bluuebunny/crossref_metadata_2025 huggingface dataset:
Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection
Authors: Cormier Stephania A. , Shrestha Bishwas , Saravia Jordy , Lee Greg I. , Shen Li , DeVincenzo John P. , Kim Young-in , You Dahui
Published: June 2014

Respiratory syncytial virus (RSV) infection is the number one cause of bronchiolitis in infants, yet no vaccines are available because of a lack of knowledge of the infant immune system. Using a neonatal mouse model, we previously revealed that mice initially infected with RSV as neonates develop Th2-biased immunopathophysiologies during reinfection, and we demonstrated a role for enhanced interleukin-4 receptor α (IL-4Rα) expression on T helper cells in these responses. Here we show that RSV infection in neonates induced limited type I interferon (IFN) and plasmacytoid dendritic cell (pDC) responses. IFN alpha (IFN-α) treatment or adoptive transfer of adult pDCs capable of inducing IFN-α prior to neonatal RSV infection decreased Th2-biased immunopathogenesis during reinfection. A reduced viral load and downregulation of IL-4Rα on Th2 cells were observed in IFN-α-treated neonatal mice, suggesting dual mechanisms of action.

IMPORTANCE
Respiratory syncytial virus (RSV) is the most significant cause of lower respiratory tract infection in infancy worldwide. Despite the dire need, we have failed to produce efficacious RSV vaccines or therapeutics. Part of the reason for this failure is our lack of understanding of how RSV interacts with the infant immune system to suppress the development of protective immunity. In the study described in the present paper, we used a neonatal mouse model, which more closely mimics human infants, to study the role of the innate immune system, particularly type I interferons (IFNs) and plasmacytoid dendritic cells (pDCs), in the pathogenesis of RSV infection. RSV infection in neonates induced limited type I IFN and pDC responses. IFN-α treatment or adoptive transfer of adult pDCs capable of producing IFN-α prior to neonatal RSV infection decreased Th2-biased immunopathogenesis during reinfection. These data suggest that IFN-α is a promising target for future RSV vaccine design.
Hepatitis A Virus 3C Protease Cleaves NEMO To Impair Induction of Beta Interferon
Authors: Wang Dang , Fang Liurong , Wei Dahai , Zhang Huan , Luo Rui , Chen Huanchun , Li Kui , Xiao Shaobo
Published: June 2014

NEMO (NF-κB essential modulator) is a bridging adaptor indispensable for viral activation of interferon (IFN) antiviral response. Herein, we show that hepatitis A virus (HAV) 3C protease (3C
pro
) cleaves NEMO at the Q304 residue, negating its signaling adaptor function and abrogating viral induction of IFN-β synthesis via the retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 (RIG-I/MDA5) and Toll-like receptor 3 (TLR3) pathways. NEMO cleavage and IFN antagonism, however, were lost upon ablation of the catalytic activity of 3C
pro
. These data describe a novel immune evasion mechanism of HAV.
Molecular Mechanism of the Airborne Transmissibility of H9N2 Avian Influenza A Viruses in Chickens
Authors: Zhong Lei , Wang Xiaoquan , Li Qunhui , Liu Dong , Chen Hongzhi , Zhao Mingjun , Gu Xiaobing , He Liang , Liu Xiaowen , Gu Min , Peng Daxin , Liu Xiufan
Published: June 2014

H9N2 avian influenza virus has been prevalent in poultry in many parts of the world since the 1990s and occasionally crosses the host barrier, transmitting to mammals, including humans. In recent years, these viruses have contributed genes to H5N1 and H7N9 influenza viruses, threatening public health. To explore the molecular mechanism for the airborne transmission of H9N2 virus, we compared two genetically close strains isolated from chickens in 2001, A/chicken/Shanghai/7/2001(SH7) and A/chicken/Shanghai/14/2001 (SH14). SH7 is airborne transmissible between chickens, whereas SH14 is not. We used reverse genetics and gene swapping to derive recombinant SH7 (rSH7), rSH14, and a panel of reassortant viruses. Among the reassortant viruses, we identified segments HA and PA as governing the airborne transmission among chickens. In addition, the NP and NS genes also contributed to a lesser extent. Furthermore, the mutational analyses showed the transmissibility phenotype predominantly mapped to the HA and PA genes, with HA-K363 and PA-L672 being important for airborne transmissibility among chickens. In addition, the viral infectivity and acid stability are related to the airborne transmissibility. Importantly, airborne transmission studies of 18 arbitrarily chosen H9N2 viruses from our collections confirmed the importance of both 363K in HA and 672L in PA in determining their levels of transmissibility. Our finding elucidates the genetic contributions to H9N2 transmissibility in chickens and highlights the importance of their prevalence in poultry.

IMPORTANCE
Our study investigates the airborne transmissibility of H9N2 viruses in chickens and the subsequent epidemic. H9N2 virus is the donor for several prevalent reassortant influenza viruses, such as H7N9/2013 and the H5N1 viruses. Poultry as the reservoir hosts of influenza virus is closely associated with human society. Airborne transmission is an efficient pathway for influenza virus transmission among flocks and individuals. Exploring the mechanism of the airborne transmission of the H9N2 virus in chickens could provide essential data regarding prevention and control of influenza endemics and pandemics.
CD40L-Adjuvanted DNA/Modified Vaccinia Virus Ankara Simian Immunodeficiency Virus SIV239 Vaccine Enhances SIV-Specific Humoral and Cellular Immunity and Improves Protection against a Heterologous SIVE660 Mucosal Challenge
Authors: Kwa Suefen , Lai Lilin , Gangadhara Sailaja , Siddiqui Mariam , Pillai Vinod B. , Labranche Celia , Yu Tianwei , Moss Bernard , Montefiori David C. , Robinson Harriet L. , Kozlowski Pamela A. , Amara Rama Rao
Published: June 2014

