bluuebunny/crossref_metadata_2025_split huggingface dataset:
In VivoAblation of Type I Interferon Receptor from Cardiomyocytes Delays Coxsackieviral Clearance and Accelerates Myocardial Disease
Authors: Althof Nadine , Harkins Stephanie , Kemball Christopher C. , Flynn Claudia T. , Alirezaei Mehrdad , Whitton J. Lindsay 
Published: February 2014

ABSTRACTAcute coxsackievirus B3 (CVB3) infection is one of the most prevalent causes of acute myocarditis, a disease that frequently is identified only after the sudden death of apparently healthy individuals. CVB3 infects cardiomyocytes, but the infection is highly focal, even in the absence of a strong adaptive immune response, suggesting that virus spread within the heart may be tightly constrained by the innate immune system. Type I interferons (T1IFNs) are an obvious candidate, and T1IFN receptor (T1IFNR) knockout mice are highly susceptible to CVB3 infection, succumbing within a few days of challenge. Here, we investigated the role of T1IFNs in the heart using a mouse model in which the T1IFNR gene can be ablatedin vivo, specifically in cardiomyocytes. We found that T1IFN signaling into cardiomyocytes contributed substantially to the suppression of viral replication and infectious virus yield in the heart; in the absence of such signaling, virus titers were markedly elevated by day 3 postinfection (p.i.) and remained high at day 12 p.i., a time point at which virus was absent from genetically intact littermates, suggesting that the T1IFN-unresponsive cardiomyocytes may act as a safe haven for the virus. Nevertheless, in these mice the myocardial infection remained highly focal, despite the cardiomyocytes' inability to respond to T1IFN, indicating that other factors, as yet unidentified, are sufficient to prevent the more widespread dissemination of the infection throughout the heart. The absence of T1IFN signaling into cardiomyocytes also was accompanied by a profound acceleration and exacerbation of myocarditis and by a significant increase in mortality.IMPORTANCEAcute coxsackievirus B3 (CVB3) infection is one of the most common causes of acute myocarditis, a serious and sometimes fatal disease. To optimize treatment, it is vital that we identify the immune factors that limit virus spread in the heart and other organs. Type I interferons play a key role in controlling many virus infections, but it has been suggested that they may not directly impact CVB3 infection within the heart. Here, using a novel line of transgenic mice, we show that these cytokines signal directly into cardiomyocytes, limiting viral replication, myocarditis, and death.
PrP Expression Level and Sensitivity to Prion Infection
Authors: Douet Jean-Yves , Lacroux Caroline , Corbière Fabien , Litaise Claire , Simmons Hugh , Lugan Séverine , Costes Pierrette , Cassard Hervé , Weisbecker Jean-Louis , Schelcher François , Andreoletti Olivier 
Published: February 2014

ABSTRACT
Mice overexpressing the prion protein (PrP) sequence from various host species are widely used for measuring infectious titers in prion disease. However, the impact that the transgene expression level might have on the susceptibility to infection raises some concerns about the final biological relevance of these models. Here we report that endpoint titration of a sheep scrapie isolate in sheep and in mice overexpressing the ovine PrP results in similar estimates of the infectious titer.
Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model
Authors: Kim Eun , Okada Kaori , Beeler Judy A. , Crim Roberta L. , Piedra Pedro A. , Gilbert Brian E. , Gambotto Andrea 
Published: February 2014

ABSTRACT

The lack of a vaccine against respiratory syncytial virus (RSV) is a challenging and serious gap in preventive medicine. Herein, we characterize the immunogenicity of an adenovirus serotype 5-based RSV vaccine encoding the fusion (F) protein (Ad5.RSV-F) and the protection provided following immunization with Ad5.RSV-F and assess its potential for producing enhanced disease in a cotton rat (CR) model. Animals were immunized intranasally (i.n.) and/or intramuscularly (i.m.) and subsequently challenged with RSV/A/Tracy (i.n.) to assess protection. Robust immune responses were seen in CRs vaccinated with Ad5.RSV-F given i.m. or i.n., and these responses correlated with reduced replication of the virus in noses and lungs after challenge. Neutralizing antibody responses following immunization with a single dose of Ad5.RSV-F at 1 × 10
11
viral particles (v.p.) elicited antibody titers 64- to 256-fold greater than those seen after natural infection. CRs boosted with Ad5.RSV-F i.n. 28 days after an i.m. dose also had significant increases in neutralizing antibody titers. Antibody affinity for different F-protein antigenic sites revealed substantial differences between antibodies elicited by Ad5.RSV-F and those seen after RSV infection; differences in antibody profiles were also seen between CRs given Ad5.RSV-F i.m. and CRs given Ad5.RSV-F i.n. Ad5.RSV-F priming did not result in enhanced disease following live-virus challenge, in contrast to the histopathology seen in CRs given the formalin-inactivated RSV/A/Burnett vaccine.

