- Volume 95, Issue 7, 2014
Volume 95, Issue 7, 2014
- Review
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Molecular and cellular mechanisms underlying potyvirus infection
More LessPotyviruses represent one of the most economically important and widely distributed groups of plant viruses. Despite considerable progress towards understanding the cellular and molecular basis of their pathogenicity, many questions remain about the mechanisms by which potyviruses suppress host defences and create an optimal intracellular environment for viral translation, replication, assembly and spread. The review focuses on the multifunctional roles of potyviral proteins and their interplay with various host factors in different compartments of the infected cell. We place special emphasis on the recently discovered and currently putative mechanisms by which potyviruses subvert the normal functions of different cellular organelles in order to establish an efficient and productive infection.
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- Animal Viruses
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- Negative-strand RNA
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Perpetuation of H5N1 and H9N2 avian influenza viruses in natural water bodies
More LessWater bodies are an important route for the spread and transmission of avian influenza virus (AIV). The determining factor for an AIV to transmit through diffusion in water is the term of viability of the virus in the water body. To better understand the perpetuation of AIV in natural water bodies, and thus the risks of AIV spread and transmission via such bodies, we systematically studied the inactivation dynamics of two AIV strains (H5N1 and H9N2) at different temperatures in water bodies of important migratory bird habitats within China (Dongting Lake, Poyang Lake, the Hubei segment of the Yangtze River and Qinghai Lake). We also studied the impact of water-borne micro-organisms on the perpetuation of AIV. Our findings indicated that water is very likely an important route for the epidemic spread of AIV, especially during the autumn and winter seasons. In addition, water-borne micro-organisms might antagonize the persistence of AIV.
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Sunguru virus: a novel virus in the family Rhabdoviridae isolated from a chicken in north-western Uganda
Sunguru virus (SUNV), a novel virus belonging to the highly diverse Rhabdoviridae family, was isolated from a domestic chicken in the district of Arua, Uganda, in 2011. This is the first documented isolation of a rhabdovirus from a chicken. SUNV is related to, but distinct from, Boteke virus and other members of the unclassified Sandjimba group. The genome is 11 056 nt in length and contains the five core rhabdovirus genes plus an additional C gene (within the ORF of a phosphoprotein gene) and a small hydrophobic protein (between the matrix and glycoprotein genes). Inoculation of vertebrate cells with SUNV resulted in significant viral growth, with a peak titre of 7.8 log10 p.f.u. ml−1 observed in baby hamster kidney (BHK) cells. Little to no growth was observed in invertebrate cells and in live mosquitoes, with Anopheles gambiae mosquitoes having a 47.4 % infection rate in the body but no dissemination of the virus to the salivary glands; this suggests that this novel virus is not arthropod borne as some other members of the family Rhabdoviridae.
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Molecular characterization of avian influenza H5N1 virus in Egypt and the emergence of a novel endemic subclade
Clade 2.2 highly pathogenic H5N1 viruses have been in continuous circulation in Egyptian poultry since 2006. Their persistence caused significant genetic drift that led to the reclassification of these viruses into subclades 2.2.1 and 2.2.1.1. Here, we conducted full-genome sequence and phylogenetic analyses of 45 H5N1 isolated during 2006–2013 through systematic surveillance in Egypt, and 53 viruses that were sequenced previously and available in the public domain. Results indicated that H5N1 viruses in Egypt continue to evolve and a new distinct cluster has emerged. Mutations affecting viral virulence, pathogenicity, transmission, receptor-binding preference and drug resistance were studied. In light of our findings that H5N1 in Egypt continues to evolve, surveillance and molecular studies need to be sustained.
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Genetic diversity of feline morbilliviruses isolated in Japan
Feline morbillivirus (FmoPV) is an emerging virus in domestic cats and considered to be associated with tubulointerstitial nephritis. Although FmoPV was first described in China in 2012, there has been no report of the isolation of this virus in other countries. In this report, we describe the isolation and characterization of FmoPV from domestic cats in Japan. By using reverse transcription (RT)-PCR, we found that three of 13 urine samples from cats brought to veterinary hospitals were positive for FmoPV. FmoPV strains SS1 to SS3 were isolated from the RT-PCR-positive urine samples. Crandell-Rees feline kidney (CRFK) cells exposed to FmoPV showed cytopathic effects with syncytia formation, and FmoPV N protein was detected by indirect immunofluorescence assays. In addition, pleomorphic virus particles with apparent glycoprotein envelope spikes were observed by electron microscopy. By sequence analysis of FmoPV H and L genes, we found that FmoPVs showed genetic diversity; however, signatures of positive selection were not identified.