It remains a challenge to develop a successful human immunodeficiency virus (HIV) vaccine that is capable of preventing infection. Here, we utilized the benefits of CD40L, a costimulatory molecule that can stimulate both dendritic cells (DCs) and B cells, as an adjuvant for our simian immunodeficiency virus (SIV) DNA vaccine in rhesus macaques. We coexpressed the CD40L with our DNA/SIV vaccine such that the CD40L is anchored on the membrane of SIV virus-like particle (VLP). These CD40L containing SIV VLPs showed enhanced activation of DCsin vitro. We then tested the potential of DNA/SIV-CD40L vaccine to adjuvant the DNA prime of a DNA/modified vaccinia virus Ankara (MVA) vaccine in rhesus macaques. Our results demonstrated that the CD40L adjuvant enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV CD8 and CD4 T cell responses, significantly delayed the acquisition of heterologous mucosal SIV infection, and improved viral control. Notably, the CD40L adjuvant enhanced the control of viral replication in the gut at the site of challenge that was associated with lower mucosal CD8 immune activation, one of the strong predictors of disease progression. Collectively, our results highlight the benefits of CD40L adjuvant for enhancing antiviral humoral and cellular immunity, leading to enhanced protection against a pathogenic SIV. A single adjuvant that enhances both humoral and cellular immunity is rare and thus underlines the importance and practicality of CD40L as an adjuvant for vaccines against infectious diseases, including HIV-1.

IMPORTANCEDespite many advances in the field of AIDS research, an effective AIDS vaccine that can prevent infection remains elusive. CD40L is a key stimulator of dendritic cells and B cells and can therefore enhance T cell and antibody responses, but its overly potent nature can lead to adverse effects unless used in small doses. In order to modulate local expression of CD40L at relatively lower levels, we expressed CD40L in a membrane-bound form, along with SIV antigens, in a nucleic acid (DNA) vector. We tested the immunogenicity and efficacy of the CD40L-adjuvanted vaccine in macaques using a heterologous mucosal SIV infection. The CD40L-adjuvanted vaccine enhanced the functional quality of anti-Env antibody response and breadth of anti-SIV T cell responses and improved protection. These results demonstrate that VLP-membrane-bound CD40L serves as a novel adjuvant for an HIV vaccine.
Poly(I:C) Treatment Leads to Interferon-Dependent Clearance of Hepatitis B Virus in a Hydrodynamic Injection Mouse Model
Authors: Wu Jun , Huang Shunmei , Zhao Xiaoli , Chen Mingfa , Lin Yong , Xia Youchen , Sun Chan , Yang Xuecheng , Wang Junzhong , Guo Yan , Song Jingjiao , Zhang Ejuan , Wang Baoju , Zheng Xin , Schlaak Joerg F. , Lu Mengji , Yang Dongliang
Published: June 2014

We have previously shown that poly(I:C) activates murine hepatic cells to produce interferon (IFN) and suppresses hepatitis B virus (HBV) replication
in vitro
. Therefore, we addressed whether poly(I:C) is able to induce the clearance of HBV
in vivo
. The chronic HBV replication mouse model was established by the hydrodynamic injection (HI) of pAAV-HBV1.2 into the tail veins of wild-type and IFN-α/βR-, IFN-γ-, and CXCR3-deficient C57BL/6 mice. Fourteen days post-HI of pAAV-HBV1.2, mice were administered poly(I:C) by intraperitoneal injection, intramuscular injection, or HI. Only treatment of poly(I:C) by HI led to HBV clearance in wild-type C57BL/6 mice. Serum HBsAg disappeared within 40 days postinfection (dpi) in mice that received poly(I:C) by HI, and this was accompanied by the appearance of anti-HBs antibodies. HBV-specific T-cell and antibody responses were significantly enhanced by HI of poly(I:C). HBV replication intermediates and HBcAg-positive hepatocytes were eliminated in the liver. HI of poly(I:C) induced the production of IFNs in mice and enhanced the levels of cytokines, IFN-stimulated genes, and T-cell markers in the liver. Importantly, poly(I:C)-induced HBV clearance was impaired in IFN-α/βR-, IFN-γ-, and CXCR3-deficient mice, indicating that the induction of type I IFN and the stimulation and recruitment of T cells into the liver are essential for HBV clearance in this model. Taken together, the application of poly(I:C) by HI into the liver enhances innate and adaptive immune responses and leads to HBV clearance in an HBV mouse model, implicating the potential of intrahepatic Toll-like receptor 3 (TLR3) activation for the treatment of chronic hepatitis B patients.

