bluuebunny/crossref_metadata_2025_split huggingface dataset:
Highly Pathogenic Avian Influenza H5N6 Viruses Exhibit Enhanced Affinity for Human Type Sialic Acid Receptor and In-Contact Transmission in Model Ferrets
Authors: Sun Honglei , Pu Juan , Wei Yandi , Sun Yipeng , Hu Jiao , Liu Litao , Xu Guanlong , Gao Weihua , Li Chong , Zhang Xuxiao , Huang Yinhua , Chang Kin-Chow , Liu Xiufan , Liu Jinhua 
Published: April 2016

ABSTRACT
Since May 2014, highly pathogenic avian influenza H5N6 virus has been reported to cause six severe human infections three of which were fatal. The biological properties of this subtype, in particular its relative pathogenicity and transmissibility in mammals, are not known. We characterized the virus receptor-binding affinity, pathogenicity, and transmissibility in mice and ferrets of four H5N6 isolates derived from waterfowl in China from 2013-2014. All four H5N6 viruses have acquired a binding affinity for human-like SAα2,6Gal-linked receptor to be able to attach to human tracheal epithelial and alveolar cells. The emergent H5N6 viruses, which share high sequence similarity with the human isolate A/Guangzhou/39715/2014 (H5N6), were fully infective and highly transmissible by direct contact in ferrets but showed less-severe pathogenicity than the parental H5N1 virus. The present results highlight the threat of emergent H5N6 viruses to poultry and human health and the need to closely track their continual adaptation in humans.

IMPORTANCE
Extended epizootics and panzootics of H5N1 viruses have led to the emergence of the novel 2.3.4.4 clade of H5 virus subtypes, including H5N2, H5N6, and H5N8 reassortants. Avian H5N6 viruses from this clade have caused three fatalities out of six severe human infections in China since the first case in 2014. However, the biological properties of this subtype, especially the pathogenicity and transmission in mammals, are not known. Here, we found that natural avian H5N6 viruses have acquired a high affinity for human-type virus receptor. Compared to the parental clade 2.3.4 H5N1 virus, emergent H5N6 isolates showed less severe pathogenicity in mice and ferrets but acquired efficient in-contact transmission in ferrets. These findings suggest that the threat of avian H5N6 viruses to humans should not be ignored.
Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis
Authors: Rife Brittany D. , Nolan David J. , Lamers Susanna L. , Autissier Patrick , Burdo Tricia , Williams Kenneth C. , Salemi Marco 
Published: April 2016

ABSTRACTThe emergence of a distinct subpopulation of human or simian immunodeficiency virus (HIV/SIV) sequences within the brain (compartmentalization) during infection is hypothesized to be linked to AIDS-related central nervous system (CNS) neuropathology. However, the exact evolutionary mechanism responsible for HIV/SIV brain compartmentalization has not been thoroughly investigated. Using extensive viral sampling from several different peripheral tissues and cell types and from three distinct regions within the brain from two well-characterized rhesus macaque models of the neurological complications of HIV infection (neuroAIDS), we have been able to perform in-depth evolutionary analyses that have been unattainable in HIV-infected subjects. The results indicate that, despite multiple introductions of virus into the brain over the course of infection, brain sequence compartmentalization in macaques with SIV-associated CNS neuropathology likely results from late viral entry of virus that has acquired through evolution in the periphery sufficient adaptation for the distinct microenvironment of the CNS.IMPORTANCEHIV-associated neurocognitive disorders remain prevalent among HIV type 1-infected individuals, whereas our understanding of the critical components of disease pathogenesis, such as virus evolution and adaptation, remains limited. Building upon earlier findings of specific viral subpopulations in the brain, we present novel yet fundamental results concerning the evolutionary patterns driving this phenomenon in two well-characterized animal models of neuroAIDS and provide insight into the timing of entry of virus into the brain and selective pressure associated with viral adaptation to this particular microenvironment. Such knowledge is invaluable for therapeutic strategies designed to slow or even prevent neurocognitive impairment associated with AIDS.
Colony-Stimulating Factor 1 Receptor Antagonists Sensitize Human Immunodeficiency Virus Type 1-Infected Macrophages to TRAIL-Mediated Killing
Authors: Cunyat Francesc , Rainho Jennifer N. , West Brian , Swainson Louise , McCune Joseph M. , Stevenson Mario 
Published: April 2016

