bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a Critical and Conformational Neutralizing Epitope in Human Adenovirus Type 4 Hexon
Authors: Tian Xingui , Qiu Hongling , Zhou Zhichao , Wang Shouli , Fan Ye , Li Xiao , Chu Ruiai , Li Haitao , Zhou Rong , Wang Hui 
Published: November 2017

ABSTRACT
Human adenovirus type 4 (HAdV-4) is an epidemic virus that contributes to serious acute respiratory disease (ARD) in both pediatric and adult patients. However, no licensed drug or vaccine is currently available to the civilian population. The identification of neutralizing epitopes of HAdV-4 should allow the development of a novel antiviral vaccine and a novel gene transfer vector, and an effective neutralizing monoclonal antibody (MAb) will be useful in developing appropriate antiviral drugs. In this study, we report that MAb MN4b shows strong neutralizing activity against HAdV-4. MN4b recognizes a conformational epitope (418AGSEK422) within hypervariable region 7 (HVR7). Mutations within this site permitted HAdV-4 mutants to escape neutralization by MN4b and to resist neutralization by animal and human anti-HAdV-4 sera. A recombinant virus, rAd3-A4R7-1, containing the identified neutralizing epitope in the HVR7 region of HAdV-3 hexon, successfully induced antiserum that inhibited HAdV-4 infection. These results indicate that a small surface loop of HAdV-4 hexon is a critical neutralization epitope for this virus. The generation of MN4b and the identification of this neutralizing epitope may be useful in developing therapeutic treatment, a subunit vaccine, and a novel vector that can escape preexisting neutralization for HAdV-4.

IMPORTANCE
Neutralizing antibodies are considered good tools for the prevention of human adenovirus type 4 (HAdV-4) infections. The identification of the epitopes recognized by such neutralizing antibodies is important for the generation of recombinant antiviral vaccines. However, until now, no neutralizing epitope has been reported for HAdV-4. Here, we developed a serotype-specific neutralizing MAb directed against HAdV-4, MN4b. We provide evidence that MN4b recognizes a conformational epitope within HVR7 of HAdV-4 hexon. Antisera generated to this conformational epitope displayed on HAdV-3 hexon inhibited infection of AD293 cells by HAdV-4. Our findings are very important for the development of therapeutic treatment, a subunit vaccine, and a novel vector for HAdV-4.
Isolation and Characterization of vΔI3 Confirm that Vaccinia Virus SSB Plays an Essential Role in Viral Replication
Authors: Greseth Matthew D. , Czarnecki Maciej W. , Bluma Matthew S. , Traktman Paula 
Published: November 2017

ABSTRACTVaccinia virus is unusual among DNA viruses in replicating exclusively in the cytoplasm of infected cells. The single-stranded DNA (ssDNA) binding protein (SSB) I3 is among the replication machinery encoded by the 195-kb genome, although direct genetic analysis of I3 has been lacking. Herein, we describe a complementing cell line (CV1-I3) that fully supports the replication of a null virus (vΔI3) lacking the I3 open reading frame (ORF). In noncomplementing CV1-CAT cells, vΔI3 shows a severe defect in the production of infectious virus (≥200-fold reduction). Early protein synthesis and core disassembly occur normally. However, DNA replication is profoundly impaired (≤0.2% of wild-type [WT] levels), and late proteins do not accumulate. When several other noncomplementing cell lines are infected with vΔI3, the yield of infectious virus is also dramatically reduced (168- to 1,776-fold reduction). Surprisingly, the residual levels of DNA accumulation vary from 1 to 12% in the different cell lines (CV1-CAT < A549 < BSC40 < HeLa); however, any nascent DNA that can be detected is subgenomic in size. Although this subgenomic DNA supports late protein expression, it does not support the production of infectious virions. Electron microscopy (EM) analysis of vΔI3-infected BSC40 cells reveals that immature virions are abundant but no mature virions are observed. Aberrant virions characteristic of a block to genome encapsidation are seen instead. Finally, we demonstrate that a CV1 cell line encoding a previously described I3 variant with impaired ssDNA binding activity is unable to complement vΔI3. This report provides definitive evidence that the vaccinia virus I3 protein is the replicative SSB and is essential for productive viral replication.IMPORTANCEPoxviruses are of historical and contemporary importance as infectious agents, vaccines, and oncolytic therapeutics. The cytoplasmic replication of poxviruses is unique among DNA viruses of mammalian cells and necessitates that the double-stranded DNA (dsDNA) genome encode the viral replication machinery. This study focuses on the I3 protein. As a ssDNA binding protein (SSB), I3 has been presumed to play essential roles in genome replication, recombination, and repair, although genetic analysis has been lacking. Herein, we report the characterization of an I3 deletion virus. In the absence of I3 expression, DNA replication is severely compromised and viral yield profoundly decreased. The production of infectious virus can be restored in a cell line expressing WT I3 but not in a cell line expressing an I3 mutant that is defective in ssDNA binding activity. These data show conclusively that I3 is an essential viral protein and functions as the viral replicative SSB.
MicroRNA-Based Attenuation of Influenza Virus across Susceptible Hosts
Authors: Waring Barbara M. , Sjaastad Louisa E. , Fiege Jessica K. , Fay Elizabeth J. , Reyes Ismarc , Moriarity Branden , Langlois Ryan A. 
Published: November 2017

