bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantification of the Dynamics of Enterovirus 71 Infection by Experimental-Mathematical Investigation
Authors: Fukuhara Mitsuko , Iwami Shingo , Sato Kei , Nishimura Yorihiro , Shimizu Hiroyuki , Aihara Kazuyuki , Koyanagi Yoshio 
Published: October 2012

ABSTRACTEnterovirus 71 (EV71) is the causative agent of hand-foot-and-mouth disease and can trigger neurological disorders. EV71 outbreaks are a major public health concern in Asia-Pacific countries. By performing experimental-mathematical investigation, we demonstrate here that viral productivity and transmissibility but not viral cytotoxicity are drastically different among EV71 strains and can be associated with their epidemiological backgrounds. This is the first report demonstrating the dynamics of nonenveloped virus replication in cell culture using mathematical modeling.
A Novel Function of RNAs Arising From the Long Terminal Repeat of Human Endogenous Retrovirus 9 in Cell Cycle Arrest
Authors: Xu Lai , Elkahloun Abdel G. , Candotti Fabio , Grajkowski Andrzej , Beaucage Serge L. , Petricoin Emanuel F. , Calvert Valerie , Juhl Hartmut , Mills Frederick , Mason Karen , Shastri Neal , Chik Josh , Xu Cynthia , Rosenberg Amy S. 
Published: October 2012

ABSTRACT
The human genome contains approximately 50 copies of the replication-defective human endogenous retrovirus 9 (ERV-9) and thousands of copies of its solitary long term repeat (sLTR) element. While some sLTRs are located upstream of critical genes and have enhancer activity, other sLTRs are located within introns and may be transcribed as RNAs. We found that intronic RNAs arising from U3 sLTRs of ERV-9 were expressed as both sense (S) and antisense (AS) transcripts in all human cells tested but that expression levels differed in malignant versus nonmalignant cells. In nonmalignant cells, AS was expressed at higher levels than S and at higher levels than in malignant cells; in malignant cells, AS was expressed at amounts equivalent to those of S RNA. Critically, U3 AS RNA was found to physically bind to key transcription factors for cellular proliferation, including NF-Y, p53, and sp1, indicating that such RNA transcripts may function as decoy targets or traps for NF-Y and thus inhibit the growth of human cancer cells. Indeed, short U3 oligodeoxynucleotides (ODNs) based on these RNA sequences ably inhibited proliferation of cancer cell lines driven by cyclins B1/B2, the gene targets of NF-Y.
Cellular LITAF Interacts with Frog Virus 3 75L Protein and Alters Its Subcellular Localization
Authors: Eaton Heather E. , Ferreira Lacerda Andressa , Desrochers Guillaume , Metcalf Julie , Angers Annie , Brunetti Craig R. 
Published: October 2012

ABSTRACT

Iridoviruses are a family of large double-stranded DNA (dsDNA) viruses that are composed of 5 genera, including the
Lymphocystivirus
,
Ranavirus
,
Megalocytivirus
,
Iridovirus
, and
Chloriridovirus
genera. The frog virus 3 (FV3) 75L gene is a nonessential gene that is highly conserved throughout the members of the
Ranavirus
genus but is not found in other iridoviruses. FV3 75L shows high sequence similarity to a conserved domain found in the C terminus of LITAF, a small cellular protein with unknown function. Here we show that FV3 75L localizes to early endosomes, while LITAF localizes to late endosomes/lysosomes. Interestingly, when FV3 75L and LITAF are cotransfected into cells, LITAF can alter the subcellular localization of FV3 75L to late endosomes/lysosomes, where FV3 75L then colocalizes with LITAF. In addition, we demonstrated that virally produced 75L colocalizes with LITAF. We confirmed a physical interaction between LITAF and FV3 75L but found that this interaction was not mediated by two PPXY motifs in the N terminus of LITAF. Mutation of two PPXY motifs in LITAF did not affect the colocalization of LITAF and FV3 75L but did change the location of the two proteins from late endosomes/lysosomes to early endosomes.
Cooperativity in Virus Neutralization by Human Monoclonal Antibodies to Two Adjacent Regions Located at the Amino Terminus of Hepatitis C Virus E2 Glycoprotein
Authors: Keck Zhenyong , Wang Wenyan , Wang Yong , Lau Patrick , Carlsen Thomas H. R. , Prentoe Jannick , Xia Jinming , Patel Arvind H. , Bukh Jens , Foung Steven K. H. 
Published: October 2012