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- Positive-strand RNA
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Relationship between genotypes and serotypes of genogroup 1 recoviruses: a model for human norovirus antigenic diversity
More LessHuman norovirus (NoV) research greatly relies on cell culture-propagable surrogate caliciviruses, including murine NoVs and the prototype ‘recovirus’ (ReCV), Tulane virus. However, the extreme biological diversity of human NoVs cannot be modelled by a uniform group of viruses or single isolate. Based on a diverse group of recently described ReCVs, a more advanced model reflecting human NoV biological diversity is currently under development. Here, we have reported the genotypic and serotypic relationships among 10 G1 ReCV isolates, including Tulane virus and nine other recent cell culture-adapted strains. Based on the amino acid sequences of virus capsid protein, VP1, and classification constraints established for NoVs, G1 ReCVs were separated into three genotypes, with variable organization of the three open reading frames. Interestingly, cross-neutralization plaque assays revealed the existence of four distinct serotypes, two of which were detected among the G1.2 strains. The amino acid (aa) difference between the two G1.2 ReCV serotypes (12%) was less than the minimum 13 % difference established between NoV genotypes. Interestingly, one of the G1.3 ReCVs was equally neutralized by antisera raised against the G1.3 (6 % aa difference) and G1.1 (25 % aa difference) representative strains. These results imply the existence of a large number of human NoV serotypes, but also shared cross-neutralization epitopes between some strains of different genotypes. In conclusion, the newly developed ReCV surrogate model can be applied to address biologically relevant questions pertaining to enteric CV diversity.
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Full-length genomes of 16 hepatitis C virus genotype 1 isolates representing subtypes 1c, 1d, 1e, 1g, 1h, 1i, 1j and 1k, and two new subtypes 1m and 1n, and four unclassified variants reveal ancestral relationships among subtypes
More LessWe characterized the full-length genomes of 16 distinct hepatitis C virus genotype 1 (HCV-1) isolates. Among them, four represented the first full-length genomes for subtypes 1d (QC103), 1i (QC181), 1j (QC329) and 1k (QC82), and another four corresponded to subtypes 1c (QC165), 1g (QC78), 1h (QC156) and 1e (QC172). Both QC196 and QC87 were assigned into a new subtype 1m, and QC113 and QC74 into another new subtype 1n. The remaining four (QC60, QC316, QC152 and QC180) did not classify among the established subtypes and corresponded to four new lineages. Subtypes 1j, 1k, 1m, 1n and the unclassified isolate QC60 were identified in Haitian immigrants. In the updated HCV nomenclature of 2005, a total of 12 subtypes of HCV-1 were designated. Including the data from the present study, all but subtype 1f now have their full-length genomes defined. Further analysis of partial NS5B sequences available in GenBank denoted a total of 21 unclassified lineages, indicating the taxonomic complexity of HCV-1. Among them, six have had their full-length genomes characterized. Based on the available full-length genome sequences, a timescale phylogenetic tree was reconstructed which estimated important time points in the evolution of HCV-1. It revealed that subtype 1a diverged from its nearest relatives 135 years ago and subtype 1b diverged from its nearest relatives 112 years ago. When subtypes 1a, 1j, 1k, 1m, 1n and six close relatives (all but one from Haitian immigrants) were considered as a whole, the divergence time was 176 years ago. This diversification was concurrent with the time period when the transatlantic slave trade was active. When taking all the HCV-1 isolates as a single lineage, the divergence time was 326 years ago. This analysis suggested the existence of a recent common ancestor for subtype 1a and the Haitian variants; a co-origin for subtypes 1b, 1i and 1d was also implied.
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Differential restriction patterns of mRNA decay factor AUF1 during picornavirus infections
More LessDuring infection by picornaviruses, the cellular environment is modified to favour virus replication. This includes the modification of specific host proteins, including the recently discovered viral proteinase cleavage of mRNA decay factor AU-rich binding factor 1 (AUF1). This cellular RNA-binding protein was shown previously to act as a restriction factor during poliovirus, rhinovirus and coxsackievirus infection. During infection by these viruses, AUF1 relocalizes to the cytoplasm and is cleaved by the viral 3C/3CD proteinase. In this study, we demonstrated that replication of encephalomyocarditis virus (EMCV), a picornavirus belonging to the genus Cardiovirus, is AUF1 independent. During EMCV infection, AUF1 relocalized to the cytoplasm; however, unlike what is seen during enterovirus infections, AUF1 was not cleaved to detectable levels, even at late times after infection. This suggests that AUF1 does not act broadly as an inhibitor of picornavirus infections but may instead act as a selective restriction factor targeting members of the genus Enterovirus.