IMPORTANCE
It has become well accepted that immunomodulation is a potentially useful approach to treat chronic viral infection. Recently, combinations of antiviral treatment and therapeutic vaccinations were evaluated for therapies of chronic hepatitis B virus (HBV) infection. Activation of the innate immune branch may also be important for viral control and contributes to HBV clearance. Our present study demonstrated that hepatic TLR3 activation led to clearance of hepatitis B virus in an HBV mouse model. For the first time, we showed that HBV clearance in this model is dependent not only on type I interferon (IFN) but also on type II IFN, indicating a coordinated action of innate and adaptive immune responses. T-cell recruitment appeared to be critical for the success of TLR3-mediated antiviral action. These findings implicate the potential of intrahepatic TLR3 activation for the treatment of chronic HBV infection.
Vaccine-Induced HIV-1 Envelope gp120 Constant Region 1-Specific Antibodies Expose a CD4-Inducible Epitope and Block the Interaction of HIV-1 gp140 with Galactosylceramide
Authors: Dennison S. Moses , Anasti Kara M. , Jaeger Frederick H. , Stewart Shelley M. , Pollara Justin , Liu Pinghuang , Kunz Erika L. , Zhang Ruijun , Vandergrift Nathan , Permar Sallie , Ferrari Guido , Tomaras Georgia D. , Bonsignori Mattia , Michael Nelson L. , Kim Jerome H. , Kaewkungwal Jaranit , Nitayaphan Sorachai , Pitisuttithum Punnee , Rerks-Ngarm Supachai , Liao Hua-Xin , Haynes Barton F. , Alam S. Munir
Published: June 2014

Mucosal epithelial cell surface galactosylceramide (Galcer) has been postulated to be a receptor for HIV-1 envelope (Env) interactions with mucosal epithelial cells. Disruption of the HIV-1 Env interaction with such alternate receptors could be one strategy to prevent HIV-1 entry through the mucosal barrier. To study antibody modulation of HIV-1 Env-Galcer interactions, we used Galcer-containing liposomes to assess whether natural- and vaccine-induced monoclonal antibodies can block HIV-1 Env binding to Galcer. HIV-1 Env gp140 proteins bound to Galcer liposomes with

K
d

s (dissociation constants) in the nanomolar range. Several HIV-1 ALVAC/AIDSVAX vaccinee-derived monoclonal antibodies (MAbs) specific for the gp120 first constant (C1) region blocked Galcer binding of a transmitted/founder HIV-1 Env gp140. Among the C1-specific MAbs that showed Galcer blocking, the antibody-dependent cellular cytotoxicity-mediating CH38 IgG and its natural IgA isotype were the most potent blocking antibodies. C1-specific IgG monoclonal antibodies that blocked Env binding to Galcer induced upregulation of the gp120 CD4-inducible (CD4i) epitope bound by MAb 17B, demonstrating that a conformational change in gp120 may be required for Galcer blocking. However, the MAb 17B itself did not block Env-Galcer binding, suggesting that the C1 antibody-induced gp120 conformational changes resulted in alteration in a Galcer binding site distant from the CD4i 17B MAb binding site.

IMPORTANCE
Galactosyl ceramide, a glycosphingolipid, has been postulated to be a receptor for the HIV-1 envelope glycoprotein (Env) interaction with mucosal epithelial cells. Here, we have mimicked this interaction by using an artificial membrane containing synthetic Galcer and recombinant HIV-1 Env proteins to identify antibodies that would block the HIV-1 Env-Galcer interaction. Our study revealed that a class of vaccine-induced human antibodies potently blocks HIV-1 Env-Galcer binding by perturbing the HIV-1 Env conformation.
Genomic Flexibility of Human Endogenous Retrovirus Type K
Authors: Dube Derek , Contreras-Galindo Rafael , He Shirley , King Steven R. , Gonzalez-Hernandez Marta J. , Gitlin Scott D. , Kaplan Mark H. , Markovitz David M.
Published: June 2014

Human endogenous retrovirus type K (HERV-K) proviruses are scattered throughout the human genome, but as no infectious HERV-K virus has been detected to date, the mechanism by which these viruses replicated and populated the genome remains unresolved. Here, we provide evidence that, in addition to the RNA genomes that canonical retroviruses package, modern HERV-K viruses can contain reverse-transcribed DNA (RT-DNA) genomes. Indeed, reverse transcription of genomic HERV-K RNA into the DNA form is able to occur in three distinct times and locations: (i) in the virus-producing cell prior to viral release, yielding a DNA-containing extracellular virus particle similar to the spumaviruses; (ii) within the extracellular virus particle itself, transitioning from an RNA-containing particle to a DNA-containing particle; and (iii) after entry of the RNA-containing virus into the target cell, similar to canonical retroviruses, such as murine leukemia virus and HIV. Moreover, using a resuscitated HERV-K virus construct, we show that both viruses with RNA genomes and viruses with DNA genomes are capable of infecting target cells. This high level of genomic flexibility historically could have permitted these viruses to replicate in various host cell environments, potentially assisting in their many integration events and resulting in their high prevalence in the human genome. Moreover, the ability of modern HERV-K viruses to proceed through reverse transcription and package RT-DNA genomes suggests a higher level of replication competency than was previously understood, and it may be relevant in HERV-K-associated human diseases.

IMPORTANCE
Retroviral elements comprise at least 8% of the human genome. Of all the endogenous retroviruses, HERV-K viruses are the most intact and biologically active. While a modern infectious HERV-K has yet to be found, HERV-K activation has been associated with cancers, autoimmune diseases, and HIV-1 infection. Thus, determining how this virus family became such a prevalent member of our genome and what it is capable of in its current form are of the utmost importance. Here, we provide evidence that HERV-K viruses currently found in the human genome are able to proceed through reverse transcription and historically utilized a life cycle with a surprising degree of genomic flexibility in which both RNA- and DNA-containing viruses were capable of mediating infection.
West Nile Virus-Induced Activation of Mammalian Target of Rapamycin Complex 1 Supports Viral Growth and Viral Protein Expression
Authors: Shives Katherine D. , Beatman Erica L. , Chamanian Mastooreh , O'Brien Caitlin , Hobson-Peters Jody , Beckham J. David
Published: June 2014