ABSTRACT

Strategies aimed at eliminating persistent viral reservoirs from HIV-1-infected individuals have focused on CD4
+
T-cell reservoirs. However, very little attention has been given to approaches that could promote elimination of tissue macrophage reservoirs. HIV-1 infection of macrophages induces phosphorylation of colony-stimulating factor 1 receptor (CSF-1R), which confers resistance to apoptotic pathways driven by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), thereby promoting viral persistence. In this study, we assessed whether CSF-1R antagonists (PLX647, PLX3397, and PLX5622) restored apoptotic sensitivity of HIV-1-infected macrophages
in vitro
. PLX647, PLX3397, and PLX5622 at clinically relevant concentrations blocked the activation of CSF-1R and reduced the viability of infected macrophages, as well as the extent of viral replication. Our data show that strategies targeting monocyte colony-stimulating factor (MCSF) signaling could be used to promote elimination of HIV-1-infected myeloid cells and to contribute to the elimination of persistent viral reservoirs.

IMPORTANCE
As the HIV/AIDS research field explores approaches to eliminate HIV-1 in individuals on suppressive antiviral therapy, those approaches will need to eliminate both CD4
+
T-cell and myeloid cell reservoirs. Most of the attention has focused on CD4
+
T-cell reservoirs, and scant attention has been paid to myeloid cell reservoirs. The distinct nature of the infection in myeloid cells versus CD4
+
T cells will likely dictate different approaches in order to achieve their elimination. For CD4
+
T cells, most strategies focus on promoting virus reactivation to promote immune-mediated clearance and/or elimination by viral cytopathicity. Macrophages resist viral cytopathic effects and CD8
+
T-cell killing. Therefore, we have explored clearance strategies that render macrophages sensitive to viral cytopathicity. This research helps inform the design of strategies to promote clearance of the macrophage reservoir in infected individuals on suppressive antiviral therapy.
Human Norovirus Interactions with Histo-Blood Group Antigens and Human Milk Oligosaccharides
Authors: Schroten Horst , Hanisch Franz-Georg , Hansman Grant S. 
Published: April 2016

ABSTRACT
Human noroviruses interact with both human histo-blood group antigens (HBGAs) and human milk oligosaccharides (HMOs). The former are believed to be important for a virus infection, while the latter might act as natural decoys in the host during an infection. However, certain noroviruses are known to bind poorly to HBGAs and yet still cause infections; some interact with numerous HBGA types but are nonprevalent; and yet others bind HBGAs and seem to be increasing in prevalence. HBGAs and HMOs can be found as soluble antigens in humans, can be structurally alike, and can interact with equivalent residues at identical binding pockets on the capsid. In this Gem, we discuss HBGA and HMO binding studies for human noroviruses, concentrating on the clinically important genogroup II noroviruses. In short, the roles of HBGA and HMO interactions in norovirus infections are still unclear.
Comparison of Antibody-Dependent Cell-Mediated Cytotoxicity and Virus Neutralization by HIV-1 Env-Specific Monoclonal Antibodies
Authors: von Bredow Benjamin , Arias Juan F. , Heyer Lisa N. , Moldt Brian , Le Khoa , Robinson James E. , Zolla-Pazner Susan , Burton Dennis R. , Evans David T. 
Published: April 2016

