bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Innate Recognition of Herpes Simplex Virus in Human Primary Macrophages Is Mediated via the MDA5/MAVS-Dependent and MDA5/MAVS/RNA Polymerase III-Independent Pathways
Authors: Melchjorsen Jesper , Rintahaka Johanna , Søby Stine , Horan Kristy A. , Poltajainen Alina , Østergaard Lars , Paludan Søren R. , Matikainen Sampsa 
Published: August 2010

ABSTRACT
Innate recognition of viruses is mediated by pattern recognition receptors (PRRs) triggering expression of antiviral interferons (IFNs) and proinflammatory cytokines. In mice, Toll-like receptor 2 (TLR2) and TLR9 as well as intracellular nucleotide-sensing pathways have been shown to recognize herpes simplex virus (HSV). Here, we describe how human primary macrophages recognize early HSV infection via intracellular pathways. A number of inflammatory cytokines, IFNs, and IFN-stimulated genes were upregulated after HSV infection. We show that early recognition of HSV and induction of IFNs and inflammatory cytokines are independent of TLR2 and TLR9, since inhibition of TLR2 using TLR2 neutralizing antibodies did not affect virus-induced responses and the macrophages were unresponsive to TLR9 stimulation. Instead, HSV recognition involves intracellular recognition systems, since induction of tumor necrosis factor alpha (TNF-α) and IFNs was dependent on virus entry and replication. Importantly, expression of IFNs was strongly inhibited by small interfering RNA (siRNA) knockdown of MAVS, but this MAVS-dependent IFN induction occurred independently of the recently discovered polymerase III (Pol III)/RIG-I DNA sensing system. In contrast, induction of TNF-α was largely independent of MAVS, suggesting that induction of inflammatory cytokines during HSV infection proceeds via a novel pathway. Transfection with ODN2006, a broad inhibitor of intracellular nucleotide recognition, revealed that nucleotide-sensing systems are employed to induce both IFNs and TNF-α. Finally, using siRNA knockdown, we found that MDA5, but not RIG-I, was the primary mediator of HSV recognition. Thus, innate recognition of HSV by human primary macrophages occurs via two distinct intracellular nucleotide-sensing pathways responsible for induction of IFNs and inflammatory cytokine expression, respectively.
Pathogenesis of Hepatitis E Virus and Hepatitis C Virus in Chimpanzees: Similarities and Differences
Authors: Yu Claro , Boon Denali , McDonald Shannon L. , Myers Timothy G. , Tomioka Keiko , Nguyen Hanh , Engle Ronald E. , Govindarajan Sugantha , Emerson Suzanne U. , Purcell Robert H. 
Published: August 2010

ABSTRACTThe chimpanzee is the only animal model for investigating the pathogenesis of viral hepatitis types A through E in humans. Studies of the host response, including microarray analyses, have relied on the close relationship between these two primate species: chimpanzee samples are commonly tested with human-based reagents. In this study, the host responses to two dissimilar viruses, hepatitis E virus (HEV) and hepatitis C virus (HCV), were compared in multiple experimentally infected chimpanzees. Affymetrix U133 + 2.0 human microarray chips were used to assess the entire transcriptome in serial liver biopsies obtained over the course of the infections. Respecting the limitations of microarray probes designed for human target transcripts to effectively assay chimpanzee transcripts, we conducted probe-level analysis of the microarray data in conjunction with a custom mapping of the probe sequences to the most recent human and chimpanzee genome sequences. Time points for statistical comparison were chosen based on independently measured viremia levels. Regardless of the viral infection, the alignment of differentially expressed genes to the human genome sequence resulted in a larger number of genes being identified when compared with alignment to the chimpanzee genome sequence. This probably reflects the lesser refinement of gene annotation for chimpanzees. In general, the two viruses demonstrated very distinct temporal changes in host response genes, although both RNA viruses induced genes that were involved in many of the same biological systems, including interferon-induced genes. The host response to HCV infection was more robust in the magnitude and number of differentially expressed genes compared to HEV infection.
Modification of Human Papillomavirus Minor Capsid Protein L2 by Sumoylation
Authors: Marušič Martina Bergant , Mencin Nina , Ličen Mia , Banks Lawrence , Grm Helena Šterlinko 
Published: August 2010

