bluuebunny/crossref_metadata_2025_split huggingface dataset:
Varicella-Zoster Virus Infection of Differentiated Human Neural Stem Cells
Authors: Pugazhenthi Subbiah , Nair Sreekala , Velmurugan Kalpana , Liang Qiaoling , Mahalingam Ravi , Cohrs Randall J. , Nagel Maria A. , Gilden Don 
Published: April 2011

ABSTRACT

Primary varicella-zoster virus (VZV) infection in humans produces varicella (chickenpox), after which the virus becomes latent in ganglionic neurons. Analysis of the physical state of viral nucleic acid and virus gene expression during latency requires postmortem acquisition of fresh human ganglia. To provide an additional way to study the VZV-host relationship in neurons, we developed an
in vitro
model of infected differentiated human neural stem cells (NSCs). NSCs were induced to differentiate in culture dishes coated with poly-
l
-lysine and mouse laminin in the presence of fibroblast growth factor 2 (FGF-2), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), dibutyryl cyclic AMP, and retinoic acid. Immunostaining with neuronal (MAP2a and β-tubulin), astrocyte (GFAP), and oligodendrocyte (CNPase) markers revealed that differentiated neurons constituted approximately 90% of the cell population. These neurons were maintained in culture for up to 8 weeks. No cytopathic effect (CPE) developed in neurons infected with cell-free VZV (Zostavax vaccine) compared to human fetal lung fibroblasts infected with VZV. Weeks later, VZV DNA virus-specific transcripts (open reading frames [ORFs] 21, 29, 62, and 63) were detected in infected neurons, and dual immunofluorescence staining revealed the presence of VZV IE63 and gE exclusively in healthy-appearing neurons, but not in astrocytes. Neither the tissue culture medium nor a homogenate prepared from VZV-infected neurons produced a CPE in fibroblasts. VZV induced apoptosis in fibroblasts, as shown by activation of caspase 3 and by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, but not in neurons. This model provides a unique
in vitro
system to study the VZV-neuronal relationship.
Multimerization of Adenovirus Serotype 3 Fiber Knob Domains Is Required for Efficient Binding of Virus to Desmoglein 2 and Subsequent Opening of Epithelial Junctions
Authors: Wang Hongjie , Li ZongYi , Yumul Roma , Lara Stephanie , Hemminki Akseli , Fender Pascal , Lieber André 
Published: April 2011

ABSTRACT

Recently, we identified desmoglein 2 (DSG2) as the main receptor for a group of species B adenoviruses (Ads), including Ad3, a serotype that is widely distributed in the human population (H. Wang et al., Nat. Med.
17:
96–104, 2011). In this study, we have attempted to delineate structural details of the Ad3 interaction with DSG2. For CAR- and CD46-interacting Ad serotypes, attachment to cells can be completely blocked by an excess of recombinant fiber knob protein, while soluble Ad3 fiber knob only inefficiently blocks Ad3 infection. We found that the DSG2-interacting domain(s) within Ad3 is formed by several fiber knob domains that have to be in the spatial constellation that is present in viral particles. Based on this finding, we generated a small recombinant, self-dimerizing protein containing the Ad3 fiber knob (Ad3-K/S/Kn). Ad3-K/S/Kn bound to DSG2 with high affinity and blocked Ad3 infection. We demonstrated by confocal immunofluorescence and transmission electron microscopy analyses that Ad3-K/S/Kn, through its binding to DSG2, triggered the transient opening of intercellular junctions in epithelial cells. The pretreatment of epithelial cells with Ad3-K/S/Kn resulted in increased access to receptors that are localized in or masked by epithelial junctions, e.g., CAR or Her2/
neu
. Ad3-K/S/Kn treatment released CAR from tight junctions and thus increased the transduction of epithelial cells by a serotype Ad5-based vector. Furthermore, the pretreatment of Her2/
neu
-positive breast cancer cells with Ad3-K/S/Kn increased the killing of cancer cells by the Her2/
neu
-targeting monoclonal antibody trastuzumab (Herceptin). This study widens our understanding of how Ads achieve high avidity to their receptors and the infection of epithelial tissue. The small recombinant protein Ad3-K/S/Kn has practical implications for the therapy of epithelial cancer and gene/drug delivery to normal epithelial tissues.
Regulation of the Production of Infectious Genotype 1a Hepatitis C Virus by NS5A Domain III
Authors: Kim Seungtaek , Welsch Christoph , Yi MinKyung , Lemon Stanley M. 
Published: April 2011