Since its introduction in New York City, NY, in 1999, West Nile virus (WNV) has spread to all 48 contiguous states of the United States and is now the leading cause of epidemic encephalitis in North America. As a member of the family
Flaviviridae
, WNV is part of a group of clinically important human pathogens, including dengue virus and Japanese encephalitis virus. The members of this family of positive-sense, single-stranded RNA viruses have limited coding capacity and are therefore obligated to co-opt a significant amount of cellular factors to translate their genomes effectively. Our previous work has shown that WNV growth was independent of macroautophagy activation, but the role of the evolutionarily conserved mammalian target of rapamycin (mTOR) pathway during WNV infection was not well understood. mTOR is a serine/threonine kinase that acts as a central cellular censor of nutrient status and exercises control of vital anabolic and catabolic cellular responses such as protein synthesis and autophagy, respectively. We now show that WNV activates mTOR and cognate downstream activators of cap-dependent protein synthesis at early time points postinfection and that pharmacologic inhibition of mTOR (KU0063794) significantly reduced WNV growth. We used an inducible
Raptor
and
Rictor
knockout mouse embryonic fibroblast (MEF) system to further define the role of mTOR complexes 1 and 2 in WNV growth and viral protein synthesis. Following inducible genetic knockout of the major mTOR cofactors raptor (TOR complex 1 [TORC1]) and rictor (TORC2), we now show that TORC1 supports flavivirus protein synthesis via cap-dependent protein synthesis pathways and supports subsequent WNV growth.

IMPORTANCE
Since its introduction in New York City, NY, in 1999, West Nile virus (WNV) has spread to all 48 contiguous states in the United States and is now the leading cause of epidemic encephalitis in North America. Currently, the mechanism by which flaviviruses such as WNV translate their genomes in host cells is incompletely understood. Elucidation of the host mechanisms required to support WNV genome translation will provide broad understanding for the basic mechanisms required to translate capped viral RNAs. We now show that WNV activates mTOR and cognate downstream activators of cap-dependent protein synthesis at early time points postinfection. Following inducible genetic knockout of the major mTOR complex cofactors raptor (TORC1) and rictor (TORC2), we now show that TORC1 supports WNV growth and protein synthesis. This study demonstrates the requirement for TORC1 function in support of WNV RNA translation and provides insight into the mechanisms underlying flaviviral RNA translation in mammalian cells.
The Tegument Protein pp65 of Human Cytomegalovirus Acts as an Optional Scaffold Protein That Optimizes Protein Uploading into Viral Particles
Authors: Reyda Sabine , Tenzer Stefan , Navarro Pedro , Gebauer Wolfgang , Saur Michael , Krauter Steffi , Büscher Nicole , Plachter Bodo
Published: June 2014

The mechanisms that lead to the tegumentation of herpesviral particles are only poorly defined. The phosphoprotein 65 (pp65) is the most abundant constituent of the virion tegument of human cytomegalovirus (HCMV). It is, however, nonessential for virion formation. This seeming discrepancy has not met with a satisfactory explanation regarding the role of pp65 in HCMV particle morphogenesis. Here, we addressed the question of how the overall tegument composition of the HCMV virion depended on pp65 and how the lack of pp65 influenced the packaging of particular tegument proteins. To investigate this, we analyzed the proteomes of pp65-positive (pp65pos) and pp65-negative (pp65neg) virions by label-free quantitative mass spectrometry and determined the relative abundances of tegument proteins. Surprisingly, only pUL35 was elevated in pp65neg virions. As the abundance of pUL35 in the HCMV tegument is low, it is unlikely that it replaced pp65 as a structural component in pp65neg virions. A subset of proteins, including the third most abundant tegument protein, pUL25, as well as pUL43, pUL45, and pUL71, were reduced in pp65neg or pp65low virions, indicating that the packaging of these proteins was related to pp65. The levels of tegument components, like pp28 and the capsid-associated tegument proteins pp150, pUL48, and pUL47, were unaffected by the lack of pp65. Our analyses demonstrate that deletion of pp65 is not compensated for by other viral proteins in the process of virion tegumentation. The results are concordant with a model of pp65 serving as an optional scaffold protein that facilitates protein upload into the outer tegument of HCMV particles.

IMPORTANCEThe assembly of the tegument of herpesviruses is only poorly understood. Particular proteins, like HCMV pp65, are abundant tegument constituents. pp65 is thus considered to play a major role in tegument assembly in the process of virion morphogenesis. We show here that deletion of the pp65 gene leads to reduced packaging of a subset of viral proteins, indicating that pp65 acts as an optional scaffold protein mediating protein upload into the tegument.
Endosomal Trafficking of Nanoformulated Antiretroviral Therapy Facilitates Drug Particle Carriage and HIV Clearance
Authors: Guo Dongwei , Zhang Gang , Wysocki Tadeusz A. , Wysocki Beata J. , Gelbard Harris A. , Liu Xin-Ming , McMillan JoEllyn M. , Gendelman Howard E.
Published: June 2014

Limitations of antiretroviral therapy (ART) include poor patient adherence, drug toxicities, viral resistance, and failure to penetrate viral reservoirs. Recent developments in nanoformulated ART (nanoART) could overcome such limitations. To this end, we now report a novel effect of nanoART that facilitates drug depots within intracellular compartments at or adjacent to the sites of the viral replication cycle. Poloxamer 407-coated nanocrystals containing the protease inhibitor atazanavir (ATV) were prepared by high-pressure homogenization. These drug particles readily accumulated in human monocyte-derived macrophages (MDM). NanoATV concentrations were ∼1,000 times higher in cells than those that could be achieved by the native drug. ATV particles in late and recycling endosome compartments were seen following pulldown by immunoaffinity chromatography with Rab-specific antibodies conjugated to magnetic beads. Confocal microscopy provided cross validation by immunofluorescent staining of the compartments. Mathematical modeling validated drug-endosomal interactions. Measures of reverse transcriptase activity and HIV-1 p24 levels in culture media and cells showed that such endosomal drug concentrations enhanced antiviral responses up to 1,000-fold. We conclude that late and recycling endosomes can serve as depots for nanoATV. The colocalization of nanoATV at endosomal sites of viral assembly and its slow release sped antiretroviral activities. Long-acting nanoART can serve as a drug carrier in both cells and subcellular compartments and, as such, can facilitate viral clearance.

