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allelic variation in the toll-like receptor adaptor protein ticam2 contributes to sars-coronavirus pathogenesis in mice.host genetic variation is known to contribute to differential pathogenesis following infection. mouse models allow direct assessment of host genetic factors responsible for susceptibility to severe acute respiratory syndrome coronavirus (sars-cov). based on an assessment of early stage lines from the collaborative cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to sars-cov: the resistant cc003/unc and the susceptible cc053/unc. we generated ...201728592648
sars-unique fold in the rousettus bat coronavirus hku9.the coronavirus nonstructural protein 3 (nsp3) is a multifunctional protein that comprises multiple structural domains. this protein assists viral polyprotein cleavage, host immune interference, and may play other roles in genome replication or transcription. here, we report the solution nmr structure of a protein from the "sars-unique region" of the bat coronavirus hku9. the protein contains a frataxin fold or double-wing motif, which is an α + β fold that is associated with protein/protein int ...201728580734
optimization of the production process and characterization of the yeast-expressed sars-cov recombinant receptor-binding domain (rbd219-n1), a sars vaccine candidate.from 2002 to 2003, a global pandemic of severe acute respiratory syndrome (sars) spread to 5 continents and caused 8000 respiratory infections and 800 deaths. to ameliorate the effects of future outbreaks as well as to prepare for biodefense, a process for the production of a recombinant protein vaccine candidate is under development. previously, we reported the 5 l scale expression and purification of a promising recombinant sars vaccine candidate, rbd219-n1, the 218-amino acid residue receptor ...201728456726
sars coronavirus papain-like protease up-regulates the collagen expression through non-samd tgf-β1 signaling.sars coronavirus (cov) papain-like protease (plpro) reportedly induced the production of tgf-β1 through p38 mapk/stat3-meidated egr-1-dependent activation (sci. rep. 6, 25754). this study investigated the correlation of plpro-induced tgf-β1 with the expression of type i collagen in human lung epithelial cells and mouse pulmonary tissues. specific inhibitors for tgf-βri, p38 mapk, mek, and stat3 proved that sars-cov plpro induced tgf-β1-dependent up-regulation of type i collagen in vitro and in v ...201728414040
the role of epidermal growth factor receptor (egfr) signaling in sars coronavirus-induced pulmonary fibrosis.many survivors of the 2003 outbreak of severe acute respiratory syndrome (sars) developed residual pulmonary fibrosis with increased severity seen in older patients. autopsies of patients that died from sars also showed fibrosis to varying extents. pulmonary fibrosis can be occasionally seen as a consequence to several respiratory viral infections but is much more common after a sars coronavirus (sars-cov) infection. given the threat of future outbreaks of severe coronavirus disease, including m ...201728390872
characterization and phylogenetic analysis of new bat astroviruses detected in gabon, central africa.astroviruses are emerging rna viruses that cause enteropathogenic infections in humans and in other mammals. the identification of astroviruses in a wide range of animals highlights the zoonotic importance of these viruses. bats can harbor many different viruses, among which some are highly pathogenic for humans (for instance, nipah, ebola and sars coronavirus), and also several astroviruses. as some rna viruses can be directly transmitted from bats to humans, it is crucial to collect data about ...201727928918
[new coronavirus infection: new challenges, new legacies].a new highly pathogenic human coronavirus has emerged. its natural history and its determinants are still under investigation. it lacks a publication to examine all the cases identified worldwide. therefore, the objective of this paper is to describe the cases and deaths caused by the new coronavirus.201725078748
cross-neutralization of sars coronavirus-specific antibodies against bat sars-like coronaviruses. 201729134417
a novel chemical compound for inhibition of sars coronavirus helicase.we have discovered a novel chemical compound, (e)-3-(furan-2-yl)-n-(4-sulfamoylphenyl) acrylamide, that suppresses the enzymatic activities of sars coronavirus helicase. to determine the inhibitory effect, atp hydrolysis and double-stranded dna unwinding assays were performed in the presence of various concentrations of the compound. through these assays, we obtained ic50 values of 2.09 ± 0.30 µm (atp hydrolysis) and 13.2 ± 0.9 µm (dna unwinding), respectively. moreover, we found that the compou ...201728910865
the effect of inhibition of pp1 and tnfα signaling on pathogenesis of sars coronavirus.the complex interplay between viral replication and host immune response during infection remains poorly understood. while many viruses are known to employ anti-immune strategies to facilitate their replication, highly pathogenic virus infections can also cause an excessive immune response that exacerbates, rather than reduces pathogenicity. to investigate this dichotomy in severe acute respiratory syndrome coronavirus (sars-cov), we developed a transcriptional network model of sars-cov infectio ...201627663205
immunodominant sars coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates.severe acute respiratory syndrome (sars) is caused by a coronavirus (sars-cov) and has the potential to threaten global public health and socioeconomic stability. evidence of antibody-dependent enhancement (ade) of sars-cov infection in vitro and in non-human primates clouds the prospects for a safe vaccine. using antibodies from sars patients, we identified and characterized sars-cov b-cell peptide epitopes with disparate functions. in rhesus macaques, the spike glycoprotein peptides s471-503, ...201627627203
immunodominant sars coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates.severe acute respiratory syndrome (sars) is caused by a coronavirus (sars-cov) and has the potential to threaten global public health and socioeconomic stability. evidence of antibody-dependent enhancement (ade) of sars-cov infection in vitro and in non-human primates clouds the prospects for a safe vaccine. using antibodies from sars patients, we identified and characterized sars-cov b-cell peptide epitopes with disparate functions. in rhesus macaques, the spike glycoprotein peptides s471-503, ...201627627203
antibody-dependent enhancement of sars coronavirus infection and its role in the pathogenesis of sars. 201627390007
sars coronavirus fusion peptide-derived sequence suppresses collagen-induced arthritis in dba/1j mice.during the co-evolution of viruses and their hosts, the viruses have evolved numerous strategies to counter and evade host antiviral immune responses in order to establish a successful infection, replicate and persist in the host. recently, based on our model of immune signaling, the signaling chain homooligomerization (school) model, we suggested specific molecular mechanisms used by different viruses such as severe acute respiratory syndrome coronavirus (sars-cov) to modulate the host immune r ...201627349522
