bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis C Virus NS4B Can Suppress STING Accumulation To Evade Innate Immune Responses
Authors: Yi Guanghui , Wen Yahong , Shu Chang , Han Qingxia , Konan Kouacou V. , Li Pingwei , Kao C. Cheng
Published: October 2015

The cyclic dinucleotide 2′,3′-cGAMP can bind the adaptor protein STING (stimulator of interferon [IFN] genes) to activate the production of type I IFNs and proinflammatory cytokines. We found that cGAMP added to the culture medium could suppress the replication of the hepatitis C virus (HCV) genotype 1b strain Con1 subgenomic replicon in human hepatoma cells. Knockdown of STING expression diminished the inhibitory effect on replicon replication, while overexpression of STING enhanced the inhibitory effects of cGAMP. The addition of cGAMP into 1b/Con1 replicon cells significantly increased the expression of type I IFNs and antiviral interferon-stimulated genes. Unexpectedly, replication of the genotype 2a JFH1 replicon and infectious JFH1 virus was less sensitive to the inhibitory effect of cGAMP than was that of 1b/Con1 replicon. Using chimeric replicons, 2a NS4B was identified to confer resistance to cGAMP. Transient expression of 2a NS4B resulted in a pronounced inhibitory effect on STING-mediated beta IFN (IFN-β) reporter activation compared to that of 1b NS4B. 2a NS4B was found to suppress STING accumulation in a dose-dependent manner. The predicted transmembrane domain of 2a NS4B was required to inhibit STING accumulation. These results demonstrate a novel genotype-specific inhibition of the STING-mediated host antiviral immune response.

IMPORTANCE
The cyclic dinucleotide cGAMP was found to potently inhibit the replication of HCV genotype 1b Con1 replicon but was less effective for the 2a/JFH1 replicon and infectious JFH1 virus. The predicted transmembrane domain in 2a NS4B was shown to be responsible for the decreased sensitivity to cGAMP. The N terminus of NS4B has been reported to suppress STING-mediated signaling by disrupting the interaction of STING and TBK1 and/or MAVS. We show that 2a/JFH1 NS4B has an additional mechanism to evade STING signaling through suppressing STING accumulation.
Comparative Efficacy of Monoclonal Antibodies That Bind to Different Epitopes of the 2009 Pandemic H1N1 Influenza Virus Neuraminidase
Authors: Jiang Lianlian , Fantoni Giovanna , Couzens Laura , Gao Jin , Plant Ewan , Ye Zhiping , Eichelberger Maryna C. , Wan Hongquan
Published: October 2015

Antibodies against the neuraminidase (NA) of influenza virus correlate with resistance against disease, but the effectiveness of antibodies against different NA epitopes has not been compared. In the present study, we evaluated the
in vitro
and
in vivo
efficacies of four monoclonal antibodies (MAbs): HF5 and CD6, which are specific to two different epitopes in the NA of 2009 pandemic H1N1 (pH1N1) virus, and 4E9 and 1H5, which are specific to a conserved epitope in the NA of both H1N1 and H5N1 viruses. In the
in vitro
assays, HF5 and CD6 inhibited virus spread and growth more effectively than 4E9 and 1H5, with HF5 being the most effective inhibitor. When administered prophylactically at 5 mg/kg of body weight, HF5 and CD6 protected ∼90 to 100% of DBA/2 mice against lethal wild-type pH1N1 virus challenge; however, at a lower dose (1 mg/kg), HF5 protected ∼90% of mice, whereas CD6 protected only 25% of mice. 4E9 and 1H5 were less effective than HF5 and CD6, as indicated by the partial protection achieved even at doses as high as 15 mg/kg. When administered therapeutically, HF5 protected a greater proportion of mice against lethal pH1N1 challenge than CD6. However, HF5 quickly selected pH1N1 virus escape mutants in both prophylactic and therapeutic treatments, while CD6 did not. Our findings confirm the important role of NA-specific antibodies in immunity to influenza virus and provide insight into the properties of NA antibodies that may serve as good candidates for therapeutics against influenza.

IMPORTANCE
Neuraminidase (NA) is one of the major surface proteins of influenza virus, serving as an important target for antivirals and therapeutic antibodies. The impact of NA-specific antibodies on NA activity and virus replication is likely to depend on where the antibody binds. Using
in vitro
assays and the mouse model, we compared the inhibitory/protective efficacy of four mouse monoclonal antibodies (MAbs) that bind to different sites within the 2009 pandemic H1N1 (pH1N1) virus NA. The ability of each MAb to protect mice against lethal pH1N1 infection corresponded to its ability to inhibit NA activity
in vitro
; however, the MAb that was the most effective inhibitor of NA activity selected pH1N1 escape variants
in vivo
. One of the tested MAbs, which binds to a conserved region in the NA of pH1N1 virus, inhibited NA activity but did not result in escape variants, highlighting its suitability for development as a therapeutic agent.
Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin
Authors: Brazzoli Michela , Magini Diletta , Bonci Alessandra , Buccato Scilla , Giovani Cinzia , Kratzer Roland , Zurli Vanessa , Mangiavacchi Simona , Casini Daniele , Brito Luis M. , De Gregorio Ennio , Mason Peter W. , Ulmer Jeffrey B. , Geall Andrew J. , Bertholet Sylvie
Published: October 2015

