bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enterovirus 71 Proteins 2A and 3D Antagonize the Antiviral Activity of Gamma Interferon via Signaling Attenuation
Authors: Wang Li-Chiu , Chen Su-O , Chang Shih-Ping , Lee Yi-Ping , Yu Chun-Keung , Chen Chia-Ling , Tseng Po-Chun , Hsieh Chia-Yuan , Chen Shun-Hua , Lin Chiou-Feng 
Published: April 2015

ABSTRACTEnterovirus 71 (EV71) infection causes severe mortality involving multiple possible mechanisms, including cytokine storm, brain stem encephalitis, and fulminant pulmonary edema. Gamma interferon (IFN-γ) may confer anti-EV71 activity; however, the claim that disease severity is highly correlated to an increase in IFN-γ is controversial and would indicate an immune escape initiated by EV71. This study, investigating the role of IFN-γ in EV71 infection using a murine model, showed that IFN-γ was elevated. Moreover, IFN-γ receptor-deficient mice showed higher mortality rates and more severe disease progression with slower viral clearance than wild-type mice.In vitroresults showed that IFN-γ pretreatment reduced EV71 yield, whereas EV71 infection caused IFN-γ resistance with attenuated IFN-γ signaling in IFN regulatory factor 1 (IRF1) gene transactivation. To study the immunoediting ability of EV71 proteins in IFN-γ signaling, 11 viral proteins were stably expressed in cells without cytotoxicity; however, viral proteins 2A and 3D blocked IFN-γ-inducedIRF1transactivation following a loss of signal transducer and activator of transcription 1 (STAT1) nuclear translocation. Viral 3D attenuated IFN-γ signaling accompanied by a STAT1 decrease without interfering with IFN-γ receptor expression. Restoration of STAT1 or blocking 3D activity was able to rescue IFN-γ signaling. Interestingly, viral 2A attenuated IFN-γ signaling using another mechanism by reducing the serine phosphorylation of STAT1 following the inactivation of extracellular signal-regulated kinase without affecting STAT1 expression. These results demonstrate the anti-EV71 ability of IFN-γ and the immunoediting ability by EV71 2A and 3D, which attenuate IFN-γ signaling through different mechanisms.IMPORTANCEImmunosurveillance by gamma interferon (IFN-γ) may confer anti-enterovirus 71 (anti-EV71) activity; however, the claim that disease severity is highly correlated to an increase in IFN-γ is controversial and would indicate an immune escape initiated by EV71. IFN-γ receptor-deficient mice showed higher mortality and more severe disease progression, indicating the anti-EV71 property of IFN-γ. However, EV71 infection caused cellular insusceptibility in response to IFN-γ stimulation. We used anin vitrosystem with viral protein expression to explore the novel IFN-γ inhibitory properties of the EV71 2A and 3D proteins through the different mechanisms. According to this study, targeting either 2A or 3D pharmacologically and/or genetically may sustain a cellular susceptibility in response to IFN-γ, particularly for IFN-γ-mediated anti-EV71 activity.
New Noncoding Lytic Transcripts Derived from the Epstein-Barr Virus Latency Origin of Replication,
oriP
, Are Hyperedited, Bind the Paraspeckle Protein, NONO/p54nrb, and Support Viral Lytic Transcription
Authors: Cao Subing , Moss Walter , O'Grady Tina , Concha Monica , Strong Michael J. , Wang Xia , Yu Yi , Baddoo Melody , Zhang Kun , Fewell Claire , Lin Zhen , Dong Yan , Flemington Erik K. 
Published: April 2015