recognition of lys48-linked di-ubiquitin and deubiquitinating activities of the sars coronavirus papain-like protease.deubiquitinating enzymes (dubs) recognize and cleave linkage-specific polyubiquitin (polyub) chains, but mechanisms underlying specificity remain elusive in many cases. the severe acute respiratory syndrome (sars) coronavirus papain-like protease (plpro) is a dub that cleaves isg15, a two-domain ub-like protein, and lys48-linked polyub chains, releasing diub(lys48) products. to elucidate this specificity, we report the 2.85 å crystal structure of sars plpro bound to a diub(lys48) activity-based ...201627203180
sars coronavirus papain-like protease inhibits the tlr7 signaling pathway through removing lys63-linked polyubiquitination of traf3 and traf6.severe acute respiratory syndrome coronavirus (sars-cov) papain-like protease (plpro) reportedly inhibits the production of type i interferons (ifns) and pro-inflammatory cytokines in toll-like receptor 3 (tlr3) and retinoic acid-inducible gene 1 (rig-i) pathways. the study investigated the inhibitory effect and its antagonistic mechanism of sars-cov plpro on tlr7-mediated cytokine production. tlr7 agonist (imiquimod (imq)) concentration-dependently induced activation of isre-, nf-κb- and ap-1-l ...201627164085
coexistence of multiple coronaviruses in several bat colonies in an abandoned mineshaft.since the 2002-2003 severe acute respiratory syndrome (sars) outbreak prompted a search for the natural reservoir of the sars coronavirus, numerous alpha- and betacoronaviruses have been discovered in bats around the world. bats are likely the natural reservoir of alpha- and betacoronaviruses, and due to the rich diversity and global distribution of bats, the number of bat coronaviruses will likely increase. we conducted a surveillance of coronaviruses in bats in an abandoned mineshaft in mojian ...201626920708
coexistence of multiple coronaviruses in several bat colonies in an abandoned mineshaft.since the 2002-2003 severe acute respiratory syndrome (sars) outbreak prompted a search for the natural reservoir of the sars coronavirus, numerous alpha- and betacoronaviruses have been discovered in bats around the world. bats are likely the natural reservoir of alpha- and betacoronaviruses, and due to the rich diversity and global distribution of bats, the number of bat coronaviruses will likely increase. we conducted a surveillance of coronaviruses in bats in an abandoned mineshaft in mojian ...201626920708
antigen production in plant to tackle infectious diseases flare up: the case of sars.severe acute respiratory syndrome (sars) is a dangerous infection with pandemic potential. it emerged in 2002 and its aetiological agent, the sars coronavirus (sars-cov), crossed the species barrier to infect humans, showing high morbidity and mortality rates. no vaccines are currently licensed for sars-cov and important efforts have been performed during the first outbreak to develop diagnostic tools. here we demonstrate the transient expression in nicotiana benthamiana of two important antigen ...201626904039
design and synthesis of a series of serine derivatives as small molecule inhibitors of the sars coronavirus 3cl protease.synthesis of serine derivatives having the essential functional groups for the inhibitor of sars 3cl protease and evaluation of their inhibitory activities using sars 3cl r188i mutant protease are described. the lead compounds, functionalized serine derivatives, were designed based on the tetrapeptide aldehyde and bai's cinnamoly inhibitor, and additionally performed with simulation on gold softwear. structure activity relationship studies of the candidate compounds were given reasonable inhibit ...201626879854
conformational flexibility of a short loop near the active site of the sars-3clpro is essential to maintain catalytic activity.the sars 3c-like proteinase (sars-3clpro), which is the main proteinase of the sars coronavirus, is essential to the virus life cycle. this enzyme has been shown to be active as a dimer in which only one protomer is active. however, it remains unknown how the dimer structure maintains an active monomer conformation. it has been observed that the ser139-leu141 loop forms a short 3(10)-helix that disrupts the catalytic machinery in the inactive monomer structure. we have tried to disrupt this heli ...201626879383
sars-cov and ifn: too little, too late.dysregulated type i interferon (ifn-i) expression can lead to severe pathology and disease. in this issue of cell host & microbe, channappanavar et al. (2016) use a sars-coronavirus animal model to describe how rapid and robust virus replication with delayed ifn-i can lead to lung immunopathology, with fatal outcomes.201626867172
spatiotemporal interplay of severe acute respiratory syndrome coronavirus and respiratory mucosal cells drives viral dissemination in rhesus macaques.innate immune responses have a critical role in the control of early virus replication and dissemination. it remains unknown, however, how severe acute respiratory syndrome coronavirus (sars-cov) evades respiratory innate immunity to establish a systemic infection. here we show in chinese macaques that sars-cov traversed the mucosa through the respiratory tract within 2 days, resulting in extensive mucosal infiltration by t cells, mac387(+), and cd163(+) monocytes/macrophages followed by limited ...201626647718
identification of a lineage d betacoronavirus in cave nectar bats (eonycteris spelaea) in singapore and an overview of lineage d reservoir ecology in se asian bats.coronaviruses are a diverse group of viruses that infect mammals and birds. bats are reservoirs for several different coronaviruses in the alphacoronavirus and betacoronavirus genera. they also appear to be the natural reservoir for the ancestral viruses that generated the severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus outbreaks. here, we detected coronavirus sequences in next-generation sequence data created from eonycteris spelaea faeces and urin ...201627637887
sars-cov fusion peptides induce membrane surface ordering and curvature.viral membrane fusion is an orchestrated process triggered by membrane-anchored viral fusion glycoproteins. the s2 subunit of the spike glycoprotein from severe acute respiratory syndrome (sars) coronavirus (cov) contains internal domains called fusion peptides (fp) that play essential roles in virus entry. although membrane fusion has been broadly studied, there are still major gaps in the molecular details of lipid rearrangements in the bilayer during fusion peptide-membrane interactions. here ...201627892522
sars coronavirus papain-like protease induces egr-1-dependent up-regulation of tgf-β1 via ros/p38 mapk/stat3 pathway.sars coronavirus (sars-cov) papain-like protease (plpro) has been identified in tgf-β1 up-regulation in human promonocytes (proteomics 2012, 12: 3193-205). this study investigates the mechanisms of sars-cov plpro-induced tgf-β1 promoter activation in human lung epithelial cells and mouse models. sars-cov plpro dose- and time-dependently up-regulates tgf-β1 and vimentin in a549 cells. dual luciferase reporter assays with tgf-β1 promoter plasmids indicated that tgf-β1 promoter region between -175 ...201627173006