ABSTRACTInfluenza A virus drives significant morbidity and mortality in humans and livestock. Annual circulation of the virus in livestock and waterfowl contributes to severe economic disruption and increases the risk of zoonotic transmission of novel strains into the human population, where there is no preexisting immunity. Seasonal vaccinations in humans help prevent infection and can reduce symptoms when infection does occur. However, current vaccination regimens available for livestock are limited in part due to safety concerns regarding reassortment/recombination with circulating strains. Therefore, inactivated vaccines are used instead of the more immunostimulatory live attenuated vaccines. MicroRNAs (miRNAs) have been used previously to generate attenuated influenza A viruses for use as a vaccine. Here, we systematically targeted individual influenza gene mRNAs using the same miRNA to determine the segment(s) that yields maximal attenuation potential. This analysis demonstrated that targeting of NP mRNA most efficiently ablates replication. We further increased the plasticity of miRNA-mediated attenuation of influenza A virus by exploiting a miRNA, miR-21, that is ubiquitously expressed across influenza-susceptible hosts. In order to construct this targeted virus, we used CRISPR/Cas9 to eliminate the universally expressed miR-21 from MDCK cells. miR-21-targeted viruses were attenuated in human, mouse, canine, and avian cells and drove protective immunity in mice. This strategy has the potential to enhance the safety of live attenuated vaccines in humans and zoonotic reservoirs.IMPORTANCEInfluenza A virus circulates annually in both avian and human populations, causing significant morbidity, mortality, and economic burden. High incidence of zoonotic infections greatly increases the potential for transmission to humans, where no preexisting immunity or vaccine exists. There is a critical need for new vaccine strategies to combat emerging influenza outbreaks. MicroRNAs were used previously to attenuate influenza A viruses. We propose the development of a novel platform to produce live attenuated vaccines that are highly customizable, efficacious across a broad species range, and exhibit enhanced safety over traditional vaccination methods. This strategy exploits a microRNA that is expressed abundantly in influenza virus-susceptible hosts. By eliminating this ubiquitous microRNA from a cell line, targeted viruses that are attenuated across susceptible strains can be generated. This approach greatly increases the plasticity of the microRNA targeting approach and enhances vaccine safety.
The Ubiquitin-Proteasome System Is Necessary for Efficient Replication of Human Astrovirus
Authors: Casorla-Pérez Luis A. , López Tomás , López Susana , Arias Carlos F. 
Published: November 2017

ABSTRACT

Astroviruses, members of the family
Astroviridae
, represent an important cause of human gastroenteritis in the world. The cellular factors required for astrovirus replication have been poorly studied. In this work, we evaluated the relevance of the ubiquitin-proteasome system (UPS) in the replication of Yuc8, a human astrovirus serotype 8 strain. We found that proteasome inhibitors decrease the production of infectious viral progeny at a step in the replication cycle subsequent to virus entry. The inhibition of proteasome activity decreases viral RNA levels and viral protein synthesis; similarly, the inhibition of ubiquitination by chemical inhibitors or RNA interference (RNAi) reduces the production of viral progeny as well as viral protein synthesis. The effect on viral progeny production induced by proteasome inhibitors is not explained by a reduction in the pool of monoubiquitin or the induction of early apoptosis or autophagy. Our observations are consistent with the need of the proteolytic activity of the UPS for the efficient replication of the virus and suggest that UPS is necessary for the production of genomic and subgenomic RNA but not for antigenomic RNA.

