bluuebunny/crossref_metadata_2025_split huggingface dataset:
Downregulation of Gamma Interferon Receptor 1 by Kaposi's Sarcoma-Associated Herpesvirus K3 and K5
Authors: Li Qinglin , Means Robert , Lang Sabine , Jung Jae U. 
Published: December 2006

ABSTRACT
Upon viral infection, the major defense mounted by the host immune system is activation of the interferon (IFN)-mediated antiviral pathway. In order to complete their life cycles, viruses must modulate the host IFN-mediated immune response. The K3 and K5 proteins of a human tumor-inducing herpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV), have been shown to downregulate the surface expression of host immune modulatory receptors by increasing their endocytosis rates, which leads to suppression of cell-mediated immunity. In this report, we demonstrate that K3 and K5 both specifically target gamma interferon receptor 1 (IFN-γR1) and induce its ubiquitination, endocytosis, and degradation, resulting in downregulation of IFN-γR1 surface expression and, thereby, inhibition of IFN-γ action. Mutational analysis indicated that K5 appeared to downregulate IFN-γR1 more strongly than K3 and that the amino-terminal ring finger motif and the carboxyl-terminal region of K5 were necessary for IFN-γR1 downregulation. These results suggest that KSHV K3 and K5 suppress both cytokine-mediated and cell-mediated immunity, which ensures efficient viral avoidance of host immune controls.
A Multicomponent RNA-Based Control System Regulates Subgenomic mRNA Transcription in a Tombusvirus
Authors: Lin Han-Xin , Xu Wei , White K. Andrew 
Published: December 2006

ABSTRACT
During infections, positive-strand RNA tombusviruses transcribe two subgenomic (sg) mRNAs that allow for the expression of a subset of their genes. This process is thought to involve an unconventional mechanism involving the premature termination of the virally encoded RNA-dependent RNA polymerase while it is copying the virus genome. The 3′ truncated minus strands generated by termination are then used as templates for sg mRNA transcription. In addition to requiring an extensive network of long-distance RNA-RNA interactions (H.-X. Lin and K. A. White, EMBO J. 23:3365-3374, 2004), the transcription of tombusvirus sg mRNAs also involves several additional RNA structures. In vivo analysis of these diverse RNA elements revealed that they function at distinct steps in the process by facilitating the formation or stabilization of the long-distance interactions, modulating minus-strand template production, or promoting the initiation of sg mRNA transcription. All of the RNA elements characterized could be readily incorporated into a premature termination model for sg mRNA transcription. Overall, the analyses revealed a complex system that displays a high level of structural integration and functional coordination. This multicomponent RNA-based control system may serve as a useful paradigm for understanding related transcriptional processes in other positive-sense RNA viruses.
Degradation of Tyrosine Phosphatase PTPN3 (PTPH1) by Association with Oncogenic HumanPapillomavirus E6 Proteins
Authors: Jing Ming , Bohl Joanna , Brimer Nicole , Kinter Michael , Vande Pol Scott B. 
Published: December 2006

ABSTRACT

Oncoproteins from DNA tumor viruses associate with critical cellular proteins to
regulate cell proliferation, survival, and differentiation.Human papillomavirus (HPV) E6 oncoproteins have been previously shown
to associate with a cellular HECT domain ubiquitin ligase termed E6AP
(UBE3A). Here we show that the E6-E6AP complex associates with and
targets the degradation of the protein tyrosine phosphatase PTPN3
(PTPH1) in vitro and in living cells. PTPN3 is a membrane-associated
tyrosine phosphatase with FERM, PDZ, and PTP domains previously
implicated in regulating tyrosine phosphorylation of growth factor
receptors and p97 VCP (valosin-containing protein, termed Cdc48 in
Saccharomyces cerevisiae
) and is mutated in a
subset of colon cancers. Degradation of PTPN3 by E6 requires E6AP, the
proteasome, and an interaction between the carboxy terminus of E6 and
the PDZ domain of PTPN3. In transduced keratinocytes, E6 confers
reduced growth factor requirements, a function that requires the PDZ
ligand of E6 and that can in part be replicated by inhibiting the
expression of PTPN3. This report demonstrates the potential of E6 to
regulate phosphotyrosine metabolism through the targeted degradation of
a tyrosine
phosphatase.
HLA-A2-Restricted Protection against Lethal Lymphocytic Choriomeningitis
Authors: Botten Jason , Whitton J. Lindsay , Barrowman Polly , Sidney John , Whitmire Jason K. , Alexander Jeff , Ting Joey P. C. , Bui Huynh-Hoa , Sette Alessandro , Buchmeier Michael J. 
Published: December 2006