ABSTRACTAlthough antibodies to the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein have been studied extensively for their ability to block viral infectivity, little data are currently available on nonneutralizing functions of these antibodies, such as their ability to eliminate virus-infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 Env-specific antibodies of diverse specificities, including potent broadly neutralizing and nonneutralizing antibodies, were therefore tested for ADCC against cells infected with a lab-adapted HIV-1 isolate (HIV-1NL4-3), a primary HIV-1 isolate (HIV-1JR-FL), and a simian-human immunodeficiency virus (SHIV) adapted for pathogenic infection of rhesus macaques (SHIVAD8-EO). In accordance with the sensitivity of these viruses to neutralization, HIV-1NL4-3-infected cells were considerably more sensitive to ADCC, both in terms of the number of antibodies and magnitude of responses, than cells infected with HIV-1JR-FLor SHIVAD8-EO. ADCC activity generally correlated with antibody binding to Env on the surfaces of virus-infected cells and with viral neutralization; however, neutralization was not always predictive of ADCC, as instances of ADCC in the absence of detectable neutralization, and vice versa, were observed. These results reveal incomplete overlap in the specificities of antibodies that mediate these antiviral activities and provide insights into the relationship between ADCC and neutralization important for the development of antibody-based vaccines and therapies for combating HIV-1 infection.IMPORTANCEThis study provides fundamental insights into the relationship between antibody-dependent cell-mediated cytotoxicity (ADCC) and virus neutralization that may help to guide the development of antibody-based vaccines and immunotherapies for the prevention and treatment of HIV-1 infection.
Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection
Authors: Jiang Jingwen , Li Jing , Fan Wenhui , Zheng Weinan , Yu Meng , Chen Can , Sun Lei , Bi Yuhai , Ding Chan , Gao George F. , Liu Wenjun 
Published: April 2016

ABSTRACT
Influenza A and B virus infections both cause a host innate immunity response. Here, we report that the robust production of type I and III interferons (IFNs), IFN-stimulated genes, and proinflammatory factors can be induced by influenza B virus rather than influenza A virus infection in alveolar epithelial (A549) cells during early infection. This response is mainly dependent on the retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway. Infection by influenza B virus promotes intense Lys63-linked ubiquitination of RIG-I, resulting in cytokine eruption. It is known that the influenza A virus NS1 protein (NS1-A) interacts with RIG-I and TRIM25 to suppress the activation of RIG-I-mediated signaling. However, the present results indicate that the influenza B virus NS1 protein (NS1-B) is unable to interact with RIG-I but engages in the formation of a RIG-I/TRIM25/NS1-B ternary complex. Furthermore, we demonstrate that the N-terminal RNA-binding domain (RBD) of NS1-B is responsible for interaction with TRIM25 and that this interaction blocks the inhibitory effect of the NS1-B C-terminal effector domain (TED) on RIG-I ubiquitination. Our findings reveal a novel mechanism for the host cytokine response to influenza B virus infection through regulatory interplay between host and viral proteins.

IMPORTANCE
Influenza B virus generally causes local mild epidemics but is occasionally lethal to individuals. Existing studies describe the broad characteristics of influenza B virus epidemiology and pathology. However, to develop better prevention and treatments for the disease, determining the concrete molecular mechanisms of pathogenesis becomes pivotal to understand how the host reacts to the challenge of influenza B virus. Thus, we aimed to characterize the host innate immune response to influenza B virus infection. Here, we show that vigorous Lys63-linked ubiquitination of RIG-I and cytokine eruption dependent on RIG-I-mediated signal transduction are induced by virus infection. Additionally, TRIM25 positively regulates RIG-I-mediated signaling by ablating the inhibitory function of NS1-B on RIG-I ubiquitination.
Biphasic CD8
+
T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization
Authors: Iseda Sumire , Takahashi Naofumi , Poplimont Hugo , Nomura Takushi , Seki Sayuri , Nakane Taku , Nakamura Midori , Shi Shoi , Ishii Hiroshi , Furukawa Shota , Harada Shigeyoshi , Naruse Taeko K. , Kimura Akinori , Matano Tetsuro , Yamamoto Hiroyuki 
Published: April 2016