Seasonal influenza is a vaccine-preventable disease that remains a major health problem worldwide, especially in immunocompromised populations. The impact of influenza disease is even greater when strains drift, and influenza pandemics can result when animal-derived influenza virus strains combine with seasonal strains. In this study, we used the SAM technology and characterized the immunogenicity and efficacy of a self-amplifying mRNA expressing influenza virus hemagglutinin (HA) antigen [SAM(HA)] formulated with a novel oil-in-water cationic nanoemulsion. We demonstrated that SAM(HA) was immunogenic in ferrets and facilitated containment of viral replication in the upper respiratory tract of influenza virus-infected animals. In mice, SAM(HA) induced potent functional neutralizing antibody and cellular immune responses, characterized by HA-specific CD4 T helper 1 and CD8 cytotoxic T cells. Furthermore, mice immunized with SAM(HA) derived from the influenza A virus A/California/7/2009 (H1N1) strain (Cal) were protected from a lethal challenge with the heterologous mouse-adapted A/PR/8/1934 (H1N1) virus strain (PR8). Sera derived from SAM(H1-Cal)-immunized animals were not cross-reactive with the PR8 virus, whereas cross-reactivity was observed for HA-specific CD4 and CD8 T cells. Finally, depletion of T cells demonstrated that T-cell responses were essential in mediating heterologous protection. If the SAM vaccine platform proves safe, well tolerated, and effective in humans, the fully synthetic SAM vaccine technology could provide a rapid response platform to control pandemic influenza.

IMPORTANCE
In this study, we describe protective immune responses in mice and ferrets after vaccination with a novel HA-based influenza vaccine. This novel type of vaccine elicits both humoral and cellular immune responses. Although vaccine-specific antibodies are the key players in mediating protection from homologous influenza virus infections, vaccine-specific T cells contribute to the control of heterologous infections. The rapid production capacity and the synthetic origin of the vaccine antigen make the SAM platform particularly exploitable in case of influenza pandemic.
Ebolavirus Glycoprotein Directs Fusion through NPC1
+
Endolysosomes
Authors: Simmons James A. , D'Souza Ryan S. , Ruas Margarida , Galione Antony , Casanova James E. , White Judith M.
Published: October 2015

Ebolavirus, a deadly hemorrhagic fever virus, was thought to enter cells through endolysosomes harboring its glycoprotein receptor, Niemann-Pick C1. However, an alternate model was recently proposed in which ebolavirus enters through a later NPC1-negative endosome that contains two-pore Ca
2+
channel 2 (TPC2), a newly identified ebolavirus entry factor. Here, using live cell imaging, we obtained evidence that in contrast to the new model, ebolavirus enters cells through endolysosomes that contain both NPC1 and TPC2.
The Phosphatidylserine and Phosphatidylethanolamine Receptor CD300a Binds Dengue Virus and Enhances Infection
Authors: Carnec Xavier , Meertens Laurent , Dejarnac Ophélie , Perera-Lecoin Manuel , Hafirassou Mohamed Lamine , Kitaura Jiro , Ramdasi Rasika , Schwartz Olivier , Amara Ali
Published: October 2015

Dengue virus (DENV) is the etiological agent of the major human arboviral disease. We previously demonstrated that the TIM and TAM families of phosphatidylserine (PtdSer) receptors involved in the phagocytosis of apoptotic cells mediate DENV entry into target cells. We show here that human CD300a, a recently identified phospholipid receptor, also binds directly DENV particles and enhances viral entry. CD300a facilitates infection of the four DENV serotypes, as well as of other mosquito-borne viruses such as West Nile virus and Chikungunya virus. CD300a acts as an attachment factor that enhances DENV internalization through clathrin-mediated endocytosis. CD300a recognizes predominantly phosphatidylethanolamine (PtdEth) and to a lesser extent PtdSer associated with viral particles. Mutation of residues in the IgV domain critical for phospholipid binding abrogate CD300a-mediated enhancement of DENV infection. Finally, we show that CD300a is expressed at the surface of primary macrophages and anti-CD300a polyclonal antibodies partially inhibited DENV infection of these cells. Overall, these data indicate that CD300a is a novel DENV binding receptor that recognizes PtdEth and PtdSer present on virions and enhance infection.