IMPORTANCE
Astroviruses are a major cause of gastroenteritis in young humans and animals, and recently, it was associated with fatal encephalitis in humans. The role of the ubiquitin-proteasome system in the replication of these viruses has not been studied previously. In this work, we present evidence that supports that the proteolytic activity of the proteasome is necessary for efficient viral progeny production and that this proteolytic system is required for the accumulation of both genomic and subgenomic viral RNAs.
Are objective measures of physical capability related to accelerated epigenetic age? Findings from a British birth cohort
Authors: Simpkin Andrew J , Cooper Rachel , Howe Laura D , Relton Caroline L , Davey Smith George , Teschendorff Andrew , Widschwendter Martin , Wong Andrew , Kuh Diana , Hardy Rebecca 
Published: November 2017

ObjectivesOur aim was to investigate the association of epigenetic age and physical capability in later life. Having a higher epigenetic than chronological age (known as age acceleration (AA)) has been found to be associated with an increased rate of mortality. Similarly, physical capability has been proposed as a marker of ageing due to its consistent associations with mortality.SettingThe MRC National Survey of Health and Development (NSHD) cohort study.ParticipantsWe used data from 790 women from the NSHD who had DNA methylation data available.DesignEpigenetic age was calculated using buccal cell (n=790) and matched blood tissue (n=152) from 790 female NSHD participants. We investigated the association of AA at age 53 with changes in physical capability in women from ages 53 to 60–64. Regression models of change in each measure of physical capability on AA were conducted. Secondary analysis focused on the relationship between AA and smoking, alcohol, body mass index (BMI) and socioeconomic position.Outcome measuresThree objective measures of physical capability were used: grip strength, standing balance time and chair rise speed.ResultsEpigenetic age was lower than chronological age (mean 53.4) for both blood (50.3) and buccal cells (42.8). AA from blood was associated with a greater decrease in grip strength from ages 53 to 60–64 (0.42 kg decrease per year of AA, 95% CI 0.03, 0.82 kg; p=0.03, n=152), but no associations were observed with standing balance time or chair rise speed. Current smoking and lower BMI were associated with lower epigenetic age from buccal cells.ConclusionsWe found evidence that AA in blood is associated with a greater decrease in grip strength in British females aged between 53 and 60–64, but no association with standing balance time or chair rise speed was found.
Influence of socioeconomic factors on pregnancy outcome in women with structural heart disease
Authors: van Hagen Iris M , Baart Sara , Fong Soe Khioe Rebekah , Sliwa-Hahnle Karen , Taha Nasser , Lelonek Malgorzata , Tavazzi Luigi , Maggioni Aldo Pietro , Johnson Mark R , Maniadakis Nikolaos , Fordham Richard , Hall Roger , Roos-Hesselink Jolien W 
Published: November 2017

ObjectiveCardiac disease is the leading cause of indirect maternal mortality. The aim of this study was to analyse to what extent socioeconomic factors influence the outcome of pregnancy in women with heart disease.MethodsThe Registry of Pregnancy and Cardiac disease is a global prospective registry. For this analysis, countries that enrolled ≥10 patients were included. A combined cardiac endpoint included maternal cardiac death, arrhythmia requiring treatment, heart failure, thromboembolic event, aortic dissection, endocarditis, acute coronary syndrome, hospitalisation for cardiac reason or intervention. Associations between patient characteristics, country characteristics (income inequality expressed as Gini coefficient, health expenditure, schooling, gross domestic product, birth rate and hospital beds) and cardiac endpoints were checked in a three-level model (patient–centre–country).ResultsA total of 30 countries enrolled 2924 patients from 89 centres. At least one endpoint occurred in 645 women (22.1%). Maternal age, New York Heart Association classification and modified WHO risk classification were associated with the combined endpoint and explained 37% of variance in outcome. Gini coefficient and country-specific birth rate explained an additional 4%. There were large differences between the individual countries, but the need for multilevel modelling to account for these differences disappeared after adjustment for patient characteristics, Gini and country-specific birth rate.ConclusionWhile there are definite interregional differences in pregnancy outcome in women with cardiac disease, these differences seem to be mainly driven by individual patient characteristics. Adjustment for country characteristics refined the results to a limited extent, but maternal condition seems to be the main determinant of outcome.
Use of oral anticoagulants in combination with antiplatelet(s) in atrial fibrillation
Authors: Sindet-Pedersen Caroline , Staerk Laila , Lamberts Morten , Gerds Thomas Alexander , Berger Jeffrey S , Nissen Bonde Anders , Langtved Pallisgaard Jannik , Hansen Morten Lock , Torp-Pedersen Christian , Gislason Gunnar H , Bjerring Olesen Jonas 
Published: November 2017