IMPORTANCEThe need for long-acting ART is significant and highlighted by limitations in drug access, toxicity, adherence, and reservoir penetrance. We propose that targeting nanoformulated drugs to infected tissues, cells, and subcellular sites of viral replication may improve clinical outcomes. Endosomes are sites for human immunodeficiency virus assembly, and increasing ART concentrations in such sites enhances viral clearance. The current work uncovers a new mechanism by which nanoART can enhance viral clearance over native drug formulations.
Newcastle Disease Virus Vector Producing Human Norovirus-Like Particles Induces Serum, Cellular, and Mucosal Immune Responses in Mice
Authors: Kim Shin-Hee , Chen Shun , Jiang Xi , Green Kim Y. , Samal Siba K.
Published: June 2014

Human norovirus infection is the most common cause of viral gastroenteritis worldwide. Development of an effective vaccine is required for reducing norovirus outbreaks. The inability to grow human norovirus in cell culture has hindered the development of live-attenuated vaccines. To overcome this obstacle, we generated a recombinant Newcastle disease virus (rNDV)-vectored experimental norovirus vaccine by expressing the capsid protein (VP1) of norovirus strain VA387. We compared two different NDV vectors, a conventional rNDV vector and a modified rNDV vector, for their efficiencies in expressing VP1 protein. Our results showed that the modified vector replicated to higher titers and expressed higher levels of VP1 protein in DF1 cells and in allantoic fluid of embryonated chicken eggs than did the conventional vector. We further demonstrated that the VP1 protein produced by rNDVs was able to self-assemble into virus-like particles (VLPs) that are morphologically similar to baculovirus-expressed VLPs. Evaluation of their immunogenicity in mice showed that the modified rNDV vector induced a higher level of IgG response than those induced by the conventional vector and by the baculovirus-expressed VLPs. The rNDV vectors predominantly induced IgG2a subclass antibody for the Th1 response, and specifically, high levels of gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) were detected in splenocytes. In addition, the modified rNDV vector induced a higher level of fecal IgA response in mice than did baculovirus-expressed VLPs. Our findings suggest that the rNDV vector is an efficient system to produce cost-effective VLPs in embryonated chicken eggs and has the potential to be used as a live-attenuated vaccine in humans.

IMPORTANCE
Noroviruses are the major cause of viral gastroenteritis worldwide. Currently, effective vaccines against norovirus infection are not available. In this study, we have evaluated Newcastle disease virus (NDV) as a vaccine vector for norovirus. Our results suggest that NDV can be used not only as a cost-effective method for large-scale production of norovirus-like particle vaccines but also as a live-attenuated vectored vaccine.
Penetrating foreign body in the nasal floor through nasolacrimal duct
Authors: Santoro Roberto , Mannella Valentina Katia , Freni Francesco , Galletti Francesco
Published: June 2014

Clinical otolaryngologists frequently encounter nasal foreign bodies (FBs) particularly among children. The removal of nasal FBs is a common otolaryngological practice. However, occasionally trauma results from FBs being lodged in the nasal cavity especially through the nasolacrimal duct. In this article we present an unusual case of a FB that from the left medial canthus went inside the nasolacrimal duct, then through the inferior turbinate and stuck in the floor of the nose. We describe the transnasal endoscopic approach used and we recommend that the treatment be done as soon as possible to avoid complications.
Basal cell adenocarcinoma of the parotid gland detected in a patient with breast cancer
Authors: Ozgun Alpaslan , Tuncel Tolga , Emirzeoglu Levent , Haholu Abdullah
Published: June 2014

Basal cell adenocarcinoma (BCAC) is a rare tumour of the salivary glands and often associated with a good prognosis. The present case had BCAC of the parotid gland as the second primary tumour in addition to breast cancer. The patient was a 66-year-old woman who underwent mastectomy due to breast cancer. She then underwent adjuvant chemotherapy and adjuvant hormone therapy. After 4 years of disease-free follow-up, the patient presented with a swelling on the left cheek. The examination of the biopsy specimen revealed BCAC of the parotid gland. The patient then underwent left parathyroidectomy plus left neck dissection. Adjuvant radiotherapy was performed. Despite the therapy, the patient developed four local recurrences within 1 year, and then developed metastasis to the pleura. A swelling in the parotid gland in a patient with breast cancer should be carefully screened for the presence of a second primary tumour.
Spontaneous bladder perforation unrelated to trauma or surgery
Authors: Cusano Antonio , Abarzua-Cabezas Fernando , Meraney Anoop
Published: June 2014