ABSTRACT
The human papillomavirus (HPV) minor capsid protein L2 plays important roles in the generation of infectious viral particles and in the initial steps of infection. Here we show that HPV-16 L2 protein is sumoylated at lysine 35 and that sumoylation affects its stability. Interestingly, the sumoylated form of L2 cannot bind to the major capsid protein L1, suggesting a mechanism by which capsid assembly may be modulated in an infected cell. Additionally, L2 appears to modulate the overall sumoylation status of the host cell. These observations indicate a complex interplay between the HPV L2 protein and the host sumoylation machinery.
Host Insect Inhibitor-of-Apoptosis SfIAP Functionally Replaces Baculovirus IAP but Is Differentially Regulated by Its N-Terminal Leader
Authors: Cerio Rebecca J. , Vandergaast Rianna , Friesen Paul D. 
Published: August 2010

ABSTRACT

The inhibitor-of-apoptosis (IAP) proteins encoded by baculoviruses bear a striking resemblance to the cellular IAP homologs of their invertebrate hosts. By virtue of the acquired selective advantage of blocking virus-induced apoptosis, baculoviruses may have captured cellular IAP genes that subsequently evolved for virus-specific objectives. To compare viral and host IAPs, we defined antiapoptotic properties of SfIAP, the principal cellular IAP of the lepidopteran host
Spodoptera frugiperda
. We report here that SfIAP prevented virus-induced apoptosis as well as viral Op-IAP3 (which is encoded by the
Orgyia pseudotsugata
nucleopolyhedrovirus) when overexpressed from the baculovirus genome. Like Op-IAP3, SfIAP blocked apoptosis at a step prior to caspase activation. Both of the baculovirus IAP repeats (BIRs) were required for SfIAP function. Moreover, deletion of the C-terminal RING motif generated a loss-of-function SfIAP that interacted and dominantly interfered with wild-type SfIAP. Like Op-IAP3, wild-type SfIAP formed intracellular homodimers, suggesting that oligomerization is a functional requirement for both cellular and viral IAPs. SfIAP possesses a ∼100-residue N-terminal leader domain, which is absent among all viral IAPs. Remarkably, deletion of the leader yielded a fully functional SfIAP with dramatically increased protein stability. Thus, the SfIAP leader contains an instability motif that may confer regulatory options for cellular IAPs that baculovirus IAPs have evolved to bypass for maximal stability and antiapoptotic potency. Our findings that SfIAP and viral IAPs have common motifs, share multiple biochemical properties including oligomerization, and act at the same step to block apoptosis support the hypothesis that baculoviral IAPs were derived by acquisition of host insect IAPs.
Identification of a Previously Unrecognized Promoter That Drives Expression of the UXP Transcription Unit in the Human Adenovirus Type 5 Genome
Authors: Ying Baoling , Tollefson Ann E. , Wold William S. M. 
Published: August 2010

ABSTRACT

We previously identified an adenovirus (Ad) protein named U exon protein (UXP) encoded by a leftward-strand (
l
-strand) transcription unit. Here we identify and characterize the UXP promoter. Primer extension and RNase protection assays mapped the transcription initiation site at 32 nucleotides upstream of the UXP gene initiation codon. A series of viral mutants with mutations at two putative inverted CCAAT (I-CCAAT) boxes and two E2F sites were generated. With mutants lacking the proximal I-CCAAT box, the UXP mRNA level decreased significantly to 30% of the Ad type 5 (Ad5) mRNA level as measured by quantitative reverse transcription-PCR. Decreased UXP was also observed by immunoblotting and immunofluorescence. UXP mRNA and protein levels were similar to those of Ad5 for mutants lacking the distal I-CCAAT box or both putative E2F sites. Ad DNA levels were similar in mutant- and wild-type Ad5-infected cells during the late stage of infection, strongly suggesting that the decreased UXP mRNA and protein from mutants lacking the proximal I-CCAAT box was due to decreased promoter activity. Electrophoretic mobility shift assays (EMSA) indicated that a cellular factor binds specifically to the proximal I-CCAAT box of the UXP promoter. An
in vitro
luciferase reporter assay demonstrated that basal promoter activity lies between bp −158 and +30 of the transcription initiation site. No E1A-mediated promoter transactivation was observed in 293 cells compared with A549 cells. Thus, we propose that there is a previously unidentified Ad5 promoter that drives expression of the UXP transcription unit. This promoter is embedded within the gene for fiber, and it contains a proximal I-CCAAT box critical for UXP mRNA transcription.
Hepatitis C Virus RNA Replication Requires a Conserved Structural Motif within the Transmembrane Domain of the NS5B RNA-Dependent RNA Polymerase
Authors: Brass Volker , Gouttenoire Jérôme , Wahl Anja , Pal Zsuzsanna , Blum Hubert E. , Penin François , Moradpour Darius 
Published: August 2010