IMPORTANCE
Dengue disease, caused by dengue virus (DENV), has emerged as the most important mosquito-borne viral disease of humans and is a major global health concern. The molecular bases of DENV-host cell interactions during virus entry are poorly understood, hampering the discovery of new targets for antiviral intervention. We recently discovered that the TIM and TAM proteins, two receptor families involved in the phosphatidylserine (PtdSer)-dependent phagocytic removal of apoptotic cells, interact with DENV particles-associated PtdSer through a mechanism that mimics the recognition of apoptotic cells and mediate DENV infection. In this study, we show that CD300a, a novel identified phospholipid receptor, mediates DENV infection. CD300a-dependent DENV infection relies on the direct recognition of phosphatidylethanolamine and to a lesser extent PtdSer associated with viral particles. This study provides novel insights into the mechanisms that mediate DENV entry and reinforce the concept that DENV uses an apoptotic mimicry strategy for viral entry.
Natural Killer Cells and Innate Interferon Gamma Participate in the Host Defense against Respiratory Vaccinia Virus Infection
Authors: Abboud Georges , Tahiliani Vikas , Desai Pritesh , Varkoly Kyle , Driver John , Hutchinson Tarun E. , Salek-Ardakani Shahram
Published: October 2015

In establishing a respiratory infection, vaccinia virus (VACV) initially replicates in airway epithelial cells before spreading to secondary sites of infection, mainly the draining lymph nodes, spleen, gastrointestinal tract, and reproductive organs. We recently reported that interferon gamma (IFN-γ) produced by CD8 T cells ultimately controls this disseminated infection, but the relative contribution of IFN-γ early in infection is unknown. Investigating the role of innate immune cells, we found that the frequency of natural killer (NK) cells in the lung increased dramatically between days 1 and 4 postinfection with VACV. Lung NK cells displayed an activated cell surface phenotype and were the primary source of IFN-γ prior to the arrival of CD8 T cells. In the presence of an intact CD8 T cell compartment, depletion of NK cells resulted in increased lung viral load at the time of peak disease severity but had no effect on eventual viral clearance, disease symptoms, or survival. In sharp contrast, RAG−/−mice devoid of T cells failed to control VACV and succumbed to infection despite a marked increase in NK cells in the lung. Supporting an innate immune role for NK cell-derived IFN-γ, we found that NK cell-depleted or IFN-γ-depleted RAG−/−mice displayed increased lung VACV titers and dissemination to ovaries and a significantly shorter mean time to death compared to untreated NK cell-competent RAG−/−controls. Together, these findings demonstrate a role for IFN-γ in aspects of both the innate and adaptive immune response to VACV and highlight the importance of NK cells in T cell-independent control of VACV in the respiratory tract.

IMPORTANCEHerein, we provide the first systematic evaluation of natural killer (NK) cell function in the lung after infection with vaccinia virus, a member of thePoxviridaefamily. The respiratory tract is an important mucosal site for entry of many human pathogens, including poxviruses, but precisely how our immune system defends the lung against these invaders remains unclear. Natural killer cells are a type of cytotoxic lymphocyte and part of our innate immune system. In recent years, NK cells have received increasing levels of attention following the discovery that different tissues contain specific subsets of NK cells with distinctive phenotypes and function. They are abundant in the lung, but their role in defense against respiratory viruses is poorly understood. What this study demonstrates is that NK cells are recruited, activated, and contribute to protection of the lung during a severe respiratory infection with vaccinia virus.
Interaction between ORF24 and ORF34 in the Kaposi's Sarcoma-Associated Herpesvirus Late Gene Transcription Factor Complex Is Essential for Viral Late Gene Expression
Authors: Davis Zoe H. , Hesser Charles R. , Park Jimin , Glaunsinger Britt A.
Published: October 2015

Transcription of herpesviral late genes is stimulated after the onset of viral DNA replication but otherwise restricted. Late gene expression in gammaherpesviruses requires the coordination of six early viral proteins, termed viral transactivation factors (vTFs). Here, we mapped the organization of this protein complex for Kaposi's sarcoma-associated herpesvirus. Disruption of this complex via point mutation of the interaction interface between the open reading frame 24 (ORF24) and ORF34 vTFs ablated both late gene expression and viral replication.
The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II
Authors: Quinn Laura L. , Williams Luke R. , White Claire , Forrest Calum , Zuo Jianmin , Rowe Martin
Published: October 2015

The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8+cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8+cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8+cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4+cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8+and CD4+T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner.

IMPORTANCEImmune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8+T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8+T cells specific for early lytic cycle antigens. The present work identifies an additional immune evasion protein, BDLF3, that is expressed late in the lytic cycle and impairs CD8+T cell recognition by targeting cell surface MHC class I molecules for ubiquitination and proteasome-dependent downregulation. Interestingly, BDLF3 also targets MHC class II molecules to impair CD4+T cell recognition. BDLF3 is therefore a rare example of a viral protein that impairs both the MHC class I and class II antigen-presenting pathways.
Dynamic Response of IFI16 and Promyelocytic Leukemia Nuclear Body Components to Herpes Simplex Virus 1 Infection
Authors: Everett Roger D.
Published: October 2015