a bat-derived putative cross-family recombinant coronavirus with a reovirus gene.the emergence of severe acute respiratory syndrome coronavirus (sars-cov) in 2002 and middle east respiratory syndrome coronavirus (mers-cov) in 2012 has generated enormous interest in the biodiversity, genomics and cross-species transmission potential of coronaviruses, especially those from bats, the second most speciose order of mammals. herein, we identified a novel coronavirus, provisionally designated rousettus bat coronavirus gccdc1 (ro-batcov gccdc1), in the rectal swab samples of rousett ...201627676249
abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus fusion.the highly pathogenic severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov) cause significant morbidity and morality. there is currently no approved therapeutic for highly pathogenic coronaviruses, even as mers-cov is spreading throughout the middle east. we previously screened a library of fda-approved drugs for inhibitors of coronavirus replication in which we identified abelson (abl) kinase inhibitors, including the anticancer dru ...201627466418
development of monoclonal antibody and diagnostic test for middle east respiratory syndrome coronavirus using cell-free synthesized nucleocapsid antigen.protein nativity is one of the most critical factors for the quality of antigens used as immunogens and the reactivities of the resultant antibodies. the preparation and purification of native viral antigens in conventional cell-based protein expression systems are often accompanied by technical hardships. these challenges are attributable mainly to protein aggregation and insolubility during expression and purification, as well as to very low expression levels associated with the toxicity of so ...201627148198
genetic diversity of coronaviruses in miniopterus fuliginosus bats.coronaviruses, such as severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus, pose significant public health threats. bats have been suggested to act as natural reservoirs for both these viruses, and periodic monitoring of coronaviruses in bats may thus provide important clues about emergent infectious viruses. the eastern bent-wing bat miniopterus fuliginosus is distributed extensively throughout china. we therefore analyzed the genetic diversity of coro ...201627125516
development of a sars coronavirus vaccine from recombinant spike protein plus delta inulin adjuvant.given periodic outbreaks of fatal human infections caused by coronaviruses, development of an optimal coronavirus vaccine platform capable of rapid production is an ongoing priority. this chapter describes the use of an insect cell expression system for rapid production of a recombinant vaccine against severe acute respiratory syndrome coronavirus (sars). detailed methods are presented for expression, purification, and release testing of sars recombinant spike protein antigen, followed by adjuva ...201627076136
memory t cell responses targeting the sars coronavirus persist up to 11 years post-infection.severe acute respiratory syndrome (sars) is a highly contagious infectious disease which first emerged in late 2002, caused by a then novel human coronavirus, sars coronavirus (sars-cov). the virus is believed to have originated from bats and transmitted to human through intermediate animals such as civet cats. the re-emergence of sars-cov remains a valid concern due to the continual persistence of zoonotic sars-covs and sars-like covs (sl-covs) in bat reservoirs. in this study, the screening fo ...201626954467
glycopeptide antibiotics potently inhibit cathepsin l in the late endosome/lysosome and block the entry of ebola virus, middle east respiratory syndrome coronavirus (mers-cov), and severe acute respiratory syndrome coronavirus (sars-cov).ebola virus infection can cause severe hemorrhagic fever with a high mortality in humans. the outbreaks of ebola viruses in 2014 represented the most serious ebola epidemics in history and greatly threatened public health worldwide. the development of additional effective anti-ebola therapeutic agents is therefore quite urgent. in this study, via high throughput screening of food and drug administration-approved drugs, we identified that teicoplanin, a glycopeptide antibiotic, potently prevents ...201626953343
comparative epidemiology of human infections with middle east respiratory syndrome and severe acute respiratory syndrome coronaviruses among healthcare personnel.the largest nosocomial outbreak of middle east respiratory syndrome (mers) occurred in south korea in 2015. health care personnel (hcp) are at high risk of acquiring mers-coronavirus (mers-cov) infections, similar to the severe acute respiratory syndrome (sars)-coronavirus (sars-cov) infections first identified in 2003. this study described the similarities and differences in epidemiological and clinical characteristics of 183 confirmed global mers cases and 98 sars cases in taiwan associated wi ...201626930074
middle east respiratory syndrome coronavirus intra-host populations are characterized by numerous high frequency variants.middle east respiratory syndrome coronavirus (mers-cov) is an emerging human pathogen related to sars virus. in vitro studies indicate this virus may have a broad host range suggesting an increased pandemic potential. genetic and epidemiological evidence indicate camels serve as a reservoir for mers virus but the mechanism of cross species transmission is unclear and many questions remain regarding the susceptibility of humans to infection. deep sequencing data was obtained from the nasal sample ...201626790002
kinetic, mutational, and structural studies of the venezuelan equine encephalitis virus nonstructural protein 2 cysteine protease.the venezuelan equine encephalitis virus (veev) nonstructural protein 2 (nsp2) cysteine protease (ec 3.4.22.-) is essential for viral replication and is involved in the cytopathic effects (cpe) of the virus. the veev nsp2 protease is a member of merops clan cn and characteristically contains a papain-like protease linked to an s-adenosyl-l-methionine-dependent rna methyltransferase (sam mtase) domain. the protease contains an alternative active site motif, (475)nvcwak(480), which differs from pa ...201627030368
sars and mers: recent insights into emerging coronaviruses.the emergence of middle east respiratory syndrome coronavirus (mers-cov) in 2012 marked the second introduction of a highly pathogenic coronavirus into the human population in the twenty-first century. the continuing introductions of mers-cov from dromedary camels, the subsequent travel-related viral spread, the unprecedented nosocomial outbreaks and the high case-fatality rates highlight the need for prophylactic and therapeutic measures. scientific advancements since the 2002-2003 severe acute ...201627344959
mers-cov infection of alpaca in a region where mers-cov is endemic. 201627070501