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A novel approach to propagate flavivirus infectious cDNA clones in bacteria by introducing tandem repeat sequences upstream of virus genome
More LessDespite tremendous efforts to improve the methodology for constructing flavivirus infectious cDNAs, the manipulation of flavivirus cDNAs remains a difficult task in bacteria. Here, we successfully propagated DNA-launched type 2 dengue virus (DENV2) and Japanese encephalitis virus (JEV) infectious cDNAs by introducing seven repeats of the tetracycline-response element (7×TRE) and a minimal cytomegalovirus (CMVmin) promoter upstream of the viral genome. Insertion of the 7×TRE-CMVmin sequence upstream of the DENV2 or JEV genome decreased the cryptic E. coli promoter (ECP) activity of the viral genome in bacteria, as measured using fusion constructs containing DENV2 or JEV segments and the reporter gene Renilla luciferase in an empty vector. The growth kinetics of recombinant viruses derived from DNA-launched DENV2 and JEV infectious cDNAs were similar to those of parental viruses. Similarly, RNA-launched DENV2 infectious cDNAs were generated by inserting 7×TRE-CMVmin, five repeats of the GAL4 upstream activating sequence, or five repeats of BamHI linkers upstream of the DENV2 genome. All three tandem repeat sequences decreased the ECP activity of the DENV2 genome in bacteria. Notably, 7×TRE-CMVmin stabilized RNA-launched JEV infectious cDNAs and reduced the ECP activity of the JEV genome in bacteria. The growth kinetics of recombinant viruses derived from RNA-launched DENV2 and JEV infectious cDNAs displayed patterns similar to those of the parental viruses. These results support a novel methodology for constructing flavivirus infectious cDNAs, which will facilitate research in virology, viral pathogenesis and vaccine development of flaviviruses and other RNA viruses.
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Modulation of the host microenvironment by a common non-oncolytic mouse virus leads to inhibition of plasmacytoma development through NK cell activation
Although many cells undergo transformation, few actually develop into tumours, due to successful mechanisms of immunosurveillance. To investigate whether an infectious agent may play a role in this process, the growth of a plasmacytoma was investigated in mice infected by lactate dehydrogenase-elevating virus. Acutely infected animals were significantly protected against tumour development. The mechanisms responsible for this protection were analysed in mice deficient for relevant immune cells or molecules and after in vivo cell depletion. This protection by viral infection correlated with NK cell activation and with IFN-γ production. It might also be related to activation of NK/T-cells, although this remains to be proven formally. Therefore, our results indicated that infections with benign micro-organisms may protect the host against cancer development, through non-specific stimulation of the host's innate immune system and especially of NK cells.
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Nuclear receptor 4 group A member 1 determines hepatitis C virus entry efficiency through the regulation of cellular receptor and apolipoprotein E expression
Orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) is a transcription factor stimulated by many factors and plays pivotal roles in metabolism, proliferation and apoptosis. In this study, the expression of NR4A1 in Huh7.5.1 cells was significantly upregulated by hepatitis C virus (HCV) infection. The silencing of NR4A1 inhibited the entry of HCV and reduced the specific infectivity of secreted HCV particles but had only minor or no effect on the genome replication and translation, virion assembly and virus release steps of the virus life cycle. Further experiments demonstrated that the silencing of NR4A1 affected virus entry through pan-downregulation of the expression of HCV receptors scavenger receptor BI, occludin, claudin-1 and epidermal growth factor receptor but not CD81. The reduced specific infectivity of HCV in the knockdown cells was due to decreased apolipoprotein E (ApoE) expression. These results explain the delayed spread of HCV in NR4A1 knockdown Huh7.5.1 cells. Thus, NR4A1 plays a role in HCV replication through regulating the expression of HCV receptors and ApoE, and facilitates HCV entry and spread.