ABSTRACTThe consequences of human lymphocytic choriomeningitis virus (LCMV) infection can be severe, including aseptic meningitis in immunocompetent individuals, hydrocephalus or chorioretinitis in fetal infection, or a highly lethal outcome in immunosuppressed individuals. In murine models of LCMV infection, CD8+T cells play a primary role in providing protective immunity, and there is evidence that cellular immunity may also be important in related arenavirus infections in humans. For this reason, we sought to identify HLA-A2 supertype-restricted epitopes from the LCMV proteome and evaluate them as vaccine determinants in HLA transgenic mice. We identified four HLA-A*0201-restricted peptides—nucleoprotein NP69-77, glycoprotein precursor GPC10-18, GPC447-455, and zinc-binding protein Z49-58—that displayed high-affinity binding (≤275 nM) to HLA-A*0201, induced CD8+T-cell responses of high functional avidity in HLA-A*0201 transgenic mice, and were naturally processed from native LCMV antigens in HLA-restricted human antigen presenting cells. One of the epitopes (GPC447-455), after peptide immunization of HLA-A*0201 mice, induced CD8+T cells capable of killing peptide-pulsed HLA-A*0201-restricted target cells in vivo and protected mice against lethal intracranial challenge with LCMV.
Basolateral Entry and Release of Crimean-Congo Hemorrhagic Fever Virus in Polarized MDCK-1 Cells
Authors: Connolly-Andersen Anne-Marie , Magnusson Karl-Erik , Mirazimi Ali 
Published: December 2006

ABSTRACT
Crimean-Congo hemorrhagic fever virus (CCHFV) is an etiological agent of a disease with mortality rates in patients averaging 30%. The disease is characterized by fever, myalgia, and hemorrhage. Mechanisms underlying the hemorrhage have to our knowledge not been elucidated for CCHFV. Possibly, a direct or indirect viral effect on tight junctions (TJ) could cause the hemorrhage observed in patients, as TJ play a crucial role in vascular homeostasis and can cause leakage upon deregulation. Moreover, there is no knowledge regarding the site of entry and release of CCHFV in polarized epithelial cells. Such cells represent a barrier to virus dissemination within the host, and as a site of viral entry and release, they could play a key role in further spread. For the first time, we have shown preferential basolateral entry of CCHFV in Madin-Darby canine kidney 1 (MDCK-1) epithelial cells. Furthermore, we demonstrated basolateral release of CCHFV in polarized epithelial cells. Interestingly, by measuring transepithelial electrical resistance, we found no effect of CCHFV replication on the function of TJ in this study. Neither did we observe any difference in the localization of the TJ proteins ZO-1 and occludin in CCHFV-infected cells compared to mock-infected cells.
The Cytoplasmic Tail of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Contains a Novel Endoplasmic Reticulum Retrieval Signal That Binds COPI and Promotes Interaction with Membrane Protein
Authors: McBride Corrin E. , Li Jie , Machamer Carolyn E. 
Published: December 2006

ABSTRACT
Like
other coronaviruses, severe acute respiratory syndrome coronavirus
(SARS CoV) assembles at and buds into the lumen of the endoplasmic
reticulum (ER)-Golgi intermediate compartment (ERGIC). Accumulation of
the viral envelope proteins at this compartment is a prerequisite for
virus assembly. Previously, we reported the identification of a dibasic
motif (KxHxx) in the cytoplasmic tail of the SARS CoV spike (S) protein
that was similar to a canonical dilysine ER retrieval signal. Here we
demonstrate that this motif is a novel and functional ER retrieval
signal which reduced the rate of traffic of the full-length S protein
through the Golgi complex. The KxHxx motif also partially retained two
different reporter proteins in the ERGIC region and reduced their rates
of trafficking, although the motif was less potent than the canonical
dilysine signal. The dibasic motif bound the coatomer complex I (COPI)
in an in vitro binding assay, suggesting that ER retrieval may
contribute to the accumulation of SARS CoV S protein near the virus
assembly site for interaction with other viral structural proteins. In
support of this, we found that the dibasic motif on the SARS S protein
was required for its localization to the ERGIC/Golgi region when
coexpressed with SARS membrane (M) protein. Thus, the cycling of SARS S
through the ER-Golgi system may be required for its incorporation into
assembling virions in the
ERGIC.
The Cellular Protein P58
IPK
Regulates Influenza Virus mRNA Translation and Replication through a PKR-Mediated Mechanism
Authors: Goodman Alan G. , Smith Jennifer A. , Balachandran Siddharth , Perwitasari Olivia , Proll Sean C. , Thomas Matthew J. , Korth Marcus J. , Barber Glen N. , Schiff Leslie A. , Katze Michael G. 
Published: December 2006

