) frequently infect the cns and, together with other enteroviruses, are the most common cause of viral meningitis in humans. newborn infants are particularly vulnerable, and cvb also can infect the fetus, leading to mortality, or to neurodevelopmental defects in surviving infants. using a mouse model of neonatal cvb infection, we previously demonstrated that coxsackievirus b3 (cvb3) could infect neuronal progenitor cells in the subventricular zone (svz). here we exten ...200515745971
elevated expression of pdgf-c in coxsackievirus b3-induced chronic myocarditis.coxsackievirus b3 (cvb3) is a frequent cause of human chronic myocarditis and subsequent fibrosis, leading to dilated cardiomyopathy. the molecular processes underlying the development of fibrosis are poorly understood. enhanced levels of platelet-derived growth factors (pdgfs), especially pdgf-c, have recently been linked with the development of different forms of fibrosis. therefore, the expression of pdgf was analysed in hearts of cvb3-infected major histocompatability complex class ii knocko ...200515757958
myocardial injury occurs earlier than myocardial inflammation in acute experimental viral myocarditis.endomyocardial biopsy often fails to show myocardial inflammation for patients with clinically suspected myocarditis. the serum isoforms of troponin t (ctnt) level is a very sensitive marker of myocardial injury and it is elevated even in the absence of myocardial inflammation. we investigated the correlations for myocardial injury, virus titers and inflammation in acute viral infection. using the murine coxsackievirus group b3 (cvb3) myocarditis model, the histopathologic findings and virus tit ...200515761252
dual functions of murine gammadelta cells in inflammation and autoimmunity in coxsackievirus b3-induced myocarditis: role of vgamma1+ and vgamma4+ cells.coxsackieviruses are a cause of clinical myocarditis. both virus replication and host defense mechanisms, including virus-induced autoimmunity, mediate heart injury and cardiac dysfunction. vgamma4+ cells kill infected cardiocytes and virus-specific cd4+ th2 cells through fas-dependent apoptosis and cd1d. the cd4+ th1 response is necessary for activation of the autoimmune cd8+ t cells, which kill uninfected cardiocytes through perforin-dependent mechanisms.200515777711
a proline-rich region in the coxsackievirus 3a protein is required for the protein to inhibit endoplasmic reticulum-to-golgi transport.the ability of the 3a protein of coxsackievirus b (cvb) to inhibit protein secretion was investigated for this study. here we show that the ectopic expression of cvb 3a blocked the transport of both the glycoprotein of vesicular stomatitis virus, a membrane-bound secretory marker, and the alpha-1 protease inhibitor, a luminal secretory protein, at a step between the endoplasmic reticulum (er) and the golgi complex. cvb 3a contains a conserved proline-rich region in its n terminus. the importance ...200515795300
characterization of nonpolio enteroviruses recovered from patients with aseptic meningitis in korea.we attempted to characterize nonpolio enteroviruses recovered from korean patients with aseptic meningitis.200515812181
distribution of viral rna in mouse tissues during acute phase of coxsackievirus b5 infection.to investigate histopathological changes and distribution of coxsackievirus b5 (cvb5) rna in mouse heart, liver, and pancreas during the acute phase of infection.200515812189
eye anomalies: seasonal variation and maternal viral infections.eye anomalies, including anophthalmos and microphthalmos (absent eye and small eye), are common features in congenital infection syndromes such as rubella. influenza, coxsackie virus, and parvovirus are less well-established teratogens. we report an ecologic analysis of anophthalmia/microphthalmia prevalence in england in relation to temporal variation in these infections using routine infection data.200515824546
more recent swine vesicular disease virus isolates retain binding to coxsackie-adenovirus receptor, but have lost the ability to bind human decay-accelerating factor (cd55).swine vesicular disease virus (svdv) evolved from coxsackie b virus serotype 5 (cvb5) in the recent past, crossing the species barrier from humans to pigs. here, svdv isolates from early and recent outbreaks have been compared for their capacity to utilize the progenitor virus receptors coxsackie-adenovirus receptor (car) and decay-accelerating factor (daf; cd55). virus titre of cvb5 and svdv isolates it'66 and uk'72 on human hela cells was reduced by pre-incubation with either anti-daf or anti- ...200515831949
long-term cardiac gene expression using a coxsackieviral vector.efficient myocardial gene transfer in the intact adult heart is difficult using conventional transfer vectors. since coxsackievirus b3 (cvb3) is cardiotropic, it may be possible to exploit its cardiotropic characteristics to design a vector for gene transfer to the intact heart. we generated a recombinant cvb3 cdna by inserting a green fluorescent protein (gfp) gene immediately upstream from the vp0 capsid protein of cvb3. the infectious virus (rcvb3-gfp) was recovered from the supernatants of t ...200515850568
[group b coxsackie virus infection with fatal myocarditis in the neonate after early discharge from maternity unit]. 200515885556
5'-terminal deletions occur in coxsackievirus b3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral rna.adult human enteroviral heart disease is often associated with the detection of enteroviral rna in cardiac muscle tissue in the absence of infectious virus. passage of coxsackievirus b3 (cvb3) in adult murine cardiomyocytes produced cvb3 that was noncytolytic in hela cells. detectable but noncytopathic cvb3 was also isolated from hearts of mice inoculated with cvb3. sequence analysis revealed five classes of cvb3 genomes with 5' termini containing 7, 12, 17, 30, and 49 nucleotide deletions. stru ...200515890942