IMPORTANCE
Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in infants and young children and a serious health threat in the immunocompromised and the elderly. Infection severity increased in children in an immunization trial, hampering the over 4-decade-long quest for a successful RSV vaccine. In this study, we show that a genetically engineered RSV-F-encoding adenoviral vector provides protective immunity against RSV challenge without enhanced lung disease in cotton rats (CRs). CRs were vaccinated under a number of different regimens, and the immunity induced by the recombinant adenoviral RSV vaccine administered by use of an intramuscular prime-intranasal boost regimen may provide the best protection for young infants and children at risk of RSV infection, since this population is naive to adenoviral preformed immunity. Overall, this report describes a potential RSV vaccine candidate that merits further evaluation in a phase I clinical study in humans.
Upolu virus and Aransas Bay virus, Two Presumptive Bunyaviruses, Are Novel Members of the Family Orthomyxoviridae
Authors: Briese Thomas , Chowdhary Rashmi , Travassos da Rosa Amelia , Hutchison Stephen K. , Popov Vsevolod , Street Craig , Tesh Robert B. , Lipkin W. Ian 
Published: February 2014

ABSTRACT

Emerging and zoonotic pathogens pose continuing threats to human health and ongoing challenges to diagnostics. As nucleic acid tests are playing increasingly prominent roles in diagnostics, the genetic characterization of molecularly uncharacterized agents is expected to significantly enhance detection and surveillance capabilities. We report the identification of two previously unrecognized members of the family
Orthomyxoviridae
, which includes the influenza viruses and the tick-transmitted Thogoto and Dhori viruses. We provide morphological, serologic, and genetic evidence that
Upolu virus
(UPOV) from Australia and
Aransas Bay virus
(ABV) from North America, both previously considered potential bunyaviruses based on electron microscopy and physicochemical features, are orthomyxoviruses instead. Their genomes show up to 68% nucleotide sequence identity to Thogoto virus (segment 2; ∼74% at the amino acid level) and a more distant relationship to Dhori virus, the two prototype viruses of the recognized species of the genus
Thogotovirus
. Despite sequence similarity, the coding potentials of UPOV and ABV differed from that of Thogoto virus, instead being like that of Dhori virus. Our findings suggest that the tick-transmitted viruses UPOV and ABV represent geographically distinct viruses in the genus
Thogotovirus
of the family
Orthomyxoviridae
that do not fit in the two currently recognized species of this genus.

IMPORTANCE
Upolu virus
(UPOV) and
Aransas Bay virus
(ABV) are shown to be orthomyxoviruses instead of bunyaviruses, as previously thought. Genetic characterization and adequate classification of agents are paramount in this molecular age to devise appropriate surveillance and diagnostics. Although more closely related to Thogoto virus by sequence, UPOV and ABV differ in their coding potentials by lacking a proposed pathogenicity factor. In this respect, they are similar to Dhori virus, which, despite the lack of a pathogenicity factor, can cause disease. These findings enable further studies into the evolution and pathogenicity of orthomyxoviruses.
Anti-Lyssaviral Activity of Interferons κ and ω from the Serotine Bat, Eptesicus serotinus
Authors: He Xiaocui , Korytář Tomáš , Schatz Juliane , Freuling Conrad M. , Müller Thomas , Köllner Bernd 
Published: February 2014