a mouse model for mers coronavirus-induced acute respiratory distress syndrome.middle east respiratory syndrome coronavirus (mers-cov) is a novel virus that emerged in 2012, causing acute respiratory distress syndrome (ards), severe pneumonia-like symptoms and multi-organ failure, with a case fatality rate of ∼36%. limited clinical studies indicate that humans infected with mers-cov exhibit pathology consistent with the late stages of ards, which is reminiscent of the disease observed in patients infected with severe acute respiratory syndrome coronavirus. models of mers-c ...201627892925
detection of the severe acute respiratory syndrome-related coronavirus and alphacoronavirus in the bat population of taiwan.bats have been demonstrated to be natural reservoirs of severe acute respiratory syndrome coronavirus (sars cov) and middle east respiratory syndrome (mers) cov. faecal samples from 248 individuals of 20 bat species were tested for partial rna-dependent rna polymerase gene of cov and 57 faecal samples from eight bat species were tested positive. the highest detection rate of 44% for scotophilus kuhlii, followed by 30% for rhinolophus monoceros. significantly higher detection rates of coronaviral ...201627178103
infectious bronchitis coronavirus limits interferon production by inducing a host shutoff that requires accessory protein 5b.during infection of their host cells, viruses often inhibit the production of host proteins, a process that is referred to as host shutoff. by doing this, viruses limit the production of antiviral proteins and increase production capacity for viral proteins. coronaviruses from the genera alphacoronavirus and betacoronavirus, such as severe acute respiratory syndrome coronavirus (sars-cov), establish host shutoff via their nonstructural protein 1 (nsp1). the gammacoronavirus and deltacoronavirus ...201627279618
p53 down-regulates sars coronavirus replication and is targeted by the sars-unique domain and plpro via e3 ubiquitin ligase rchy1.highly pathogenic severe acute respiratory syndrome coronavirus (sars-cov) has developed strategies to inhibit host immune recognition. we identify cellular e3 ubiquitin ligase ring-finger and chy zinc-finger domain-containing 1 (rchy1) as an interacting partner of the viral sars-unique domain (sud) and papain-like protease (pl(pro)), and, as a consequence, the involvement of cellular p53 as antagonist of coronaviral replication. residues 95-144 of rchy1 and 389-652 of sud (sud-nm) subdomains ar ...201627519799
fatal outcome of human coronavirus nl63 infection despite successful viral elimination by ifn-alpha in a patient with newly diagnosed all.human coronavirus nl63 (hcov-nl63) is one of four common human respiratory coronaviruses. despite high incidence, hcov infections are grossly understudied. we here report a case of hcov infection in a leukemia patient with fatal ards despite successful virus elimination by pegylated interferon-alpha (peg-ifn-α).201626854965
high-resolution analysis of coronavirus gene expression by rna sequencing and ribosome profiling.members of the family coronaviridae have the largest genomes of all rna viruses, typically in the region of 30 kilobases. several coronaviruses, such as severe acute respiratory syndrome-related coronavirus (sars-cov) and middle east respiratory syndrome-related coronavirus (mers-cov), are of medical importance, with high mortality rates and, in the case of sars-cov, significant pandemic potential. other coronaviruses, such as porcine epidemic diarrhea virus and avian coronavirus, are important ...201626919232
cathepsin l helps to defend mice from infection with influenza a.host-derived proteases can augment or help to clear infections. this dichotomy is exemplified by cathepsin l (ctsl), which helps hendra virus and sars coronavirus to invade cells, but is essential for survival in mice with mycoplasma pneumonia. the present study tested the hypothesis that ctsl protects mice from serious consequences of infection by the orthomyxovirus influenza a, which is thought to be activated by host-supplied proteases other than ctsl. ctsl-/- mice infected with influenza a/p ...201627716790
pains and gains from china's experiences with emerging epidemics: from sars to h7n9.over the recent decades, china experienced several emerging virus outbreaks including those caused by the severe acute respiratory syndrome- (sars-) coronavirus (cov), h5n1 virus, and h7n9 virus. the sars tragedy revealed faults in china's infectious disease prevention system, propelling the chinese government to enact reforms that enabled better combating of the subsequent h1n1 and h7n9 avian flu epidemics. the system is buttressed by three fundamental, mutually reinforcing components: (1) endu ...201627525272
wildlife trade and human health in lao pdr: an assessment of the zoonotic disease risk in markets.although the majority of emerging infectious diseases can be linked to wildlife sources, most pathogen spillover events to people could likely be avoided if transmission was better understood and practices adjusted to mitigate risk. wildlife trade can facilitate zoonotic disease transmission and represents a threat to human health and economies in asia, highlighted by the 2003 sars coronavirus outbreak, where a chinese wildlife market facilitated pathogen transmission. additionally, wildlife tra ...201627008628
distribution and evolutionary history of the mobile genetic element s2m in coronaviruses.the mobile genetic element s2m has been described in several families of single-stranded rna viruses. the function remains elusive, but an increasing number of s2m-containing sequences are being deposited in publicly available databases. currently, more than 700 coronavirus sequences containing s2m can be found in genbank, including the severe acute respiratory syndrome (sars) coronavirus genome. this is an updated review of the pattern of s2m in coronaviruses, the possible functional implicatio ...201628933407
[advances in the animal models of mers-cov].the middle east respiratory syndrome coronavirus (mers-cov) was first isolated in 2012 from patients that died from severe pneumonia. it was another coronavirus which resulted in severe infection of humans, apart from the severe acute respiratory syndrome coronavirus. the development of an appropriate animal model is necessary to study the pathogenesis and to evaluate the intervening measures against mers-cov infection. to date, several small animals(e.g., mice, syrian hamsters, and ferrets) hav ...201629963837
orf8-related genetic evidence for chinese horseshoe bats as the source of human severe acute respiratory syndrome coronavirus.several lineage b betacoronaviruses termed severe acute respiratory syndrome (sars)-like covs (sl-covs) were identified from rhinolophus bats in china. these viruses are characterized by a set of unique accessory open reading frames (orfs) that are located between the m and n genes. among unique accessory orfs, orf8 is most hypervariable. in this study, the orf8s of all sl-covs were classified into 3 types, and, for the first time, it was found that very few sl-covs from rhinolophus sinicus have ...201626433221
