bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oligonucleotide Motifs That Disappear during the Evolution of Influenza Virus in Humans Increase Alpha Interferon Secretion by Plasmacytoid Dendritic Cells
Authors: Jimenez-Baranda Sonia , Greenbaum Benjamin , Manches Olivier , Handler Jesse , Rabadán Raúl , Levine Arnold , Bhardwaj Nina 
Published: February 2011

ABSTRACTCpG motifs in an A/U context have been preferentially eliminated from classical H1N1 influenza virus genomes during virus evolution in humans. The hypothesis of the current work is that CpG motifs in a uracil context represent sequence patterns with the capacity to induce an immune response, and the avoidance of this immunostimulatory signal is the reason for the observed preferential decline. To analyze the immunogenicity of these domains, we used plasmacytoid dendritic cells (pDCs). pDCs express pattern recognition receptors, including Toll-like receptor 7 (TLR7), which recognizes guanosine- and uridine-rich viral single-stranded RNA (ssRNA), including influenza virus ssRNA. The signaling through TLR7 results in the induction of inflammatory cytokines and type I interferon (IFN-I), an essential process for the induction of specific adaptive immune responses and for mounting a robust antiviral response mediated by IFN-α. Secretion of IFN-α is also linked to the activation of other immune cells, potentially amplifying the effect of an initial IFN-α secretion. We therefore also examined the role of IFN-α-driven activation of NK cells as another source of selective pressure on the viral genome. We found direct evidence that CpG RNA motifs in a U-rich context control pDC activation and IFN-α-driven activation of NK cells, likely through TLR7. These data provide a potential explanation for the loss of CpG motifs from avian influenza viruses as they adapt to mammalian hosts. The selective decrease of CpG motifs surrounded by U/A may be a viral strategy to avoid immune recognition, a strategy likely shared by highly expressed human immune genes.
The Changing Role of mTOR Kinase in the Maintenance of Protein Synthesis during Human Cytomegalovirus Infection
Authors: Clippinger Amy J. , Maguire Tobi G. , Alwine James C. 
Published: February 2011

ABSTRACT

The mammalian target of rapamycin (mTOR) kinase occurs in mTOR complex 1 (mTORC1) and complex 2 (mTORC2), primarily differing by the substrate specificity factors raptor (in mTORC1) and rictor (in mTORC2). Both complexes are activated during human cytomegalovirus (HCMV) infection. mTORC1 phosphorylates eukaryotic initiation factor 4E (eIF4E)-binding protein (4E-BP1) and p70S6 kinase (S6K) in uninfected cells, and this activity is lost upon raptor depletion. In infected cells, 4E-BP1 and S6K phosphorylation is maintained when raptor or rictor is depleted, suggesting that either mTOR complex can phosphorylate 4E-BP1 and S6K. Studies using the mTOR inhibitor Torin1 show that phosphorylation of 4E-BP1 and S6K in infected cells depends on mTOR kinase. The total levels of 4E-BP1 and viral proteins representative of all temporal classes were lowered by Torin1 treatment and by raptor, but not rictor, depletion, suggesting that mTORC1 is involved in the production of all classes of HCMV proteins. We also show that Torin1 inhibition of mTOR kinase is rapid and most deleterious at early times of infection. While Torin1 treatment from the beginning of infection significantly inhibited translation of viral proteins, its addition at later time points had far less effect. Thus, with respect to mTOR's role in translational control, HCMV depends on it early in infection but can bypass it at later times of infection. Depletion of 4E-BP1 by use of short hairpin RNAs (shRNAs) did not rescue HCMV growth in Torin1-treated human fibroblasts as it has been shown to in murine cytomegalovirus (MCMV)-infected 4E-BP1
−/−
mouse embryo fibroblasts (MEFs), suggesting that during HCMV infection mTOR kinase has additional roles other than phosphorylating and inactivating 4E-BP1. Overall, our data suggest a dynamic relationship between HCMV and mTOR kinase which changes during the course of infection.
Kaposi's Sarcoma-Associated Herpesvirus Bacterial Artificial Chromosome Contains a Duplication of a Long Unique-Region Fragment within the Terminal Repeat Region
Authors: Yakushko Yuri , Hackmann Christian , Günther Thomas , Rückert Jessica , Henke Marc , Koste Lars , Alkharsah Khaled , Bohne Jens , Grundhoff Adam , Schulz Thomas F. , Henke-Gendo Cornelia 
Published: February 2011

