bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ifit1 Inhibits Japanese Encephalitis Virus Replication through Binding to 5′ Capped 2′-O Unmethylated RNA
Authors: Kimura Taishi , Katoh Hiroshi , Kayama Hisako , Saiga Hiroyuki , Okuyama Megumi , Okamoto Toru , Umemoto Eiji , Matsuura Yoshiharu , Yamamoto Masahiro , Takeda Kiyoshi 
Published: July 2013

ABSTRACT
The interferon-inducible protein with tetratricopeptide (IFIT) family proteins inhibit replication of some viruses by recognizing several types of RNAs, including 5′-triphosphate RNA and 5′ capped 2′-O unmethylated mRNA. However, it remains unclear how IFITs inhibit replication of some viruses through recognition of RNA. Here, we analyzed the mechanisms by which Ifit1 exerts antiviral responses. Replication of a Japanese encephalitis virus (JEV) 2′-O methyltransferase (MTase) mutant was markedly enhanced in mouse embryonic fibroblasts and macrophages lacking Ifit1. Ifit1 bound 5′-triphosphate RNA but more preferentially associated with 5′ capped 2′-O unmethylated mRNA. Ifit1 inhibited the translation of mRNA and thereby restricted the replication of JEV mutated in 2′-O MTase. Thus, Ifit1 inhibits replication of MTase-defective JEV by inhibiting mRNA translation through direct binding to mRNA 5′ structures.
Single Hemagglutinin Mutations That Alter both Antigenicity and Receptor Binding Avidity Influence Influenza Virus Antigenic Clustering
Authors: Li Yang , Bostick David L. , Sullivan Colleen B. , Myers Jaclyn L. , Griesemer Sara B. , StGeorge Kirsten , Plotkin Joshua B. , Hensley Scott E. 
Published: July 2013

ABSTRACT
The hemagglutination inhibition (HAI) assay is the primary measurement used for identifying antigenically novel influenza virus strains. HAI assays measure the amount of reference sera required to prevent virus binding to red blood cells. Receptor binding avidities of viral strains are not usually taken into account when interpreting these assays. Here, we created antigenic maps of human H3N2 viruses that computationally account for variation in viral receptor binding avidities. These new antigenic maps differ qualitatively from conventional antigenic maps based on HAI measurements alone. We experimentally focused on an antigenic cluster associated with a single N145K hemagglutinin (HA) substitution that occurred between 1992 and 1995. Reverse-genetics experiments demonstrated that the N145K HA mutation increases viral receptor binding avidity. Enzyme-linked immunosorbent assays (ELISA) revealed that the N145K HA mutation does not prevent antibody binding; rather, viruses possessing this mutation escape antisera in HAI assays simply by attaching to cells more efficiently. Unexpectedly, we found an asymmetric antigenic effect of the N145K HA mutation. Once H3N2 viruses acquired K145, an epitope involving amino acid 145 became antigenically dominant. Antisera raised against an H3N2 strain possessing K145 had reduced reactivity to H3N2 strains possessing N145. Thus, individual mutations in HA can influence antigenic groupings of strains by altering receptor binding avidity and by changing the dominance of antibody responses. Our results indicate that it will be important to account for variation in viral receptor binding avidity when performing antigenic analyses in order to identify genuine antigenic differences among influenza virus variants.
Herpes Simplex Virus 1-Encoded Tegument Protein VP16 Abrogates the Production of Beta Interferon (IFN) by Inhibiting NF-κB Activation and Blocking IFN Regulatory Factor 3 To Recruit Its Coactivator CBP
Authors: Xing Junji , Ni Liwen , Wang Shuai , Wang Kezhen , Lin Rongtuan , Zheng Chunfu 
Published: July 2013

ABSTRACT

Host cells activate innate immune signaling pathways to defend against invading pathogens. To survive within an infected host, viruses have evolved intricate strategies to counteract host immune responses. Herpesviruses, including herpes simplex virus type 1 (HSV-1), have large genomes and therefore have the capacity to encode numerous proteins that modulate host innate immune responses. Here we define the contribution of HSV-1 tegument protein VP16 in the inhibition of beta interferon (IFN-β) production. VP16 was demonstrated to significantly inhibit Sendai virus (SeV)-induced IFN-β production, and its transcriptional activation domain was not responsible for this inhibition activity. Additionally, VP16 blocked the activation of the NF-κB promoter induced by SeV or tumor necrosis factor alpha treatment and expression of NF-κB-dependent genes through interaction with p65. Coexpression analysis revealed that VP16 selectively blocked IFN regulatory factor 3 (IRF-3)-mediated but not IRF-7-mediated transactivation. VP16 was able to bind to IRF-3 but not IRF-7
in vivo
, based on coimmunoprecipitation analysis, but it did not affect IRF-3 dimerization, nuclear translocation, or DNA binding activity. Rather, VP16 interacted with the CREB binding protein (CBP) coactivator and efficiently inhibited the formation of the transcriptional complexes IRF-3–CBP in the context of HSV-1 infection. These results illustrate that VP16 is able to block the production of IFN-β by inhibiting NF-κB activation and interfering with IRF-3 to recruit its coactivator CBP, which may be important to the early events leading to HSV-1 infection.
Mortality by education level at late-adult ages in Turin: a survival analysis using frailty models with period and cohort approaches
Authors: Zarulli Virginia , Marinacci Chiara , Costa Giuseppe , Caselli Graziella 
Published: July 2013