vaccine development against middle east respiratory syndrome.various types of vaccines are under pre-clinical and clinical development to address the recent appearance of middle east respiratory syndrome or mers, an emerging infectious disease that has already caused over 600 deaths and remains a threat to world health. the causative agent for this respiratory disease is a member of the betacoronavirus genus, phylogenetically closely related to the sars coronavirus that caused an international health emergency in 2002. with lessons learned from the outbre ...201632226714
identification of a novel small molecule inhibitor against sars coronavirus helicase.a new chemical inhibitor against severe acute respiratory syndrome (sars) coronavirus helicase, 7-ethyl-8-mercapto-3-methyl-3,7-dihydro-1h-purine-2,6-dione, was identified. we investigated the inhibitory effect of the compound by conducting colorimetry-based atp hydrolysis assay and fluorescence resonance energy transfer-based double-stranded dna unwinding assay. the compound suppressed both atp hydrolysis and double-stranded dna unwinding activities of helicase with ic50 values of 8.66 ± 0.26 μ ...201526387819
severe acute respiratory syndrome (sars) coronavirus orf8 protein is acquired from sars-related coronavirus from greater horseshoe bats through recombination.despite the identification of horseshoe bats as the reservoir of severe acute respiratory syndrome (sars)-related coronaviruses (sarsr-covs), the origin of sars-cov orf8, which contains the 29-nucleotide signature deletion among human strains, remains obscure. although two sars-related rhinolophus sinicus bat covs (sarsr-rs-batcovs) previously detected in chinese horseshoe bats (rhinolophus sinicus) in yunnan, rsshc014 and rs3367, possessed 95% genome identities to human and civet sarsr-covs, th ...201526269185
severe acute respiratory syndrome (sars) coronavirus orf8 protein is acquired from sars-related coronavirus from greater horseshoe bats through recombination.despite the identification of horseshoe bats as the reservoir of severe acute respiratory syndrome (sars)-related coronaviruses (sarsr-covs), the origin of sars-cov orf8, which contains the 29-nucleotide signature deletion among human strains, remains obscure. although two sars-related rhinolophus sinicus bat covs (sarsr-rs-batcovs) previously detected in chinese horseshoe bats (rhinolophus sinicus) in yunnan, rsshc014 and rs3367, possessed 95% genome identities to human and civet sarsr-covs, th ...201526269185
this could be the start of something big-20 years since the identification of bats as the natural host of hendra virus.hendra virus was first described in 1994 in australia, causally associated with a cluster of fatal equine and human cases at a thoroughbred racing stable in the brisbane suburb of hendra. this year marks the twentieth anniversary of the identification of pteropid bats (flying-foxes) as the natural host of the virus, and it is timely to reflect on a pivotal meeting of an eclectic group of scientists in that process. they included animal and public health experts, environmental scientists, veterin ...201528616459
structural basis and functional analysis of the sars coronavirus nsp14-nsp10 complex.nonstructural protein 14 (nsp14) of coronaviruses (cov) is important for viral replication and transcription. the n-terminal exoribonuclease (exon) domain plays a proofreading role for prevention of lethal mutagenesis, and the c-terminal domain functions as a (guanine-n7) methyl transferase (n7-mtase) for mrna capping. the molecular basis of both these functions is unknown. here, we describe crystal structures of severe acute respiratory syndrome (sars)-cov nsp14 in complex with its activator no ...201526159422
a g-quadruplex-binding macrodomain within the "sars-unique domain" is essential for the activity of the sars-coronavirus replication-transcription complex.the multi-domain non-structural protein 3 of sars-coronavirus is a component of the viral replication/transcription complex (rtc). among other domains, it contains three sequentially arranged macrodomains: the x domain and subdomains sud-n as well as sud-m within the "sars-unique domain". the x domain was proposed to be an adp-ribose-1"-phosphatase or a poly(adp-ribose)-binding protein, whereas sud-nm binds oligo(g)-nucleotides capable of forming g-quadruplexes. here, we describe the application ...201526149721
the sars-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (sars-cov) emerged from the guangdong province of china. despite the fact that the sars-cov pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat sars-cov infections. the recent emergence of the deadly human coronavirus ...201525554382
acquisition of new protein domains by coronaviruses: analysis of overlapping genes coding for proteins n and 9b in sars coronavirus.acquisition of new proteins by viruses usually occurs through horizontal gene transfer or through gene duplication, but another, less common mechanism is the usage of completely or partially overlapping reading frames. a case of acquisition of a completely new protein through introduction of a start codon in an alternative reading frame is the protein encoded by open reading frame (orf) 9b of sars coronavirus. this gene completely overlaps with the nucleocapsid (n) gene (orf9a). our findings ind ...201525410051
the role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis.host genetic factors have frequently been implicated in respiratory infectious diseases, often with inconsistent results in replication studies. we identified 386 studies from the total of 24,823 studies identified in a systematic search of four bibliographic databases. we performed meta-analyses of studies on tuberculosis, influenza, respiratory syncytial virus, sars-coronavirus and pneumonia. one single-nucleotide polymorphism from il4 gene was significant for pooled respiratory infections (rs ...201526524966
the virus-host interplay: biogenesis of +rna replication complexes.positive-strand rna (+rna) viruses are an important group of human and animal pathogens that have significant global health and economic impacts. notable members include west nile virus, dengue virus, chikungunya, severe acute respiratory syndrome (sars) coronavirus and enteroviruses of the picornaviridae family.unfortunately, prophylactic and therapeutic treatments against these pathogens are limited. +rna viruses have limited coding capacity and thus rely extensively on host factors for succes ...201526287230
middle east respiratory syndrome coronavirus: transmission, virology and therapeutic targeting to aid in outbreak control.middle east respiratory syndrome coronavirus (mers-cov) causes high fever, cough, acute respiratory tract infection and multiorgan dysfunction that may eventually lead to the death of the infected individuals. mers-cov is thought to be transmitted to humans through dromedary camels. the occurrence of the virus was first reported in the middle east and it subsequently spread to several parts of the world. since 2012, about 1368 infections, including ~487 deaths, have been reported worldwide. nota ...201526315600
compounds derived from epigallocatechin-3-gallate (egcg) as a novel approach to the prevention of viral infections.pathogenic viral infections pose major health risks to humans and livestock due to viral infection-associated illnesses such as chronic or acute inflammation in crucial organs and systems, malignant and benign lesions. these lead to large number of illnesses and deaths worldwide each year. outbreaks of emerging lethal viruses, such as ebola virus, severe acute respiratory syndrome (sars) virus and middle east respiratory syndrome (mers) virus, could lead to epidemics or even pandemics if they ar ...201526490660
