bluuebunny/crossref_metadata_2025_split huggingface dataset:
DC-SIGN Mediates Cell-Free Infection and Transmission of Human T-Cell Lymphotropic Virus Type 1 by Dendritic Cells
Authors: Jain Pooja , Manuel Sharrón L. , Khan Zafar K. , Ahuja Jaya , Quann Kevin , Wigdahl Brian 
Published: August 2009

ABSTRACTDespite the susceptibility of dendritic cells (DCs) to human T-cell lymphotropic virus type 1 (HTLV-1) infection and the defined role of these cells in disease pathogenesis, the mechanisms of viral binding to DCs have not been fully delineated. Recently, a glucose transporter, GLUT-1, heparan sulfate proteoglycans (HSPGs), and neuropilin-1 (NRP-1) were demonstrated to facilitate HTLV-1 entry into T cells. DCs express their own array of antigen receptors, the most important being the DC-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing nonintegrin (DC-SIGN) with respect to retrovirus binding. Consequently, the role of DC-SIGN and other HTLV-1 attachment factors was analyzed in viral binding, transmission, and productive infection using monocyte-derived DCs (MDDCs), blood myeloid DCs, and B-cell lines expressing DC-SIGN. The relative expression of DC-SIGN, GLUT-1, HSPGs, and NRP-1 first was examined on both DCs and B-cell lines. Although the inhibition of these molecules reduced viral binding, HTLV-1 transmission from DCs to T cells was mediated primarily by DC-SIGN. DC-SIGN also was shown to play a role in the infection of MDDCs as well as model B-cell lines. The HTLV-1 infection of MDDCs also was achieved in blood myeloid DCs following the enhancement of virus-induced interleukin-4 production and subsequent DC-SIGN expression in this cell population. This study represents the first comprehensive analysis of potential HTLV-1 receptors on DCs and strongly suggests that DC-SIGN plays a critical role in HTLV-1 binding, transmission, and infection, thereby providing an attractive target for the development of antiretroviral therapeutics and microbicides.
The Pre-Transmembrane Domain of the
Autographa californica
Multicapsid Nucleopolyhedrovirus GP64 Protein Is Critical for Membrane Fusion and Virus Infectivity
Authors: Li Zhaofei , Blissard Gary W. 
Published: August 2009

ABSTRACT

The envelope glycoprotein, GP64, of the baculovirus
Autographa californica
multicapsid nucleopolyhedrovirus (AcMNPV) is a class III viral fusion protein that mediates pH-triggered membrane fusion during virus entry. Viral fusion glycoproteins from many viruses contain a short region in the ectodomain and near the transmembrane domain, referred to as the pre-transmembrane (PTM) domain. In some cases, the PTM domain is rich in aromatic amino acids and plays an important role in membrane fusion. Although the 23-amino-acid (aa) PTM domain of AcMNPV GP64 lacks aromatic amino acids, we asked whether this region might also play a significant role in membrane fusion. We generated alanine scanning and single and multiple amino acid substitutions in the GP64 PTM domain. We specifically focused on amino acid positions conserved between baculovirus GP64 and thogotovirus GP75 proteins, as well as hydrophobic and charged amino acids. For each PTM-modified construct, we examined trimerization, cell surface localization, and membrane fusion activity. Membrane merger and pore formation were also examined. We identified eight aa positions that are important for membrane fusion activity. Critical positions were not clustered in the linear sequence but were distributed throughout the PTM domain. While charged residues were not critical or essential, three hydrophobic amino acids (L465, L476, and L480) played an important role in membrane fusion activity and appear to be involved in formation of the fusion pore. We also asked whether selected GP64 constructs were capable of rescuing a
gp64
null AcMNPV virus. These studies suggested that several conserved residues (T463, G460, G462, and G474) were not required for membrane fusion but were important for budding and viral infectivity.
VP5* Rearranges when Rotavirus Uncoats
Authors: Yoder Joshua D. , Trask Shane D. , Vo Phuoc T. , Binka Mawuena , Feng Ningguo , Harrison Stephen C. , Greenberg Harry B. , Dormitzer Philip R. 
Published: August 2009

