bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Activation Mechanism of Avian Influenza Virus H9N2 by Furin
Authors: Tse Longping V. , Hamilton Alice M. , Friling Tamar , Whittaker Gary R. 
Published: November 2013

ABSTRACT

Avian influenza virus H9N2 is prevalent in waterfowl and has become endemic in poultry in Asia and the Middle East. H9N2 influenza viruses have served as a reservoir of internal genes for other avian influenza viruses that infect humans, and several cases of human infection by H9N2 influenza viruses have indicated its pandemic potential. Fortunately, an extensive surveillance program enables close monitoring of H9N2 influenza viruses worldwide and has generated a large repository of virus sequences and phylogenetic information. Despite the large quantity of sequences in different databases, very little is known about specific virus isolates and their pathogenesis. Here, we characterize a low-pathogenicity avian influenza virus, A/chicken/Israel/810/2001 (H9N2) (Israel810), which is representative of influenza virus strains that have caused severe morbidity and mortality in poultry farms. We show that under certain circumstances the Israel810 hemagglutinin (HA) can be activated by furin, a hallmark of highly pathogenic avian influenza virus. We demonstrate that Israel810 HA can be cleaved in cells with high levels of furin expression and that a mutation that eliminates a glycosylation site in HA
1
allows the Israel810 HA to gain universal cleavage in cell culture. Pseudoparticles generated from Israel810 HA, or the glycosylation mutant, transduce cells efficiently. In contrast, introduction of a polybasic cleavage site into Israel810 HA leads to pseudoviruses that are compromised for transduction. Our data indicate a mechanism for an H9N2 evolutionary pathway that may allow it to gain virulence in a distinct manner from H5 and H7 influenza viruses.
Impact of Potential Permissive Neuraminidase Mutations on Viral Fitness of the H275Y Oseltamivir-Resistant Influenza A(H1N1)pdm09 VirusIn Vitro, in Mice and in Ferrets
Authors: Abed Yacine , Pizzorno Andrés , Bouhy Xavier , Rhéaume Chantal , Boivin Guy 
Published: November 2013

ABSTRACTNeuraminidase (NA) mutations conferring resistance to NA inhibitors (NAIs) generally compromise the fitness of influenza viruses. The only NAI-resistant virus that widely spread in the population, the A/Brisbane/59/2007 (H1N1) strain, contained permissive mutations that restored the detrimental effect caused by the H275Y change. Computational analysis predicted other permissive NA mutations for A(H1N1)pdm09 viruses. Here, we investigated the effect of T289M and N369K mutations on the viral fitness of the A(H1N1)pdm09 H275Y variant. Recombinant wild-type (WT) A(H1N1)pdm09 and the H275Y, H275Y/T289M, H275Y/N369K, and H275Y/V241I/N369K (a natural variant) NA mutants were generated by reverse genetics. Replication kinetics were performed by using ST6GalI-MDCK cells. Virulence was assessed in C57BL/6 mice, and contact transmission was evaluated in ferrets. The H275Y mutation significantly reduced viral titers during the first 12 to 36 h postinfection (p.i.)in vitro. Nevertheless, the WT and H275Y viruses induced comparable mortality rates, weight loss, and lung titers in mice. The T289M mutation eliminated the detrimental effect caused by the H275Y changein vitrowhile causing greater weight loss and mortality in mice, with significantly higher lung viral titers on days 3 and 6 p.i. than with the H275Y mutant. In index ferrets, the WT, H275Y, H275Y/T289M, and H275Y/V241I/N369K recombinants induced comparable fever, weight loss, and nasal wash viral titers. All tested viruses were transmitted at comparable rates in contact ferrets, with the H275Y/V241I/N369K recombinant demonstrating higher nasal wash viral titers than the H275Y mutant. Permissive mutations may enhance the fitness of A(H1N1)pdm09 H275Y virusesin vitroandin vivo. The emergence of such variants should be carefully monitored.
Highly Pathological Influenza A Virus Infection Is Associated with Augmented Expression of PD-1 by Functionally Compromised Virus-Specific CD8+T Cells
Authors: Rutigliano John A. , Sharma Shalini , Morris Melissa Y. , Oguin Thomas H. , McClaren Jennifer L. , Doherty Peter C. , Thomas Paul G. 
Published: November 2013