bats as reservoirs of severe emerging infectious diseases.in recent years severe infectious diseases have been constantly emerging, causing panic in the world. now we know that many of these terrible diseases are caused by viruses originated from bats (table 1), such as ebola virus, marburg, sars coronavirus (sars-cov), mers coronavirus (mers-cov), nipah virus (niv) and hendra virus (hev). these viruses have co-evolved with bats due to bats' special social, biological and immunological features. although bats are not in close contact with humans, spill ...201525997928
analysis of cathepsin and furin proteolytic enzymes involved in viral fusion protein activation in cells of the bat reservoir host.bats of different species play a major role in the emergence and transmission of highly pathogenic viruses including ebola virus, sars-like coronavirus and the henipaviruses. these viruses require proteolytic activation of surface envelope glycoproteins needed for entry, and cellular cathepsins have been shown to be involved in proteolysis of glycoproteins from these distinct virus families. very little is currently known about the available proteases in bats. to determine whether the utilizatio ...201525706132
protease inhibitors targeting coronavirus and filovirus entry.in order to gain entry into cells, diverse viruses, including ebola virus, sars-coronavirus and the emerging mers-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. the respective enzymes are thus excellent targets for antiviral intervention. in cell culture, activation of ebola virus, as well as sars- and mers-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin l (ctsl) and cathepsin b (ctsb). in addition, sars- and mers-coronavi ...201525666761
contrasted patterns of variation and evolutionary convergence at the antiviral oas1 gene in old world primates.the oligoadenylate synthetase 1 (oas1) enzyme acts as an innate sensor of viral infection and plays a major role in the defense against a wide diversity of viruses. polymorphisms at oas1 have been shown to correlate with differential susceptibility to several infections of great public health significance, including hepatitis c virus, sars coronavirus, and west nile virus. population genetics analyses in hominoids have revealed interesting evolutionary patterns. in central african chimpanzee, oa ...201526156123
contrasted patterns of variation and evolutionary convergence at the antiviral oas1 gene in old world primates.the oligoadenylate synthetase 1 (oas1) enzyme acts as an innate sensor of viral infection and plays a major role in the defense against a wide diversity of viruses. polymorphisms at oas1 have been shown to correlate with differential susceptibility to several infections of great public health significance, including hepatitis c virus, sars coronavirus, and west nile virus. population genetics analyses in hominoids have revealed interesting evolutionary patterns. in central african chimpanzee, oa ...201526156123
the role of c5a in acute lung injury induced by highly pathogenic viral infections.the complement system, an important part of innate immunity, plays a critical role in pathogen clearance. unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ali) induced by highly pathogenic virus including influenza a viruses h5n1, h7n9, and severe acute respiratory syndrome (sars) coronavirus. in highly pathogenic virus-induced acute lung diseases, high levels of chemotactic and anaphylatoxic c5a were produced as a result of excessive c ...201526060601
transcriptome profiling of the virus-induced innate immune response in pteropus vampyrus and its attenuation by nipah virus interferon antagonist functions.bats are important reservoirs for several viruses, many of which cause lethal infections in humans but have reduced pathogenicity in bats. as the innate immune response is critical for controlling viruses, the nature of this response in bats and how it may differ from that in other mammals are of great interest. using next-generation transcriptome sequencing (mrna-seq), we profiled the transcriptional response of pteropus vampyrus bat kidney (pvk) cells to newcastle disease virus (ndv), an avian ...201525972557
the proteome of the infectious bronchitis virus beau-r virion.infectious bronchitis is a highly contagious respiratory disease of poultry caused by the coronavirus infectious bronchitis virus (ibv). it was thought that coronavirus virions were composed of three major viral structural proteins until investigations of other coronaviruses showed that the virions also include viral non-structural and genus-specific accessory proteins as well as host-cell proteins. to study the proteome of ibv virions, virus was grown in embryonated chicken eggs, purified by su ...201527257648
vhl negatively regulates sars coronavirus replication by modulating nsp16 ubiquitination and stability.eukaryotic cellular and most viral rnas carry a 5'-terminal cap structure, a 5'-5' triphosphate linkage between the 5' end of the rna and a guanosine nucleotide (cap-0). sars coronavirus (sars-cov) nonstructural protein nsp16 functions as a methyltransferase, to methylate mrna cap-0 structure at the ribose 2'-o position of the first nucleotide to form cap-1 structures. however, whether there is interplay between nsp16 and host proteins was not yet clear. in this report, we identified several pot ...201525732088
detection of coronavirus genomes in moluccan naked-backed fruit bats in indonesia.bats have been shown to serve as natural reservoirs for numerous emerging viruses including severe acute respiratory syndrome coronavirus (sars-cov). in the present study, we report the discovery of bat cov genes in indonesian moluccan naked-backed fruit bats (dobsonia moluccensis). a partial rna-dependent rna polymerase gene sequence was detected in feces and tissues samples from the fruit bats, and the region between the rdrp and helicase genes could also be amplified from fecal samples. phylo ...201525643817
coronaviruses: an overview of their replication and pathogenesis.coronaviruses (covs), enveloped positive-sense rna viruses, are characterized by club-like spikes that project from their surface, an unusually large rna genome, and a unique replication strategy. coronaviruses cause a variety of diseases in mammals and birds ranging from enteritis in cows and pigs and upper respiratory disease in chickens to potentially lethal human respiratory infections. here we provide a brief introduction to coronaviruses discussing their replication and pathogenicity, and ...201525720466
development of animal models against emerging coronaviruses: from sars to mers coronavirus.two novel coronaviruses have emerged to cause severe disease in humans. while bats may be the primary reservoir for both viruses, sars coronavirus (sars-cov) likely crossed into humans from civets in china, and mers coronavirus (mers-cov) has been transmitted from camels in the middle east. unlike sars-cov that resolved within a year, continued introductions of mers-cov present an on-going public health threat. animal models are needed to evaluate countermeasures against emerging viruses. with s ...201525791336