ABSTRACT

Identifying human immunodeficiency virus type 1 (HIV-1) control mechanisms by neutralizing antibodies (NAbs) is critical for anti-HIV-1 strategies. Recent
in vivo
studies on animals infected with simian immunodeficiency virus (SIV) and related viruses have shown the efficacy of postinfection NAb passive immunization for viremia reduction, and one suggested mechanism is its occurrence through modulation of cellular immune responses. Here, we describe SIV control in macaques showing biphasic CD8
+
cytotoxic T lymphocyte (CTL) responses following acute-phase NAb passive immunization. Analysis of four SIV
mac239
-infected rhesus macaque pairs matched with major histocompatibility complex class I haplotypes found that counterparts receiving day 7 anti-SIV polyclonal NAb infusion all suppressed viremia for up to 2 years without accumulating viral CTL escape mutations. In the first phase of primary viremia control attainment, CD8
+
cells had high capacities to suppress SIVs carrying CTL escape mutations. Conversely, in the second, sustained phase of SIV control, CTL responses converged on a pattern of immunodominant CTL preservation. During this sustained phase of viral control, SIV epitope-specific CTLs showed retention of phosphorylated extracellular signal-related kinase (ERK)
hi
/phosphorylated AMP-activated protein kinase (AMPK)
lo
subpopulations, implying their correlation with SIV control. The results suggest that virus-specific CTLs functionally boosted by acute-phase NAbs may drive robust AIDS virus control.

IMPORTANCE
In early HIV infection, NAb responses are lacking and CTL responses are insufficient, which leads to viral persistence. Hence, it is important to identify immune responses that can successfully control such HIV replication. Here, we show that monkeys receiving NAb passive immunization in early SIV infection strictly control viral replication for years. Passive infusion of NAbs with CTL cross-priming capacity resulted in induction of functionally boosted early CTL responses showing enhanced suppression of CTL escape mutant virus replication. Accordingly, the NAb-infused animals did not show accumulation of viral CTL escape mutations during sustained SIV control, and immunodominant CTL responses were preserved. This early functional augmentation of CTLs by NAbs provides key insights into the design of lasting and viral escape mutation-free protective immunity against HIV-1 infection.
Fully automated PCR detection of KRAS mutations on pancreatic endoscopic ultrasound fine-needle aspirates
Authors: de Biase Dario , de Luca Caterina , Gragnano Gianluca , Visani Michela , Bellevicine Claudio , Malapelle Umberto , Tallini Giovanni , Troncone Giancarlo 
Published: April 2016

AimsIn cystic and solid pancreatic lesions,KRASmutational status refines the diagnosis of uncertain endoscopic ultrasound (EUS) aspirates. This test should have a fast turnaround time and ideally be performed at the centre where the patient is diagnosed. The Idylla KRAS Mutation Test enables standardisation even in units without molecular expertise.MethodsThe Idylla test was designed for use with formalin-fixed paraffin-embedded (FFPE) sections. However, we directly pipetted 3 µL (corresponding to 1/10th of a DNA preparation from the aspirate sample) in the cartridge, which was automatically run as if an FFPE sample had been inserted. The performance was compared with Sanger sequencing, Allele Specific Locked Nucleic Acid PCR (ASLNAqPCR), and 454 Next Generation Sequencing (454-NGS) in light of clinicopathological end points.ResultsIdylla yielded valid results in 49/52 (94.2%) cases, in 2 h. A total of 18/49 cases showed mutation either in KRAS exon 2 (14/18) or in exon 3 (4/18). Idylla KRAS test had 100% specificity and a sensitivity (55.1%) higher than Sanger sequencing (41.3%) and identical to ASLNAqPCR (55.1%). When the low-abundant mutant allele (<5%) cases were excluded from the analysis, the Idylla KRAS Mutation Test clinical sensitivity increased to 61.9% approaching that of 454-NGS (66.6%).ConclusionsThis is the first study that applied the novel Idylla KRAS test to the clinical setting of pancreatic cancer. In particular, this system can be easily implemented in the routine assessment of pancreatic EUS-fine-needle aspiration-derived DNA samples to quickly provide information on KRAS mutational status to supplement cytological evaluation.
Formally Modeling and Analyzing the Reliability of Cloud Applications
Authors: Fan Guisheng , Yu Huiqun , Chen Liqiong 
Published: April 2016