ABSTRACT
Although hepatitis C virus (HCV) assembly remains incompletely understood, recent studies with the genotype 2a JFH-1 strain suggest that it is dependent upon the phosphorylation of Ser residues near the C terminus of NS5A, a multifunctional nonstructural protein. Since genotype 1 viruses account for most HCV disease yet differ substantially in sequence from that of JFH-1, we studied the role of NS5A in the production of the H77S virus. While less efficient than JFH-1, genotype 1a H77S RNA produces infectious virus when transfected into permissive Huh-7 cells. The exchange of complete NS5A sequences between these viruses was highly detrimental to replication, while exchanges of the C-terminal domain III sequence (46% amino acid sequence identity) were well tolerated, with little effect on RNA synthesis. Surprisingly, the placement of the H77S domain III sequence into JFH-1 resulted in increased virus yields; conversely, H77S yields were reduced by the introduction of domain III from JFH-1. These changes in infectious virus yield correlated well with changes in the abundance of NS5A in RNA-transfected cells but not with RNA replication or core protein expression levels. Alanine replacement mutagenesis of selected Ser and Thr residues in the C-terminal domain III sequence revealed no single residue to be essential for infectious H77S virus production. However, virus production was eliminated by Ala substitutions at multiple residues and could be restored by phosphomimetic Asp substitutions at these sites. Thus, despite low overall sequence homology, the production of infectious virus is regulated similarly in JFH-1 and H77S viruses by a conserved function associated with a C-terminal Ser/Thr cluster in domain III of NS5A.
Temporal Variations in the Hepatitis C Virus Intrahost Population during Chronic Infection
Authors: Ramachandran Sumathi , Campo David S. , Dimitrova Zoya E. , Xia Guo-liang , Purdy Michael A. , Khudyakov Yury E. 
Published: April 2011

ABSTRACT
The intrahost evolution of hepatitis C virus (HCV) holds keys to understanding mechanisms responsible for the establishment of chronic infections and to development of a vaccine and therapeutics. In this study, intrahost variants of two variable HCV genomic regions, HVR1 and NS5A, were sequenced from four treatment-naïve chronically infected patients who were followed up from the acute stage of infection for 9 to 18 years. Median-joining network analysis indicated that the majority of the HCV intrahost variants were observed only at certain time points, but some variants were detectable at more than one time point. In all patients, these variants were found organized into communities or subpopulations. We hypothesize that HCV intrahost evolution is defined by two processes: incremental changes within communities through random mutation and alternations between coexisting communities. The HCV population was observed to incrementally evolve within a single community during approximately the first 3 years of infection, followed by dispersion into several subpopulations. Two patients demonstrated this pattern of dispersion for the rest of the observation period, while HCV variants in the other two patients converged into another single subpopulation after ∼9 to 12 years of dispersion. The final subpopulation in these two patients was under purifying selection. Intrahost HCV evolution in all four patients was characterized by a consistent increase in negative selection over time, suggesting the increasing HCV adaptation to the host late in infection. The data suggest specific staging of HCV intrahost evolution.
Proteomic Characterization of Pseudorabies Virus Extracellular Virions
Authors: Kramer T. , Greco T. M. , Enquist L. W. , Cristea I. M. 
Published: April 2011

ABSTRACT

Pseudorabies virus (PRV), a member of the
Alphaherpesvirinae
, has a complex multilayered extracellular virion that is structurally conserved among other herpesviruses. PRV virions contain a double-stranded DNA genome within a proteinaceous capsid surrounded by the tegument, a layer of viral and cellular proteins. The envelope layer, which encloses the capsid and tegument, contains viral transmembrane proteins anchored in a phospholipid bilayer. The viral and host proteins contained within virions execute important functions during viral spread and pathogenesis, but a detailed understanding of the composition of PRV virions has been lacking. In this report, we present the first comprehensive proteomic characterization of purified PRV virions by mass spectrometry using two complementary approaches. To exclude proteins present in the extracellular medium that may nonspecifically associate with virions, we also analyzed virions treated with proteinase K and samples prepared from mock-infected cells. Overall, we identified 47 viral proteins associated with PRV virions, 40 of which were previously localized to the capsid, tegument, and envelope layers using traditional biochemical approaches. Additionally, we identified seven viral proteins that were previously undetected in virions, including pUL8, pUL20, pUL32, pUL40 (RR2), pUL42, pUL50 (dUTPase), and Rsp40/ICP22. Furthermore, although we did not enrich for posttranslational modifications, we detected phosphorylation of four virion proteins: pUL26, pUL36, pUL46, and pUL48. Finally, we identified 48 host proteins associated with PRV virions, many of which have known functions in important cellular pathways such as intracellular signaling, mRNA translation and processing, cytoskeletal dynamics, and membrane organization. This analysis extends previous work aimed at determining the composition of herpesvirus virions and provides novel insights critical for understanding the mechanisms underlying PRV entry, assembly, egress, spread, and pathogenesis.
MicroRNAs Are Independent Predictors of Outcome in Diffuse Large B-Cell Lymphoma Patients Treated with R-CHOP
Authors: Alencar Alvaro J. , Malumbres Raquel , Kozloski Goldi A. , Advani Ranjana , Talreja Neha , Chinichian Shideh , Briones Javier , Natkunam Yasodha , Sehn Laurie H. , Gascoyne Randy D. , Tibshirani Rob , Lossos Izidore S. 
Published: April 2011

