bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viral Adaptation to an Antiviral Protein Enhances the Fitness Level to Above That of the Uninhibited Wild Type
Authors: Cherwa James E. , Sanchez-Soria Pablo ,   Members of the University of Arizona Virology Laboratory Course 2007, Wichman Holly A. , Fane Bentley A. 
Published: September 2009

ABSTRACT
Viruses often evolve resistance to antiviral agents. While resistant strains are able to replicate in the presence of the agent, they generally exhibit lower fitness than the wild-type strain in the absence of the inhibitor. In some cases, resistant strains become dependent on the antiviral agent. However, the agent rarely, if ever, elevates dependent strain fitness above the uninhibited wild-type level. This would require an adaptive mechanism to convert the antiviral agent into a beneficial growth factor. Using an inhibitory scaffolding protein that specifically blocks φX174 capsid assembly, we demonstrate that such mechanisms are possible. To obtain the quintuple-mutant resistant strain, the wild-type virus was propagated for approximately 150 viral life cycles in the presence of increasing concentrations of the inhibitory protein. The expression of the inhibitory protein elevated the strain's fitness significantly above the uninhibited wild-type level. Thus, selecting for resistance coselected for dependency, which was characterized and found to operate on the level of capsid nucleation. To the best of our knowledge, this is the first report of a virus evolving a mechanism to productively utilize an antiviral agent to stimulate its fitness above the uninhibited wild-type level. The results of this study may be predictive of the types of resistant phenotypes that could be selected by antiviral agents that specifically target capsid assembly.
Infection with “Escaped” Virus Variants Impairs Control of Simian Immunodeficiency Virus SIVmac239 Replication inMamu-B*08-Positive Macaques
Authors: Valentine Laura E. , Loffredo John T. , Bean Alex T. , León Enrique J. , MacNair Caitlin E. , Beal Dominic R. , Piaskowski Shari M. , Klimentidis Yann C. , Lank Simon M. , Wiseman Roger W. , Weinfurter Jason T. , May Gemma E. , Rakasz Eva G. , Wilson Nancy A. , Friedrich Thomas C. , O'Connor David H. , Allison David B. , Watkins David I. 
Published: September 2009

ABSTRACTAn understanding of the mechanism(s) by which some individuals spontaneously control human immunodeficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I alleleMamu-B*08become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infectedMamu-B*08-positive (Mamu-B*08+) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8+T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8+T-cell epitopes to investigate the contribution of epitope-specific CD8+T-cell responses to the development of the control of viral replication. TenMamu-B*08+macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infectedMamu-B*08+macaques. The five most immunodominant Mamu-B*08-restricted CD8+T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infectedMamu-B*08+animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infectedMamu-B*08+animals had viral loads of <20,000 vRNA copy eq/ml (P= 0.04). Our results suggest that these epitope-specific CD8+T-cell responses may play a role in establishing the control of viral replication inMamu-B*08+macaques.
Epitope Specificity and Relative Clonal Abundance Do Not Affect CD8 Differentiation Patterns during Lymphocytic Choriomeningitis Virus Infection
Authors: Munitic Ivana , Decaluwe Hélène , Evaristo César , Lemos Sara , Wlodarczyk Myriam , Worth Andrew , Le Bon Agnès , Selin Liisa K. , Rivière Yves , Di Santo James P. , Borrow Persephone , Rocha Benedita 
Published: September 2009