ABSTRACT
A challenge for hepatitis C virus (HCV) vaccine development is defining conserved epitopes that induce protective antibodies against this highly diverse virus. An envelope glycoprotein (E2) segment located at amino acids (aa) 412 to 423 contains highly conserved neutralizing epitopes. While polyclonal antibodies to aa 412 to 423 from HCV-infected individuals confirmed broad neutralization, conflicting findings have been reported on polyclonal antibodies to an adjacent region, aa 434 to 446, that may or may not interfere with neutralization by antibodies to aa 412 to 423. To define the interplay between these antibodies, we isolated human monoclonal antibodies (HMAbs) to aa 412 to 423, designated HC33-related HMAbs (HC33 HMAbs), and characterized their interactions with other HMAbs to aa 434 to 446. A subset of the HC33 HMAbs neutralized genotype 1 to 6 infectious cell culture-derived HCV virions (HCVcc) with various activities. Although nonneutralizing HC33 HMAbs were isolated, they had lower binding affinities than neutralizing HC33 HMAbs. These antibodies could be converted to neutralizing antibodies by affinity maturation. Unidirectional competition for binding to E2 was observed between HC33 HMAbs and HMAbs to aa 434 to 446. When HMAbs to aa 434 to 446, which mediated neutralization, were combined with neutralizing HC33 HMAbs, biphasic patterns in neutralization were observed. A modest degree of antagonism was observed at lower concentrations, and a modest degree of synergism was observed at higher concentrations. However, the overall effect was additive neutralization. A similar pattern was observed when these antibodies were combined to block E2 binding to the HCV coreceptor, CD81. These findings demonstrate that both of these E2 regions participate in epitopes mediating virus neutralization and that the antibodies to aa 412 to 423 and aa 434 to 446 do not hinder their respective virus-neutralizing activities.
The C-Terminal Region of Rift Valley Fever Virus NSm Protein Targets the Protein to the Mitochondrial Outer Membrane and Exerts Antiapoptotic Function
Authors: Terasaki Kaori , Won Sungyong , Makino Shinji 
Published: October 2012

ABSTRACT

The NSm nonstructural protein of Rift Valley fever virus (family
Bunyaviridae
, genus
Phlebovirus
) has an antiapoptotic function and affects viral pathogenesis. We found that NSm integrates into the mitochondrial outer membrane and that the protein's N terminus is exposed to the cytoplasm. The C-terminal region of NSm, which contains a basic amino acid cluster and a putative transmembrane domain, targeted the protein to the mitochondrial outer membrane and exerted antiapoptotic function.
Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor
Authors: Tan Chee Wah , Poh Chit Laa , Sam I-Ching , Chan Yoke Fun 
Published: October 2012