Intrinsic immunity is an aspect of antiviral defense that operates through diverse mechanisms at the intracellular level through a wide range of constitutively expressed cellular proteins. In the case of herpesviruses, intrinsic resistance involves the repression of viral gene expression during the very early stages of infection, a process that is normally overcome by viral tegument and/or immediate-early proteins. Thus, the balance between cellular repressors and virus-counteracting proteins determines whether or not a cell becomes productively infected. One aspect of intrinsic resistance to herpes simplex virus 1 (HSV-1) is conferred by components of promyelocytic leukemia nuclear bodies (PML NBs), which respond to infection by accumulating at sites that are closely associated with the incoming parental HSV-1 genomes. Other cellular proteins, including IFI16, which has been implicated in sensing pathogen DNA and initiating signaling pathways that lead to an interferon response, also respond to viral genomes in this manner. Here, studies of the dynamics of the response of PML NB components and IFI16 to invading HSV-1 genomes demonstrated that this response is extremely rapid, occurring within the first hour after addition of the virus, and that human Daxx (hDaxx) and IFI16 respond more rapidly than PML. In the absence of HSV-1 regulatory protein ICP0, which counteracts the recruitment process, the newly formed, viral-genome-induced PML NB-like foci can fuse with existing PML NBs. These data are consistent with a model involving viral genome sequestration into such structures, thereby contributing to the low probability of initiation of lytic infection in the absence of ICP0.

IMPORTANCE
Herpesviruses have intimate interactions with their hosts, with infection leading either to the productive lytic cycle or to a quiescent infection in which viral gene expression is suppressed while the viral genome is maintained in the host cell nucleus. Whether a cell becomes lytically or quiescently infected can be determined through the competing activities of cellular repressors and viral activators, some of which counteract cell-mediated repression. Therefore, the events that occur within the earliest stages of infection can be of crucial importance. This paper describes the extremely rapid response to herpes simplex virus 1 infection of cellular protein IFI16, a sensor of pathogen DNA, and also of the PML nuclear body proteins PML and hDaxx, as revealed by live-cell microscopy. The data imply that these proteins can accumulate on or close to the viral genomes in a sequential manner which may lead to their sequestration and repression.
Interferon-Regulatory Factor 5-Dependent Signaling Restricts Orthobunyavirus Dissemination to the Central Nervous System
Authors: Proenca-Modena Jose Luiz , Hyde Jennifer L. , Sesti-Costa Renata , Lucas Tiffany , Pinto Amelia K. , Richner Justin M. , Gorman Matthew J. , Lazear Helen M. , Diamond Michael S.
Published: October 2015

Interferon (IFN)-regulatory factor 5 (IRF-5) is a transcription factor that induces inflammatory responses after engagement and signaling by pattern recognition receptors. To define the role of IRF-5 during bunyavirus infection, we evaluated Oropouche virus (OROV) and La Crosse virus (LACV) pathogenesis and immune responses in primary cells and in mice with gene deletions in
Irf3
,
Irf5
, and
Irf7
or in
Irf5
alone. Deletion of
Irf3
,
Irf5
, and
Irf7
together resulted in uncontrolled viral replication in the liver and spleen, hypercytokinemia, extensive liver injury, and an early-death phenotype. Remarkably, deletion of
Irf5
alone resulted in meningoencephalitis and death on a more protracted timeline, 1 to 2 weeks after initial OROV or LACV infection. The clinical signs in OROV-infected
Irf5
−/−
mice were associated with abundant viral antigen and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in several regions of the brain. Circulating dendritic cell (DC) subsets in
Irf5
−/−
mice had higher levels of OROV RNA
in vivo
yet produced lower levels of type I IFN than wild-type (WT) cells. This result was supported by data obtained
in vitro
, since a deficiency of IRF-5 resulted in enhanced OROV infection and diminished type I IFN production in bone marrow-derived DCs. Collectively, these results indicate a key role for IRF-5 in modulating the host antiviral response in peripheral organs that controls bunyavirus neuroinvasion in mice.

IMPORTANCE
Oropouche virus (OROV) and La Crosse virus (LACV) are orthobunyaviruses that are transmitted by insects and cause meningitis and encephalitis in subsets of individuals in the Americas. Recently, we demonstrated that components of the type I interferon (IFN) induction pathway, particularly the regulatory transcription factors IRF-3 and IRF-7, have key protective roles during OROV infection. However, the lethality in
Irf3
−/−
Irf7
−/−
(DKO) mice infected with OROV was not as rapid or complete as observed in
Ifnar
−/−
mice, indicating that other transcriptional factors associated with an IFN response contribute to antiviral immunity against OROV. Here, we evaluated bunyavirus replication, tissue tropism, and cytokine production in primary cells and mice lacking IRF-5. We demonstrate an important role for IRF-5 in preventing neuroinvasion and the ensuing encephalitis caused by OROV and LACV.
Parameters of Mosquito-Enhanced West Nile Virus Infection
Authors: Moser Lindsey A. , Lim Pei-Yin , Styer Linda M. , Kramer Laura D. , Bernard Kristen A.
Published: October 2015