ABSTRACT
Trypsin primes rotavirus for efficient infectivity by cleaving the spike protein, VP4, into VP8* and VP5*. A recombinant VP5* fragment has a trimeric, folded-back structure. Comparison of this structure with virion spikes suggests that a rearrangement, analogous to those of enveloped virus fusion proteins, may mediate membrane penetration by rotavirus during entry. To detect this inferred rearrangement of virion-associated authentic VP5*, we raised conformation-specific monoclonal antibodies against the recombinant VP5* fragment in its putative post-membrane penetration conformation. Using one of these antibodies, we demonstrate that rotavirus uncoating triggers a conformational change in the cleaved VP4 spike to yield rearranged VP5*.
Homodimerization of the Meq Viral Oncoprotein Is Necessary for Induction of T-Cell Lymphoma by Marek's Disease Virus
Authors: Brown Andrew C. , Smith Lorraine P. , Kgosana Lydia , Baigent Susan J. , Nair Venugopal , Allday Martin J. 
Published: August 2009

ABSTRACT

Marek's disease virus (MDV) is a lymphotropic alphaherpesvirus that induces fatal rapid-onset T-cell lymphomas in chickens, its natural host. The MDV-encoded nuclear oncoprotein Meq is essential for lymphomagenesis and acts as a regulator of transcription. Meq has structural features, including a basic domain adjacent to a leucine zipper motif (B-ZIP), that suggest it is related to the Jun/Fos family of transcription factors. Via the leucine zipper, Meq can form homodimers or heterodimerize with c-Jun. Meq/Meq homodimers are associated with transrepression, and Meq/Jun heterodimers can transactivate target genes carrying an AP-1-like binding site. In order to determine the role of the leucine zipper and of Meq dimerization in T lymphomagenesis, specific point mutations were engineered into the highly oncogenic RB-1B strain of MDV to produce virus completely lacking a functional Meq leucine zipper (RB-1B Meq
BZIP/BZIP
) or virus encoding Meq that cannot homodimerize but can still bind to c-Jun and an AP-1-like site on DNA (RB-1B Meq
Hom/Hom
). Both of these mutant viruses were capable of replication in cultured chicken embryo fibroblasts. However both mutations resulted in a complete loss of oncogenicity, since no lymphomas were produced up to 90 days postinfection in experimentally infected chicks. We conclude that the leucine zipper is necessary for the oncogenic activity of Meq and/or the efficient establishment of long-term MDV latency in T cells. Moreover, it appears that the ability to form homodimers is an absolute requirement and the ability to bind c-Jun alone is insufficient for the T-cell lymphomagenesis associated with virulent MDV.
Theiler's Virus Infection Induces a Predominant Pathogenic CD4+T Cell Response to RNA Polymerase in Susceptible SJL/J Mice
Authors: Jin Young-Hee , Kang Bongsu , Kim Byung S. 
Published: August 2009

ABSTRACTTheiler's murine encephalomyelitis virus (TMEV)-induced immune-mediated demyelinating disease in susceptible mouse strains has been extensively investigated as a relevant model for human multiple sclerosis. Previous investigations of antiviral T-cell responses focus on immune responses to viral capsid proteins, while virtually nothing is reported on immune responses to nonstructural proteins. In this study, we have identified noncapsid regions recognized by CD4+T cells from TMEV-infected mice using an overlapping peptide library. Interestingly, a greater number of CD4+T cells recognizing an epitope (3D21-36) of the 3D viral RNA polymerase, in contrast to capsid epitopes, were detected in the CNS of TMEV-infected SJL mice, whereas only a minor population of CD4+T cells from infected C57BL/6 mice recognized this region. The effects of preimmunization and tolerization with these epitopes on the development of demyelinating disease indicated that capsid-specific CD4+T cells are protective during the early stages of viral infection, whereas 3D21-36-specific CD4+T cells exacerbate disease development. Therefore, protective versus pathogenic CD4+T-cell responses directed to TMEV appear to be epitope dependent, and the differences in CD4+T-cell responses to these epitopes between susceptible and resistant mice may play an important role in the resistance or susceptibility to virally induced demyelinating disease.
Attenuated Strains of Influenza A Viruses Do Not Induce Degradation of RNA Polymerase II
Authors: Rodriguez Ariel , Pérez-González Alicia , Hossain M. Jaber , Chen Li-Mei , Rolling Thierry , Pérez-Breña Pilar , Donis Ruben , Kochs Georg , Nieto Amelia 
Published: August 2009