ABSTRACT

We have previously shown that the Epstein-Barr virus (EBV) likely encodes hundreds of viral long noncoding RNAs (vlncRNAs) that are expressed during reactivation. Here we show that the EBV latency origin of replication (
oriP
) is transcribed bi-directionally during reactivation and that both leftward (oriPtLs) and rightward (oriPtRs) transcripts are largely localized in the nucleus. While the oriPtLs are most likely noncoding, at least some of the oriPtRs contain the BCRF1/vIL10 open reading frame. Nonetheless, oriPtR transcripts with long 5′ untranslated regions may partially serve noncoding functions. Both oriPtL and oriPtR transcripts are expressed with late kinetics, and their expression is inhibited by phosphonoacetic acid. RNA sequencing (RNA-seq) analysis showed that oriPtLs and oriPtRs exhibited extensive “hyperediting” at their Family of Repeat (FR) regions. RNA secondary structure prediction revealed that the FR region of both oriPtLs and oriPtRs may form large evolutionarily conserved and thermodynamically stable hairpins. The double-stranded RNA-binding protein and RNA-editing enzyme ADAR was found to bind to oriPtLs, likely facilitating editing of the FR hairpin. Further, the multifunctional paraspeckle protein, NONO, was found to bind to oriPt transcripts, suggesting that oriPts interact with the paraspeckle-based innate antiviral immune pathway. Knockdown and ectopic expression of oriPtLs showed that it contributes to global viral lytic gene expression and viral DNA replication. Together, these results show that these new vlncRNAs interact with cellular innate immune pathways and that they help facilitate progression of the viral lytic cascade.

IMPORTANCE
Recent studies have revealed that the complexity of lytic herpesviral transcriptomes is significantly greater than previously appreciated with hundreds of viral long noncoding RNAs (vlncRNAs) being recently discovered. Work on cellular lncRNAs over the past several years has just begun to give us an initial appreciation for the array of functions they play in complex formation and regulatory processes in the cell. The newly identified herpesvirus lncRNAs are similarly likely to play a variety of different functions, although these functions are likely tailored to specific needs of the viral infection cycles. Here we describe novel transcripts derived from the EBV latency origin of replication. We show that they are hyperedited, that they interact with a relatively newly appreciated antiviral pathway, and that they play a role in facilitating viral lytic gene expression. These investigations are a starting point to unraveling the complex arena of vlncRNA function in herpesvirus lytic replication.
Design and Structure of an Engineered Disulfide-Stabilized Influenza Virus Hemagglutinin Trimer
Authors: Lee Peter S. , Zhu Xueyong , Yu Wenli , Wilson Ian A. 
Published: April 2015

ABSTRACT

We engineered a disulfide-stabilized influenza virus hemagglutinin (HA) trimer, termed HA
3
-SS, by introducing cysteine residues into the HA stem to covalently bridge the three protomers. HA
3
-SS has increased thermostability compared to wild-type HA, and binding of head- and stem-targeted antibodies (Abs) is preserved; only minor structural changes are found in the vicinity of the additional disulfide. This platform has been applied to H1 and H3 HAs and provides prospects for design of intact, stabilized influenza virus HA immunogens.
The Nectin-4/Afadin Protein Complex and Intercellular Membrane Pores Contribute to Rapid Spread of Measles Virus in Primary Human Airway Epithelia
Authors: Singh Brajesh K. , Hornick Andrew L. , Krishnamurthy Sateesh , Locke Anna C. , Mendoza Crystal A. , Mateo Mathieu , Miller-Hunt Catherine L. , Cattaneo Roberto , Sinn Patrick L. 
Published: April 2015

ABSTRACT
The discovery that measles virus (MV) uses the adherens junction protein nectin-4 as its epithelial receptor provides a new vantage point from which to characterize its rapid spread in the airway epithelium. We show here that in well-differentiated primary cultures of airway epithelial cells from human donors (HAE), MV infectious centers form rapidly and become larger than those of other respiratory pathogens: human respiratory syncytial virus, parainfluenza virus 5, and Sendai virus. While visible syncytia do not form after MV infection of HAE, the cytoplasm of an infected cell suddenly flows into an adjacent cell, as visualized through wild-type MV-expressed cytoplasmic green fluorescent protein (GFP). High-resolution video microscopy documents that GFP flows through openings that form on the lateral surfaces between columnar epithelial cells. To assess the relevance of the protein afadin, which connects nectin-4 to the actin cytoskeleton, we knocked down its mRNA. This resulted in more-limited infectious-center formation. We also generated a nectin-4 mutant without the afadin-binding site in its cytoplasmic tail. This mutant was less effective than wild-type human nectin-4 at promoting MV infection in primary cultures of porcine airway epithelia. Thus, in airway epithelial cells, MV spread requires the nectin-4/afadin complex and is based on cytoplasm transfer between columnar cells. Since the viral membrane fusion apparatus may open the passages that allow cytoplasm transfer, we refer to them as intercellular membrane pores. Virus-induced intercellular pores may contribute to extremely efficient measles contagion by promoting the rapid spread of the virus through the upper respiratory epithelium.