ObjectivesNeglecting the presence of unobserved heterogeneity in survival analysis models has been showed to potentially lead to underestimating the effect of the covariates included in the analysis. This study aimed to investigate the role of unobserved heterogeneity of frailty on the estimation of mortality differentials from age 50 on by education level.DesignLongitudinal mortality follow-up of the census-based Turin population linked with the city registry office.SettingItalian North-Western city of Turin, observation window 1971–2007.Population391 170 men and 456 216 women followed from age 50.Primary outcome measuresMortality rate ratios obtained from survival analysis regression. Models were estimated with and without the component of unobserved heterogeneity of frailty and controlling for mortality improvement over time from both cohort and period perspectives.ResultsIn the majority of cases, the models without frailty estimated a smaller educational gradient than the models with frailty.ConclusionsThe results draw the attention of the potential underestimation of the mortality inequalities by socioeconomic levels in survival analysis models when not controlling for unobserved heterogeneity of frailty.
Frequent callers to and users of emergency medical systems: a systematic review
Authors: Scott Jason , Strickland Annette Patricia , Warner Karen , Dawson Pamela 
Published: July 2013

BackgroundThere appears to be a paucity of studies examining the characteristics and impact of frequent users upon emergency medical services (EMS).ObjectiveTo review current primary research on frequent users of EMS and to identify possible gaps in the literature.MethodsOvid, PubMed and CINAHL/Medline were systematically searched for articles that were published in English and either referred to frequent callers to or users of an EMS, or referred to frequent users of other services where admissions were via ambulance. Studies were included regardless of quality.FindingsEighteen studies were included. Ten were emergency department based, seven in EMS and one in a psychiatric emergency service. In emergency department studies, frequent users were more likely to arrive via ambulance than infrequent users. In EMS studies, between 0.2% and 23% of patients using EMS were frequent users accounting for 1.4% to 40% of all ambulance use. No two EMS studies used the same definition of a frequent user. No studies focused on characteristics of callers to EMS. Two studies explored interventions for frequent callers to EMS, with mixed results in reducing ambulance use.DiscussionIt is unknown to what extent frequent callers impact upon EMS resources. Research should identify predictors and characteristics of frequent users of EMS, and a consistent definition of a frequent caller to or user of EMS would provide greater comparability. The lack of studies identified in this review suggests that further research is needed in order to inform policy and practice.
THERM: the Resuscitation Management score. A prognostic tool to identify critically ill patients in the emergency department
Authors: Cattermole G N , Liow E C H , Graham C A , Rainer T H 
Published: July 2013

IntroductionPrognostic scores are widely used in the emergency department (ED) to stratify risk for critically ill patients. The Prince of Wales ED Score (PEDS) was derived specifically for patients in an ED resuscitation room to predict death or intensive care unit (ICU) admission. We aimed to validate and refine this score, in comparison with other scores including the National Early Warning Score (NEWS).MethodsThis was a single-centre prospective study of adult resuscitation-room patients over 3 months.Comparison of scores was made using receiver operating characteristic analysis. Physiological and blood test variables were compared according to the composite primary outcome: admission to ICU or death within 7 days of attendance. Multivariate logistic regression was used to derive a new prediction score, which was validated in comparison with NEWS using the historic dataset from which PEDS had been derived.Results234 patients were included; 37 were admitted to ICU or died within 7 days. PEDS performed adequately but was not superior to other scores. A simple pragmatic score, The Resuscitation Management score (THERM) was derived which outperformed NEWS in derivation and validation sets.ConclusionsPEDS is at least as good as other scores, including NEWS. However, it is unwieldy and relies on results not immediately accessible in the ED. THERM is a new score, derived and validated in an ED setting, using variables readily available, and simple to calculate and stratify. THERM outperforms NEWS and could be used in preference in critically ill ED patients.
Constraints on Antarctic Ice Sheet configuration during and following the Last Glacial Maximum and its episodic contribution to sea-level rise
Authors: Anderson John B. , Kirshner Alexandra E. , Simms Alexander R. 
Published: July 2013