ABSTRACT
We have previously shown that infection with laboratory-passaged strains of influenza virus causes both specific degradation of the largest subunit of the RNA polymerase II complex (RNAP II) and inhibition of host cell transcription. When infection with natural human and avian isolates belonging to different antigenic subtypes was examined, we observed that all of these viruses efficiently induce the proteolytic process. To evaluate whether this process is a general feature of nonattenuated viruses, we studied the behavior of the influenza virus strains A/PR8/8/34 (PR8) and the cold-adapted A/Ann Arbor/6/60 (AA), which are currently used as the donor strains for vaccine seeds due to their attenuated phenotype. We have observed that upon infection with these strains, degradation of the RNAP II does not occur. Moreover, by runoff experiments we observe that PR8 has a reduced ability to inhibit cellular mRNA transcription. In addition, a hypervirulent PR8 (hvPR8) variant that multiplies much faster than standard PR8 (lvPR8) in infected cells and is more virulent in mice than the parental PR8 virus, efficiently induces RNAP II degradation. Studies with reassortant viruses containing defined genome segments of both hvPR8 and lvPR8 indicate that PA and PB2 subunits individually contribute to the ability of influenza virus to degrade the RNAP II. In addition, recently it has been reported that the inclusion of PA or PB2 from hvPR8 in lvPR8 recombinant viruses, highly increases their pathogenicity. Together, the data indicate that the capacity of the influenza virus to degrade RNAP II and inhibit the host cell transcription machinery is a feature of influenza A viruses that might contribute to their virulence.
Human Immunodeficiency Virus Type 1 Is Trapped by Acidic but Not by Neutralized Human Cervicovaginal Mucus
Authors: Lai Samuel K. , Hida Kaoru , Shukair Shetha , Wang Ying-Ying , Figueiredo Anna , Cone Richard , Hope Thomas J. , Hanes Justin 
Published: August 2009

ABSTRACTTo reliably infect a primate model for human immunodeficiency virus (HIV), ∼10,000-fold more virus must be delivered vaginally than intravenously. However, the vaginal mechanisms that help protect against HIV are poorly understood. Here, we report that human cervicovaginal mucus (CVM), obtained from donors with normal lactobacillus-dominated vaginal flora, efficiently traps HIV, causing it to diffuse more than 1,000-fold more slowly than it does in water. Lactobacilli acidify CVM to pH ∼4 by continuously producing lactic acid. At this acidic pH, we found that lactic acid, but not HCl, abolished the negative surface charge on HIV without lysing the virus membrane. In contrast, in CVM neutralized to pH 6 to 7, as occurs when semen temporarily neutralizes the vagina, HIV maintained its native surface charge and diffused only 15-fold more slowly than it would in water. Thus, methods that can maintain both a high lactic acid content and acidity for CVM during coitus may contribute to both vaginal and penile protection by trapping HIV before it can reach target cells. Our results reveal that CVM likely plays an important but currently unappreciated role in decreasing the rate of HIV sexual transmission.
Crystal Structure of Porcine Reproductive and Respiratory Syndrome Virus Leader Protease Nsp1α
Authors: Sun Yuna , Xue Fei , Guo Yu , Ma Ming , Hao Ning , Zhang Xuejun C. , Lou Zhiyong , Li Xuemei , Rao Zihe 
Published: August 2009

ABSTRACTPorcine reproductive and respiratory syndrome (PRRS) virus (PRRSV), a positive-strand RNA virus that belongs to theArteriviridaefamily ofNidovirales, has been identified as the causative agent of PRRS. Nsp1α is the amino (N)-terminal protein in a polyprotein encoded by the PRRSV genome and is reported to be crucial for subgenomic mRNA synthesis, presumably by serving as a transcription factor. Before functioning in transcription, nsp1α proteolytically releases itself from nsp1β. However, the structural basis for the self-releasing and biological functions of nsp1α remains elusive. Here we report the crystal structure of nsp1α of PRRSV (strain XH-GD) in its naturally self-processed form. Nsp1α contains a ZF domain (which may be required for its biological function), a papain-like cysteine protease (PCP) domain with a zinc ion unexpectedly bound at the active site (which is essential for proteolytic self-release of nsp1α), and a carboxyl-terminal extension (which occupies the substrate binding site of the PCP domain). Furthermore, we determined the exact location of the nsp1α self-processing site at Cys-Ala-Met180↓Ala-Asp-Val by use of crystallographic data and N-terminal amino acid sequencing. The crystal structure also suggested an incisself-processing mechanism for nsp1α. Furthermore, nsp1α appears to have a dimeric architecture both in solution and as a crystal, with a hydrophilic groove on the molecular surface that may be related to nsp1α's biological function. Compared with existing structure and function data, our results suggest that PRRSV nsp1α functions differently from other reported viral leader proteases, such as that of foot-and-mouth disease.
Case volumes of intra-arterial and intravenous treatment of ischemic stroke in the USA
Authors: Hirsch J A , Yoo A J , Nogueira R G , Verduzco L A , Schwamm L H , Pryor J C , Rabinov J D , González R G 
Published: August 2009