IMPORTANCE
Measles virus (MV), while targeted for eradication, still causes about 120,000 deaths per year worldwide. The recent reemergence of measles in insufficiently vaccinated populations in Europe and North America reminds us that measles is extremely contagious, but the processes favoring its spread in the respiratory epithelium remain poorly defined. Here we characterize wild-type MV spread in well-differentiated primary cultures of human airway epithelial cells. We observed that viral infection promotes the flow of cytoplasmic contents from infected to proximal uninfected columnar epithelial cells. Cytoplasm flows through openings that form on the lateral surfaces. Infectious-center growth is facilitated by afadin, a protein connecting the adherens junction and the actin cytoskeleton. The viral fusion apparatus may open intercellular pores, and the cytoskeleton may stabilize them. Rapid homogenization of cytoplasmic contents in epithelial infectious centers may favor rapid spread and contribute to the extremely contagious nature of measles.
Risk behaviours and prevalence of sexually transmitted infections and HIV in a group of Dominican gay men, other men who have sex with men and transgender women
Authors: Brito Maximo O , Hodge David , Donastorg Yeycy , Khosla Shaveta , Lerebours Leonel , Pope Zachary 
Published: April 2015

ObjectivesThe objectives of this study were to estimate the point prevalence of sexually transmitted infection (STI) and to investigate the sexual practices and behaviours associated with STIs in a group of gay men, other men who have sex with men and transgender women (GMT) in the province of La Romana, Dominican Republic.DesignA cross-sectional study of a convenience sample of GMT persons.SettingThe study was conducted in the province of La Romana, Dominican Republic, in June–July 2013.ParticipantsOut of 117 GMT persons screened, a total of 100 completed the study. Participants had to be at least 18 years of age, reside in La Romana and have had sex with another man in the preceding 12 months. All participants were interviewed and tested for STI.Primary outcome measureThe main outcome of interest was the detection of any STI (HIV, herpes simplex virus type 2 (HSV-2), syphilis, hepatitis B or C) by serology.ResultsAmong 100 participants, the median age was 22 years (range 18–65). One-third had consumed illicit drugs the preceding year and only 43% consistently used condoms. Prevalence was 38% for HSV-2, 5% for HIV and 13% for syphilis. There were no cases of hepatitis B or C. Factors associated with the odds of a STI were age >22 years (OR=11.1, 95% CI 3.6 to 34.5), receptive anal intercourse (OR=4.2, 95% CI 1.3 to 13.6) and having ≥2 male sexual partners during the preceding month (OR=4, 95% CI 1.3 to 12.5).ConclusionsIn this group of GMT persons, seroprevalence of STI was high, and a number of risk behaviours were associated with STI. These preliminary data will help inform policy and programmes to prevent HIV/STI in GMT persons in the region.
PTEN expression in endothelial cells is down-regulated by uPAR to promote angiogenesis
Authors: Unseld Matthias , Chilla Anastasia , Pausz Clemens , Mawas Rula , Breuss Johannes , Zielinski Christoph , Schabbauer Gernot , Prager Gerald 
Published: April 2015