ABSTRACT
To evaluate the impact of immunodominance on CD8 T-cell properties, we compared the functional properties of dominant and subdominant populations in the response to lymphocytic choriomeningitis virus (LCMV). To improve functional discrimination, in addition to the usual tests of phenotype and function, we used a sensitive technique that allows the screening of all CD8 effector genes simultaneously in single cells. Surprisingly, these methods failed to reveal a major impact of clonal dominance in CD8 properties throughout the response. Aiming to increase clonal dominance, we examined high-frequency transferred P14 T-cell receptor transgenic (TCR Tg) cells. Under these conditions LCMV is cleared faster, and accordingly we found an accelerated response. However, when Tg and endogenous cells were studied in the same mice, where they should be subjected to the same antigen load, they showed overlapping properties, and the presence of P14 cells did not modify endogenous responses to other LCMV epitopes or a perturbed immunodominance hierarchy in the memory phase. Using allotype-labeled Tg cells, we found that during acute infection up to 80% downregulated their TCR and were undetectable by tetramer binding, and that tetramer-negative and tetramer-positive cells had very different features. Since Tg cells are not available to evaluate immune responses in humans and, in many cases, are not available from the mouse, the tetramer-based evaluation of early immune responses in most situations of high viremia may be incomplete and biased.
The AKV Murine Leukemia Virus Is Restricted and Hypermutated by Mouse APOBEC3
Authors: Langlois Marc-André , Kemmerich Kristin , Rada Cristina , Neuberger Michael S. 
Published: September 2009

ABSTRACT
APOBEC3 proteins are potent restriction factors against retroviral infection in primates. This restriction is accompanied by hypermutations in the retroviral genome that are attributable to the cytidine deaminase activity of the APOBEC3 proteins. Studies of nucleotide sequence diversity among endogenous gammaretroviruses suggest that the evolution of endogenous retroelements could have been shaped by the mutagenic cytidine deaminase activity of APOBEC3. In mice, however, APOBEC3 appears to restrict exogenous murine retroviruses in the absence of detectable levels of deamination. AKV is an endogenous retrovirus that is involved in causing a high incidence of thymic lymphoma in AKR mice. A comparative analysis of several mouse strains revealed a relatively low level of APOBEC3 expression in AKR mice. Here we show that endogenous mouse APOBEC3 restricts AKV infection and that this restriction likely reflects polymorphisms affecting APOBEC3 abundance rather than differences in the APOBEC3 isoforms expressed. We also observe that restriction of AKV by APOBEC3 is accompanied by G→A hypermutations in the viral genome. Our findings demonstrate that APOBEC3 acts as a restriction factor in rodents affecting the strain tropism of AKV, and they provide good support for the proposal that APOBEC3-mediated hypermutation contributed to the evolution of endogenous rodent retroviral genomes.
General and Target-Specific RNA Binding Properties of Epstein-Barr Virus SM Posttranscriptional Regulatory Protein
Authors: Han Zhao , Verma Dinesh , Hilscher Chelsey , Dittmer Dirk P. , Swaminathan Sankar 
Published: September 2009

ABSTRACT
Epstein-Barr virus (EBV) SM protein is an essential nuclear shuttling protein expressed by EBV early during the lytic phase of replication. SM acts to increase EBV lytic gene expression by binding EBV mRNAs and enhancing accumulation of the majority of EBV lytic cycle mRNAs. SM increases target mRNA stability and nuclear export, in addition to modulating RNA splicing. SM and its homologs in other herpesvirus have been hypothesized to function in part by binding viral RNAs and recruiting cellular export factors. Although activation of gene expression by SM is gene specific, it is unknown whether SM binds to mRNA in a specific manner or whether its RNA binding is target independent. SM-mRNA complexes were isolated from EBV-infected B-lymphocyte cell lines induced to permit lytic EBV replication, and a quantitative measurement of mRNAs corresponding to all known EBV open reading frames was performed by real-time quantitative reverse transcription-PCR. The results showed that although SM has broad RNA binding properties, there is a clear hierarchy of affinities among EBV mRNAs with respect to SM complex formation. In vitro binding assays with two of the most highly SM-associated transcripts suggested that SM binds preferentially to specific sequences or structures present in noncoding regions of some EBV mRNAs. Furthermore, the presence of these sequences conferred responsiveness to SM. These data are consistent with a mechanism of action similar to that of hnRNPs, which exert sequence-specific effects on gene expression despite having multiple degenerate consensus binding sites common to a large number of RNAs.
Peripheral Immunization Blocks Lethal Actions of Vesicular Stomatitis Virus within the Brain
Authors: Ozduman Koray , Wollmann Guido , Ahmadi Sebastian A. , van den Pol Anthony N. 
Published: September 2009