Background and purposeIschemic stroke is a major cause of disability and death in the USA. Intravenous tissue plasminogen activator (t-PA) remains underutilized. With the development of newer intra-arterial reperfusion therapies, there is increased opportunity to address the more devastating large-vessel occlusions. We seek to identify the numbers of patients with stroke treated with intravenous and intra-arterial therapies, as well as to estimate the potential number of intra-arterial cases in the foreseeable future.MethodsWe performed a literature search to determine case volumes of intravenous t-PA use. We extrapolated the current case volume of intra-arterial stroke therapies from the numbers of cases in which the Merci retrieval device was used. In order to estimate the potential numbers of intra-arterial stroke cases, we characterized the percentage of patients with stroke who received intra-arterial therapy at two leading stroke centers. We applied these percentages to the numbers of patients with stroke seen at the top 100, 200 and 500 stroke centers by volume.ResultsThe rate of intravenous t-PA use is 2.4–3.6%, resulting in 15 000–22 000 cases/year in the USA. The estimated case volume of intra-arterial therapies is 3500–7200 in 2006. Based on data from St. Luke's Brain and Stroke Institute and Massachusetts General Hospital, approximately 5–20% of patients with ischemic stroke can be treated with intra-arterial therapies. Extrapolating this to the top 500 stroke centers by volume, the potential number of intra-arterial cases in the USA is 10 400–41 500/year.ConclusionBased on the current numbers of intra-arterial cases, our theoretical model identifies a potential for significant growth of this stroke therapy.
Long term clinical and angiographic outcomes with the Wingspan stent for treatment of symptomatic 50–99% intracranial atherosclerosis: single center experience in 51 cases
Authors: Wolfe T J , Fitzsimmons B F , Hussain S I , Lynch J R , Zaidat O O 
Published: August 2009

Background and aimTwo independent post-approval registries have reported favorable periprocedural and short term outcomes with the use of the Wingspan stent for treatment of intracranial arterial stenosis. Data on long term clinical and imaging outcomes after Wingspan stent placement are limited.MethodsAll patients treated with the Wingspan stent in a single academic center from January 2006 to February 2008 were identified. Data on stenting indication, severity of stenosis, technical success, re-stenosis and clinical outcome were collected.Results51 patients were treated with the Wingspan stent system for a symptomatic intracranial atherosclerotic stenosis of 50–99%. The technical success rate was 98%. The mean pre- and post-stent stenoses were 73 (11)% and 21 (7)%. Any stroke or death within 24 h of the procedure occurred in 1/51 (2%). The frequency of any stroke or death within 30 days or ipsilateral stroke beyond 30 days was 5/51 (10.0%) at a mean follow-up time of 14.6 months (range 8–30). The frequency of ≥ 50% re-stenosis on follow-up imaging was 7/29 (24%) at 8.6 (4.4) months (range 3–20); all were detected on the initial imaging within 3–6 months, and only one was symptomatic.ConclusionThe use of the Wingspan stent in patients with ≥50% symptomatic intracranial stenosis is associated with good long term clinical outcome. One stroke occurred after the first 30 days, suggesting a significant stabilization of the adverse event rate after the first month.
Incidence and time course of carotid in-stent restenosis in a consecutive series of 295 patients
Authors: Heck D 
Published: August 2009