ObjectivesTo investigate temporal trends in the use of non-vitamin K oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) in combination with aspirin and/or clopidogrel in patients with atrial fibrillation (AF) following acute myocardial infarction (MI) and/or percutaneous coronary intervention (PCI).MethodsUsing Danish nationwide registries, all patients with AF who survived 30 days after discharge from MI and/or PCI between 22 August 2011 and 30 September 2016 were identified.ResultsA total of 2946 patients were included in the study population, of whom 1967 (66.8%) patients were treated with VKA in combination with antiplatelet(s) (VKA+aspirin n=477, VKA+clopidogrel n=439, VKA+aspirin+clopidogrel n=1051) and 979 (33.2%) patients were treated with NOAC in combination with antiplatelet(s) (NOAC+aspirin n=252, NOAC+clopidogrel n=218, NOAC+aspirin+clopidogrel n=509). The overall study population had a median age of 76 years [IQR: 69–82] and consisted of 1995 (67.7%) men. Patients with MI as inclusion event accounted for 1613 patients (54.8%). Patients with high CHA2DS2-VASc score(congestive heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, history of stroke/transient ischemic attack/systemic thromboembolism (2 points), vascular disease, age 65-75 years, and female sex) accounted for 132 2814 (95.5%) of patients, and patients with high HAS-BLED score (hypertension, abnormal renal/liver function, history of stroke, history of bleeding, age >65 years, non-steroidal anti-inflammatory drug usages, or alcohol abuse, leaving out labile international normalized ratio (not available), and use of antiplatelets (exposure variable)) accounted for 934 (31.7%) of patients. There was an increase from 10% in 2011 to 52% in 2016 in the use of NOACs in combination with antiplatelet(s).ConclusionFrom 2011 to 2016, the use of NOAC in combination with antiplatelet(s) increased in patients with AF following MI/PCI and exceeded the use of VKA in combination with antiplatelet(s) by 2016.
A propensity score-adjusted analysis of clinical outcomes after pulmonary valve replacement in tetralogy of Fallot
Authors: Bokma Jouke P , Geva Tal , Sleeper Lynn A , Babu Narayan Sonya V , Wald Rachel , Hickey Kelsey , Jansen Katrijn , Wassall Rebecca , Lu Minmin , Gatzoulis Michael A , Mulder Barbara JM , Valente Anne Marie 
Published: November 2017

ObjectiveTo determine the association of pulmonary valve replacement (PVR) with death and sustained ventricular tachycardia (VT) in patients with repaired tetralogy of Fallot (rTOF).MethodsSubjects with rTOF and cardiac magnetic resonance from an international registry were included. A PVR propensity score was created to adjust for baseline differences. PVR consensus criteria were predefined as pulmonary regurgitation >25% and ≥2 of the following criteria: right ventricular (RV) end-diastolic volume >160 mL/m2, RV end-systolic volume >80 mL/m2, RV ejection fraction (EF) <47%, left ventricular EF <55% and QRS duration >160 ms. The primary outcome included (aborted) death and sustained VT. The secondary outcome included heart failure, non-sustained VT and sustained supraventricular tachycardia.ResultsIn 977 rTOF subjects (age 26±15 years, 45% PVR, follow-up 5.3±3.1 years), the primary and secondary outcomes occurred in 41 and 88 subjects, respectively. The HR for subjects with versus without PVR (time-varying covariate) was 0.65 (95% CI 0.31 to 1.36; P=0.25) for the primary outcome and 1.43 (95% CI 0.83 to 2.46; P=0.19) for the secondary outcome after adjusting for propensity and other factors. In subjects (n=426) not meeting consensus criteria, the HR for subjects with (n=132) versus without (n=294) PVR was 2.53 (95% CI 0.79 to 8.06; P=0.12) for the primary outcome and 2.31 (95% CI 1.07 to 4.97; P=0.03) for the secondary outcome.ConclusionIn this large multicentre rTOF cohort, PVR was not associated with a reduced rate of death and sustained VT at an average follow-up of 5.3 years. Additionally, there were more events after PVR compared with no PVR in subjects not meeting consensus criteria.
The ageing heart: the systemic and coronary circulation
Authors: Nanayakkara Shane , Marwick Thomas H , Kaye David M 
Published: November 2017