SummaryThe tumour suppressor phosphatase and tensin homologue (PTEN), mutated or lost in many human cancers, is a major regulator of angiogenesis. However, the cellular mechanism of PTEN regulation in endothelial cells so far remains elusive. Here, we characterise the urokinase receptor (uPAR, CD87) and its tumour-derived soluble form, suPAR, as a key molecule of regulating PTEN in endothelial cells. We observed uPAR-deficient endothelial cells to express enhanced PTEN mRNA- and protein levels. Consistently, uPAR expression in endogenous negative uPAR cells, down-regulated PTEN and activated the PI3K/Akt pathway. Additionally, we found that integrin adhesion receptors act as trans-membrane signaling partners for uPAR to repress PTEN transcription in a NF-κB-dependent manner. Functional in vitro assays with endothelial cells, derived from uPAR-deficient and PTEN heterozygous crossbred mice, demonstrated the impact of uPAR- dependent PTEN regulation on cell motility and survival. In an in vivo murine angiogenesis model uPAR-deficient PTEN heterozygous animals increased the impaired angiogenic phenotype of uPAR knockout mice and were able to reverse the high invasive potential of PTEN heterozygots. Our data provide first evidence that endogenous as well as exogenous soluble uPAR down-regulated PTEN in endothelial cells to support angiogenesis. The uPAR-induced PTEN regulation might represent a novel target for drug interference, and may lead to the development of new therapeutic strategies in anti-angiogenic treatment.
Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease
Authors: Vranckx Pascal , Leebeek Frank , Tijssen Jan , Koolen Jacques , Stammen Francis , Herman Jean-Paul , de Winter Robbert , van t Hof Arnout , Backx Bianca , Lindeboom Wietze , Kim So-Young , Kirsch Bodo , van Eickels Martin , Misselwitz Frank , Verheugt Freek 
Published: April 2015

SummaryPatients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6–8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin–antithrombin complex values at 2 h post-PCI were 3.90 [6.8] μg/l and 3.90 [10.1] μg/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin–antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting.Clinical trial registration: Clinical Trials.gov Identifier: NCT01442792 URL: EudraCT. Unique identifier: No: 2011–001094–58.
Health Literacy and Mortality: A Cohort Study of Patients Hospitalized for Acute Heart Failure
Authors: McNaughton Candace D. , Cawthon Courtney , Kripalani Sunil , Liu Dandan , Storrow Alan B. , Roumie Christianne L. 
Published: April 2015

Background
More than 30% of patients hospitalized for heart failure are rehospitalized or die within 90 days of discharge. Lower health literacy is associated with mortality among outpatients with chronic heart failure; little is known about this relationship after hospitalization for acute heart failure.

Methods and Results

Patients hospitalized for acute heart failure and discharged home between November 2010 and June 2013 were followed through December 31, 2013. Nurses administered the Brief Health Literacy Screen at admission; low health literacy was defined as Brief Health Literacy Screen
≤
9. The primary outcome was all‐cause mortality. Secondary outcomes were time to first rehospitalization and, separately, time to first emergency department visit within 90 days of discharge. Cox proportional hazards models determined their relationships with health literacy, adjusting for age, gender, race, insurance, education, comorbidity, and hospital length of stay. For the 1379 patients, average age was 63.1 years, 566 (41.0%) were female, and 324 (23.5%) had low health literacy. Median follow‐up was 20.7 months (interquartile range 12.8 to 29.6 months), and 403 (29.2%) patients died. Adjusted hazard ratio for death among patients with low health literacy was 1.32 (95%
CI
1.05, 1.66,
P
=0.02) compared to Brief Health Literacy Screen >9. Within 90 days of discharge, there were 415 (30.1%) rehospitalizations and 201 (14.6%) emergency department visits, with no evident association with health literacy.

Conclusions
Lower health literacy was associated with increased risk of death after hospitalization for acute heart failure. There was no evident relationship between health literacy and 90‐day rehospitalization or emergency department visits.
Improved Spread–Error Relationship and Probabilistic Prediction from the CFS-Based Grand Ensemble Prediction System
Authors: Abhilash S. , Sahai A. K. , Borah N. , Joseph S. , Chattopadhyay R. , Sharmila S. , Rajeevan M. , Mapes B. E. , Kumar A. 
Published: April 2015