Abstract

Marine geological studies provide a record of diachronous expansion and retreat of the Antarctic Peninsula Ice Sheet, West Antarctic Ice Sheet and East Antarctic Ice Sheet during the past
c.
30 000 cal yr BP. Retreat of these ice sheets and Antarctica’s contribution to sea-level rise was largely complete by the early Holocene. Estimates of ice sheet thickness, based on maximum grounding depths, range from 640 to 1640 m on the inner continental shelf. Grounding depths on the outer continental shelf equate to minimum thicknesses of 410–950 m. Geomorphic features indicate that retreat from the continental shelf was mostly step-wise around the continent, a result of the different factors that control ice sheet behaviour and the degree to which these factors vary regionally. Thus, the nature of post-LGM (Last Glacial Maximum) sea-level rise was episodic and believed to have been punctuated by rapid pulses triggered by individual ice stream collapse. Most of these pulses would have been of sub-metre magnitudes and below the resolution of existing sea-level curves, but they would have had significant impact on coastal evolution, especially along low-gradient coasts.
Chemopreventive Activity of Plant Flavonoid Isorhamnetin in Colorectal Cancer Is Mediated by Oncogenic Src and β-Catenin
Authors: Saud Shakir M. , Young Matthew R. , Jones-Hall Yava L. , Ileva Lilia , Evbuomwan Moses O. , Wise Jennifer , Colburn Nancy H. , Kim Young S. , Bobe Gerd 
Published: July 2013

Abstract
Analysis of the Polyp Prevention Trial showed an association between an isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism behind the chemoprotective effects of isorhamnetin remains unclear. Here, we show that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. MRI, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than the control diet. Isorhamnetin inhibited AOM/DSS–induced oncogenic c-Src activation and β-catenin nuclear translocation, while promoting the expression of C-terminal Src kinase (CSK), a negative regulator of Src family of tyrosine kinases. Similarly, in HT-29 colon cancer cells, isorhamnetin inhibited oncogenic Src activity and β-catenin nuclear translocation by inducing expression of csk, as verified by RNA interference knockdown of csk. Our observations suggest the chemoprotective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that are dependent on CSK expression. Cancer Res; 73(17); 5473–84. ©2013 AACR.
Defining Risks of Taxane Neuropathy: Insights from Randomized Clinical Trials
Authors: Kudlowitz David , Muggia Franco 
Published: July 2013

Abstract
Sensory neuropathy is a common but difficult to quantify complication encountered during treatment of various cancers with taxane-containing regimens. Docetaxel, paclitaxel, and its nanoparticle albumin-bound formulation have been extensively studied in randomized clinical trials comparing various dose and schedules for the treatment of breast, lung, and ovarian cancers. This review highlights differences in extent of severe neuropathies encountered in such randomized trials and seeks to draw conclusions in terms of known pharmacologic factors that may lead to neuropathy. This basic knowledge provides an essential background for exploring pharmacogenomic differences among patients in relation to their susceptibility of developing severe manifestations. In addition, the differences highlighted may lead to greater insight into drug and basic host factors (such as age, sex, and ethnicity) contributing to axonal injury from taxanes. Clin Cancer Res; 19(17); 4570–7. ©2013 AACR.
MET and ERBB2 Are Coexpressed in ERBB2+ Breast Cancer and Contribute to Innate Resistance
Authors: Paulson Amanda K. , Linklater Erik S. , Berghuis Bree D. , App Colleen A. , Oostendorp Leon D. , Paulson Jayne E. , Pettinga Jane E. , Melnik Marianne K. , Vande Woude George F. , Graveel Carrie R. 
Published: July 2013

Abstract
Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2+ tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET−/ERBB2+, MET+/ERBB2−, and MET+/ERBB2+. In a MET+/ERBB2+ breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2+ breast cancers express MET and contain MET+/ERBB2+ subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance.
Implications: ERBB2+ breast cancers with MET+/ERBB2+ subpopulations may have an innate resistance to ERBB2 inhibition and may benefit from combined MET and ERBB2 inhibition. Mol Cancer Res; 11(9); 1112–21. ©2013 AACR.
Comprehensive Cardiac Magnetic Resonance Imaging and Spectroscopy Reveal a High Burden of Myocardial Disease in HIV Patients
Authors: Holloway Cameron J. , Ntusi Ntobeko , Suttie Joseph , Mahmod Masliza , Wainwright Emma , Clutton Genevieve , Hancock Gemma , Beak Philip , Tajar Abdelouahid , Piechnik Stefan K. , Schneider Jurgen E. , Angus Brian , Clarke Kieran , Dorrell Lucy , Neubauer Stefan 
Published: July 2013

Background—
HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy.