ABSTRACTOne question that continues to challenge influenza A research is why some strains of virus are so devastating compared to their more mild counterparts. We approached this question from an immunological perspective, investigating the CD8+T cell response in a mouse model system comparing high- and low-pathological influenza virus infections. Our findings reveal that the early (day 0 to 5) viral titer was not the determining factor in the outcome of disease. Instead, increased numbers of antigen-specific CD8+T cells and elevated effector function on a per-cell basis were found in the low-pathological infection and correlated with reduced illness and later-time-point (day 6 to 10) viral titer. High-pathological infection was associated with increased PD-1 expression on influenza virus-specific CD8+T cells, and blockade of PD-L1in vivoled to reduced virus titers and increased CD8+T cell numbers in high- but not low-pathological infection, though T cell functionality was not restored. These data show that high-pathological acute influenza virus infection is associated with a dysregulated CD8+T cell response, which is likely caused by the more highly inflamed airway microenvironment during the early days of infection. Therapeutic approaches specifically aimed at modulating innate airway inflammation may therefore promote efficient CD8+T cell activity.IMPORTANCEWe show that during a severe influenza virus infection, one type of immune cell, the CD8 T cell, is less abundant and less functional than in a more mild infection. This dysregulated T cell phenotype correlates with a lower rate of virus clearance in the severe infection and is partially regulated by the expression of a suppressive coreceptor called PD-1. Treatment with an antibody that blocks PD-1 improves T cell functionality and increases virus clearance.
A Lytic Viral Long Noncoding RNA Modulates the Function of a Latent Protein
Authors: Campbell Mel , Kim Kevin Y. , Chang Pei-Ching , Huerta Steve , Shevchenko Bogdan , Wang Don-Hong , Izumiya Chie , Kung Hsing-Jien , Izumiya Yoshihiro 
Published: November 2013

ABSTRACT
Latent Kaposi's sarcoma-associated herpesvirus (KSHV) episomes are coated with viral latency-associated nuclear antigen (LANA). In contrast, LANA rapidly disassociates from episomes during reactivation. Lytic KSHV expresses polyadenylated nuclear RNA (PAN RNA), a long noncoding RNA (lncRNA). We report that PAN RNA promotes LANA-episome disassociation through an interaction with LANA which facilitates LANA sequestration away from KSHV episomes during reactivation. These findings suggest that KSHV may have evolved an RNA aptamer to regulate latent protein function.
A multifaceted intervention to improve sepsis management in general hospital wards with evaluation using segmented regression of interrupted time series
Authors: Marwick Charis A , Guthrie Bruce , Pringle Jan E C , Evans Josie M M , Nathwani Dilip , Donnan Peter T , Davey Peter G 
Published: November 2013

ProblemAntibiotic administration to inpatients developing sepsis in general hospital wards was frequently delayed. We aimed to reproduce improvements in sepsis management reported in other settings.ContextNinewells Hospital, an 860-bed teaching hospital with quality improvement (QI) experience, in Scotland, UK. The intervention wards were 22 medical, surgical and orthopaedic inpatient wards.DesignA multifaceted intervention, informed by baseline process data and questionnaires and interviews with junior doctors, evaluated using segmented regression analysis of interrupted time series (ITS) data.Measures for improvementPrimary outcome measure: antibiotic administration within 4 hours of sepsis onset. Secondary measures: antibiotics within 8 hours; mean and median time to antibiotics; medical review within 30 min for patients with a standardised early warning system score ≥4; blood cultures taken before antibiotic administration; blood lactate level measured.Strategies for changeThe intervention included printed and electronic clinical guidance, educational clinical team meetings including baseline performance data, audit and monthly feedback on performance.Effects of changePerformance against all study outcome measures improved postintervention but differences were small and ITS analysis did not attribute the observed changes to the intervention.Lessons learntRigorous analysis of this carefully designed improvement intervention could not confirm significant effects. Statistical analysis of many such studies is inadequate, and there is insufficient reporting of negative studies. In light of recent evidence, involving senior clinical team members in verbal feedback and action planning may have made the intervention more effective. Our focus on rigorous intervention design and evaluation was at the expense of iterative refinement, which likely reduced the effect. This highlights the necessary, but challenging, requirement to invest in all three components for effective QI.
Constraints on the movement history of the Carboneras Fault Zone (SE Spain) from stratigraphy and
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Ar–
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Ar dating of Neogene volcanic rocks
Authors: Rutter E. H. , Burgess R. , Faulkner D. R. 
Published: November 2013