molecular pathology of emerging coronavirus infections.respiratory viruses can cause a wide spectrum of pulmonary diseases, ranging from mild, upper respiratory tract infections to severe and life-threatening lower respiratory tract infections, including the development of acute lung injury (ali) and acute respiratory distress syndrome (ards). viral clearance and subsequent recovery from infection require activation of an effective host immune response; however, many immune effector cells may also cause injury to host tissues. severe acute respirato ...201525270030
the effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.administration of convalescent plasma, serum, or hyperimmune immunoglobulin may be of clinical benefit for treatment of severe acute respiratory infections (saris) of viral etiology. we conducted a systematic review and exploratory meta-analysis to assess the overall evidence.201525030060
reconstitution of the receptor-binding motif of the sars coronavirus.the severe acute respiratory syndrome (sars) coronavirus (cov) identified in 2003 has infected ∼8000 people worldwide, killing nearly 10% of them. the infection of target cells by the sars cov is mediated through the interaction of the viral spike (s) protein (1255 amino acids) and its cellular receptor, angiotensin-converting enzyme 2 (ace2). the sars cov receptor-binding domain (amino acids n318-t509 of s protein) harbors an extended excursion along its periphery that contacts ace2 and is desi ...201526487711
modeling the structure of sars 3a transmembrane protein using a minimum unfavorable contact approach.3a is an accessory protein from sars coronavirus that is known to play a significant role in the proliferation of the virus by forming tetrameric ion channels. although the monomeric units are known to consist of three transmembrane (tm) domains, there are no solved structures available for the complete monomer. the present study proposes a structural model for the transmembrane region of the monomer by employing our previously tested approach, which predicts potential orientations of tm α-helic ...201532218650
crystal structure of the papain-like protease of mers coronavirus reveals unusual, potentially druggable active-site features.the middle-east respiratory syndrome coronavirus (mers-cov) causes severe acute pneumonia and renal failure. the mers-cov papain-like protease (pl(pro)) is a potential target for the development of antiviral drugs. to facilitate these efforts, we determined the three-dimensional structure of the enzyme by x-ray crystallography. the molecule consists of a ubiquitin-like domain and a catalytic core domain. the catalytic domain displays an extended right-hand fold with a zinc ribbon and embraces a ...201424992731
serological assays for emerging coronaviruses: challenges and pitfalls.more than a decade after the emergence of severe acute respiratory syndrome coronavirus (sars-cov) in 2002/2003 the occurrence of a novel cov termed middle east respiratory syndrome (mers) cov challenges researchers and public health authorities. to control spread and finally contain novel viruses, rapid identification and subsequent isolation of infected individuals and their contacts is of utmost importance. next to methods for nucleic acid detection, validated serological assays are particula ...201424670324
active replication of middle east respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis.middle east respiratory syndrome coronavirus (mers-cov) infection caused severe pneumonia and multiorgan dysfunction and had a higher crude fatality rate (around 50% vs. 10%) than sars coronavirus (sars-cov) infection. to understand the pathogenesis, we studied viral replication, cytokine/chemokine response, and antigen presentation in mers-cov-infected human monocyte-derived macrophages (mdms) versus sars-cov-infected mdms. only mers-cov can replicate in mdms. both viruses were unable to signif ...201424065148
from sars to mers: crystallographic studies on coronaviral proteases enable antiviral drug design.this review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (m(pro) ) and the papain-like protease (pl(pro) ). the role of x-ray crystallography in structure-assisted drug discovery against these targets is discussed. aspects dealt with in this review include the emergence of the sars coronavirus in 2002-2003 and of the mers coronaviru ...201425039866
protection from sars coronavirus conferred by live measles vaccine expressing the spike glycoprotein.the recent identification of a novel human coronavirus responsible of a sars-like illness in the middle-east a decade after the sars pandemic, demonstrates that reemergence of a sars-like coronavirus from an animal reservoir remains a credible threat. because sars is contracted by aerosolized contamination of the respiratory tract, a vaccine inducing mucosal long-term protection would be an asset to control new epidemics. to this aim, we generated live attenuated recombinant measles vaccine (mv) ...201424606680
characterization of a novel betacoronavirus related to middle east respiratory syndrome coronavirus in european hedgehogs.bats are known to host viruses closely related to important human coronaviruses (hcovs), such as hcov-229e, severe-acute respiratory syndrome coronavirus (sars-cov), and middle east respiratory syndrome cov (mers-cov). as rna viruses may coevolve with their hosts, we sought to investigate the closest sister taxon to bats, the eulipotyphla, and screened european hedgehogs (erinaceus europaeus) from germany for cov by nested reverse transcriptase pcr. a novel betacoronavirus species in a phylogene ...201424131722
substitution at aspartic acid 1128 in the sars coronavirus spike glycoprotein mediates escape from a s2 domain-targeting neutralizing monoclonal antibody.the severe acute respiratory syndrome coronavirus (sars-cov) is the etiological agent for the infectious disease, sars, which first emerged 10 years ago. sars-cov is a zoonotic virus that has crossed the species barriers to infect humans. bats, which harbour a diverse pool of sars-like covs (sl-covs), are believed to be the natural reservoir. the sars-cov surface spike (s) protein is a major antigenic determinant in eliciting neutralizing antibody production during sars-cov infection. in our pre ...201425019613
accessory proteins of sars-cov and other coronaviruses.the huge rna genome of sars coronavirus comprises a number of open reading frames that code for a total of eight accessory proteins. although none of these are essential for virus replication, some appear to have a role in virus pathogenesis. notably, some sars-cov accessory proteins have been shown to modulate the interferon signaling pathways and the production of pro-inflammatory cytokines. the structural information on these proteins is also limited, with only two (p7a and p9b) having their ...201424995382
sars coronavirus without reservoir originated from an unnatural evolution, experienced the reverse evolution, and finally disappeared in the world. 201424985597