Most cardiovascular disease (CVD) occurs in patients over the age of 60. However, most evidence-based current cardiovascular guidelines lack evidence in an older population, due to the under-representation of older patients in randomised trials. Blood pressure rises with age due to increasing arterial stiffness, and stricter control results in improved outcomes. Myocardial ischaemia is also more common with increasing age, due to a combination of coronary artery disease and myocardial changes. However, despite higher rates of adverse outcomes, older patients are offered guideline-based therapy less frequently. Frailty is an independent predictor of mortality in adults over the age of 60, yet remains poorly assessed; slow gait speed is a key marker for the development of frailty and for adverse outcomes following intervention. Few trials have assessed frailty independent of age; however, there is evidence that non-frail older patients derive significant benefit from therapy, highlighting the urgent need to include frailty as a measure in clinical trials of treatment in CVD.In this review, the authors appraise the literature in regard to the cardiovascular changes with ageing, specifically in relation to the systemic and coronary circulation and with a particular emphasis on frailty and its implication in the evaluation and treatment of CVD.
Flow diversion for anterior choroidal artery (AChA) aneurysms: a multi-institutional experience
Authors: Srinivasan Visish M , Ghali Michael George Zaki , Cherian Jacob , Mokin Maxim , Puri Ajit S , Grandhi Ramesh , Chen Stephen R , Johnson Jeremiah N , Kan Peter 
Published: November 2017

BackgroundAnterior choroidal artery (AChA) aneurysms represent a small subset of cerebral aneurysms. The Pipeline Embolization Device (PED) has been successfully applied to various aneurysms of the supraclinoid internal carotid artery (ICA). The treatment of these aneurysms requires special attention due to the eloquent territory supplied by the AChA. We report the largest and first dedicated series of flow diversion treatment of AChA aneurysms.MethodsFour institutional neurointerventional databases were reviewed for cases of intracranial aneurysms treated with PED. Patient and aneurysm data as well as angiographic imaging were reviewed for all cases of AChA aneurysms treated with PED. AChA aneurysms were defined as aneurysms distal to the AChA and proximal to the ICA terminus, with or without the incorporation of the AChA.ResultsEighteen AChA aneurysms were treated during the study period. All aneurysms were successfully treated with a mean follow-up of 19.1 months. The large majority of aneurysms (15/18, 83.3%) were completely obliterated. No patients suffered from intra- or post-procedural complications. A1 stenosis was a common occurrence, seen in 10 of 16 (62.5%) covered anterior cerebral arteries (ACAs), although all were asymptomatic. All AChAs remained patent at last follow-up.ConclusionsThe PED can be used successfully in AChA aneurysms with a good safety and efficacy profile. All AChAs remained patent. Collateral flow networks, especially for the ACA, affect long-term branch vessel patency. Treatment with PED for AChA aneurysms appears to be a reasonable option to consider and should be evaluated in a larger cohort.
Flexible and efficient memory object metadata
Authors: Liu Zhengyang , Criswell John 
Published: November 2017

Compiler-based tools can protect software from attack and find bugs within programs. To support programs written in type-unsafe languages such as C, such tools need to add code into a program that must, at run-time, take a pointer into a memory object and locate metadata for that memory object. Current methods of locating metadata are either flexible (supporting metadata of varying sizes) at the expense of speed and scalability or are fast (e.g., by using shadow tables) at the cost of flexibility (metadata is small and must always be the same size).
This paper presents a new method of attaching metadata to memory objects, named Padding Area MetaData (PAMD), that is both flexible and efficient. Metadata can be any size, and different memory objects can have different sized metadata. While flexible, the algorithm for finding the metadata given a pointer into the memory object takes constant time. Our method extends Baggy Bounds with Accurate Checking (BBAC) which attaches constant-sized metadata to memory objects for performing precise dynamic bounds checks. Our design supports variable-sized metadata, and our implementation supports larger programs.
We evaluated the performance and scalability of PAMD using dynamic bounds checking as an exemplar of our method. Our results show that our method adds at most 33% overhead to an identical dynamic bounds checking tool that trades precision for performance by using a simple shadow table. Our results also show that our method, while having the same flexibility as splay trees, performs significantly faster and scales better as a program allocates more memory.