Abstract

The Carboneras Fault Zone (CFZ) of SE Spain separates the volcanic Cabo de Gata terrain to the SE (accumulated over 18 to 6 Ma BP) from the tract of uplifted Alpine metamorphic basement blocks and post-orogenic basins that comprise the Betic Cordilleras to the NW. The CFZ cuts metamorphic basement and folded post-orogenic sediments and volcanic rocks, and acted as a conduit for upper Miocene calc-alkaline volcanic rocks to the surface. NW of the CFZ, unconformities and deformation episodes affect successive sedimentary formations of upper Miocene age (upper Serravallian through Messinian). CFZ movements are constrained stratigraphically by an unconformity within the volcanic sequence. Older, pre-faulting volcanic rocks are uptilted against the CFZ whilst the youngest volcanic rocks step across it.
40
Ar–
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Ar age determinations on amphibole crysts from the volcanic rocks show the main CFZ movements began 11–12 Ma BP and ended about 6 Ma. Lesser movement rates continue today. The CFZ is interpreted as part of a transform fault system separating NE–SW stretched and NW–SE shortened crust deformed above a southwestward-retreating subducted slab, from a less deformed terrain lying to the SE. Locally, total offset on the CFZ may be up to 40 km but is at least 15 km.
Risk of Hepatitis B Transmission After Amniocentesis in Chronic Hepatitis B Carriers
Authors: Alexander James M. , Ramus Ronald , Jackson Gregory , Sercely Barbara , Wendel George D. 
Published: November 2013

Objective: To measure the risk of perinatal transmission of HBV in chronic carriers who undergo amniocentesis.Methods: This was a prospective, longitudinal study from 1990 to 1995 ofwomen who were HBV carriers and underwent amniocentesis. The infants of these women were followed from birth to one year of age. Maternal data examined included HBV antigen and antibody status, liver function tests (LFTs) and the amniocentesis report.Results: Twenty‐eight women were identified. Two of 28 neonates were stillborn unrelated to hepatitis. Five infants were lost to follow‐up leaving 21 mother‐child pairs to evaluate. All 21 women were chronic HBV carriers at the time of amniocentesis for delivery. No mother had abnormal LFTs, and only one of 21 women was positive for hepatitis B e antigen (HBeAg). Thirteen amniocenteses were for advanced maternal age, and four were for abnormal maternal serum alphafetoprotein (MSAFP) screening. None of the amniocenteses were recorded as bloody, and the placenta was anterior in 6 of 21 procedures. None of the 21 infants (95% CI: 0–16.8%) were
positive for HbsAg during the first month of life or at 12 months of age. All infants received HBV vaccine and HBIG immunoprophylaxis.Conclusion: The risk of transmission of HBV to the fetus after amniocentesis in women who are HBV carriers is low. Immunoprophylaxis in these infants was successful. Infect. Dis. Obstet. Gynecol. 7:283–286; 1999.
Nonclinical Evaluation of the Serum Pharmacodynamic Biomarkers HGF and Shed MET following Dosing with the Anti-MET Monovalent Monoclonal Antibody Onartuzumab
Authors: Mai Elaine , Zheng Zhong , Chen Youjun , Peng Jing , Severin Christophe , Filvaroff Ellen , Romero Mally , Mallet William , Kaur Surinder , Gelzleichter Thomas , Nijem Ihsan , Merchant Mark , Young Judy C. 
Published: November 2013

AbstractOnartuzumab, a humanized, monovalent monoclonal anti-MET antibody, antagonizes MET signaling by inhibiting binding of its ligand, hepatocyte growth factor (HGF). We investigated the effects of onartuzumab on cell-associated and circulating (shed) MET (sMET) and circulating HGF in vitro and nonclinically to determine their utility as pharmacodynamic biomarkers for onartuzumab. Effects of onartuzumab on cell-associated MET were assessed by flow cytometry and immunofluorescence. sMET and HGF were measured in cell supernatants and in serum or plasma from multiple species (mouse, cynomolgus monkey, and human) using plate-based immunoassays. Unlike bivalent anti-MET antibodies, onartuzumab stably associates with MET on the surface of cells without inducing MET internalization or shedding. Onartuzumab delayed the clearance of human xenograft tumor-produced sMET from the circulation of mice, and endogenous sMET in cynomolgus monkeys. In mice harboring MET-expressing xenograft tumors, in the absence of onartuzumab, levels of human sMET correlated with tumor size, and may be predictive of MET-expressing tumor burden. Because binding of sMET to onartuzumab in circulation resulted in increasing sMET serum concentrations due to reduced clearance, this likely renders sMET unsuitable as a pharmacodynamic biomarker for onartuzumab. There was no observed effect of onartuzumab on circulating HGF levels in xenograft tumor-bearing mice or endogenous HGF in cynomolgus monkeys. Although sMET and HGF may serve as predictive biomarkers for MET therapeutics, these data do not support their use as pharmacodynamic biomarkers for onartuzumab. Mol Cancer Ther; 13(2); 540–52. ©2013 AACR.
Improvement of fibrin clot structure after factor VIII injection in haemophilia A patients treated on demand
Authors: Mikovic Danijela , Elezovic Ivo , Zabczyk Michael , Hutenby Kjell , Antovic Jovan P. , Antovic Aleksandra 
Published: November 2013