ABSTRACT
Use of the Kaposi's sarcoma-associated herpesvirus (KSHV) bacterial artificial chromosome 36 (KSHV-BAC36) genome permits reverse genetics approaches to study KSHV biology. While sequencing the complete KSHV-BAC36 genome, we noted a duplication of a 9-kb fragment of the long unique region in the terminal repeat region. This duplication covers a part of open reading frame (ORF) 19, the complete ORFs 18, 17, 16, K7, K6, and K5, and the putative ORF in the left origin of lytic replication, and it contains the BAC cassette. This observation needs to be kept in mind if viral genes located within the duplicated region are to be mutated in KSHV-BAC36.
The IRF-3/Bax-Mediated Apoptotic Pathway, Activated by Viral Cytoplasmic RNA and DNA, Inhibits Virus Replication
Authors: Chattopadhyay Saurabh , Yamashita Michifumi , Zhang Ying , Sen Ganes C. 
Published: February 2011

ABSTRACT

Induction of apoptosis in cells infected by Sendai virus (SeV), which triggers the cytosolic RIG-I pathway, requires the presence of interferon regulatory factor 3 (IRF-3). Independent of IRF-3's transcriptional role, a novel IRF-3 activation pathway causes its interaction with the proapoptotic protein Bax and its mitochondrial translocation to induce apoptosis. Here we report that two other RNA viruses, vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV), may also activate the same pathway. Moreover, cytosolic DNA, produced by adenovirus or introduced by transfection, activated the pathway in an RNA polymerase III-dependent fashion. To evaluate the contribution of this newly discovered apoptotic pathway to the host's overall antiviral response, we measured the efficiencies of replication of various viruses
in vitro
and viral pathogenesis
in vivo
, using cells and mice that are selectively deficient in components required for the apoptotic pathway of IRF-3. Our results clearly demonstrate that the IRF-3/Bax-mediated apoptotic signaling branch contributes significantly to the host's protection from viral infection and consequent pathogenesis.
The Role of LAT in Increased CD8
+
T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1
Authors: Allen Sariah J. , Hamrah Pedram , Gate David , Mott Kevin R. , Mantopoulos Dimosthenis , Zheng Lixin , Town Terrence , Jones Clinton , von Andrian Ulrich H. , Freeman Gordon J. , Sharpe Arlene H. , BenMohamed Lbachir , Ahmed Rafi , Wechsler Steven L. , Ghiasi Homayon 
Published: February 2011

ABSTRACT

Herpes simplex virus (HSV) infection is a classic example of latent viral infection in humans and experimental animal models. The HSV-1 latency-associated transcript (LAT) plays a major role in the HSV-1 latency reactivation cycle and thus in recurrent disease. Whether the presence of LAT leads to generation of dysfunctional T cell responses in the trigeminal ganglia (TG) of latently infected mice is not known. To address this issue, we used LAT-positive [LAT(+)] and LAT-deficient [LAT(−)] viruses to evaluate the effect of LAT on CD8 T cell exhaustion in TG of latently infected mice. The amount of latency as determined by quantitative reverse transcription-PCR (qRT-PCR) of viral DNA in total TG extracts was 3-fold higher with LAT(+) than with LAT(−) virus. LAT expression and increased latency correlated with increased mRNA levels of CD8, PD-1, and Tim-3. PD-1 is both a marker for exhaustion and a primary factor leading to exhaustion, and Tim-3 can also contribute to exhaustion. These results suggested that LAT(+) TG contain both more CD8
+
T cells and more CD8
+
T cells expressing the exhaustion markers PD-1 and Tim-3. This was confirmed by flow cytometry analyses of expression of CD3/CD8/PD-1/Tim-3, HSV-1, CD8
+
T cell pentamer (specific for a peptide derived from residues 498 to 505 of glycoprotein B [gB
498–505
]), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α). The functional significance of PD-1 and its ligands in HSV-1 latency was demonstrated by the significantly reduced amount of HSV-1 latency in PD-1- and PD-L1-deficient mice. Together, these results may suggest that both PD-1 and Tim-3 are mediators of CD8
+
T cell exhaustion and latency in HSV-1 infection.
Chimeric Porcine Circoviruses (PCV) Containing Amino Acid Epitope Tags in the C Terminus of the Capsid Gene Are Infectious and Elicit both Anti-Epitope Tag Antibodies and Anti-PCV Type 2 Neutralizing Antibodies in Pigs
Authors: Beach Nathan M. , Smith Sara M. , Ramamoorthy Sheela , Meng Xiang-Jin 
Published: February 2011