Urinary bladder ruptures (UBR) typically result from either blunt or penetrating trauma, or from iatrogenic surgical injuries. Patients typically present with symptoms including lower abdominal pain, haematuria, dysuria and anuria. Here, we report on a rare case of spontaneous bladder perforation. A 60-year-old, Caucasian woman initially presented with lower abdominal pain and diarrhoea, and was subsequently found to have an elevated serum creatinine level. A CT cystogram revealed a leak from the bladder. The patient consented to exploratory laparotomy and repair of the non-traumatic bladder perforation. At the time of the last follow-up, given the fact that the patient’s urodynamics were unremarkable and that she was emptying her bladder well (repeat postvoid residual was zero), the patient was informed that she did not require future urological follow-up unless difficulties arise.
Delayed presentation of an undiscovered nasopharyngeal foreign body
Authors: Ramdoo Krishan , Manjaly Joseph G , Tatla Taran
Published: June 2014

Suspected paediatric aerodigestive tract foreign body (FB) ingestion or aspiration is a commonly encountered emergency. Management may require a general anaesthetic for retrieval with bronchoscopy, laryngoscopy and oesophagoscopy, each dependent on the history and investigations of the case in question. We describe the case of a foreign body, which was missed in the nasopharynx for more than 3 years and also discuss how pressures on National Health Service (NHS) referral and follow-up patterns may have altered the time course of the eventual discovery.
An unusual presentation of peripheral ossifying fibroma in an elderly man
Authors: Parmar Yuvaraj Suryakant , Tarsariya Vivek Muljibhai , Jayam Cheranjeevi , Bandlapalli Anila
Published: June 2014

Peripheral ossifying fibroma is a common solitary gingival overgrowth thought to arise from the gingival corium, periosteum or periodontal ligament. Ossifying fibroma has the propensity to occur in cranial bones, but the peripheral variety shows a close relationship with the periodontal ligament and adjacent alveolar bone. It is more commonly seen in women (predilection of 3:1) and usually at a young age. This report describes an unusual presentation in an elderly man and presents a systematic way of diagnosing and treating peripheral ossifying fibroma.
Pneumococcal vaccine failure: Can it be a primary immunodeficiency?
Authors: Moinho Rita , Brett Ana , Ferreira Gisela , Lemos Sónia
Published: June 2014

Vaccine failure is a rare condition and the need to investigate a primary immunodeficiency is controversial. We present the case of a 4-year-old boy, with complete antipneumococcal vaccination, who had necrotising pneumonia with pleural effusion and severe pancytopaenia with need for transfusion. A vaccine-serotypeStreptococcus pneumoniaewas isolated in the blood culture. On follow-up, detailed medical history, laboratory and genetic investigation led to the diagnosis of X linked dyskeratosis congenita. Dyskeratosis congenita is an inherited disorder that causes shortening or dysfunction of telomeres, affecting mainly rapidly dividing cells (particularly in the skin and haematopoietic system). It leads to bone marrow failure, combined immunodeficiency and predisposition to cancer. The confirmation of this diagnosis allows genetic counselling and medical monitoring of these patients, in order to detect early complications such as bone marrow aplasia or malignancies.
User-generated quality standards for youth mental health in primary care: a participatory research design using mixed methods
Authors: Graham Tanya , Rose Diana , Murray Joanna , Ashworth Mark , Tylee André
Published: June 2014

Objectives

To develop user-generated quality standards for young people with mental health problems in primary care using a participatory research model.

Methods

50 young people aged 16–25 from community settings and primary care participated in focus groups and interviews about their views and experiences of seeking help for mental health problems in primary care, cofacilitated by young service users and repeated to ensure respondent validation. A second group of young people also aged 16–25 who had sought help for any mental health problem from primary care or secondary care within the last 5 years were trained as focus groups cofacilitators (n=12) developed the quality standards from the qualitative data and participated in four nominal groups (n=28).

Results

46 quality standards were developed and ranked by young service users. Agreement was defined as 100% of scores within a two-point region. Group consensus existed for 16 quality standards representing the following aspects of primary care: better advertising and information (three); improved competence through mental health training and skill mix within the practice (two); alternatives to medication (three); improved referral protocol (three); and specific questions and reassurances (five). Alternatives to medication and specific questions and reassurances are aspects of quality which have not been previously reported.

Conclusions

We have demonstrated the feasibility of using participatory research methods in order to develop user-generated quality standards. The development of patient-generated quality standards may offer a more formal method of incorporating the views of service users into quality improvement initiatives. This method can be adapted for generating quality standards applicable to other patient groups.
Reducing time to reperfusion for ST elevation myocardial infarction patients by a simple process change in the Emergency Department
Authors: Byrne Jill
Published: June 2014

Current reperfusion guidelines from the European Society of Cardiology (ESC) recommend that First Medical Contact to Balloon times (FMC-B) for ST elevation myocardial infarction (STEMI) should not exceed 120 minutes. Many factors can cause delay in door to balloon times for patients suffering from STEMI. Previous studies have found that longest times for FMC-B occur if the patient presents initially to a non-percutaneous intervention (PCI) capable hospital. As a non-PCI capable site we looked at ways of reducing FMC-B times. Audit revealed that registration to electrocardiogram (ECG) times were sometimes prolonged due to undertriage, long waiting times and lack of space and staff to record an ECG, resulting in some prolonged FMC-B times.

To address this, we have changed the system so that patients bypass triage and go directly to a dedicated investigation cubicle for an ECG. The patient books on at reception with chest pain and is immediately directed to the investigation cubicle. The ECG is reviewed immediately and the patient is either kept in the department for further management or allowed back to the waiting room to await triage if the ECG is non-diagnostic and history not worrying.

Data on patients presenting with STEMI on the initial ECG were collected for one year pre-intervention (n =21 )and one year post-intervention (n=17). The median FMC-B time for the pre-intervention group was 108.5 minutes (IQR 96 – 143.5). Median FMC-B time for the post-intervention group was 82 minutes (IQR 66.5 - 93.5).