The arthropod-borne West Nile virus (WNV) emerged in New York State in 1999 and quickly spread throughout the United States. Transmission is maintained in an enzootic cycle in which infected mosquitoes transmit the virus to susceptible hosts during probing and feeding. Arthropod-derived components within the viral inoculum are increasingly acknowledged to play a role in infection of vertebrate hosts. We previously showed that
Culex tarsalis
mosquito saliva and salivary gland extract (SGE) enhance the
in vivo
replication of WNV. Here, we characterized the effective dose, timing, and proximity of saliva and SGE administration necessary for enhancement of WNV viremia using a mouse model. Mosquito saliva and SGE enhanced viremia in a dose-dependent manner, and a single mosquito bite or as little as 0.01 μg of SGE was effective at enhancing viremia, suggesting a potent active salivary factor. Viremia was enhanced when SGE was injected in the same location as virus inoculation from 24 h before virus inoculation through 12 h after virus inoculation. These results were confirmed with mosquito saliva deposited by uninfected mosquitoes. When salivary treatment and virus inoculation were spatially separated, viremia was not enhanced. In summary, the effects of mosquito saliva and SGE were potent, long lasting, and localized, and these studies have implications for virus transmission in nature, where vertebrate hosts are fed upon by both infected and uninfected mosquitoes over time. Furthermore, our model provides a robust system to identify the salivary factor(s) responsible for enhancement of WNV replication.

IMPORTANCE
Mosquito-borne viruses are a significant class of agents causing emerging infectious diseases. WNV has caused over 18,000 cases of neuroinvasive disease in the United States since its emergence. We have shown that
Culex tarsalis
mosquito saliva and SGE enhance the replication of WNV. We now demonstrate that saliva and SGE have potent, long-lasting, and localized effects. Our model provides a robust system to identify the salivary factor(s) and characterize the mechanism responsible for enhancement of WNV replication. These studies could lead to the identification of novel prophylactic or treatment options useful in limiting the spread of WNV, other mosquito-borne viruses, and the diseases that they cause.
M2 Macrophages Play Critical Roles in Progression of Inflammatory Liver Disease in Hepatitis C Virus Transgenic Mice
Authors: Ohtsuki Takahiro , Kimura Kiminori , Tokunaga Yuko , Tsukiyama-Kohara Kyoko , Tateno Chise , Hayashi Yukiko , Hishima Tsunekazu , Kohara Michinori
Published: October 2015

Macrophages in liver tissue are widely defined as important inflammatory cells in chronic viral hepatitis due to their proinflammatory activity. We reported previously that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) play significant roles in causing chronic hepatitis in hepatitis C virus (HCV) transgenic mice (S. Sekiguchi et al., PLoS One
7:
e51656, 2012,
http://dx.doi.org/10.1371/journal.pone.0051656
). In addition, we showed that recombinant vaccinia viruses expressing an HCV nonstructural protein (rVV-N25) could protect against the progression of chronic hepatitis by suppression of macrophage activation. Here, we focus on the role of macrophages in liver disease progression in HCV transgenic mice and examine characteristic features of macrophages following rVV-N25 treatment. The number of CD11b
+
F4/80
+
CD11c
−
CD206
+
(M2) macrophages in the liver of HCV transgenic mice was notably increased compared to that of age-matched control mice. These M2 macrophages in the liver produced elevated levels of IL-6 and TNF-α. rVV-N25 infection suppressed the number and activation of M2 macrophages in liver tissue. These results suggested that inflammatory cytokines produced by M2-like macrophages contribute to the induction of chronic liver inflammation in HCV transgenic mice. Moreover, the therapeutic effect of rVV-N25 might be induced by the suppression of the number and activation of hepatic macrophages.

IMPORTANCE
HCV causes persistent infections that can lead to chronic liver diseases, liver fibrosis, and hepatocellular carcinoma; the search for an HCV curative is the focus of ongoing research. Recently, effective anti-HCV drugs have been developed; however, vaccine development still is required for the prevention and therapy of infection by this virus. We demonstrate here that M2 macrophages are important for the pathogenesis of HCV-caused liver diseases and additionally show that M2 macrophages contribute to the therapeutic mechanism observed following rVV-N25 treatment.
Kaposi's Sarcoma-Associated Herpesvirus Reduces Cellular Myeloid Differentiation Primary-Response Gene 88 (MyD88) Expression via Modulation of Its RNA
Authors: Lingel Amy , Ehlers Erica , Wang Qianli , Cao Mingxia , Wood Charles , Lin Rongtuan , Zhang Luwen
Published: October 2015

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a human gammaherpesvirus associated with several human malignancies. The replication and transcription activator (RTA) is necessary and sufficient for the switch from KSHV latency to lytic replication. Interleukin 1 (IL-1) is a major mediator for inflammation and plays an important role in both innate and adaptive immunity. Myeloid differentiation primary response gene 88 (MyD88) is an essential adaptor molecule for IL-1 as well as most Toll-like receptor signaling. In this study, we identified a novel mechanism by which KSHV interferes with host inflammation and immunity. KSHV RTA specifically reduces the steady-state protein levels of MyD88, and physiological levels of MyD88 are downregulated during KSHV lytic replication when RTA is expressed. The N-terminal region of RTA is required for the reduction of MyD88. Additional studies demonstrated that RTA targets MyD88 expression at the RNA level, inhibits RNA synthesis of MyD88, and may bind MyD88 RNA. Finally, RTA inhibits IL-1-mediated activation of NF-κB. Because IL-1 is abundant in the KS microenvironment and inhibits KSHV replication, this work may expand our understanding of how KSHV evades host inflammation and immunity for its survival
in vivo
.