Methods and Results—

Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (
P
<0.003) and 74% higher median plasma triglyceride levels (both
P
<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (
P
<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders.

Conclusions—
Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV.
Factor Xa Activation of Factor V Is of Paramount Importance in Initiating the Coagulation System
Authors: Schuijt Tim J. , Bakhtiari Kamran , Daffre Sirlei , DePonte Kathleen , Wielders Simone J.H. , Marquart J. Arnoud , Hovius Joppe W. , van der Poll Tom , Fikrig Erol , Bunce Matthew W. , Camire Rodney M. , Nicolaes Gerry A.F. , Meijers Joost C.M. , van ‘t Veer Cornelis 
Published: July 2013

Background—
Generation of active procoagulant cofactor factor Va (FVa) and its subsequent association with the enzyme activated factor X (FXa) to form the prothrombinase complex is a pivotal initial event in blood coagulation and has been the subject of investigative effort, speculation, and controversy. The current paradigm assumes that FV activation is initiated by limited proteolysis by traces of (meizo) thrombin.

Methods and Results—
Recombinant tick salivary protein TIX-5 was produced and anticoagulant properties were studied with the use of plasma, whole blood, and purified systems. Here, we report that TIX-5 specifically inhibits FXa-mediated FV activation involving the B domain of FV and show that FXa activation of FV is pivotal for plasma and blood clotting. Accordingly, tick feeding is impaired on TIX-5 immune rabbits, displaying the in vivo importance of TIX-5.

Conclusions—
Our data elucidate a unique molecular mechanism by which ticks inhibit the host’s coagulation system. From our data, we propose a revised blood coagulation scheme in which direct FXa-mediated FV activation occurs in the initiation phase during which thrombin-mediated FV activation is restrained by fibrinogen and inhibitors.
Prognostic Equation for Radar Radial Velocity Derived by Considering Atmospheric Refraction and Earth Curvature
Authors: Xu Qin , Wei Li 
Published: July 2013

Abstract
The prognostic equation for the radial velocity field observed with a Doppler radar is derived to include the effects of atmospheric refraction and earth curvature on radar-beam height and slope angle. The derived equation, called the radial velocity equation, contains a high-order small term that can be truncated. The truncated radial velocity equation is shown to be much more accurate than its counterpart radial velocity equation derived without considering the effects of atmospheric refraction and earth curvature. The truncated equation has the same concise form as its counterpart radial velocity equation but remains to be sufficiently accurate as a useful dynamic constraint for radar wind analysis and assimilation (in normal situations) even up to the farthest 300-km radial range of operational Weather Surveillance Radar-1988 Doppler (WSR-88D) scans where its counterpart radial velocity equation becomes erroneous.
Different Pacific Ocean Warming Decaying Types and Northwest Pacific Tropical Cyclone Activity
Authors: Ha Yao , Zhong Zhong , Yang Xiuqun , Sun Yuan 
Published: July 2013

AbstractThis study focuses on statistical analysis of anomalous tropical cyclone (TC) activities and the physical mechanisms behind these anomalies. Different patterns of decaying of the warm sea surface temperature anomaly (SSTA) over the equatorial central-eastern Pacific are categorized into three types: eastern Pacific warming decaying to La Niña (EPWDL), eastern Pacific warming decaying to a neutral phase (EPWDN), and a central Pacific warming decaying year (CPWD). Differences in TC activity over the western North Pacific (WNP) corresponding to the above three types are discussed, and possible mechanisms are proposed. For EPWDL, TC genesis shows a significant positive (negative) anomaly over the northwestern (southeastern) WNP and more TCs move westward and make landfall over the southern East Asian coast. This is attributed primarily to the combined modulation of La Niña and the warm equatorial east Indian Ocean SSTA. For EPWDN, enhanced TC genesis is observed over the northeastern WNP, and suppressed TC activity is located mainly in the zonal region extending from the Philippine Sea to the eastern WNP, close to 160°E. Most of the TCs formed over the eastern WNP experience early recurvature east of 140°E, then move northeastward; hence, fewer TCs move northwestward to make landfall over the East Asian coast. For CPWD, the enhanced TC activity appears over the western WNP. This is due to the weak anomalous cyclonic circulation over the Philippines, primarily caused by the weaker, more westward-shifting warm SSTA compared to that in the previous warming year over the central Pacific.