AbstractPurpose: Diffuse large B-cell lymphoma (DLBCL) heterogeneity has prompted investigations for new biomarkers that can accurately predict survival. A previously reported 6-gene model combined with the International Prognostic Index (IPI) could predict patients' outcome. However, even these predictors are not capable of unambiguously identifying outcome, suggesting that additional biomarkers might improve their predictive power.Experimental Design: We studied expression of 11 microRNAs (miRNA) that had previously been reported to have variable expression in DLBCL tumors. We measured the expression of each miRNA by quantitative real-time PCR analyses in 176 samples from uniformly treated DLBCL patients and correlated the results to survival.Results: In a univariate analysis, the expression of miR-18a correlated with overall survival (OS), whereas the expression of miR-181a and miR-222 correlated with progression-free survival (PFS). A multivariate Cox regression analysis including the IPI, the 6-gene model–derived mortality predictor score and expression of the miR-18a, miR-181a, and miR-222, revealed that all variables were independent predictors of survival except the expression of miR-222 for OS and the expression of miR-18a for PFS.Conclusion: The expression of specific miRNAs may be useful for DLBCL survival prediction and their role in the pathogenesis of this disease should be examined further. Clin Cancer Res; 17(12); 4125–35. ©2011 AACR.
Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 Trial
Authors: Davies D. Mark , de Vries Petrus J. , Johnson Simon R. , McCartney Deborah L. , Cox Jane A. , Serra Andreas L. , Watson Peter C. , Howe Christopher J. , Doyle Tim , Pointon Kate , Cross Justin J. , Tattersfield Anne E. , Kingswood J. Chris , Sampson Julian R. 
Published: April 2011

Abstract
Purpose: Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders.
Experimental Design: In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function.
Results: The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus.
Conclusions: This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation. Clin Cancer Res; 17(12); 4071–81. ©2011 AACR.
Induction ofIn VitroandIn VivoNK Cell Cytotoxicity Using High-Avidity Immunoligands Targeting Prostate-Specific Membrane Antigen in Prostate Carcinoma
Authors: Jachimowicz Ron D. , Fracasso Giulio , Yazaki Paul J. , Power Barbara E. , Borchmann Peter , Engert Andreas , Hansen Hinrich P. , Reiners Katrin S. , Marie Madlener , von Strandmann Elke Pogge , Rothe Achim 
Published: April 2011

AbstractCancer that might develop as host natural killer (NK) cells fail to detect ligands for their activating NK receptors. Immunoligands represent promising immunotherapeutic tools to overcome this deficit. These are fusion proteins containing a single-chain antibody fragment (scFv) to target an available tumor antigen and ULBP2 to activate host NK cells by targeting the activatory receptor NKG2D. Prostate-specific membrane antigen (PSMA) is an integral non-shed type 2 membrane protein that is highly and specifically expressed on prostate epithelial cells and strongly upregulated in prostate cancer. Here, we compare the impact of various anti-PSMA immunoligand formats on the therapeutic efficacy against prostate carcinoma cells by activating NK cells via NKG2D. Shortening of the linker separating the heavy and light chain antibody domain leads to the formation of dimers, trimers, and higher molecular mass oligomers. NK cells are most efficiently activated by multimeric immunoligands, thus showing an altered cytokine release pattern. The high avidity format is also superior in in vitro NK-mediated tumor cell targeting as shown in cytotoxicity assays. Finally, the efficacy of a multimeric immunoligand is shown in a prostate carcinoma mouse xenograft model showing a strong activity against advanced established tumors. Mol Cancer Ther; 10(6); 1036–45. ©2011 AACR.
A Stochastic Model for the Transition to Strong Convection
Authors: Stechmann Samuel N. , Neelin J. David 
Published: April 2011