SummaryPatients with haemophilia A have seriously impaired thrombin generation due to an inherited deficiency of factor (F)VIII, making them form unstable fibrin clots that are unable to maintain haemostasis. Data on fibrin structure in haemophilia patients remain limited. Fibrin permeability, assessed by a flow measurement technique, was investigated in plasma from 20 patients with severe haemophilia A treated on demand, before and 30 minutes after FVIII injection. The results were correlated with concentrations of fibrinogen, FVIII and thrombin-activatable fibrinolysis inhibitor (TAFI), and global haemostatic markers: endogenous thrombin potential (ETP) and overall haemostatic potential (OHP). Fibrin structure was visualised using scanning electron microscopy (SEM). The permeability coefficient Ks decreased significantly after FVIII treatment. Ks correlated significantly with FVIII levels and dosage, and with ETP, OHP and levels of TAFI. SEM images revealed irregular, porous fibrin clots composed of thick and short fibers before FVIII treatment. The clots had recovered after FVIII replacement almost to levels in control samples, revealing compact fibrin with smaller intrinsic pores. To the best of our knowledge, this is the first description of fibrin porosity and structure before and after FVIII treatment of selected haemophilia patients. It seems that thrombin generation is the main determinant of fibrin structure in haemophilic plasma.
‘VASPFix’ for measurement of VASP phosphorylation in platelets and for monitoring effects of P2Y12 antagonists
Authors: Dovlatova Natalia , White Ann E. , Dhillon Kiren , Heptinstall Stan , Fox Susan C. , Glenn Jacqueline R. 
Published: November 2013

SummaryVasodilator-stimulated phosphoprotein (VASP) is phosphorylated and dephosphorylated consequent to increases and decreases in cyclic nucleotide levels. Monitoring changes in VASP phosphorylation is an established method for indirect measurement of cyclic nucleotides. Here we describe the use of an innovative cocktail, VASPFix, which allows sensitive and reproducible measurement of phosphorylated VASP (VASP-P) in a simple, single-step procedure using cytometric bead technology. Frozen VASPFix-treated samples are stable for at least six months prior to analysis. We successfully used VASPFix to measure VASP-P in platelets in both platelet-rich plasma and blood in response to compounds that increase (dibutyryl cAMP, adenosine, iloprost, PGE1) and decrease (ADP, PGE1) cAMP, and to determine the effects of certain receptor antagonists on the results obtained. The change in VASP-P brought about by adding ADP to PGE1-stimulated platelets is a combination of the effect of ADP at the P2Y12 receptor and of PGE1 at both IP and EP3 receptors. For iloprost-stimulated platelets EP3 receptors are not involved. A procedure in which iloprost, ADP and VASPFix were used to determine effectiveness of clopidogrel and prasugrel in patients was compared with an established commercial procedure that uses PGE1 and ADP; the latter produced higher platelet reactivity values that were the result of PGE1 interacting with platelet EP3 receptors. We conclude that VASPFix can be used both as a research tool and for clinical investigations and provides better specificity for P2Y12 receptor inhibition. The latter confers a distinct advantage over existing methods used to monitor effects of P2Y12 antagonists on platelet function.
Application of Statistical Models to the Prediction of Seasonal Rainfall Anomalies over the Sahel
Authors: Badr Hamada S. , Zaitchik Benjamin F. , Guikema Seth D. 
Published: November 2013