AbstractThis study describes an attempt to overcome the underdispersive nature of single-model ensembles (SMEs). As an Indo–U.S. collaboration designed to improve the prediction capabilities of models over the Indian monsoon region, the Climate Forecast System (CFS) model framework, developed at the National Centers for Environmental Prediction (NCEP-CFSv2), is selected. This article describes a multimodel ensemble prediction system, using a suite of different variants of the CFSv2 model to increase the spread without relying on very different codes or potentially inferior models. The SMEs are generated not only by perturbing the initial condition, but also by using different resolutions, parameters, and coupling configurations of the same model (CFS and its atmosphere component, the Global Forecast System). Each of these configurations was created to address the role of different physical mechanisms known to influence error growth on the 10–20-day time scale. Last, the multimodel consensus forecast is developed, which includes ensemble-based uncertainty estimates. Statistical skill of this CFS-based Grand Ensemble Prediction System (CGEPS) is better than the best participating SME configuration, because increased ensemble spread reduces overconfidence errors.
Thermodynamic Constraints on the Morphology of Simulated Midlatitude Squall Lines
Authors: Alfaro Diego A. , Khairoutdinov Marat 
Published: April 2015

Abstract
This study examines how environmental thermodynamics constrain the morphology of simulated idealized midlatitude squall lines (SLs). The thermodynamic soundings used for simulating various SLs are specified primarily by prescribed vertical profiles of the convective available potential energy (CAPE) and the level of free convection. This framework, which contemplates the latent instability properties of both low- and midtropospheric air, is considered to be convenient for investigating layer-lifting convective phenomena.
Results show that frequently used CAPE indices are unsuitable for diagnosing SL characteristics, while integrated CAPE (ICAPE) discriminates the amplitude of the storm-induced heating for a given value of environmental shear. The skill of ICAPE follows from its relation to the buoyancy attained by low- and midtropospheric parcels as they ascend over the cold pool under layer-lifting convection. Environmental kinematics also affect the storm-induced heating, with stronger low-level shear leading to a greater proportion of inflowing latent unstable air among total storm-relative inflow, thus producing higher temperatures aloft. The precipitable water accounts for much of the precipitation-rate variation for a given value of shear. The precipitation efficiency is lower in environments with weaker shear and dryer midtropospheric conditions.
Cold pool temperatures are slightly affected by environmental variations beneath the layer of minimum moist static energy, with drier midtropospheric conditions and weaker shear leading to warmer cold pools. SLs with a small vertical gradient of cold pool buoyancy propagate less rapidly and produce small surface wind speeds. Cold pool properties could be affected by a descending branch of the front-to-rear flow, which crosses over with the rear inflow jet.
The Effect of Pressure Glove Tightness on Forearm Muscle Activity and Psychophysical Responses
Authors: Yu Annie , Yick Kit Lun , Ng Sun Pui , Yip Joanne 
Published: April 2015

Objective: The impact of pressure glove tightness on maximum grip force, muscle activity, and psychophysical responses is investigated to facilitate the prescription of a suitable reduction factor (RF) for pressure treatment. Background: The wearing of pressure therapy gloves is often considered to hinder hand performance and cause discomfort, resulting in unsatisfactory treatment adherence during burn rehabilitation. Method: A wear trial was carried out with 10 participants for three custom-made pressure gloves that consist of different RFs—10%, 15% and 20%—as well as for the bare hand. The surface electromyography of three forearm muscles was measured during tasks that involve moving marbles, buttoning a shirt, and typing. The psychophysical responses were also recorded. Results: The use of pressure gloves results in a reduction in the maximum gripping force. Gloves with tighter pressure contribute to lower perceived comfort and ease of hand motion. Increased glove tightness (with RFs of 15% and 20%) decreases muscle activity as compared to the bare-hand condition when buttoning a shirt. In terms of typing, the forearm muscle activity increases with high glove pressure (RF of 20%). Conclusion: The forearm muscles are significantly affected by glove tightness in performing different daily tasks that required gripping, pinching, and typing. The increase of RF of pressure gloves causes negative impact on psychophysical response and handgrip strength. Glove tightness in relation to hand performance and comfort is important in prescribing an optimal pressure therapy glove for hypertrophic scar treatment. Application: The findings give insight into the impacts of pressure glove tightness on muscle activity, thus providing a reference for glove development.