Abstract
A simple stochastic model is designed and analyzed in order to further understand the transition to strong convection. The transition has been characterized recently in observational data by an array of statistical measures, including (i) a sharp transition in mean precipitation, and a peak in precipitation variance, at a critical value of column water vapor (CWV), (ii) an approximate power law in the probability density of precipitation event size, (iii) exponential tails in the probability density of CWV values, when conditioned on either precipitating or nonprecipitating locations, and (iv) long and short autocorrelation times of CWV and precipitation, respectively, with approximately exponential and power-law decays in their autocorrelation functions, respectively. The stochastic model presented here captures these four statistical features in time series of CWV and precipitation at a single location. In addition, analytic solutions are given for the exponential tails, which directly relates the tails to model parameters. The model parameterization includes three stochastic components: a stochastic trigger turns the convection on and off (a two-state Markov jump process), and stochastic closures represent variability in precipitation and in “external” forcing (Gaussian white noise). This stochastic external forcing is seen to be crucial for obtaining extreme precipitation events with high CWV and long lifetimes, because it can occasionally compensate for the heavy precipitation and encourage more of it. This stochastic model can also be seen as a simplified stochastic convective parameterization, and it demonstrates simple ways to turn a deterministic parameterization—the trigger and/or closure—into a stochastic one.
Characteristics of Head-Mounted Displays and Their Effects on Simulator Sickness
Authors: Moss Jason D. , Muth Eric R. 
Published: April 2011

Objective: We examined the effects of several display characteristics of head-mounted displays (HMDs) on simulator sickness (SS). Background: Technological limitations, such as display delay and reduced field of view (FOV), affect perception when using an HMD and are often thought to be related to SS. Few studies have examined the relationship between FOV and geometric FOV (image scale factor) or how HMD characteristics may interact. Method: Participants made active head movements to locate objects when viewing a live video via an HMD. Results: Compared with no added delay, an additional 200 ms of display delay did not result in increased SS, as measured by the Simulator Sickness Questionnaire. Furthermore, an effect of image scale factor on SS was not revealed. However, SS was greater when peripheral vision was occluded than when it was not. Peripheral vision moderated the effects of image scale factor and delay on head movement velocity. Conclusion: Occluding peripheral vision may subject HMD users to the potential detrimental consequences of HMD characteristics more than when peripheral vision of the external environment is available, resulting in more SS. Future research should investigate to what extent peripheral vision can be occluded without increasing SS and without sacrificing realism and presence. Application: To reduce the occurrence of SS, a degree of peripheral vision of the external world should be provided. Furthermore, users and designers should be aware that head movement behavior may be affected by HMD characteristics.
Modelling and analysis of a three-revolute parallel micro-positioning mechanism
Authors: Tian Y , Shirinzadeh B , Zhang D , Zhong Y 
Published: April 2011

This article presents the modelling and analysis methodologies of a three-degree-of-freedom (DOF) flexure-based mechanism. The mechanical design and working principle of a three revolute parallel mechanism is briefly provided. The kinematics of the proposed mechanism is established by simplifying flexure hinges into the revolute joints. The relationship of velocity between the Cartesian space and joint space is established. For small displacements of piezoelectric actuators, this velocity mapping can be simplified as the displacement relationship for the flexure-based mechanism. Two simplified methodologies, linearizing triangular functions and constant Jacobian, are utilized to conduct computational analysis for the flexure-based mechanism. The reachable workspace and theoretical resolution are also investigated. A novel empirical displacement mapping model is proposed based on finite-element analysis. Experiments are carried out to verify the established models of the three-DOF flexure-based mechanism. The maximum reachable workspace can reach up to approximately±68 and±76 μm in x and y directions, and the translational and rotational resolutions of the flexure-based mechanism are approximately 3 nm and 0.4 μrad, respectively.
Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with high-altitude pulmonary oedema: a meta-analysis
Authors: Qi Yue , Sun Jiayi , Zhu Tongchun , Wang Wei , Liu Jing , Zhou Wenyu , Qiu Changchun , Zhao Dong 
Published: April 2011

Background and objective: High-altitude pulmonary oedema (HAPE) is a non-cardiogenic hydrostatic oedema involving a genetic component. Considering the low incidence of HAPE, sample sizes in current reports are relatively limited. We aimed to assess the association between the angiotensin-converting enzyme (ACE) I/D polymorphism and HAPE via a meta-analysis of published and unpublished data. Materials and methods: We searched PubMed, CBM, CNKI, and Cochrane Library Database before 20 November 2010. A random-effects model was applied (STATA) and study quality was assessed in duplicate. Results: A total of five studies including 305 cases and 662 controls were meta-analysed. The summary odds ratio (OR) indicated that no significant differences in risk of developing HAPE were found between carriers of ACE D and I alleles (OR = 1.20; 95% confidence interval (CI), 0.98–1.48; p = 0.084). Lack of association persisted for genotypes under the recessive mode. However, genotype association under the dominant mode showed D allele carriers significantly conferred a 1.55-fold increased HAPE risk compared with II genotype carriers (95% CI, 1.15–2.08; p = 0.004). Funnel plot and Egger’s test suggested no evidence of publication bias. Conclusions: Our results supported the notion that ACE D allele carriers were at significant increased risk of developing HAPE.