ABSTRACT

Interferons (IFNs) are cytokines produced by host cells in response to the infection with pathogens. By binding to the corresponding receptors, IFNs trigger different pathways to block intracellular replication and growth of pathogens and to impede the infection of surrounding cells. Due to their key role in host defense against viral infections, as well as for clinical therapies, the IFN responses and regulation mechanisms are well studied. However, studies of type I IFNs have mainly focused on alpha interferon (IFN-α) and IFN-β subtypes. Knowledge of IFN-κ and IFN-ω is limited. Moreover, most studies are performed in humans or mouse models but not in the original host of zoonotic pathogens. Bats are important reservoirs and transmitters of zoonotic viruses such as lyssaviruses. A few studies have shown an antiviral activity of IFNs in fruit bats. However, the function of type I IFNs against lyssaviruses in bats has not been studied yet. Here, IFN-κ and IFN-ω genes from the European serotine bat,
Eptesicus serotinus
, were cloned and functionally characterized.
E. serotinus
IFN-κ and IFN-ω genes are intronless and well conserved between microchiropteran species. The promoter regions of both genes contain essential regulatory elements for transcription factors.
In vitro
studies indicated a strong activation of IFN signaling by recombinant IFN-ω, whereas IFN-κ displayed weaker activation. Noticeably, both IFNs inhibit to different extents the replication of different lyssaviruses in susceptible bat cell lines. The present study provides functional data on the innate host defense against lyssaviruses in endangered European bats.

IMPORTANCE
We describe here for the first time the molecular and functional characterization of two type I interferons (IFN-κ and -ω) from European serotine bat (
Eptesicus serotinus
). The importance of this study is mainly based on the fact that very limited information about the early innate immune response against bat lyssaviruses in their natural host serotine bats is yet available. Generally, whereas the antiviral activity of other type I interferons is well studied, the functional involvement of IFN-κ and -ω has not yet been investigated.
Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9
Authors: Reynaud Joséphine M. , Jégou Jean-François , Welsch Jérémy C. , Horvat Branka 
Published: February 2014

ABSTRACT
Human herpesvirus 6 (HHV-6) is widely spread in the human population and has been associated with several neuroinflammatory diseases, including multiple sclerosis. To develop a small-animal model of HHV-6 infection, we analyzed the susceptibility of several lines of transgenic mice expressing human CD46, identified as a receptor for HHV-6. We showed that HHV-6A (GS) infection results in the expression of viral transcripts in primary brain glial cultures from CD46-expressing mice, while HHV-6B (Z29) infection was inefficient. HHV-6A DNA persisted for up to 9 months in the brain of CD46-expressing mice but not in the nontransgenic littermates, whereas HHV-6B DNA levels decreased rapidly after infection in all mice. Persistence in the brain was observed with infectious but not heat-inactivated HHV-6A. Immunohistological studies revealed the presence of infiltrating lymphocytes in periventricular areas of the brain of HHV-6A-infected mice. Furthermore, HHV-6A stimulated the production of a panel of proinflammatory chemokines in primary brain glial cultures, including CCL2, CCL5, and CXCL10, and induced the expression of CCL5 in the brains of HHV-6A-infected mice. HHV-6A-induced production of chemokines in the primary glial cultures was dependent on the stimulation of toll-like receptor 9 (TLR9). Finally, HHV-6A induced signaling through human TLR9 as well, extending observations from the murine model to human infection. Altogether, this study presents a first murine model for HHV-6A-induced brain infection and suggests a role for TLR9 in the HHV-6A-initiated production of proinflammatory chemokines in the brain, opening novel perspectives for the study of virus-associated neuropathology.

IMPORTANCE
HHV-6 infection has been related to neuroinflammatory diseases; however, the lack of a suitable small-animal infection model has considerably hampered further studies of HHV-6-induced neuropathogenesis. In this study, we have characterized a new model for HHV-6 infection in mice expressing the human CD46 protein. Infection of CD46 transgenic mice with HHV-6A resulted in long-term persistence of viral DNA in the brains of infected animals and was followed by lymphocyte infiltration and upregulation of the CCL5 chemokine in the absence of clinical signs of disease. The secretion of a panel of chemokines was increased after infection in primary murine brain glial cultures, and the HHV-6-induced chemokine expression was inhibited when TLR9 signaling was blocked. These results describe the first murine model for HHV-6A-induced brain infection and suggest the importance of the TLR9 pathway in HHV-6A-initiated neuroinflammation.
Functional Analysis of Nuclear Localization Signals in VP1-2 Homologues from All Herpesvirus Subfamilies
Authors: Hennig T. , Abaitua F. , O'Hare P. 
Published: February 2014