Background and purposeIn-stent restenosis (ISR) is a potentially preventable cause of stroke in carotid artery stent (CAS) patients. Understanding the frequency and timing of ISR would be useful in developing optimal protocols for carotid stent surveillance. The time course and frequency of moderate and severe ISR in our single institution prospective registry of CAS procedures is reported here.MethodsData were collected prospectively from 296 consecutive elective CAS procedures. Doppler surveillance was performed at 1, 6 and 12 months and annually thereafter in some cases. Moderate ISR (>50%) was defined as a peak systolic velocity (PSV) > 200 cm/s. Severe ISR (>70%) was defined as PSV > 200 cm/sandend diastolic velocity > 125 cm/s or internal carotid artery/common carotid artery ratio >4. Patients with severe ISR underwent digital subtraction angiography for confirmation and possible retreatment.ResultsClinical follow-up at 1 year was 98%. Clinical and ultrasound follow-up at 1 month was 100%, at 6 months 96% and at 1 year 91%. The incidence of all ISR at 6 months was 8%; 5% moderate and 3% severe. Two patients had asymptomatic occlusions at 6 months (0.8%). Patients with moderate ISR at 6 months did not progress to severe ISR. There were two strokes caused by stent thrombosis, one acute and one delayed.ConclusionsDoppler surveillance is important for detecting ISR after CAS procedures. Severe ISR (>70%) should be retreated in most cases as ISR may progress to occlusion. Asymptomatic patients with moderate ISR (50–69%) at 6 months can be safely followed conservatively. Progression of ISR after 6–12 months is uncommon over a 2–3 year period.
Regression models for public health surveillance data: a simulation study
Authors: Kim H , Kriebel D 
Published: August 2009

Objectives:Poisson regression is now widely used in epidemiology, but researchers do not always evaluate the potential for bias in this method when the data are overdispersed. This study used simulated data to evaluate sources of overdispersion in public health surveillance data and compare alternative statistical models for analysing such data. If count data are overdispersed, Poisson regression will not correctly estimate the variance. A model called negative binomial 2 (NB2) can correct for overdispersion, and may be preferred for analysis of count data. This paper compared the performance of Poisson and NB2 regression with simulated overdispersed injury surveillance data.Methods:Monte Carlo simulation was used to assess the utility of the NB2 regression model as an alternative to Poisson regression for data which had several different sources of overdispersion. Simulated injury surveillance datasets were created in which an important predictor variable was omitted, as well as with an incorrect offset (denominator). The simulations evaluated the ability of Poisson regression and NB2 to correctly estimate the true determinants of injury and their confidence intervals.Results:The NB2 model was effective in reducing overdispersion, but it could not reduce bias in point estimates which resulted from omitting a covariate which was a confounder, nor could it reduce bias from using an incorrect offset. One advantage of NB2 over Poisson for overdispersed data was that the confidence interval for a covariate was considerably wider with the former, providing an indication that the Poisson model did not fit well.Conclusion:When overdispersion is detected in a Poisson regression model, the NB2 model should be fit as an alternative. If there is no longer overdispersion, then the NB2 results may be preferred. However, it is important to remember that NB2 cannot correct for bias from omitted covariates or from using an incorrect offset.
A cross-sectional study among detergent workers exposed to liquid detergent enzymes
Authors: van Rooy F G B G J , Houba R , Palmen N , Zengeni M M , Sander I , Spithoven J , Rooyackers J M , Heederik D J J 
Published: August 2009

Objectives:To investigate sensitisation and respiratory health among workers who produce liquid detergent products and handle liquid detergent enzymes.Methods:We performed a cross-sectional study among 109 eligible workers of a detergent products plant. 108 were interviewed for respiratory and allergic symptoms and 106 blood samples were taken from them to examine sensitisation to enzymes. Those sensitised to ⩾1 enzymes were referred for clinical evaluation. Workers and representatives were interviewed to characterise exposure qualitatively and estimate exposure semi-quantitatively. Workers were classified into three exposure groups with varying exposure profiles to enzymes, based on frequency, duration, and level of exposure.Results:Workers were exposed to proteases, α-amylase, lipase and cellulase. The highest exposures occurred in the mixing area. Liquid spills with concentrated enzyme preparations and leakage of enzymes during weighing, transportation and filling were causing workplace contaminations and subsequently leading to both dermal and inhalation exposure for workers.Workers with the highest exposures reported significantly more work-related symptoms of itching nose (prevalence ratio (PR) = 4.2, 95% CI 1.5 to 12.0) and sneezing (PR = 4.0, 95% CI 1.5 to 10.8) and marginally significant more symptoms of wheezing (PR = 2.9, 95% CI 0.9 to 8.7) compared with the least exposed group.Fifteen workers (14.2%) were sensitised to ⩾1 enzymes. A marginally statistically significant gradient in sensitisation across the exposure categories was found (p = 0.09). There was a clinical case of occupational asthma and two others with probable occupational rhinitis.Conclusions:Workers exposed to liquid detergent enzymes are at risk of developing sensitisation (14%) and respiratory allergy.