ABSTRACT
Hepatitis C virus (HCV) nonstructural protein 5B (NS5B), the viral RNA-dependent RNA polymerase (RdRp), is a tail-anchored protein with a highly conserved C-terminal transmembrane domain (TMD) that is required for the assembly of a functional replication complex. Here, we report that the TMD of the HCV RdRp can be functionally replaced by a newly identified analogous membrane anchor of the GB virus B (GBV-B) NS5B RdRp. Replicons with a chimeric RdRp consisting of the HCV catalytic domain and the GBV-B membrane anchor replicated with reduced efficiency. Compensatory amino acid changes at defined positions within the TMD improved the replication efficiency of these chimeras. These observations highlight a conserved structural motif within the TMD of the HCV NS5B RdRp that is required for RNA replication.
The role of doctors' religious faith and ethnicity in taking ethically controversial decisions during end-of-life care
Authors: Seale Clive 
Published: August 2010

Background and AimsThe prevalence of religious faith among doctors and its relationship with decision-making in end-of-life care is not well documented. The impact of ethnic differences on this is also poorly understood. This study compares ethnicity and religious faith in the medical and general UK populations, and reports on their associations with ethically controversial decisions taken when providing care to dying patients.MethodA postal survey of 3733 UK medical practitioners, of whom 2923 reported on the care of their last patient who died.FindingsSpecialists in care of the elderly were somewhat more likely to be Hindu or Muslim than other doctors; palliative care specialists were somewhat more likely to be Christian, religious and ‘white’ than others. Ethnicity was largely unrelated to rates of reporting ethically controversial decisions. Independently of speciality, doctors who described themselves as non-religious were more likely than others to report having given continuous deep sedation until death, having taken decisions they expected or partly intended to end life, and to have discussed these decisions with patients judged to have the capacity to participate in discussions. Speciality was independently related to wide variations in the reporting of decisions taken with some intent to end life, with doctors in ‘other hospital’ specialities being almost 10 times as likely to report this when compared with palliative medicine specialists, regardless of religious faith.ConclusionsGreater acknowledgement of the relationship of doctors' values with clinical decision-making is advocated.
Intraorbital access using fluoroscopic flat panel detector CT navigation and three-dimensional MRI overlay
Authors: Cooke Daniel L , Levitt Michael , Kim Louis J , Hallam Danial K , Ghodke Basavaraj 
Published: August 2010

BackgroundFlat panel detector CT (FD-CT), three-dimensional image overlay and navigation software on contemporary fluoroscopic units generate less radiation dose while performing imaging of comparable quality to conventional CT. They can superimpose MR and CT datasets and can accurately guide percutaneous procedures providing live instrument visualization and the capability of re-imaging without patient transfer. These techniques, however, have been minimally used for accessing the head.Materials and methodsUsing an Allura Xper FD20 unit (Philips Healthcare Andover, Massachusetts, USA), three-dimensional image overlay and FD-CT navigation were used for percutaneous n-butyl cyanoacrylate (nBCA) embolization of an intraorbital mass in a 69-year-old man.ResultsThree-dimensional image overlay provides accurate anatomical relationships between the optic nerve and vascular portions of the mass. Percutaneous nBCA was technically successful without non-target embolization and with no significant bleeding encountered during operative resection.ConclusionFD-CT navigation and three-dimensional image overlay provide accurate instrument guidance and spatial resolution comparable with current neuro-navigation systems while also providing real time instrument position and the ability to re-image without moving the patient. These are features not available with other types of neuro-navigation.
Economic evaluation of a workplace intervention for sick-listed employees with distress
Authors: van Oostrom Sandra H , Heymans Martijn W , de Vet Henrica C W , van Tulder Maurits W , van Mechelen Willem , Anema Johannes R 
Published: August 2010