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A bi-cistronic, reporter-encoding bovine viral diarrhea virus applied in a new, effective diagnostic test
More LessInfections with bovine viral diarrhea virus (BVDV) have a huge economic impact on cattle production and reproduction worldwide. A key factor for BVDV surveillance and eventual eradication is to efficiently detect infections and to monitor herd immunity. In this study, we generated a stable, bi-cistronic BVDV that encoded EGFP in addition to the viral proteins. Applying this recombinant virus, a new flow-cytometry-based virus neutralization test was established that enabled accurate and reliable detection of field-virus-infected and vaccinated animals. The test, which is simple and fast, is expected to support novel, effective screening procedures in eradication and vaccination programmes.
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- Double-strand RNA
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Interactions among Dendrolimus punctatus cypovirus proteins and identification of the genomic segment encoding its A-spike
More LessRevealing the interactions among cypovirus proteins would facilitate our understanding of the replication and assembly of this virus. In the present study, interactions among proteins encoded by the 10 segments of Dendrolimus punctatus cypovirus (DpCPV) were identified using yeast two-hybrid (Y2H) and far-Western blotting assays. In total, 24 pairs of interactions were detected. Twelve pairs of one-direction interactions, four pairs of binary interactions and four pairs of self-associations were identified in the Y2H assays. Another four pairs of interactions were identified by far-Western blotting. The interactions between the methyltransferase domain of the turret protein (VP3) and VP4 as well as between polyhedrin and VP4 were further confirmed by far-Western blotting and pull-down assays, respectively. In addition, immunogold labelling showed that the A-spike of DpCPV is formed by VP4. In conclusion, we obtained a protein–protein interaction network of DpCPV and showed that its A-spike is formed by VP4 encoded by genomic segment 6.
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- Small DNA
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Growth of osteosarcoma cells in a three-dimensional bone-like matrix alters their susceptibility to adeno-associated virus
More LessOsteosarcoma cells U2OS are partially susceptible to adeno-associated virus (AAV)-2 infection, allowing efficient synthesis of Rep proteins and, in a low percentage of cells, capsid production. It is not clear if this partial susceptibility to infection is due to the bone-cell-like nature of these cells or is a result of their transformed properties. Here, we grew osteosarcoma cells in a biomimetic three-dimensional bone-like matrix composed of calcium phosphate and chitosan, and tested whether this would increase or reduce their permissiveness to virus. The osteosarcoma cells grew in the matrix and began to express the alkaline phosphatase bone cell differentiation marker. This was accompanied by a block to their infection by AAV, as indicated by Rep and capsid production. Infection of cells growing in three-dimensional tissue-like matrices could be, in a wider context, a practical way to mimic in vivo conditions.
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Identification of novel anelloviruses with broad diversity in UK rodents
Anelloviruses are a family of small circular ssDNA viruses with a vast genetic diversity. Human infections with the prototype anellovirus, torque teno virus (TTV), are ubiquitous and related viruses have been described in a number of other mammalian hosts. Despite over 15 years of investigation, there is still little known about the pathogenesis and possible disease associations of anellovirus infections, arising in part due to the lack of a robust cell culture system for viral replication or tractable small-animal model. We report the identification of diverse anelloviruses in several species of wild rodents. The viruses are highly prevalent in wood mice (Apodemus sylvaticus) and field voles (Microtus agrestis), detectable at a low frequency in bank voles (Myodes glareolus), but absent from house mice (Mus musculus). The viruses identified have a genomic organization consistent with other anelloviruses, but form two clear phylogenetic groups that are as distinct from each other as from defined genera.
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- Large DNA
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Equid herpesvirus type 4 uses a restricted set of equine major histocompatibility complex class I proteins as entry receptors
Equid herpesvirus type 1 (EHV-1) was shown to use an unusual receptor for cellular entry – MHC-I molecules. Here, we demonstrated that the closely related EHV, EHV-4, also uses this strategy for cellular invasion, both in equine cells in culture and in the heterologous, non-permissive murine mastocytoma cell line (P815) after stable transfection with horse MHC-I genes. Using a panel of P815 cell lines transfected with individual horse MHC-I genes, we provided support for the hypothesis that EHV-1 and EHV-4 target classical polymorphic MHC-I molecules as viral entry receptors. All known equine MHC-I molecules from the two principal classical polymorphic loci specify alanine at position 173 (A173), whilst other MHC-I loci encoded different amino acids at this position and did not permit viral entry. Site-directed mutagenesis of position 173 diminished or enhanced viral entry, depending upon the initial amino acid. However, there were other, as yet undefined, constraints to this process: MHC-I genes from two non-classical loci carried A173 but did not enable viral entry in P815 transfectants. Our study suggested that the capacity to bind MHC-I molecules arose in the common ancestor of EHV-1 and EHV-4. The widespread occurrence of A173 in classical polymorphic horse MHC-I molecules indicated that horses of most MHC haplotypes should be susceptible to infection via this entry portal.