development of a single nucleotide polymorphism dna microarray for the detection and genotyping of the sars coronavirus.severe acute respiratory syndrome (sars), a disease that spread widely in the world during late 2002 to 2004, severely threatened public health. although there have been no reported infections since 2004, the extremely pathogenic sars coronavirus (sars-cov), as the causative agent of sars, has recently been identified in animals, showing the potential for the re-emergence of this disease. previous studies showed that 27 single nucleotide polymorphism (snp) mutations among the spike (s) gene of t ...201424950883
the yxxφ motif within the severe acute respiratory syndrome coronavirus (sars-cov) 3a protein is crucial for its intracellular transport.the sars coronavirus (sars-cov) 3a protein functions as an ion channel, induces apoptosis and is important for viral pathogenesis. it is expressed on the cell surface and contains a tyrosine-based sorting motif and a di-acidic motif, which may be crucial for its intracellular trafficking. however the role of these motifs is not fully understood in the case of 3a protein.201424762043
phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected sars coronavirus.while the 2002-2003 outbreak of severe acute respiratory syndrome (sars) resulted in 774 deaths, patients who were affected with mild pulmonary symptoms successfully recovered. the objective of the present work was to identify, using sars coronavirus (sars-cov) mouse infection models, immune factors responsible for clearing of the virus. the elimination of pulmonary sars-cov infection required the activation of b cells by cd4(+) t cells. furthermore, passive immunization (post-infection) with ho ...201424725942
outcomes of sars survivors in china: not only physical and psychiatric co-morbidities.the year 2013 marks the 10th anniversary of the outbreak of the severe acute respiratory syndrome (sars). we present a comprehensive introduction to the current situation of surviving sars victims in china where the disease originated and spread across the world 10 years ago.201424676486
multi-organ lesions in suckling mice infected with sars-associated mammalian reovirus linked with apoptosis induced by viral proteins μ1 and σ1.we reported the isolation and characterization of a novel mammalian reassortant reovirus byd1 that may have played an accomplice role with sars-coronavirus during the 2003 sars pandemic. the pathogenic mechanism of this novel reovirus is unknown. reovirus pathogenicity has been associated with virus-induced apoptosis in cultured cells and in vivo. the reovirus outer capsid protein μ1 is recognized as the primary determinant of reovirus-induced apoptosis. here, we investigated the apoptosis induc ...201424664247
how change of public transportation usage reveals fear of the sars virus in a city.the outbreaks of the severe acute respiratory syndrome (sars) epidemic in 2003 resulted in unprecedented impacts on people's daily life. one of the most significant impacts to people is the fear of contacting the sars virus while engaging daily routine activity. here we use data from daily underground ridership in taipei city and daily reported new sars cases in taiwan to model the dynamics of the public fear of the sars virus during the wax and wane of the sars period. we found that for each re ...201424647278
severe acute respiratory syndrome-coronavirus infection in aged nonhuman primates is associated with modulated pulmonary and systemic immune responses.many respiratory viruses disproportionately impact the elderly. likewise, advanced age correlated with more adverse disease outcomes following severe acute respiratory syndrome coronavirus (sars-cov) infection in humans. we used an aged african green monkey sars-cov infection model to better understand age-related mechanisms of increased susceptibility to viral respiratory infections. nonhuman primates are critical translational models for such research given their similarities to humans in immu ...201424642138
sars coronavirus papain-like protease inhibits the type i interferon signaling pathway through interaction with the sting-traf3-tbk1 complex.sars coronavirus (sars-cov) develops an antagonistic mechanism by which to evade the antiviral activities of interferon (ifn). previous studies suggested that sars-cov papain-like protease (plpro) inhibits activation of the irf3 pathway, which would normally elicit a robust ifn response, but the mechanism(s) used by sars plpro to inhibit activation of the irf3 pathway is not fully known. in this study, we uncovered a novel mechanism that may explain how sars plpro efficiently inhibits activation ...201424622840
influence of hydrophobic and electrostatic residues on sars-coronavirus s2 protein stability: insights into mechanisms of general viral fusion and inhibitor design.severe acute respiratory syndrome (sars) is an acute respiratory disease caused by the sars-coronavirus (sars-cov). sars-cov entry is facilitated by the spike protein (s), which consists of an n-terminal domain (s1) responsible for cellular attachment and a c-terminal domain (s2) that mediates viral and host cell membrane fusion. the sars-cov s2 is a potential drug target, as peptidomimetics against s2 act as potent fusion inhibitors. in this study, site-directed mutagenesis and thermal stabilit ...201424519901
[bats, viruses and humans: coronaviruses on the rise?].the outbreak of the sars coronavirus in 2002/2003 and the recent disease cases with a new human coronavirus (originally designated emc-cov, recently renamed mers-cov) have put the focus onto the virus family coronaviridae. both viruses appeared to have managed to jump over the species barrier from a bat reservoir to the human population. bats are considered to serve as a natural reservoir for coronaviruses infecting mammals. an important factor for crossing the species-barrier is the adaptation ...201424511826
kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus.the protein coded by the open-reading-frame 3a of sars coronavirus has been demonstrated to form a cation-selective channel that may become expressed in the infected cell. the activity of the channel is involved in the mechanism of virus release. drugs that inhibit the ion channel can, therefore, inhibit virus release, and they could be a source for development of novel therapeutic antiviral agents. various drugs found in chinese herbs that are well known as anticancer agents also have an antivi ...201424458263
anti-frameshifting ligand reduces the conformational plasticity of the sars virus pseudoknot.programmed -1 ribosomal frameshifting (-1 prf) stimulated by mrna pseudoknots regulates gene expression in many viruses, making pseudoknots potential targets for anti-viral drugs. the mechanism by which pseudoknots trigger -1 prf, however, remains controversial, with several competing models. recent work showed that high -1 prf efficiency was linked to high pseudoknot conformational plasticity via the formation of alternate conformers. we tested whether pseudoknots bound with an anti-frameshifti ...201424446874
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