ABSTRACT

Enterovirus 71 (EV-71) infections are usually associated with mild hand, foot, and mouth disease in young children but have been reported to cause severe neurological complications with high mortality rates. To date, four EV-71 receptors have been identified, but inhibition of these receptors by antagonists did not completely abolish EV-71 infection, implying that there is an as yet undiscovered receptor(s). Since EV-71 has a wide range of tissue tropisms, we hypothesize that EV-71 infections may be facilitated by using receptors that are widely expressed in all cell types, such as heparan sulfate. In this study, heparin, polysulfated dextran sulfate, and suramin were found to significantly prevent EV-71 infection. Heparin inhibited infection by all the EV-71 strains tested, including those with a single-passage history. Neutralization of the cell surface anionic charge by polycationic poly-
d
-lysine and blockage of heparan sulfate by an anti-heparan sulfate peptide also inhibited EV-71 infection. Interference with heparan sulfate biosynthesis either by sodium chlorate treatment or through transient knockdown of
N
-deacetylase/
N
-sulfotransferase-1 and exostosin-1 expression reduced EV-71 infection in RD cells. Enzymatic removal of cell surface heparan sulfate by heparinase I/II/III inhibited EV-71 infection. Furthermore, the level of EV-71 attachment to CHO cell lines that are variably deficient in cell surface glycosaminoglycans was significantly lower than that to wild-type CHO cells. Direct binding of EV-71 particles to heparin-Sepharose columns under physiological salt conditions was demonstrated. We conclude that EV-71 infection requires initial binding to heparan sulfate as an attachment receptor.
Efficient Herpes Simplex Virus 1 Replication Requires Cellular ATR Pathway Proteins
Authors: Mohni Kareem N. , Dee Alexander R. , Smith Samantha , Schumacher April J. , Weller Sandra K. 
Published: October 2012

ABSTRACT

Herpes simplex virus 1 (HSV-1) is a double-stranded DNA virus that replicates in the nucleus of the host cell and is known to interact with several components of the cellular DNA-damage-signaling machinery. We have previously reported that the DNA damage response kinase, ATR, is specifically inactivated in HSV-1-infected cells. On the other hand, we have also shown that ATR and its scaffolding protein, ATRIP, are recruited to viral replication compartments, where they play beneficial roles during HSV-1 replication. In order to better understand this apparent discrepancy, we tested the hypothesis that some of the components of the ATR pathway may exert an antiviral effect on infection. In fact, we learned that all 10 of the canonical ATR pathway proteins are stable in HSV-infected cells and are recruited to viral replication compartments; furthermore, short hairpin RNA (shRNA) knockdown shows that several, including ATRIP, RPA70, TopBP1, Claspin, and CINP, are required for efficient HSV-1 replication. We also determined that activation of the ATR kinase prior to infection did not affect virus yield but did result in reduced levels of recombination between coinfecting viruses. Together, these data suggest that ATR pathway proteins are not antiviral
per se
but that activation of ATR signaling may have negative consequences during viral replication, such as inhibiting recombination.
The Host Proteins Transportin SR2/TNPO3 and Cyclophilin A Exert Opposing Effects on HIV-1 Uncoating
Authors: Shah Vaibhav B. , Shi Jiong , Hout David R. , Oztop Ilker , Krishnan Lavanya , Ahn Jinwoo , Shotwell Matthew S. , Engelman Alan , Aiken Christopher 
Published: October 2012

ABSTRACT

Following entry of the HIV-1 core into target cells, productive infection depends on the proper disassembly of the viral capsid (uncoating). Although much is known regarding HIV-1 entry, the actions of host cell proteins that HIV-1 utilizes during early postentry steps are poorly understood. One such factor, transportin SR2 (TRN-SR2)/transportin 3 (TNPO3), promotes infection by HIV-1 and some other lentiviruses, and recent studies have genetically linked TNPO3 dependence of infection to the viral capsid protein (CA). Here we report that purified recombinant TNPO3 stimulates the uncoating of HIV-1 cores
in vitro
. The stimulatory effect was reduced by RanGTP, a known ligand for transportin family members. Depletion of TNPO3 in target cells rendered HIV-1 less susceptible to inhibition by PF74, a small-molecule HIV-1 inhibitor that induces premature uncoating. In contrast to the case for TNPO3, addition of the CA-binding host protein cyclophilin A (CypA) inhibited HIV-1 uncoating and reduced the stimulatory effect of TNPO3 on uncoating
in vitro
. In cells in which TNPO3 was depleted, HIV-1 infection was enhanced 4-fold by addition of cyclosporine, indicating that the requirement for TNPO3 in HIV-1 infection is modulated by CypA-CA interactions. Although TNPO3 was localized primarily to the cytoplasm, depletion of TNPO3 from target cells inhibited HIV-1 infection without reducing the accumulation of nuclear proviral DNA, suggesting that TNPO3 facilitates a stage of the virus life cycle subsequent to nuclear entry. Our results suggest that TNPO3 and cyclophilin A facilitate HIV-1 infection by coordinating proper uncoating of the core in target cells.
Molecular Imaging Reveals a Role for AKT in Resistance to Cisplatin for Ovarian Endometrioid Adenocarcinoma
Authors: Wang Hanxiao , Galbán Stefanie , Wu Rong , Bowman Brittany M. , Witte Amanda , Vetter Katrin , Galbán Craig J. , Ross Brian D. , Cho Kathleen R. , Rehemtulla Alnawaz 
Published: October 2012