ABSTRACT

We previously hypothesized that efficient translation of influenza virus mRNA requires the recruitment of P58
IPK
, the cellular inhibitor of PKR, an interferon-induced kinase that targets the eukaryotic translation initiation factor eIF2α. P58
IPK
also inhibits PERK, an eIF2α kinase that is localized in the endoplasmic reticulum (ER) and induced during ER stress. The ability of P58
IPK
to interact with and inhibit multiple eIF2α kinases suggests it is a critical regulator of both cellular and viral mRNA translation. In this study, we sought to definitively define the role of P58
IPK
during viral infection of mammalian cells. Using mouse embryo fibroblasts from P58
IPK−/−
mice, we demonstrated that the absence of P58
IPK
led to an increase in eIF2α phosphorylation and decreased influenza virus mRNA translation. The absence of P58
IPK
also resulted in decreased vesicular stomatitis virus replication but enhanced reovirus yields. In cells lacking the P58
IPK
target, PKR, the trends were reversed—eIF2α phosphorylation was decreased, and influenza virus mRNA translation was increased. Although P58
IPK
also inhibits PERK, the presence or absence of this kinase had little effect on influenza virus mRNA translation, despite reduced levels of eIF2α phosphorylation in cells lacking PERK. Finally, we showed that influenza virus protein synthesis and viral mRNA levels decrease in cells that express a constitutively active, nonphosphorylatable eIF2α. Taken together, our results support a model in which P58
IPK
regulates influenza virus mRNA translation and infection through a PKR-mediated mechanism which is independent of PERK.
Influenza Virion-Derived Viral Ribonucleoproteins Synthesize both mRNA and cRNA In Vitro
Authors: Vreede F. T. , Brownlee G. G. 
Published: December 2006

ABSTRACT
The mechanisms regulating the synthesis of mRNA, cRNA, and viral genomic RNA (vRNA) by the influenza A virus RNA-dependent RNA polymerase are not fully understood. Early results suggested that the RNA polymerase “switched” from a transcriptase to a replicase during the viral life cycle in response to the expression of viral proteins. However, recently an alternative model suggesting that replication of influenza virus is regulated by stabilization of the replicative intermediates was proposed. According to this model, the virion-associated polymerase is capable of synthesizing both mRNA and cRNA. We now demonstrate that virion-derived viral ribonucleoproteins (vvRNPs) synthesize both mRNA and cRNA in vitro in the absence of non-virion-associated RNA polymerase or nucleoproteins. The authenticity of the in vitro-transcribed mRNA and cRNA was confirmed by terminal sequence analysis. The addition of non-virion-associated polymerase or NP had no effect on vvRNP activity. De novo synthesis of cRNA was found to be more sensitive than the capped primer-dependent synthesis of mRNA to the concentration of ATP, CTP, and GTP. We conclude that vvRNPs intrinsically possess both transcriptase and replicase activities and that there is no switch in the synthesis of mRNA to cRNA during the influenza virus life cycle.
Transmembrane Domains of Hepatitis C Virus Envelope Glycoproteins: Residues Involved in E1E2 Heterodimerization and Involvement of These Domains in Virus Entry
Authors: Ciczora Yann , Callens Nathalie , Penin François , Pécheur Eve-Isabelle , Dubuisson Jean 
Published: December 2006