AbstractRainfall in the Sahel region of Africa is prone to large interannual variability, and it has exhibited a recent multidecadal drying trend. The well-documented social impacts of this variability have motivated numerous efforts at seasonal precipitation prediction, many of which employ statistical techniques that forecast Sahelian precipitation as a function of large-scale indices of surface air temperature (SAT) anomalies, sea surface temperature (SST), surface pressure, and other variables. These statistical models have demonstrated some skill, but nearly all have adopted conventional statistical modeling techniques—most commonly generalized linear models—to associate predictor fields with precipitation anomalies. Here, the results of an artificial neural network (ANN) machine-learning algorithm applied to predict summertime (July–September) Sahel rainfall anomalies using indices of springtime (April–June) SST and SAT anomalies for the period 1900–2011 are presented. Principal component analysis was used to remove multicollinearity between predictor variables. Predictive accuracy was assessed using repeatedk-fold random holdout and leave-one-out cross-validation methods. It was found that the ANN achieved predictive accuracy superior to that of eight alternative statistical methods tested in this study, and it was also superior to that of previously published predictive models of summertime Sahel precipitation. Analysis of partial dependence plots indicates that ANN skill is derived primarily from the ability to capture nonlinear influences that multiple major modes of large-scale variability have on Sahelian precipitation. These results point to the value of ANN techniques for seasonal precipitation prediction in the Sahel.
Emergence and Equilibration of Jets in Beta-Plane Turbulence: Applications of Stochastic Structural Stability Theory
Authors: Constantinou Navid C. , Farrell Brian F. , Ioannou Petros J. 
Published: November 2013

Abstract
Stochastic structural stability theory (S3T) provides analytical methods for understanding the emergence and equilibration of jets from the turbulence in planetary atmospheres based on the dynamics of the statistical mean state of the turbulence closed at second order. Predictions for formation and equilibration of turbulent jets made using S3T are critically compared with results of simulations made using the associated quasi-linear and nonlinear models. S3T predicts the observed bifurcation behavior associated with the emergence of jets, their equilibration, and their breakdown as a function of parameters. Quantitative differences in bifurcation parameter values between predictions of S3T and results of nonlinear simulations are traced to modification of the eddy spectrum which results from two processes: nonlinear eddy–eddy interactions and formation of discrete nonzonal structures. Remarkably, these nonzonal structures, which substantially modify the turbulence spectrum, are found to arise from S3T instability. Formation as linear instabilities and equilibration at finite amplitude of multiple equilibria for identical parameter values in the form of jets with distinct meridional wavenumbers is verified, as is the existence at equilibrium of finite-amplitude nonzonal structures in the form of nonlinearly modified Rossby waves. When zonal jets and nonlinearly modified Rossby waves coexist at finite amplitude, the jet structure is generally found to dominate even if it is linearly less unstable. The physical reality of the manifold of S3T jets and nonzonal structures is underscored by the existence in nonlinear simulations of jet structure at subcritical S3T parameter values that are identified with stable S3T jet modes excited by turbulent fluctuations.
Hydrological Climate-Impact Projections for the Rhine River: GCM–RCM Uncertainty and Separate Temperature and Precipitation Effects*
Authors: Bosshard Thomas , Kotlarski Sven , Zappa Massimiliano , Schär Christoph 
Published: November 2013

Abstract
Climate change is expected to affect the hydrological cycle, with considerable impacts on water resources. Climate-induced changes in the hydrology of the Rhine River (Europe) are of major importance for the riparian countries, as the Rhine River is the most important European waterway, serves as a freshwater supply source, and is prone to floods and droughts. Here regional climate model data from the Ensemble-Based Predictions of Climate Changes and their Impacts (ENSEMBLES) project is used to drive the hydrological model Precipitation–Runoff–Evapotranspiration–Hydrotope (PREVAH) and to assess the impact of climate change on the hydrology in the Rhine basin. Results suggest increases in monthly mean runoff during winter and decreases in summer. At the gauge Cologne and for the period 2070–99 under the A1B scenario of the Special Report on Emissions Scenarios, projected decreases in summer vary between −9% and −40% depending on the climate model used, while increases in winter are in the range of +4% to +51%. These projected changes in mean runoff are generally consistent with earlier studies, but the derived spread in the runoff projections appears to be larger. It is demonstrated that temperature effects (e.g., through altered snow processes) dominate in the Alpine tributaries, while precipitation effects dominate in the lower portion of the Rhine basin. Analyses are also presented for selected extreme runoff indices.