Abstract
Purpose: Ovarian cancer is the fifth leading cause of cancer-related deaths among American women. Platinum-based chemotherapy, such as cisplatin, represents the standard-of-care for ovarian cancer. However, toxicity and acquired resistance to cisplatin have proven challenging in the treatment of patients with ovarian cancer.
Experimental Design: Using a genetically engineered mouse model of ovarian endometrioid adenocarcinoma (OEA) in combination with molecular-imaging technologies, we studied the activation of the AKT serine/threonine kinase in response to long-term cisplatin therapy.
Results: Treatment of cells in culture and tumor-bearing animals with cisplatin resulted in activation of AKT, a key mediator of cell survival. On the basis of these results, we investigated the therapeutic use of AKT inhibition in combination with cisplatin, which resulted in enhanced and prolonged induction of apoptosis and in significantly improved tumor control as compared with either agent alone.
Conclusion: These results provide an impetus for clinical trials using combination therapy. To facilitate these trials, we also show the use of diffusion-weighted MRI as an imaging biomarker for evaluation of therapeutic efficacy in OEA. Clin Cancer Res; 19(1); 158–69. ©2012 AACR.
Myosin Light Chain Phosphorylation Is Critical for Adaptation to Cardiac Stress
Authors: Warren Sonisha A. , Briggs Laura E. , Zeng Huadong , Chuang Joyce , Chang Eileen I. , Terada Ryota , Li Moyi , Swanson Maurice S. , Lecker Stewart H. , Willis Monte S. , Spinale Francis G. , Maupin-Furlowe Julie , McMullen Julie R. , Moss Richard L. , Kasahara Hideko 
Published: October 2012

Background—
Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light-chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined.

Methods and Results—

We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ≈40% and cMLCK levels by ≈85%. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated
Mylk3
gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems.

Conclusions—
Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin-proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v.
Anti-Tumor Necrosis Factor-α Therapy Reduces Aortic Inflammation and Stiffness in Patients With Rheumatoid Arthritis
Authors: Mäki-Petäjä Kaisa M. , Elkhawad Maysoon , Cheriyan Joseph , Joshi Francis R. , Östör Andrew J.K. , Hall Frances C. , Rudd James H.F. , Wilkinson Ian B. 
Published: October 2012

Background—
Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-α therapy and correlates with aortic stiffness reduction.

Methods and Results—

Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-α therapy by using
18
F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02±0.22 versus 1.74±0.22,
P
=0.0001). Following therapy, aortic TBR fell to 1.90±0.29,
P
=0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50±33% to 33±27%,
P
=0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51±0.33 to 2.05±0.29,
P
<0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09±1.77 to 8.63±1.42 m/s,
P
=0.04), which correlated with the reduction of aortic TBR (
R
=0.60,
P
=0.01).