ABSTRACTVesicular stomatitis virus (VSV) is the prototype virus for 75 or more negative-strand RNA viruses in the rhabdovirus family. Some of these viruses, including VSV, can cause neurological impairment or death upon brain infection. VSV has shown promise in the prevention and treatment of disease as a vaccine vector and an oncolytic virus, but infection of the brain remains a concern. Three VSV variants, the wild-type-related VSV-G/GFP and two attenuated viruses, VSV-CT1 and VSV-CT9-M51, were compared for neuroinvasiveness and neuromorbidity. In nonimmunized mice, direct VSV-G/GFP injection into the brain invariably resulted in lethal encephalitis; in contrast, partial survival was seen after direct injection of the attenuated VSV strains. In addition, both attenuated VSV strains showed significantly reduced neuroinvasiveness after intranasal inoculation of young postnatal day 16 mice. Of the three tested variants, VSV-CT9-M51 generated the lowest degree of neuropathology. Despite its attenuated state, peripheral inoculations of VSV-CT9-M51 targeted and killed human glioblastoma implanted into the mouse brain. Importantly, we show here that intranasal or intramuscular immunization prevents the lethal effects of subsequent VSV-G/GFP, VSV-CT1, and VSV-CT9-M51 injections into the brain. These results indicate that attenuated recombinant viruses show reduced neurovirulence and that peripheral immunization blocks the lethal actions of all VSVs tested.
Cardiovascular risk factors in idiopathic compared to riskassociated venous thromboembolism: A focus on fibrinogen, factor VIII, and high-sensitivity C-reactive protein (hs-CRP)
Authors: Schmitt Joern , Humpich Marek , Glowatzki Matthias , Dressler Dejan , Seifried Erhard , Lindhoff-Last Edelgard , Luxembourg Beate 
Published: September 2009

SummaryThere have recently been reports of an increased incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism (VTE) compared to patients with risk-associated VTE. The aim of our study was to evaluate whether elevated clotting factors, which have been linked to chronic subclinical inflammation and arterial thromboembolic disease, have a higher prevalence in idiopathic VTE compared to secondary VTE.Plasma fibrinogen,factor VIII,and high-sensitivity C-reactive protein (hs-CRP) levels were determined in a cohort of sex and age-matched patients with unprovoked VTE (n=101), patients with secondary VTE (n=101), and controls (n=202). Fibrinogen and hs-CRP levels were higher in patients with idiopathic VTE (fibrinogen: median/range: 331/214-524 mg/dl; hs-CRP: median/interquartile range: 1.8/0.8-3.7 mg/l) than in those with risk-associated VTE (299/162-458 mg/dl, p=0.004; 1.5/0.8-2.2 mg/l, p=0.05) and controls (302/185-644 mg/dl, p=0.001; 1.2/0.5-2.2
The A6936G polymorphism of the endothelial protein C receptor gene is associated with the risk of unexplained foetal loss in Mediterranean European couples
Authors: Fabbro-Peray Pascale , Marès Pierre , Mismetti Patrick , Lissalde-Lavigne Géraldine , Cochery-Nouvellon Éva , Chauleur Céline , Demattei Christophe , Mercier Éric , Gris Jean-Christophe 
Published: September 2009

SummaryThe endothelial protein C receptor (EPCR) is expressed by trophoblast cells. Mid-gestation pregnancy loss is described in animals with a haemochorial placenta lacking EPCR. The A6936G allele of the EPCR gene (PROCR) may be associated with lower EPCR densities on trophoblasts, but data are lacking for its effect on the risk of pregnancy loss in humans. A 1:2 case-control study on unexplained pregnancy loss was nested in the NOHA First cohort: 3,218 case couples and 6,436 control couples were studied for PROCR A6936G, coagulation factor V gene (F5) G1691A and coagulation factor II gene (F2) G20210A polymorphisms. Ethnicity and time of pregnancy loss defined through biometry-based gestational ages (embryonic loss < 10th week ≥ foetal loss) were analysed. The PROCR A6936G allele, in mothers and fathers, was associated only with foetal loss in both Europeans and non-Europeans. Increasing probability levels of carrying a homozygous child were increasingly associated with the risk of foetal demise. The F5 G1691A and F2 G20210A alleles, only in mothers, were only and independently associated with foetal loss in Europeans. In our population, the PROCR A6936G allele describes women, but also men and thus couples, at risk for first unexplained foetal loss. This risk is independent of the foetal loss risk conferred to our local Mediterranean European women by the F5 G1691A and F2 G20210A alleles. Data confirm that the relationship between thrombophilias and pregnancy loss varies according to ethnicity and loss type.
The tumour necrosis factor superfamily ligand APRIL (TNFSF13) is released upon platelet activation and expressed in atherosclerosis
Authors: Sandberg Wiggo J. , Otterdal Kari , Gullestad Lars , Halvorsen Bente , Ragnarsson Asgrimur , Frøland Stig S. , Damås Jan K. , Øie Erik , Hansson Göran K. , Yndestad Arne , Aukrust Pål 
Published: September 2009