ABSTRACT
The herpes simplex virus (HSV) tegument protein VP1-2 contains an N-terminal nuclear localization signal (NLS) that is critical for capsid routing to the nuclear pore. Here we analyzed positionally conserved determinants in VP1-2 homologues from each of the alpha, beta, and gamma classes of human herpesviruses. The overall architectures of the VP1-2s were similar, with a conserved N-terminal ubiquitin-specific protease domain separated from an internal region by a linker that was quite poorly conserved in length and sequence. Within this linker region all herpesviruses contained a conserved, highly basic motif which nevertheless exhibited distinct class-specific features. The motif in HSV functioned as a monopartite NLS, while in varicella-zoster virus (VZV) activity required an adjacent basic section defining the motif as a bipartite NLS. Neither the beta- nor gammaherpesvirus VP1-2 motifs were identified by prediction algorithms, but they nevertheless functioned as efficient NLS motifs both in heterologous transfer assays and in HSV VP1-2. Furthermore, though with different efficiencies and with the exception of human herpesvirus 8 (HHV-8), these chimeric variants rescued the replication defect of an HSV mutant lacking its NLS motif. We demonstrate that the lysine at position 428 of HSV is critical for replication, with a single alanine substitution being sufficient to abrogate NLS function and virus growth. We conclude that the basic motifs of each of the VP1-2 proteins are likely to confer a similar function in capsid entry in the homologous setting and that while there is flexibility in the exact type of motif employed, specific individual residues are critical for function.

IMPORTANCE
To successfully infect cells, all herpesviruses, along with many other viruses, e.g., HIV, hepatitis B virus, and influenza virus, must navigate through the cytoplasmic environment and dock with nuclear pores for transport of their genomes into the nucleus. However, we still have a limited understanding of the detailed mechanisms involved. Insight into these events is needed and could offer opportunities for therapeutic intervention. This work investigated the role of a specific determinant in the structural protein VP1-2 in herpesvirus entry. We examined this determinant in representative VP1-2s from all herpesvirus subfamilies, demonstrated NLS function, dissected key residues, and showed functional relevance in rescuing replication of the mutant blocked in capsid navigation to the pore. The results are important and strongly support our conclusions of the generality that these motifs are crucial for entry of all herpesviruses. They also facilitate future analysis on selective host interactions and possible routes to disrupt function.
Cholelithiasis and the risk of liver cancer: results from cohort studies of 134 546 Chinese men and women
Authors: Vogtmann Emily , Shu Xiao-Ou , Li Hong-Lan , Chow Wong-Ho , Yang Gong , Ji Bu-Tian , Cai Hui , Yu Chang , Gao Yu-Tang , Zheng Wei , Xiang Yong-Bing 
Published: February 2014

BackgroundCholelithiasis and cholecystectomy have been proposed as risk factors for liver cancer, but findings have been inconsistent. We assessed this association using data from the Shanghai Women's and Men's Health Studies.MethodsHistory of cholelithiasis and cholecystectomy were reported at baseline and follow-up interviews, and liver cancer diagnoses were ascertained from the Shanghai Cancer Registry and Vital Statistics Unit. Adjusted hazard ratios (aHRs) and 95% CIs were calculated after adjustment for potential confounders.ResultsA history of cholelithiasis and cholecystectomy was reported by 9.5% and 3.6% of participants at baseline, respectively. After a total of 859 882 person-years of follow-up for women and 391 093 for men, incident liver cancer was detected in 160 women and 252 men. A positive association was observed between a history of cholelithiasis or cholecystectomy and liver cancer in men (aHR 1.46; 95% CI 1.02 to 2.07) and women (aHR 1.55; 95% CI 1.06 to 2.26). Similar results were observed for cholelithiasis only, but cholecystectomy did not reach statistical significance. There was no strong evidence for detection bias of liver cancer due to cholelithiasis or cholecystectomy.ConclusionsOur study suggests that cholelithiasis and possibly cholecystectomy may increase the risk of liver cancer.
Chronic pain after surgery: pathophysiology, risk factors and prevention
Authors: Reddi Danielle , Curran Natasha 
Published: February 2014