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Trimeric knob protein specifically distinguishes neutralizing antibodies to different human adenovirus species: potential application for adenovirus seroepidemiology
Adenoviruses (Ads) are non-enveloped DNA viruses that have been extensively studied and used as vectors for gene therapy and several potential vaccines. There are 57 Ad serotypes in seven species (A–G), and Ad neutralizing antibody (NAb) titres can vary by serotype and geographical location. Until now serotype- and species-specific antibodies have been detected by neutralization or haemagglutination inhibition assays. These expensive and cumbersome methods of adenovirus typing have mainly been used in epidemiological studies. Our prior work demonstrated that NAbs against the fiber protein are commonly generated during natural Ad infection in humans and the trimeric knob is preferentially recognized by fiber-induced NAbs. In this study, we expressed nine trimeric knob proteins from representative Ad serotypes of human Ad (HAdV)-A–F in Escherichia coli and found no cross-reactivity of these recombinant proteins with rabbit hyperimmune sera (among HAdV-A–F or within HAdV-C). Results of the ELISA based on Ad2 and Ad5 (both HAdV-C) knob proteins were consistent with those of neutralization assays, indicating that the trimeric knob protein would be a good candidate antigen for detecting Ad serotype-specific NAbs in sera from naturally infected subjects. We also demonstrated the primary seroepidemiology of nine Ad serotypes in 274 children using the knob-based ELISA. These results have potential implications for epidemiology of Ad serotypes and future development of Ad-based vaccines and gene therapy.
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An alternative to the adenovirus inverted terminal repeat sequence increases the viral genome replication rate and provides a selective advantage in vitro
During the development of human adenovirus 35-derived replication-incompetent (rAd35) vaccine vectors for prevention of infectious diseases, we detected mutations in the terminal 8 nt of the inverted terminal repeats (ITRs) of rAd35. The switch from the plasmid-encoded sequence 5′-CATCATCA-3′ to the alternative sequence 5′-CTATCTAT-3′ in the ITRs was found to be a general in vitro propagation phenomenon, as shown for several vectors carrying different transgenes or being derived from different adenovirus serotypes. In each tested case, the plasmid-encoded ITR sequence changed to exactly the same alternative ITR sequence, 5′-CTATCTAT-3′. The outgrowth of this alternative ITR version should result from a growth advantage conferred by the alternative ITR sequence. Indeed, replication kinetics studies of rAd35 harbouring either the original or alternative ITR sequence confirmed an increase in replication speed for rAd35 vectors with the alternative ITR sequence. These findings can be applied to generate recombinant adenoviral vectors harbouring the alternative ITR sequence, which will facilitate the generation of genetically homogeneous seed virus batches. Moreover, vector production may be accelerated by taking advantage of the observed improved replication kinetics associated with the alternative ITR sequence.
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- Insect viruses
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- DNA
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Genome sequence of a crustacean iridovirus, IIV31, isolated from the pill bug, Armadillidium vulgare
Members of the family Iridoviridae are animal viruses that infect only invertebrates and poikilothermic vertebrates. The invertebrate iridovirus 31 (IIV31) was originally isolated from adult pill bugs, Armadillidium vulgare (class Crustacea, order Isopoda, suborder Oniscidea), found in southern California on the campus of the University of California, Riverside, USA. IIV31 virions are icosahedral, have a diameter of about 135 nm, and contain a dsDNA genome 220.222 kbp in length, with 35.09 mol % G+C content and 203 ORFs. Here, we describe the complete genome sequence of this virus and its annotation. This is the eighth genome sequence of an IIV reported.