ABSTRACT

The transmembrane (TM) domains of hepatitis C virus (HCV) envelope glycoproteins E1 and E2 have been shown to play multiple roles during the biogenesis of the E1E2 heterodimer. By using alanine scanning insertion mutagenesis within the TM domains of HCV envelope glycoproteins, we have previously shown that the central regions of these domains as well as the N-terminal part of the TM domain of E1 are involved in heterodimerization. Here, we used a tryptophan replacement scan of these regions to identify individual residues that participate in those interactions. Our mutagenesis study identified at least four residues involved in heterodimerization: Gly 354, Gly 358, Lys 370, and Asp 728. Interestingly, Gly 354 and Gly 358 belong to a G
XXX
G oligomerization motif. Our tryptophan mutants were also used to generate retrovirus-based, HCV-pseudotyped particles (HCVpp) in order to analyze the effects of these mutations on virus entry. Surprisingly, two mutants consistently displayed higher infectivity compared to that of the wild type. In contrast, HCVpp infectivity was strongly affected for many mutants, despite normal E1E2 heterodimerization and normal levels of incorporation of HCV glycoproteins into HCVpp. The characterization of some of these HCVpp mutants in the recently developed in vitro fusion assay using fluorescent-labeled liposomes indicated that mutations reducing HCVpp infectivity without altering E1E2 heterodimerization affected the fusion properties of HCV envelope glycoproteins. In conclusion, this mutational analysis identified residues involved in E1E2 heterodimerization and revealed that the TM domains of HCV envelope glycoproteins play a major role in the fusion properties of these proteins.
Antiviral Protein APOBEC3G Localizes to Ribonucleoprotein Complexes Found in P Bodies and Stress Granules
Authors: Gallois-Montbrun Sarah , Kramer Beatrice , Swanson Chad M. , Byers Helen , Lynham Steven , Ward Malcolm , Malim Michael H. 
Published: December 2006

ABSTRACTMembers of the APOBEC (apolipoproteinBmRNA-editing enzymecatalytic polypeptide 1-like) family of cytidine deaminases inhibit host cell genome invasion by exogenous retroviruses and endogenous retrotransposons. Because these enzymes can edit DNA or RNA and potentially mutate cellular targets, their activities are presumably regulated; for instance, APOBEC3G (A3G) recruitment into high-molecular-weight ribonucleoprotein (RNP) complexes has been shown to suppress its enzymatic activity. We used tandem affinity purification together with mass spectrometry (MS) to identify protein components within A3G-containing RNPs. We report that numerous cellular RNA-binding proteins with diverse roles in RNA function, metabolism, and fate determination are present in A3G RNPs but that most interactions with A3G are mediated via binding to shared RNAs. Confocal microscopy demonstrated that substantial quantities of A3G localize to cytoplasmic microdomains that are known as P bodies and stress granules (SGs) and are established sites of RNA storage and metabolism. Indeed, subjecting cells to stress induces the rapid redistribution of A3G and a number of P-body proteins to SGs. Among these proteins are Argonaute 1 (Ago1) and Argonaute 2 (Ago2), factors that are important for RNA silencing and whose interactions with A3G are resistant to RNase treatment. Together, these findings reveal that A3G associates with RNPs that are found throughout the cytosol as well as in discrete microdomains. We also speculate that the interplay between A3G, RNA-silencing pathways, and cellular sites of RNA metabolism may contribute to A3G's role as an inhibitor of retroelement mobility and as a possible regulator of cellular RNA function.
Vaccinia Virus 4c (A26L) Protein on Intracellular Mature Virus Binds to the Extracellular Cellular Matrix Laminin
Authors: Chiu Wen-Ling , Lin Chi-Long , Yang Min-Hsiang , Tzou Der-Lii M. , Chang Wen 
Published: December 2006

ABSTRACT

Vaccinia virus intracellular mature virus (IMV) binds to glycosaminoglycans (GAGs) on cells via three virion proteins, H3L, A27L, and D8L. In this study, we demonstrated that binding of IMV to BSC40 cells was competitively inhibited by soluble laminin but not by fibronectin or collagen V, suggesting that this cell surface extracellular matrix (ECM) protein may play a role in vaccinia virus entry. Moreover, IMV infection of GAG
−
sog9 cells was also inhibited by laminin, demonstrating that virion binding to laminin does not involve a prior interaction with GAGs. Furthermore, comparative envelope protein analyses of wild-type vaccinia virus strain Western Reserve, which binds to laminin, and of a mutant virus, IA27L, which does not, showed that the A26L open reading frame (ORF), encoding an envelope protein, was mutated in IA27L, resulting in A26L being absent from the IMV. Expression of the wild-type A26L ORF in IA27L resulted in laminin binding activity. Moreover, recombinant A26L protein bound to laminin in vitro with a high affinity, providing direct evidence that A26L is the laminin binding protein on IMV. In summary, these results reveal a novel role for the vaccinia viral envelope protein A26L in binding to the ECM protein laminin, an association that is proposed to facilitate IMV entry.
Positive and Negative Effects of Adenovirus Type 5 Helper Functions on Adeno-Associated Virus Type 5 (AAV5) Protein Accumulation Govern AAV5 Virus Production
Authors: Nayak Ramnath , Pintel David J. 
Published: December 2006