IMPORTANCE
MyD88 is an important molecule for IL-1-mediated inflammation and Toll-like receptor (TLR) signaling. This work shows that KSHV inhibits MyD88 expression through a novel mechanism. KSHV RTA may bind to MyD88 RNA, suppresses RNA synthesis of MyD88, and inhibits IL-1-mediated signaling. This work may expand our understanding of how KSHV evades host inflammation and immunity.
Test Sample Oriented Dictionary Learning for Face Recognition
Authors: Li Zhengming
Published: October 2015

Dictionary learning (DL) algorithms have shown very good performance in face recognition. However, conventional DL algorithms exploit only the training samples to obtain the dictionary and totally neglect the test sample in the learning procedure. As a result, if DL is associated with the linear representation of test sample, DL may be able to perform better in classifying the test samples than conventional DL algorithms. In this paper, we propose a test sample oriented dictionary learning (TSODL) algorithm for face recognition. We combine the linear representation (including the [Formula: see text]-norm, [Formula: see text]-norm and [Formula: see text]-norm) of a test sample and the basic model of DL to learn a single dictionary for each test sample. Thus, it can simultaneously obtain the dictionary and representation coefficients of the test sample by minimizing only one objective function. In order to make the learning procedure more efficient, we initialize a dictionary for the new test sample by selecting from the dictionaries of previous test samples. The experimental results show that the TSODL algorithm can classify test samples more accurately than some of the state-of-the-art DL and sparse coding algorithms by using a linear classifier method on three public face databases.
Estimating Multidimensional Persistent Homology Through a Finite Sampling
Authors: Cavazza Niccolò , Ferri Massimo , Landi Claudia
Published: October 2015

An exact computation of the persistent Betti numbers of a submanifold [Formula: see text] of a Euclidean space is possible only in a theoretical setting. In practical situations, only a finite sample of [Formula: see text] is available. We show that, under suitable density conditions, it is possible to estimate the multidimensional persistent Betti numbers of [Formula: see text] from the ones of a union of balls centered on the sample points; this even yields the exact value in restricted areas of the domain.

Using these inequalities we improve a previous lower bound for the natural pseudodistance to assess dissimilarity between the shapes of two objects from a sampling of them.

Similar inequalities are proved for the multidimensional persistent Betti numbers of the ball union and the one of a combinatorial description of it.
Built-in inflation in f(G) gravity
Authors: Sharif M. , Fatima H. Ismat
Published: October 2015

In this paper, we study the role of Gauss–Bonnet term for the early and late time accelerating phases of the universe with the help of two viable [Formula: see text] models in the background of flat FRW universe model. These models show inflationary behavior as well as the present accelerating expansion of the universe. The contribution of Gauss–Bonnet term in pressure and energy density is used to calculate equation of state (EoS) parameter for the modified fluid which behaves like cosmological constant with [Formula: see text]. We discuss early inflation and late accelerating expansion of the universe through scale factor evaluated from equation of continuity numerically.
Nuclear particle decay in a multi-MeV beam ejected by pulsed-laser impact on ultra-dense hydrogen H(0)
Authors: Holmlid Leif
Published: October 2015

The multi-MeV particles ejected from pulsed laser-induced processes in ultra-dense hydrogen H(0) are observed in vacuum at three different distances up to 2[Formula: see text]m from the laser target. In previous publications, massive neutral particles with energy of 1–30[Formula: see text]MeV[Formula: see text]u[Formula: see text] were identified. Direct energy spectra of the particles show energies well above 1[Formula: see text]MeV. The particles studied here interact with metallic collectors and give signals due to several processes like secondary electron emission and lepton pair production (published). Two experimental facts are immediate: (1) the signal per sr at large distance is up to 10 times higher than at short distance, (2) the signal at large distance is faster in real time than at short distance. These results show directly that the signal at long distance is mainly due to a mixture of intermediate particles formed by decay in the beam. The decaying signals have time constants of approximately 12 and 26[Formula: see text]ns for ultra-dense deuterium D(0) and 52 ns for ultra-dense protium p(0). These decay time constants agree well with those for decay of light mesons. These particles with narrow MeV energy distributions are formed by stepwise decay from particles like H[Formula: see text](0). The main result is that a decaying particle flux is formed by the laser-induced processes. The final muons produced may be useful for muon catalyzed fusion.
APPROXIMATION BY ABSOLUTELY CONTINUOUS INVARIANT MEASURES OF ITERATED FUNCTION SYSTEMS WITH PLACE-DEPENDENT PROBABILITIES
Authors: ISLAM MD SHAFIQUL , CHANDLER STEPHEN
Published: October 2015

Let [Formula: see text] be the attractor (fractal) of a contractive iterated function system (IFS) with place-dependent probabilities. An IFS with place-dependent probabilities is a random map [Formula: see text] where the probabilities [Formula: see text] of switching from one transformation to another are functions of positions, that is, at each step, the random map [Formula: see text] moves the point [Formula: see text] to [Formula: see text] with probability [Formula: see text]. If the random map [Formula: see text] has a unique invariant measure [Formula: see text], then the support of [Formula: see text] is the attractor [Formula: see text]. For a bounded region [Formula: see text], we prove the existence of a sequence [Formula: see text] of IFSs with place-dependent probabilities whose invariant measures [Formula: see text] are absolutely continuous with respect to Lebesgue measure. Moreover, if [Formula: see text] is a compact metric space, we prove that [Formula: see text] converges weakly to [Formula: see text] as [Formula: see text] We present examples with computations.
Landscape and geotourism on the Dutch coast in the seventeenth century as depicted by landscape artists
Authors: van den Ancker J. A. M. Hanneke , Jungerius Pieter Dirk
Published: October 2015