ObjectivesTo evaluate the cost effectiveness, cost utility and cost benefit of a workplace intervention compared with usual care for sick-listed employees with distress.MethodsAn economic evaluation was conducted alongside a randomised controlled trial. Employees with distress and who were sick-listed for 2–8 weeks were randomised to a workplace intervention (n=73) or to usual care (n=72). The workplace intervention is a stepwise process involving the sick-listed employee and their supervisor, aimed at formulating a consensus-based plan for return to work (RTW). The effect outcomes were lasting RTW and quality-adjusted life years (QALYs). Healthcare utilisation was measured over 12 months. Cost effectiveness analyses (CEA) and cost utility analyses (CUA) were conducted from the societal perspective and cost benefit analyses (CBA) from the employer perspective. Bootstrapping techniques were used to estimate cost and effect differences, related CIs, and cost effectiveness and cost utility ratios. Cost effectiveness planes were presented and subgroup analyses were performed.ResultsCEA and CUA revealed no statistically significant differences in lasting RTW, QALYs or costs. The CBA indicated a statistically significant higher cost of occupational health services in the workplace intervention group. The workplace intervention was not cost effective according to the CEA, CUA and CBA.ConclusionsWidespread implementation of the workplace intervention for sick-listed employees with distress is not recommended because there was no economic benefit compared with usual care. Future trials should confirm if the workplace intervention is cost effective for the subgroup employees who intended to return to work despite symptoms.This trial has been registered at the Dutch National Trial RegisterISRCTN92307123.
A graphical tool to evaluate temporal coverage of occupational history by exposure measurements: Figure 1
Authors: Vlaanderen Jelle , Fransman Wouter , Miller Brian , Burstyn Igor , Heederik Dick , Hurley Fintan , Vermeulen Roel , Kromhout Hans 
Published: August 2010

IntroductionIn occupational epidemiology, differences in the temporal coverage of the exposure history by available exposure measurement data may affect the uncertainty of exposure estimates. In the reporting of results of studies, greater attention should be paid to the extent to which exposure assessments require extrapolation outside the timeframe for which exposure measurements are available. We propose a simple graphical method that can be used to visualise the temporal coverage of exposure history with exposure measurements and the extent of temporal extrapolation needed.MethodsWe construct a graph that displays the accumulated work history years for which exposure had to be assessed in each calendar year. Years for which exposure measurements were available are shaded. The proportion of work history years covered by exposure measurements and the proportion of work history years accrued before the first measurements are summarised. When available, the actual number of measurements available in each calendar year is shown.ResultsWe demonstrate the application of the graphical tool in three nested case–control studies that reported on leukaemia in relation to low-level benzene exposures in the petroleum industry. Considerable differences in temporal coverage between the studies were illustrated, which may have resulted in differences in the reliability of the retrospective exposure estimates derived for these studies.ConclusionWe introduce a graphical tool for visualising the temporal coverage by available exposure measurement data in epidemiological studies and encourage others to use similar graphs to derive and share better qualitative insights into the uncertainty in exposure assessment.
Prognostic Gene Expression Signature for Squamous Cell Carcinoma of Lung
Authors: Zhu Chang-Qi , Strumpf Dan , Li Chun-Yan , Li Qing , Liu Ni , Der Sandy , Shepherd Frances A. , Tsao Ming-Sound , Jurisica Igor 
Published: August 2010