ABSTRACT
Full replication of adeno-associated virus type 5 (AAV5) is sustained by adenovirus type 5 (Ad5) helper functions E1a, E1b, E2a, E4Orf6, and virus-associated (VA) RNA; however, their combined net enhancement of AAV5 replication was comprised of both positive and negative individual effects. Although Ad5 E4Orf6 was required for AAV5 genomic DNA replication, it also functioned together with E1b to degrade de novo-expressed, preassembled AAV5 capsid proteins and Rep52 in a proteosome-dependent manner. VA RNA enhanced accumulation of AAV5 protein, overcoming the degradative effects of E4Orf6, and was thus required to restore adequate amounts of AAV5 proteins necessary to achieve efficient virus production.
Public road transport crashes in a low income country
Authors: Dharmaratne S D , Stevenson M 
Published: December 2006

Objective:To assess the safety of government versus non-government public road transportation.Design:Descriptive study.Setting:Kandy Municipality Area, Sri Lanka.Subjects:All road traffic crashes reported to the Kandy Police from 1 October 1998 to 30 September 1999.Main outcome:Involvement in a road traffic crash reported to the Kandy Police in which a government bus, private bus, or a three-wheeler was involved.Results:During the study period, 132 government buses, 243 private buses, and 115 three wheelers were involved in 437 police reported road crashes. Of these crashes, eight (1.8%) were fatal and 132 (30.2%) were crashes resulting in injury requiring hospitalization. The majority of road crashes involved vehicle-vehicle interaction (63.4%) and vehicle-pedestrian interaction (17.8%), while the remainder consisted of vehicle-passenger and vehicle-road structure crashes. The research highlights an increased risk associated with travel on privately owned buses (RR = 2.0, 95% CI 1.6 to 2.5) and three wheelers (RR = 2.2, 95% CI 1.7 to 2.8) compared to travel on government buses. The disparity in crash rates between government and privately owned transportation modes can be explained, in part, by fewer safety requirements being imposed on the deregulated public transportation system.Conclusions:Recommendations are made in order to address the differential in crash rates between public and private vehicle ownership used for public transportation in Sri Lanka.
Motor vehicle crash pedestrian deaths in New York City: the plight of the older pedestrian
Authors: Nicaj L , Wilt S , Henning K 
Published: December 2006

Objective:To describe the epidemiology of pedestrian deaths due to motor vehicle crashes (MVCs) between age groups in New York City (NYC), with a comparison to national data.Methods:Review of MVC pedestrian deaths in NYC and the US from 1998 to 2002. Data on deaths were obtained from the National Highway Traffic Safety Administration.Results:Almost half (48%) of all MVC deaths in NYC were among pedestrians, compared with 12% nationally. Pedestrian death rates were highest among older age groups (⩾65 years). NYC’s older pedestrians were more likely than US older pedestrians to be killed at an intersection, during daytime and on weekdays.Conclusion:Older people constitute a major proportion of MVC pedestrian deaths in NYC. Conditions (such as traffic exposure) surrounding pedestrian MVCs may differ by age group. The high burden of MVCs among older pedestrians in NYC highlights the importance of local-level analysis to guide public health planning.
Non-firearm weapon use and injury severity: priorities for prevention
Authors: Brennan I R , Moore S C , Shepherd J P 
Published: December 2006

Objectives:To test the hypothesis that weapon-related violence (excluding firearms) results in more severe injury relative to the use of body parts (fists, feet and other body parts), and to rank order of injury severity by assault mechanism.Design:Retrospective cohort study.Participants:24 660 patients who were treated in a UK emergency department for violence-related injury.Main outcome measure:Score on the Manchester Triage Scale.Results:The use of a weapon resulted in significantly more serious injury (adjusted odds ratio (AOR) 1.13, 95% confidence interval (CI) 1.00 to 1.28). However, of all mechanisms of violent injury, the use of feet resulted in most severe injury (AOR 1.41, 95% CI 1.17 to 1.70), followed by blunt objects (AOR 1.35, 95% CI 1.14 to 1.58), other body parts (AOR 1.22, 95% CI 1.06 to 1.40) and sharp objects (AOR 1.09, 95% CI 0.91 to 1.5), compared with use of fists.Conclusions:Use of weapons resulted in more severe injury than use only of body parts. The use of feet caused the most serious injuries, whereas the use of fists caused the least severe injuries. Injury severity varied by number of assailants and age of the patient—peaking at 47 years—but not by number of injuries. Preventing the use of feet in violence, and preventing group violence should be major priorities.