The first evidence of tourism on the Dutch coast can be found in drawings and etchings from the end of the sixteenth century. In this period Holland developed into one of the most urbanized regions of Europe. The interest in landscape originated in the towns. The first scenes depicted are those of mass tourism on the beach: sensation-mongers drawn to the beach by whales, sailing cars and departing kings and queens. Somewhat later the dune landscape became a main recreational focus, in which the physical aspects of the landscape were also appreciated. Around the town of Haarlem, individuals and small groups of people started exploring the dune landscape. In the wake of this new interest, landscape painting developed as an artistic genre. It became the most popular genre in the first half of the seventeenth century, and Haarlem developed as a centre for landscape painters. This paper discusses geomorphological features and geotourism engagement as depicted in several of the early etchings and landscape paintings.
Sclerorhynchus atavus
and the convergent evolution of rostrum-bearing chondrichthyans
Authors: Underwood Charlie , Smith Moya Meredith , Johanson Zerina
Published: October 2015

The description of a partial but well-preserved head of the sclerorhynchid batoid
Sclerorhynchus atavus
Woodward, 1889 gave the first clear indication of the presence of a puzzling group of extinct rostrum-bearing rays that resembled both the Pristidae (rays) and the Pristophoridae (sharks). Despite recognizing similarities to and differences from these extant groups, Smith Woodward suggested that
Sclerorhynchus
be assigned to the Pristidae, although acknowledging that the rostra are very different. Smith Woodward did note similarities of
Sclerorhynchus
rostrum saw-teeth to those of the Pristiophoridae, including the location of these along the margin of the rostrum, rather than in deep sockets as seen along the pristid rostrum. In addition, the type specimen of
Sclerorhynchus
has not only very distinct saw-tooth denticles along the rostrum, but also modified denticles along the sides of the head, as in the Pristiophoridae. The enlarged rostral denticles of
Sclerorhynchus
also appear to rotate into position, another feature seen in the pristiophorids but not in the pristids nor in other sclerorhynchids such as
Libanopristis
. Although individual fossil rostral tooth-like denticles had been described earlier, Smith Woodward's description of a rostrum and associated rostral tooth-like denticles meant that for the first time a fossil rostrum could be compared with living forms.
Cochliodonts and chimaeroids: Arthur Smith Woodward and the holocephalians
Authors: Duffin Christopher J.
Published: October 2015

Fossil chondrichthyan teeth played an important part in the establishment of a scientific understanding of ‘formed stones’. Following a slowly emerging taxonomy, Louis Agassiz presented the first comprehensive guide to Palaeozoic chondrichthyans in the 1830s. The next contribution of any substance was Arthur Smith Woodward's
Catalogue of Fossil Fishes in the British Museum (Natural History)
with a historical, descriptive and systematic review of the chondrichthyans, a group on which he already had an impressively large publication record. Initially stimulated by his observations on an articulated petalodont dentition (
Climaxodus
), Smith Woodward erected the Bradyodonti in 1921. Defined on the possession of dentitions with very slow growth rates, only seven or eight successional teeth produced throughout the lifetime of the fish, and retention rather than shedding of earlier teeth, primarily by fusion to later ones, the bradyodonts embraced petalodonts, psammodonts, copodonts and cochliodonts. The establishment and subsequent demise of the bradyodonts is briefly reviewed here.
Stimulation of gastric acid secretion by rabbit parietal cell A2B adenosine receptor activation
Authors: Arin Rosa María , Vallejo Ana Isabel , Rueda Yuri , Fresnedo Olatz , Ochoa Begoña
Published: October 2015

Adenosine modulates different functional activities in many cells of the gastrointestinal tract; some of them are believed to be mediated by interaction with its four G protein-coupled receptors. The renewed interest in the adenosine A2B receptor (A2BR) subtype can be traced by studies in which the introduction of new genetic and chemical tools has widened the pharmacological and structural knowledge of this receptor as well as its potential therapeutic use in cancer and inflammation- or hypoxia-related pathologies. In the acid-secreting parietal cells of the gastric mucosa, the use of various radioligands for adenosine receptors suggested the presence of the A2 adenosine receptor subtype(s) on the cell surface. Recently, we confirmed A2BR expression in native, nontransformed parietal cells at rest by using flow cytometry and confocal microscopy. In this study, we show that A2BR is functional in primary rabbit gastric parietal cells, as indicated by the fact that agonist binding to A2BR increased adenylate cyclase activity and acid production. In addition, both acid production and radioligand binding of adenosine analogs to isolated cell membranes were potently blocked by selective A2BR antagonists, whereas ligands for A1, A2A, and A3 adenosine receptors failed to abolish activation. We conclude that rabbit gastric parietal cells possess functional A2BR proteins that are coupled to Gs and stimulate HCl production upon activation. Whether adenosine- and A2BR-mediated functional responses play a role in human gastric pathophysiology is yet to be elucidated.
Role of endothelin-1 in mediating changes in cardiac sympathetic nerve activity in heart failure
Authors: Abukar Yonis , May Clive N. , Ramchandra Rohit
Published: October 2015