ABSTRACT

A chimeric porcine circovirus (PCV1-2) with the capsid gene of pathogenic PCV2 cloned into the genomic backbone of nonpathogenic PCV1 is attenuated in pigs but elicits protective immunity against PCV2. In this study, short epitope tags were inserted into the C terminus of the capsid protein of the chimeric PCV1-2 vaccine virus, resulting in a tractable marker virus that is infectious both
in vitro
and
in vivo
. Pigs experimentally infected with the epitope-tagged PCV1-2 vaccine viruses produced tag-specific antibodies, as well as anti-PCV2 neutralizing antibodies, indicating that the epitope-tagged viruses could potentially serve as a positive-marker modified live-attenuated vaccine.
Bovine Plasmacytoid Dendritic Cells Are the Major Source of Type I Interferon in Response to Foot-and-Mouth Disease Virus In Vitro and In Vivo
Authors: Reid Elizabeth , Juleff Nicholas , Gubbins Simon , Prentice Helen , Seago Julian , Charleston Bryan 
Published: February 2011

ABSTRACTType I interferons (alpha/beta interferons [IFN-α/β]) are the main innate cytokines that are able to induce a cellular antiviral state, thereby limiting viral replication and disease pathology. Plasmacytoid dendritic cells (pDCs) play a crucial role in the control of viral infections, especially in response to viruses that have evolved mechanisms to block the type I IFN signal transduction pathway. Using density gradient separation and cell sorting, we have highly enriched a population of bovine cells capable of producing high levels of biologically active type I IFN. These cells represented less than 0.1% of the total lymphocyte population in blood, pseudoafferent lymph, and lymph nodes. Phenotypic analysis identified these cells as bovine pDCs (CD3−CD14−CD21−CD11c−NK−TCRδ−CD4+MHC II+CD45RB+CD172a+CD32+). High levels of type I IFN were generated by these cellsin vitroin response to Toll-like receptor 9 (TLR-9) agonist CpG and foot-and-mouth disease virus (FMDV) immune complexes. In contrast, immune complexes formed with UV-inactivated FMDV or FMDV empty capsids failed to elicit a type I IFN response. Depletion of CD4 cellsin vivoresulted in levels of type I IFN in serum early during FMDV infection that were significantly lower than those for control animals. In conclusion, pDCs interacting with immune-complexed virus are the major source of type I interferon production during acute FMDV infection in cattle.
Genome Variation in Cryptococcus gattii, an Emerging Pathogen of Immunocompetent Hosts
Authors: D’Souza C. A. , Kronstad J. W. , Taylor G. , Warren R. , Yuen M. , Hu G. , Jung W. H. , Sham A. , Kidd S. E. , Tangen K. , Lee N. , Zeilmaker T. , Sawkins J. , McVicker G. , Shah S. , Gnerre S. , Griggs A. , Zeng Q. , Bartlett K. , Li W. , Wang X. , Heitman J. , Stajich J. E. , Fraser J. A. , Meyer W. , Carter D. , Schein J. , Krzywinski M. , Kwon-Chung K. J. , Varma A. , Wang J. , Brunham R. , Fyfe M. , Ouellette B. F. F. , Siddiqui A. , Marra M. , Jones S. , Holt R. , Birren B. W. , Galagan J. E. , Cuomo C. A. 
Published: February 2011