SummaryActivated platelets release a wide range of inflammatory mediators, including members of the tumour necrosis factor (TNF) superfamily (e.g. CD40 ligand [CD40L] and LIGHT). Such platelet-mediated inflammation could be involved in atherogenesis and plaque destabilisation. In the present study we investigated whether APRIL, another member of the TNF superfamily that has been detected in megakaryocytes, could be released from platelets upon activation. The release of APRIL was studied in thrombin receptor (SFLLRN) activated platelets, and the expression of APRIL was examined in plasma and within the atherosclerotic lesion in patients with carotid and coronary atherosclerosis. Upon SFLLRN activation, there was a gradual release of APRIL, reaching maximum after 90 minutes. While this pattern is similar to that of CD40L and LIGHT, the release of APRIL was quite differently regulated. Thus, prostaglandin E1,but not inhibitors of metal-dependent proteases and actin polymerisation or the lack of GP IIb/IIIa, blocks APRIL release in activated platelets. With relevance to atherogenesis, we found that patients with coronary artery disease (n=80) had raised plasma levels of APRIL as compared with controls (n=20), and APRIL immunoreactivity was detected in aggregated platelets within the ruptured plaque in patients with myocardial infarction and within macrophages in symptomatic carotid plaques. In conclusion, activated platelets release significant amounts of APRIL in a longlasting manner, differently regulated than the gradual release of other platelet-derived TNF superfamily ligands. The enhanced expression of APRIL in atherosclerotic disorders, both systemically and within the lesion, may suggest a potential involvement of APRIL in atherogenesis.
Proliferative stimulation of the vascular endothelin-1 axis in vitro and ex vivo by infection with Chlamydia pneumoniae
Authors: Kern Jan , Maass Viola , Rupp Jan , Maass Matthias 
Published: September 2009

SummaryEndothelin-1 (ET-1) is a vasoactive peptide that modifies vascular function via the G-protein coupled transmembrane receptors, Endothelin-A receptor (ETAR) and Endothelin-B receptor (ETBR). Dysregulation of the ET-1 axis plays a role in atherosclerotic development as it triggers cell proliferation, inflammation, and vasoconstriction.The respiratory pathogen Chlamydia pneumoniae (Cp) has been recovered from atherosclerotic lesions, and related to atherogenesis, via activation of vascular small GTPases and leukocyte recruitment. Cp effectively reprograms host cell signalling and is able to enter an intracellular persistent state in vascular cells that is refractory to antibiotics. Upon chlamydial infection, vascular smooth muscle cells, which do not produce significant ET-1 under physiological conditions were switched into a fundamental source of ET-1 mRNA and protein in a p38-MAP-kinase-dependent pathway. Endothelial cells did not overproduce ET-1 but showed upregulation of mitogenic ETAR mRNA and protein while the counterbalancing ETBR, which regulates ET-1 clearance, remained unaffected.This disruption of the ET-1 axis was confirmed in an ex vivo mouse aortic ring model, and resulted in endothelial cell proliferation that could be abrogated by ETAR-siRNA and the selective ETAR-antagonist BQ-123. Chronic chlamydial infection of the vascular wall might represent a permanent noxious stimulus linked to the endothelial cell proliferation characteristic of early atherosclerosis. Suppression of this deleterious paracrine loop by ETAR antagonism opens up a new option of preventing possible vascular sequelae of otherwise untreatable chronic chlamydial infection. In conclusion, this is the first study to demonstrate infection to dysregulate the ET-1 axis towards inducing a proatherogenic proliferative phenotype.
Is perioperative point-of-care prothrombin time testing accurate compared to the standard laboratory test?
Authors: Urwyler Natalie , Staub Lukas P. , Beran Dominik , Deplazes Marcus , Lord Sarah J. , Alberio Lorenzo , Greif Robert , Theiler Lorenz 
Published: September 2009