This is a simple, low-cost intervention which could be transferable to other sites who have an interest in reducing FMC-B times. It is necessary to have a key person to carry out audit of all potential areas of delay, and a collaborative, multidisciplinary approach to making change to improve quality of care.
Application of smoothed continuous labile haemoglobin A1c reference intervals for identification of potentially spurious HbA1c results
Authors: Loh Tze Ping , Peng Weng Kung , Chen Lan , Sethi Sunil Kumar
Published: June 2014

Aims

We aim to develop smoothed continuous 2.5th and 97.5th percentile values for labile glycated haemoglobin A1cto glycated haemoglobin A1c(LHbA1c:HbA1c) ratio against HbA1c, and apply them on our patient population for identification of potentially spurious HbA1cmeasurements.

Methods

The LHbA1cand HbA1cwere measured using Bio-rad Variant II high-performance liquid chromatography system. We recorded the LHbA1cand HbA1cvalues of 1555 patients who had normal chromatograms. Using these results, the 2.5th and 97.5th percentile reference limits of the LHbA1c:HbA1cratio were described by LHbA1c:HbA1c=−0.0072×HbA1c+0.2925 and LHbA1c:HbA1c=−0.0132×HbA1c+0.5327, respectively.

Results

When the reference intervals were applied on a separate 1000 patients, 34 and 29 of them had abnormally high and low LHbA1c:HbA1cratios, respectively. Most of the observed high ratios were associated concurrently with elevated plasma glucose, anaemia, chronic liver and kidney diseases. A suppressed ratio was mostly associated with haemoglobin variants. Patients with heterozygous HbE or HbS variants tend to have lower LHbA1c:HbA1cratios while the converse is true for heterozygous HbJ.

Conclusions

The continuous LHbA1c:HbA1cratio may be used to detect confounding factors or spurious HbA1cresults, but its performance is confounded and reduced by the ambient plasma glucose.
Pressure conditions in the hole erosion test
Authors: Říha Jaromír , Jandora Jan
Published: June 2014

The hole erosion test (HET) is used in the study of soil erosion in the case of what is known as “piping” when concentrated leaks occur. The HET enables the determination of soil erosion characteristics such as the critical shear stress along the pre-formed hole (pipe) and the coefficient of soil erosion. Normally, in the HET, the hydraulic gradient is determined from the difference between the piezometric heads measured at the inflow and outflow chambers (upstream and downstream of the soil specimen). Hydraulic analysis shows that such measurements ignore losses at the entrance and exit of the hole, causing the overestimation of the hydraulic gradient along the length of the hole, and thus the calculated shear stress. In this technical note, the results of preliminary analysis using the Bernoulli principle and of numerical study of the pressure conditions in the HET apparatus are shown. The turbulent flow in the HET apparatus was calculated using ANSYS commercial CFD (computational fluid dynamics) software. The analysis was performed for various hole entrance shapes. The conclusion of this note details the differences between traditionally determined hydraulic gradients and those numerically derived along the length of a hole.
Movements and oceanographic associations of bigeye tuna (Thunnus obesus) in the Northwest Atlantic
Authors: Lam Chi Hin , Galuardi Benjamin , Lutcavage Molly E.
Published: June 2014

To address the lack of fisheries-independent information for Atlantic bigeye tuna (Thunnus obesus), we released 21 adults (131 ± 12 cm curved fork length) between 2008 and 2010 in the Sargasso Sea and Northwest Atlantic. Data from nine tags (range: 1–292 days; mean: 89 days) revealed (i) pronounced north–south movements in pelagic waters between areas including Georges Bank, Mid- and South Atlantic Bight, Caribbean Sea, and Brazilian shelf, (ii) a lack of east–west exchange, and (iii) a high-use area in the Hatteras Plain, centered southwest of Bermuda. Bigeye tuna occupied water masses of 2.7–28.2 °C and depths of 0–1280 m, with deeper depths in the daytime (daily mean ± standard deviation: 196 ± 92 m) than at nighttime (45 ± 29 m). Even though bigeye tuna are assumed to forage on the deep scattered layer during the day, generalized additive mixed models did not identify the deep scattered layer as an important predictor of daytime swimming depth. Model results highlight the importance of geographic location in influencing habitat utilization, and thus suggest the need for fisheries-independent monitoring in high-catch areas, such as the central and equatorial Atlantic.
KMS states on C*-algebras associated to local homeomorphisms
Authors: Afsar Zahra , an Huef Astrid , Raeburn Iain
Published: June 2014

For every Hilbert bimodule over a C*-algebra, there are natural gauge actions of the circle on the associated Toeplitz algebra and Cuntz–Pimsner algebra, and hence natural dynamics obtained by lifting these gauge actions to actions of the real line. We study the KMS states of these dynamics for a family of bimodules associated to local homeomorphisms on compact spaces. For inverse temperatures larger than a certain critical value, we find a large simplex of KMS states on the Toeplitz algebra, and we show that all KMS states on the Cuntz–Pimsner algebra have inverse temperature at most this critical value. We illustrate our results by considering the backward shift on the one-sided path space of a finite graph, where we can use recent results about KMS states on graph algebras to see what happens below the critical value. Our results about KMS states on the Cuntz–Pimsner algebra of the shift show that recent constraints on the range of inverse temperatures obtained by Thomsen are sharp.
Splitting a 4-manifold with infinite cyclic fundamental group, revised in a definite case
Authors: Kawauchi Akio
Published: June 2014