Heart failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan (a nonselective ETA and ETB receptor antagonist) (8 mg·kg−1·h−1) on resting levels of CSNA, arterial pressure, and heart rate were determined in conscious normal sheep ( n = 6) and sheep with pacing-induced HF ( n = 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts/100 heartbeats, P < 0.01). Infusion of tezosentan for 60 min significantly decreased resting mean aterial pressure (MAP) in both normal and HF sheep (−8 ± 4 mmHg and −4 ± 3 mmHg, respectively; P < 0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF.
Increased urinary levels of podocyte glycoproteins, matrix metallopeptidases, inflammatory cytokines, and kidney injury biomarkers in women with preeclampsia
Authors: Wang Yuping , Gu Yang , Loyd Susan , Jia Xiuyue , Groome Lynn J.
Published: October 2015

To investigate kidney injury in preeclampsia, we analyzed 14 biomarkers in urine specimen from 4 groups of pregnant women (normotensive pregnant women and those with pregnancy complicated with chronic hypertension or mild or severe preeclampsia). These biomarkers included 1) podocyte glycoproteins nephrin and podocalyxin, 2) matrix metallopeptidase (MMP)-2 and MMP-9 and their inhibitor tissue inhibitor of metalloproteinase-2, 3) inflammatory molecules and cytokines soluble VCAM-1, TNF-α, soluble TNF receptor receptor-1, IL-6, IL-8, IL-10, and IL-18, and 4) kidney injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1. Postpartum urine specimens (6–8 wk) from normotensive women and those with severe preeclampsia were also evaluated. We found that, first, urine levels of nephrin, MMP-2, MMP-9, and kidney injury molecule-1 were significantly higher before delivery in severe preeclampsia than normotensive groups. The increased levels were all reduced to levels similar to those of the normotensive control group in postpartum specimens from the severe preeclampsia group. Second, soluble VCAM-1, soluble TNF receptor-1, and neutrophil gelatinase-associated lipocalin levels were significantly increased in the severe preeclampsia group compared with the normotensive control group before delivery, but levels of these molecules were significantly reduced in postpartum specimens in both groups. Third, IL-6 and IL-8 levels were not different between preeclampsia and normotensive groups but significantly increased in pregnancy complicated with chronic hypertension. Finally, tissue inhibitor of metalloproteinase-2 and IL-18 levels were not different among the study groups before delivery but were significantly reduced in postpartum specimens from normotensive controls. Our results indicate that the kidney experiences an increased inflammatory response during pregnancy. Most interestingly, tubular epithelial cell injury may also occur in severe preeclampsia. These biomarkers could be used to assess podocyte or tubular injury and kidney inflammatory responses during pregnancy and to evaluate postpartum kidney injury recovery in pregnancy-complicated disorders.
Antioxidants, endothelial dysfunction, and DCS: in vitro and in vivo study
Authors: Wang Qiong , Mazur Aleksandra , Guerrero François , Lambrechts Kate , Buzzacott Peter , Belhomme Marc , Theron Michaël
Published: October 2015

Reactive oxygen species (ROS) production is a well-known effect in individuals after an undersea dive. This study aimed to delineate the links between ROS, endothelial dysfunction, and decompression sickness (DCS) through the use of antioxidants in vitro and in vivo. The effect of N-acetylcysteine (NAC) on superoxide and peroxynitrite, nitric oxide (NO) generation, and cell viability during in vitro diving simulation were analyzed. Also analyzed was the effect of vitamin C and NAC on plasma glutathione thiol and thiobarbituric acid reactive substances (TBARS), plasma angiotensin-converting enzyme (ACE) activity, and angiotensin-II and DCS morbidity during in vivo diving simulation. During an in vitro diving simulation, vascular endothelial cells showed overproduction of superoxide and peroxynitrite, obvious attenuation of NO generation, and promotion of cell death, all of which were reversed by NAC treatment. After in vivo diving simulation, plasma ACE activity and angiotensin-II level were not affected. The plasma level of glutathione thiol was downregulated after the dive, which was attenuated partially by NAC treatment. Plasma TBARS level was upregulated; however, either NAC or vitamin C treatment failed to prevent DCS morbidity. During in vitro simulation, endothelial superoxide and peroxynitrite-mediated oxidative stress were involved in the attenuation of NO availability and cell death. This study is the first attempt to link oxidative stress and DCS occurrence, and the link could not be confirmed in vivo. Even in the presence of antioxidants, ROS and bubbles generated during diving and/or decompression might lead to embolic or biochemical stress and DCS. Diving-induced oxidative stress might not be the only trigger of DCS morbidity.