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- Plant Viruses
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- DNA
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Mutational analysis of the helicase domain of a replication initiator protein reveals critical roles of Lys 272 of the B′ motif and Lys 289 of the β-hairpin loop in geminivirus replication
Replication initiator protein (Rep) is indispensable for rolling-circle replication of geminiviruses, a group of plant-infecting circular ssDNA viruses. However, the mechanism of DNA unwinding by circular ssDNA virus-encoded helicases is unknown. To understand geminivirus Rep function, we compared the sequence and secondary structure of Rep with those of bovine papillomavirus E1 and employed charged residue-to-alanine scanning mutagenesis to generate a set of single-substitution mutants in Walker A (K227), in Walker B (D261, 262), and within or adjacent to the B′ motif (K272, K286 and K289). All mutants were asymptomatic and viral accumulation could not be detected by Southern blotting in both tomato and N. benthamiana plants. Furthermore, the K272 and K289 mutants were deficient in DNA binding and unwinding. Biochemical studies and modelling data based on comparisons with the known structures of SF3 helicases suggest that the conserved lysine (K289) located in a predicted β-hairpin loop may interact with ssDNA, while lysine 272 in the B′ motif (K272) located on the outer surface of the protein is presumably involved in coupling ATP-induced conformational changes to DNA binding. To the best of our knowledge, this is the first time that the roles of the B′ motif and the adjacent β-hairpin loop in geminivirus replication have been elucidated.
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- Other viruses
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Viral metagenomics analysis demonstrates the diversity of viral flora in piglet diarrhoeic faeces in China
More LessTo investigate the diversity of viral flora, we used metagenomics to study the viral communities in a pooled faecal sample of 27 diarrhoeic piglets from intensive commercial farms in China. The 15 distinct mammalian viruses identified in the pooled diarrhoeic sample were, in order of abundance of nucleic acid sequence, Porcine epidemic diarrhea virus (PEDV), sapovirus, porcine bocavirus-4 (PBoV-4), sapelovirus, torovirus, coronavirus, PBoV-2, stool-associated single-stranded DNA virus (poSCV), astrovirus (AstV), kobuvirus, posavirus-1, porcine enterovirus-9 (PEV-9), porcine circovirus-like (po-circo-like) virus, picobirnavirus (PBV) and Torque teno sus virus 2 (TTSuV-2). The prevalence rate of each virus was verified from diarrhoeic and healthy piglets by PCR assay. A mean of 5.5 different viruses were shed in diarrhoeic piglets, and one piglet was in fact co-infected with 11 different viruses. By contrast, healthy piglets shed a mean of 3.2 different viruses. Compared with samples from healthy piglets, the co-infection of PEDV and PBoV had a high prevalence rate in diarrhoea samples, suggesting a correlation with the appearance of diarrhoea in piglets. Furthermore, we report here for the first time the presence of several recently described viruses in China, and the identification of novel genotypes. Therefore, our investigation results provide an unbiased survey of viral communities and prevalence in faecal samples of piglets.
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- TSE Agents
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Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, α-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys
More LessProteins aggregate in several slowly progressive neurodegenerative diseases called ‘proteinopathies’. Studies with cell cultures and transgenic mice overexpressing mutated proteins suggested that aggregates of one protein induced misfolding and aggregation of other proteins as well – a possible common mechanism for some neurodegenerative diseases. However, most proteinopathies are ‘sporadic’, without gene mutation or overexpression. Thus, proteinopathies in WT animals genetically close to humans might be informative. Squirrel monkeys infected with the classical bovine spongiform encephalopathy agent developed an encephalopathy resembling variant Creutzfeldt–Jakob disease with accumulations not only of abnormal prion protein (PrPTSE), but also three other proteins: hyperphosphorylated tau (p-tau), α-synuclein and ubiquitin; β-amyloid protein (Aβ) did not accumulate. Severity of brain lesions correlated with spongiform degeneration. No amyloid was detected. These results suggested that PrPTSE enhanced formation of p-tau and aggregation of α-synuclein and ubiquitin, but not Aβ, providing a new experimental model for neurodegenerative diseases associated with complex proteinopathies.
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Volumes and issues
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Volume 105 (2024)
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Volume 104 (2023)
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Volume 103 (2022)
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Volume 102 (2021)
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Volume 101 (2020)
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Volume 100 (2019)
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Volume 99 (2018)
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Volume 98 (2017)
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Volume 97 (2016)
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Volume 96 (2015)
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Volume 95 (2014)
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Volume 27 (1975)
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Volume 7 (1970)
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Volume 6 (1970)
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Volume 5 (1969)
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Volume 4 (1969)
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Volume 3 (1968)
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Volume 2 (1968)
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Volume 1 (1967)