[serotype distribution of enteroviruses isolated from paediatric cases prediagnosed as aseptic meningitis between 2001-2004 period].enteroviruses have major clinical and public health importance and are one of the leading causes of aseptic meningitis. there are many diseases with similar clinical symptoms and cerebrospinal fluid (csf) findings of aseptic meningitis, thus virus isolation and identification is crucial for definitive diagnosis. virological diagnosis is nonetheless important to distinguish between induced meningitis and other treatable causes of disease with a similar clinical picture. a total of 249 samples obt ...200515900836
inhibition of glycogen synthase kinase 3beta suppresses coxsackievirus-induced cytopathic effect and apoptosis via stabilization of beta-catenin.coxsackievirus b3 (cvb3), a common human pathogen for viral myocarditis, induces a direct cytopathic effect (cpe) and apoptosis on infected cells. to elucidate the mechanisms that contribute to these processes, we studied the role of glycogen synthase kinase 3beta (gsk3beta). gsk3beta activity was significantly increased after cvb3 infection and addition of tyrosine kinase inhibitors blocked cvb3-triggered gsk3beta activation. inhibition of caspase activity had no inhibitory effect on cvb3-induc ...200515905881
simultaneous type 1 diabetes onset in mother and son coincident with an enteroviral infection.enterovirus (ev) infections have been implicated in the development of type 1 diabetes. (t1d). they may cause beta-cell destruction either by cytolytic infection of the cells or indirectly by triggering the autoimmune response. virus was isolated from a woman at diagnosis of t1d (tuvemo 1) and in addition, virus was isolated from her son at diagnosis of t1d at the same day (tuvemo 2). none of the isolates could initially be serotyped by conventional methods. the tuvemo 1 virus was genotyped and ...200515911432
analysis of cytokine levels in cerebrospinal fluid in mumps meningitis: comparison with echovirus type 30 meningitis.it is unclear whether or not the csf cytokine profiles in viral meningitis differ with the kind of causative virus.200515927848
[sequence analysis of echovirus type 30 isolated from an aseptic meningitis outbreak in northern jiangsu province in 2003].to determine the partial sequence of virus strains causing an aseptic meningitis outbreak in northern part of jiangsu province in 2003 and to compare them with the same serotype strains isolated in other countries to better understand its genetic characteristics and hereditary trend of development.200515941539
pyrrolidine dithiocarbamate reduces coxsackievirus b3 replication through inhibition of the ubiquitin-proteasome pathway.coxsackievirus b3 (cvb3) is one of the most common pathogens for viral myocarditis. the lack of effective therapeutics for cvb3-caused viral diseases underscores the importance of searching for antiviral compounds. pyrrolidine dithiocarbamate (pdtc) is an antioxidant and is recently reported to inhibit ubiquitin-proteasome-mediated proteolysis. previous studies have shown that pdtc inhibits replication of rhinovirus, influenza virus, and poliovirus. in the present study, we report that pdtc is a ...200515956547
tissue tropism of recombinant coxsackieviruses in an adult mouse model.recombinant viruses, constructed by exchanging the 5' non-coding region (5'ncr), structural and non-structural protein coding sequences were used to investigate determinants responsible for differences between coxsackievirus a9 (cav9) and coxsackievirus b3 (cbv3) infections in adult mice and two cell lines. plaque assay titration of recombinant and parental viruses from different tissues from adult balb/c mice demonstrated that the structural region of cbv3 determined tropism to the liver tissue ...200515958668
cytolytic replication of coxsackievirus b2 in car-deficient rhabdomyosarcoma cells.the six coxsackievirus b serotypes (cvb1-6) use the coxsackie- and adenovirus receptor (car) for host cell entry. four of these serotypes, cvb1, 3, 5 and 6, have also shown the capacity to replicate and cause cytolysis in rhabdomyosarcoma (rd) cells, a car-deficient cell line. this extended tropism has been associated with an acquired ability to bind decay accelerating factor (daf). in this study, we have adapted the cvb2 prototype strain ohio-1 (cvb2/o) to replicate in rd cells. two types of in ...200515964091
gamma interferon-inducible protein 10 induces hela cell apoptosis through a p53-dependent pathway initiated by suppression of human papillomavirus type 18 e6 and e7 expression.gamma interferon-inducible protein 10 (ip10) is a member of the cxc family of chemokines. by differential mrna display, we have demonstrated the upregulation of ip10 in coxsackievirus b3 (cvb3)-infected mouse hearts. functional characterization of the ip10 gene in ip10-transfected tet-on hela cells has found that ip10 induced cell apoptosis and inhibited viral replication. in the characterization of the ip10-induced apoptotic pathway, we found that overexpression of ip10 upregulated p53 and resu ...200515988033
coxsackievirus b3 replication is related to activation of the late extracellular signal-regulated kinase (erk) signal.map kinase signaling has been implicated in coxsackievirus b3 (cvb3) pathogenesis and as necessary in the virus lifecycle. we studied the correlation with extracellular signal-regulated kinase 1/2 (erk1/2) signaling and virus replication in the presence of coxsackievirus and adenovirus receptor (car). in cho cells that do not expressed car, specific erk1/2 phosphorylation (perk1/2) was not detected, and progeny virus was not produced after infection. by contrast, in hela and cho-car cells, which ...200515993506
a genetically engineered attenuated coxsackievirus b3 strain protects mice against lethal infection.coxsackievirus b3 (cvb3) is a common human pathogen that is endemic throughout the world. there is currently no vaccine available, although the virus is known to be highly lethal to newborns and has been associated with heart disease and pancreatitis in older children and adults. previously, we showed that the virulence of cvb3 is reduced by a lysine-to-arginine substitution in the capsid protein vp2 (k2168r) or a glutamic acid-to-glycine substitution in vp3 (e3060g). in this report, we show tha ...200515994822
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