A sufficient condition that a closed connected definite 4-manifold with infinite cyclic fundamental group is TOP-split is given. By this condition, it is shown that every closed connected definite smooth 4-manifold with infinite cyclic fundamental group is TOP-split. By combining with an earlier result, it is confirmed that every closed connected oriented smooth 4-manifold with infinite cyclic fundamental group is TOP-split. This also implies that every smooth sphere-knot in a closed simply connected smooth 4-manifold is topologically unknotted if the fundamental group of the complement is infinite cyclic.
Cross-Sectional Return Predictability in Taiwan Stock Exchange: An Empirical Investigation
Authors: Cakici Nusret , Topyan Kudret , Wang Chia-Jane
Published: June 2014

This paper provides an analysis of the effectiveness of certain return predictors in Taiwan Stock Exchange (TWSE) from January 1990 to December 2011 by employing both portfolio method and cross-sectional regressions. While we found no statistically significant predictive power of beta, total volatility, and idiosyncratic volatility the two cheapness variables, book-to-market (BKMT) and cash-flow-to-price (FPR) ratios showed strong consistent economically and statistically significant predictive powers. In addition, our multiple regressions found predictive power in total volatility, short-term reversal (STREV), and market capitalization in the set of small stocks, while our all stock set showed predictive power only in total volatility and STREV.
Optimization of Pre-Tensioning Cable Forces in Highly Redundant Cable-Stayed Bridges
Authors: Asgari Banafsheh , Osman Siti Aminah , Bin Adnan Azlan
Published: June 2014

Cable-stayed bridges have been developing rapidly in the last decade and have become one of the most popular types of long-span bridges. One of the important issues in the design and analysis of cable-stayed bridges is determining the pre-tensioning cable forces that optimize the structural performance of the bridge. Appropriate pre-tensioning cable forces improve the damaging effect of unbalanced loading due to the deck dead load. Because the cable-stayed structure is a highly undetermined system, there is no unique solution for directly calculating the initial cable forces. Numerous studies have been conducted on the specification of cable pre-tensioning forces for cable-stayed bridges. However, most of the proposed methods are limited in their ability to optimize the structural performance. This paper presents an effective multi-constraint optimization strategy for cable-stayed bridges based on the application of an inverse problem through unit load method (ULM). The proposed method results in less stresses in the bridge members, more stability and a shorter simulation time than the existing approaches. The finite element (FE) model of the Tatara Bridge in Japan is considered in this study. The results show that the proposed method successfully restricts the pylon displacement and establishes a uniform deck moment distribution in the simulated cable-stayed bridge; thus, it might be a useful tool for designing other long-span cable-stayed bridges.
Constructing complete distinguished chains with given invariants
Authors: Aghigh Kamal , Nikseresht Azadeh
Published: June 2014

Let v be a henselian valuation of arbitrary rank of a field K with value group G(K) and residue field R(K) and [Formula: see text] be the unique extension of v to a fixed algebraic closure [Formula: see text] of K with value group [Formula: see text]. It is known that a complete distinguished chain for an element θ belonging to [Formula: see text] with respect to (K, v) gives rise to several invariants associated to θ, including a chain of subgroups of [Formula: see text], a tower of fields, together with a sequence of elements belonging to [Formula: see text] which are the same for all K-conjugates of θ. These invariants satisfy some fundamental relations. In this paper, we deal with the converse: Given a chain of subgroups of [Formula: see text] containing G(K), a tower of extension fields of R(K), and a finite sequence of elements of [Formula: see text] satisfying certain properties, it is shown that there exists a complete distinguished chain for an element [Formula: see text] associated to these invariants. We use the notion of lifting of polynomials to construct it.
Graph properties of co-maximal ideal graphs of commutative rings
Authors: Ye Meng , Wu Tongsuo , Liu Qiong , Guo Jin
Published: June 2014

In this paper, we determine the diameters of graphs [Formula: see text] and [Formula: see text] for a ring R with infinitely many maximal ideals. We also use graph blow-up to give a complete classification of rings R whose graphs [Formula: see text] are non-empty planar graphs.
New examples of asymptotically good Kummer type towers
Authors: Chara María , Toledano Ricardo
Published: June 2014

In this work, we give sufficient conditions in order to have finite ramification locus in sequences of function fields defined by different kind of Kummer extensions. These conditions can be easily implemented in a computer to generate several examples. We present some new examples of asymptotically good towers of Kummer type and we show that many known examples can be obtained from our general results.
Local multiplication maps on F[x]
Authors: Aceves Kelly , Dugas Manfred
Published: June 2014

Let F be a field and A a F-algebra. The F-linear transformation φ : A → A is a local multiplication map if for all a ∈ A there exists some ua ∈ A such that φ(a) = aua. Let [Formula: see text] denote the F-algebra of all local multiplication maps of A. If F is infinite and F[x] is the ring of polynomials over F, then it is known Lemma 1 in [J. Buckner and M. Dugas, Quasi-Localizations of ℤ, Israel J. Math.160 (2007) 349–370] that [Formula: see text]. The purpose of this paper is to study [Formula: see text] for finite fields F. It turns out that in this case [Formula: see text] is a "very" non-commutative ring of cardinality 2ℵ0 with many interesting properties.
Quaternion quadratic equations in characteristic 2
Authors: Chapman Adam
Published: June 2014

In this paper, we present a solution for any standard quaternion quadratic equation, i.e. an equation of the form z2 + μz + ν = 0 where μ and ν belong to some quaternion division algebra Q over some field F, assuming the characteristic of F is 2.