SummaryThere is no accepted way of measuring prothrombin time without time loss for patients undergoing major surgery who are at risk of intraoperative dilution and consumption coagulopathy due to bleeding and volume replacement with crystalloids or colloids. Decisions to transfuse fresh frozen plasma and procoagulatory drugs have to rely on clinical judgment in these situations. Point-of-care devices are considerably faster than the standard laboratory methods. In this study we assessed the accuracy of a Point-of-care (PoC) device measuring prothrombin time compared to the standard laboratory method. Patients undergoing major surgery and intensive care unit patients were included. PoC prothrombin time was measured by CoaguChek® XS Plus (Roche Diagnostics, Switzerland). PoC and reference tests were performed independently and interpreted under blinded conditions. Using a cut-off prothrombin time of 50%, we calculated diagnostic accuracy measures, plotted a receiver operating characteristic (ROC) curve and tested for equivalence between the two methods. PoC sensitivity and specificity were 95% (95% CI 77%, 100%) and 95% (95% CI 91%, 98%) respectively. The negative likelihood ratio was 0.05 (95% CI 0.01, 0.32). The positive likelihood ratio was 19.57 (95% CI 10.62, 36.06). The area under the ROC curve was 0.988. Equivalence between the two methods was confirmed. CoaguChek® XS Plus is a rapid and highly accurate test compared with the reference test. These findings suggest that PoC testing will be useful for monitoring intraoperative prothrombin time when coagulopathy is suspected. It could lead to a more rational use of expensive and limited blood bank resources.
Real-life anticoagulation treatment of atrial fibrillation after catheter ablation: Possible overtreatment of low-risk patients
Authors: Hindricks Gerhard , Kottkamp Hans , Sommer Philipp , Gaspar Thomas , Bode Kerstin , Arya Arash , Rallidis Loukianos S. , Kremastinos Dimitrios Th. , Piorkowski Christopher , Dagres Nikolaos 
Published: September 2009

SummaryCatheter ablation provides curative treatment for atrial fibrillation (AF). Data on anticoagulation after the procedure are sparse. We investigated real-life antithrombotic treatment after AF ablation and examined its adherence to current recommendations. Eight hundred forty-four patients (age 58 ±10 years) underwent AF ablation. Most patients had a CHADS2 score of 0 (46%) or 1 (45%). Seven-day Holter was performed at three, six and 12 months after ablation. Decision on anticoagulation treatment was made by general practitioners and referring cardiologists in consultation with the patients. At discharge, anticoagulants were prescribed for the vast majority (94–96%) of patients. This percentage remained high at three and six months (80–90%) without differences between stroke risk groups. At 12 months, the use of anticoagulants was mainly influenced by the detection of recurrence; usage exceeded 90% in all stroke risk groups in patients with recurrences. In patients without recurrences, differences between risk groups were significant but small, ranging from 42% (CHADS2=0) to 62% (CHADS2≥2) (p=0.033). In multivariate analysis, the only factor independently associated with oral anticoagulation at 12 months was the detection of recurrences (odds ratio=16.2, p<0.001), whereas the effect of the CHADS2 score was not significant (p=0.080).The effect of all other examined factors was also not significant. Contrary to current recommendations, anticoagulation after AF ablation is hardly guided by the stroke risk profile and remains high even in low-risk patients. The most important factor influencing the use of anticoagulants is the detection of recurrences during follow-up. This results in possible overtreatment of low-risk patients.