Conclusions—

This study demonstrates that RA patients have increased aortic
18
F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-α therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.
Experimental 4D-Var Assimilation of SYNOP Rain Gauge Data at ECMWF
Authors: Lopez Philippe 
Published: October 2012

Abstract
Four-dimensional variational data assimilation (4D-Var) experiments with 6-hourly rain gauge accumulations observed at synoptic stations (SYNOP) around the globe have been run over several months, both at high resolution in an ECMWF operations-like framework and at lower resolution with the reference observational coverage reduced to surface pressure data only, as would be expected in early twentieth-century periods. The key aspects of the technical implementation of rain gauge data assimilation in 4D-Var are described, which include the specification of observation errors, bias correction procedures, screening, and quality control. Results from experiments indicate that the positive impact of rain gauges on forecast scores remains limited in the operations-like context because of their competition with all other observations already available. In contrast, when only synoptic station surface pressure observations are assimilated in the data-poor control experiment, the additional assimilation of rain gauge measurements substantially improves not only surface precipitation scores, but also analysis and forecast scores of temperature, geopotential, wind, and humidity at most atmospheric levels and for forecast ranges up to 10 days. The verification against Meteosat infrared imagery also shows a slight improvement in the spatial distribution of clouds. This suggests that assimilating rain gauge data available during data-sparse periods of the past might help to improve the quality of future reanalyses and subsequent forecasts.
Impact of Graupel Parameterization Schemes on Idealized Bow Echo Simulations
Authors: Adams-Selin Rebecca D. , van den Heever Susan C. , Johnson Richard H. 
Published: October 2012

Abstract
The effect of changes in microphysical cooling rates on bow echo development and longevity are examined through changes to graupel parameterization in the Advanced Research Weather Research and Forecasting Model (ARW-WRF). Multiple simulations are performed that test the sensitivity to different graupel size distributions as well as the complete removal of graupel. It is found that size distributions with larger and denser, but fewer, graupel hydrometeors result in a weaker cold pool due to reduced microphysical cooling rates. This yields weaker midlevel (3–6 km) buoyancy and pressure perturbations, a later onset of more elevated rear inflow, and a weaker convective updraft. The convective updraft is also slower to tilt rearward, and thus bowing occurs later. Graupel size distributions with more numerous, smaller, and lighter hydrometeors result in larger microphysical cooling rates, stronger cold pools, more intense midlevel buoyancy and pressure gradients, and earlier onset of surface-based rear inflow; these systems develop bowing segments earlier. A sensitivity test with fast-falling but small graupel hydrometeors revealed that small mean size and slow fall speed both contribute to the strong cooling rates. Simulations entirely without graupel are initially weaker, because of limited contributions from cooling by melting of the slowly falling snow. However, over the next hour increased rates of melting snow result in an increasingly more intense system with new bowing. Results of the study indicate that the development of a bow echo is highly sensitive to microphysical processes, which presents a challenge to the prediction of these severe weather phenomena.
Model Bias in a Continuously Cycled Assimilation System and Its Influence on Convection-Permitting Forecasts
Authors: Romine Glen S. , Schwartz Craig S. , Snyder Chris , Anderson Jeff L. , Weisman Morris L. 
Published: October 2012

Abstract
During the spring 2011 season, a real-time continuously cycled ensemble data assimilation system using the Advanced Research version of the Weather Research and Forecasting Model (WRF) coupled with the Data Assimilation Research Testbed toolkit provided initial and boundary conditions for deterministic convection-permitting forecasts, also using WRF, over the eastern two-thirds of the conterminous United States (CONUS). In this study the authors evaluate the mesoscale assimilation system and the convection-permitting forecasts, at 15- and 3-km grid spacing, respectively. Experiments employing different physics options within the continuously cycled ensemble data assimilation system are shown to lead to differences in the mean mesoscale analysis characteristics. Convection-permitting forecasts with a fixed model configuration are initialized from these physics-varied analyses, as well as control runs from 0.5° Global Forecast System (GFS) analysis. Systematic bias in the analysis background influences the analysis fit to observations, and when this analysis initializes convection-permitting forecasts, the forecast skill is degraded as bias in the analysis background increases. Moreover, differences in mean error characteristics associated with each physical parameterization suite lead to unique errors of spatial, temporal, and intensity aspects of convection-permitting rainfall forecasts. Observation bias by platform type is also shown to impact the analysis quality.