Abstract
Purpose: This study aimed to identify and validate a gene expression signature for squamous cell carcinoma of the lung (SQCC).
Experimental Design: A published microarray dataset from 129 SQCC patients was used as a training set to identify the minimal gene set prognostic signature. This was selected using the MAximizing R Square Algorithm (MARSA), a novel heuristic signature optimization procedure based on goodness-of-fit (R square). The signature was tested internally by leave-one-out-cross-validation (LOOCV), and then externally in three independent public lung cancer microarray datasets: two datasets of non–small cell lung cancer (NSCLC) and one of adenocarcinoma (ADC) only. Quantitative-PCR (qPCR) was used to validate the signature in a fourth independent SQCC cohort.
Results: A 12-gene signature that passed the internal LOOCV validation was identified. The signature was independently prognostic for SQCC in two NSCLC datasets (total n = 223) but not in ADC. The lack of prognostic significance in ADC was confirmed in the Director's Challenge ADC dataset (n = 442). The prognostic significance of the signature was validated further by qPCR in another independent cohort containing 62 SQCC samples (hazard ratio, 3.76; 95% confidence interval, 1.10-12.87; P = 0.035).
Conclusions: We identified a novel 12-gene prognostic signature specific for SQCC and showed the effectiveness of MARSA to identify prognostic gene expression signatures. Clin Cancer Res; 16(20); 5038–47. ©2010 AACR.
The Development of Aortic Insufficiency in Left Ventricular Assist Device-Supported Patients
Authors: Cowger Jennifer , Pagani Francis D. , Haft Jonathan W. , Romano Matthew A. , Aaronson Keith D. , Kolias Theodore J. 
Published: August 2010

Background—
Aortic insufficiency (AI) following left ventricular assist device (LVAD) placement can affect device performance. The aim of this study was to examine AI development following LVAD implantation.

Methods and Results—

Echocardiograms (n=315) from 78 subjects undergoing HeartMate-XVE (n=25 [32%]) or HeartMate-II (n=53 [68%]) implantations from 2004 to 2008 were reviewed. Studies were obtained preoperatively and at 1, 3, 6, 12, 18, and 24 months after surgery. AI was graded on an interval scale (0=none, 0.5=trivial, 1=mild, 1.5=mild-moderate, 2=moderate, 2.5=moderate-severe, 3=severe), and the change in AI at follow-up was analyzed with significance tests. Kaplan–Meier estimates for freedom from moderate or worse AI at follow-up were generated. Mixed-model linear regression was used to identify correlates of AI progression during LVAD support. The median (25th, 75th percentile) duration of LVAD support was 239 (112, 455) days, and preoperative AI grade was 0.0 (0.0, 0.0). At 6 months, 89±4% of subjects (n=49 at risk) were free from moderate or worse AI, but this was reduced to 74±7% (n=29 at risk) and 49±13% (n=13 at risk) by 12 and 18 months, respectively. Correlates (slope±SE) of AI progression included female sex (0.002±0.001;
P
=0.01), smaller body surface area (−0.003±0.001 per m
2
;
P
=0.0017), and HeartMate-II model type (0.002±0.001;
P
=0.039). Correlates (β±SE) of progressive AI on postoperative echocardiogram included increasing aortic sinus diameter (0.04±0.01 per mm;
P
=0.001), an aortic valve that remained closed (0.42±0.06;
P
<0.001) or only intermittently opened (0.34±0.09;
P
<0.001), and lower left ventricular diastolic (−0.002±0.0004 per cm
3
;
P
<0.001) and systolic (−0.002±0.0004 per cm
3
;
P
<0.001) volumes.

Conclusions—
AI progresses over time in LVAD-supported patients. As we move toward an era of long-term cardiac support, more studies are needed to determine the clinical significance of these findings.
Monetary Non-neutrality in a Multisector Menu Cost Model
Authors: Nakamura Emi , Steinsson Jón 
Published: August 2010

Abstract
Empirical evidence suggests that as much as one-third of the U.S. business cycle is due to nominal shocks. We calibrate a multisector menu cost model using new evidence on the cross-sectional distribution of the frequency and size of price changes in the U.S. economy. We augment the model to incorporate intermediate inputs. We show that the introduction of heterogeneity in the frequency of price change triples the degree of monetary non-neutrality generated by the model. We furthermore show that the introduction of intermediate inputs raises the degree of monetary non-neutrality by another factor of three, without adversely affecting the model's ability to match the large average size of price changes. A single-sector model with a frequency of price change equal to the median, rather than the mean, generates monetary non-neutrality similar to that in our multisector model. Our multisector model with intermediate inputs generates variation in real output in response to calibrated aggregate nominal shocks that can account for roughly 23% of the U.S. business cycle.