Abstract
Interest in chronic pain after surgery has grown since the finding that more than a fifth of patients attending chronic pain clinics cite surgery as the cause for their chronic pain. The problem is not limited to major surgery; even common minor procedures such as hernia repair have a significant risk of chronic pain. Surgical technique can influence the development of chronic postsurgical pain (CPSP) and techniques to minimise nerve injury should be used where possible. Central nervous system changes contribute to the development of persistent pain following surgical trauma and nerve injury. Pharmacological agents that interrupt the mechanisms contributing to central sensitisation may be helpful in reducing the incidence of CPSP. Psychosocial factors are also important in the development of chronic pain and should be addressed as part of a holistic approach to perioperative care.
Mortein: Finalizing the Theme and Creative Idea
Authors: Pradhan Debasis , Agrawal Divya 
Published: February 2014

Mortein, one of the top pest repellant brands in India, was facing a stagnant market share for the past three years. Although the brand in itself stood for “power”, consumers did not perceive the vaporizer to have the same power as competitors' products. Deepak Sinha, the brand manager for Mortein, had formulated a business strategy to capture share from competition through a brand relaunch with an improved and more effective product, Mortein PowerGard. Deepak had come up with the proposal for a 360-degree activation for Mortein. Deepak had to approve the advertising copy designed and developed by a management trainee. He wanted to be doubly-sure about the target audience for the communication campaign and the decision-making units for the purchase of a mosquito repellent. There was a debate on this at Reckitt-Benckiser (hereafter referred to as RB). He wanted to be scientific about decisions like target audience selection and the appropriateness of the message strategy which was also part of the copy strategy. Deepak and the trainee had to convince the top management at RB on certain decisions that were taken and some others that were being contemplated upon.
BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma
Authors: Breunig Christian , Mueller Bernadett J. , Umansky Ludmila , Wahl Kristin , Hoffmann Katrin , Lehner Frank , Manns Michael P. , Bantel Heike , Falk Christine S. 
Published: February 2014

Abstract
Purpose: Small molecule inhibitors of the mitogen-activated protein kinase (MAPK) pathway, such as sorafenib, represent novel treatment options for advanced hepatocellular carcinoma. The aim of our study was to identify downstream targets as biomarker candidates that are directly linked to the oncogenic MAPK pathway in hepatocellular carcinoma and correlate with inhibition of this pathway by multikinase inhibitors.
Experimental Design: Hepatocellular carcinoma cell lines and fresh tumor and tumor-free liver tissues from patients with hepatocellular carcinoma were incubated with different BRaf or MEK inhibitors and analyzed for kinase phosphorylation, proliferation, induction of apoptosis, and chemokine secretion.
Results: Hepatocellular carcinoma cell lines responded differentially to these inhibitors in a dose-dependent manner, even those targeting the same kinase. Sorafenib inhibited both MEK1 and ERK1/2 phosphorylation at high but increased signaling at low concentrations. Similarly, PLX4720 increased MEK/ERK signaling independently from mutations in BRaf or NRas. MEK inhibitors decreased ERK1/2 phosphorylation in a dose-dependent manner. These signaling characteristics correlated with inhibition of proliferation, induction of apoptosis, and chemokine secretion. Fresh tissues derived from patients diagnosed with primary hepatocellular carcinoma responded to these inhibitors with changes in their microenvironment following the patterns observed in hepatocellular carcinoma cells.
Conclusions: Oncogenic signaling of the MAPK pathway influences hepatocellular carcinoma sensitivity to treatment with BRaf and MEK inhibitors about cell fate independently from mutations in BRaf and NRas. MAPK inhibitors have a strong impact on chemokine secretion as a consequence of interference with oncogenic signaling. Therefore, novel biomarker candidates associated with the hepatocellular carcinoma microenvironment may be developed for prediction and monitoring of treatment response to small molecule inhibitors. Clin Cancer Res; 20(9); 2410–23. ©2014 AACR.