Cloud computing has become an important, useful paradigm for building applications with cloud services. However, cloud services exist in heterogeneous environments on the Internet. It is challenging to guarantee the reliability of cloud applications. Although there are efforts studying cloud and grid service reliability, very few have considered the modeling and analysis of the reliability of cloud applications. To address this emerging, important problem, we propose the first systematic approach that considers both cloud application elements and their running environment so as to faithfully model the dynamics of cloud computing. First, we present a formal description language to model the different components of a cloud application, and use it to analyze the static and dynamic factors affecting the reliability of cloud applications. Second, we propose reliability assurance strategies to ensure that cloud applications dynamically meet their required reliability. Third, Computation Tree Logic (CTL) is used to convert the reliability assurance strategy into the CTL formulas. We present operational semantics and related theories of Petri nets for establishing the correctness of our proposed method. Finally, a series of simulations are performed to evaluate the efficiency of our proposed approach.
A reduction of prothrombin conversion by cardiac surgery with cardiopulmonary bypass shifts the haemostatic balance towards bleeding
Authors: Bosch Yvonne P. J. , Bloemen Saartje , de Laat Bas , Weerwind Patrick W. , Mochtar Bas , Maessen Jos G. , Wagenvoord Rob J. , Al Dieri Raed , Coenraad Hemker H. , Kremers Romy M. W. 
Published: April 2016

SummaryCardiac surgery with cardiopulmonary bypass (CPB) is associated with blood loss and post-surgery thrombotic complications. The process of thrombin generation is disturbed during surgery with CPB because of haemodilution, coagulation factor consumption and heparin administration. We aimed to investigate the changes in thrombin generation during cardiac surgery and its underlying pro- and anticoagulant processes, and to explore the clinical consequences of these changes using in silico experimentation. Plasma was obtained from 29 patients undergoing surgery with CPB before heparinisation, after heparinisation, after haemodilution, and after protamine administration. Thrombin generation was measured and prothrombin conversion and thrombin inactivation were quantified. In silico experimentation was used to investigate the reaction of patients to the administration of procoagulant factors and/or anticoagulant factors. Surgery with CPB causes significant coagulation factor consumption and a reduction of thrombin generation. The total amount of prothrombin converted and the rate of prothrombin conversion decreased during surgery. As the surgery progressed, the relative contribution of α2-macroglobulin-dependent thrombin inhibition increased, at the expense of antithrombin-dependent inhibition. In silico restoration of post-surgical prothrombin conversion to pre-surgical levels increased thrombin generation excessively, whereas co-administration of antithrombin resulted in the normalisation of post-surgical thrombin generation. Thrombin generation is reduced during surgery with cardiopulmonary bypass because of a balance shift between prothrombin conversion and thrombin inactivation. According to in silico predictions of thrombin generation, this new balance increases the risk of thrombotic complications with prothrombin complex concentrate administration, but not if antithrombin is co-administered.
Randomized Controlled Trial of Social Media: Effect of Increased Intensity of the Intervention
Authors: Fox Caroline S. , Gurary Ellen B. , Ryan John , Bonaca Marc , Barry Karen , Loscalzo Joseph , Massaro Joseph 
Published: April 2016

Background

A prior randomized controlled trial of social media exposure at
Circulation
determined that social media did not increase 30‐day page views. Whether insufficient social media intensity contributed to these results is uncertain.

Methods and Results

Original article manuscripts were randomized to social media exposure compared with no social media exposure (control) at
Circulation
beginning in January 2015. Social media exposure consisted of Facebook and Twitter posts on the journal's accounts. To increase social media intensity, a larger base of followers was built using advertising and organic growth, and posts were presented in triplicate and boosted on Facebook and retweeted on Twitter. The primary outcome was 30‐day page views. Stopping rules were established at the point that 50% of the manuscripts were randomized and had 30‐day follow‐up to compare groups on 30‐day page views. The trial was stopped for futility on September 26, 2015. Overall, 74 manuscripts were randomized to receive social media exposure, and 78 manuscripts were randomized to the control arm. The intervention and control arms were similar based on article type (
P
=0.85), geographic location of the corresponding author (
P
=0.33), and whether the manuscript had an editorial (
P
=0.80). Median number of 30‐day page views was 499.5 in the social media arm and 450.5 in the control arm; there was no evidence of a treatment effect (
P
=0.38). There were no statistically significant interactions of treatment by manuscript type (
P
=0.86), by corresponding author (
P
=0.35), by trimester of publication date (
P
=0.34), or by editorial status (
P
=0.79).

Conclusions
A more intensive social media strategy did not result in increased 30‐day page views of original research.