ABSTRACT

Cryptococcus gattii
recently emerged as the causative agent of cryptococcosis in healthy individuals in western North America, despite previous characterization of the fungus as a pathogen in tropical or subtropical regions. As a foundation to study the genetics of virulence in this pathogen, we sequenced the genomes of a strain (WM276) representing the predominant global molecular type (VGI) and a clinical strain (R265) of the major genotype (VGIIa) causing disease in North America. We compared these
C. gattii
genomes with each other and with the genomes of representative strains of the two varieties of
Cryptococcus neoformans
that generally cause disease in immunocompromised people. Our comparisons included chromosome alignments, analysis of gene content and gene family evolution, and comparative genome hybridization (CGH). These studies revealed that the genomes of the two representative
C. gattii
strains (genotypes VGI and VGIIa) are colinear for the majority of chromosomes, with some minor rearrangements. However, multiortholog phylogenetic analysis and an evaluation of gene/sequence conservation support the existence of speciation within the
C. gattii
complex. More extensive chromosome rearrangements were observed upon comparison of the
C. gattii
and the
C. neoformans
genomes. Finally, CGH revealed considerable variation in clinical and environmental isolates as well as changes in chromosome copy numbers in
C. gattii
isolates displaying fluconazole heteroresistance.

IMPORTANCE
Isolates of
Cryptococcus gattii
are currently causing an outbreak of cryptococcosis in western North America, and most of the cases occurred in the absence of coinfection with HIV. This pattern is therefore in stark contrast to the current global burden of one million annual cases of cryptococcosis, caused by the related species
Cryptococcus neoformans
, in the HIV/AIDS population. The genome sequences of two outbreak-associated major genotypes of
C. gattii
reported here provide insights into genome variation within and between cryptococcal species. These sequences also provide a resource to further evaluate the epidemiology of cryptococcal disease and to evaluate the role of pathogen genes in the differential interactions of
C. gattii
and
C. neoformans
with immunocompromised and immunocompetent hosts.
Tumour necrosis factor G-308A polymorphism modifies the effect of home dampness on childhood asthma
Authors: Tsai Ching-Hui , Tung Kuan-Yen , Chen Chang-Hao , Lee Yungling L 
Published: February 2011

ObjectivesEnvironmental exposure at home, such as dampness, has been shown to have adverse effects on respiratory health. However, few studies explored the association between home dampness and genetic polymorphisms on childhood asthma. The aim of the study is to evaluate the effects of home dampness and tumour necrosis factor-α gene (TNF-α) on asthma in Taiwanese children.MethodsThe authors investigated 3810 schoolchildren in Taiwan Children Health Study from 14 communities. Children's exposure and disease status were measured from a parental questionnaire. Multiple logistic regression models were fitted to estimate the effects of home dampness exposure andTNF-αgenotypes on the prevalence of asthma and wheeze.ResultsMildewy odour at home was significantly associated with increased prevalence of lifetime wheeze (OR=1.36, 95% CI 1.05 to 1.77, p for trend=0.04). The effects of water stamp on the wall at home were associated with lifetime asthma and lifetime wheeze. Children with water stamp on the wall at home andTNF-308A allele had increased risks on lifetime asthma, active asthma and lifetime wheeze.TNF-αshowed significant interactive effects with mildewy odour on lifetime asthma (p for interaction=0.01), and with water stamp on the wall at home on lifetime wheeze (p for interaction=0.04). Under stratification byTNF-308genotypes, we found that the frequency of water stamp on the wall was associated with increased risks of all asthma subcategories and lifetime wheeze amongTNF-308GA or AA genotypes (p for trend<0.05).ConclusionsHome dampness is a risk factor for asthma and wheeze among children, especially for those with theTNF-308A allele.
Lenalidomide Restrains Motility and Overangiogenic Potential of Bone Marrow Endothelial Cells in Patients with Active Multiple Myeloma
Authors: De Luisi Annunziata , Ferrucci Arianna , Coluccia Addolorata M.L. , Ria Roberto , Moschetta Michele , de Luca Emanuela , Pieroni Luisa , Maffia Michele , Urbani Andrea , Di Pietro Giulia , Guarini Attilio , Ranieri Girolamo , Ditonno Paolo , Berardi Simona , Caivano Antonella , Basile Antonio , Cascavilla Nicola , Capalbo Silvana , Quarta Giovanni , Dammacco Franco , Ribatti Domenico , Vacca Angelo 
Published: February 2011

AbstractPurpose: To determine the in vivo and in vitro antiangiogenic power of lenalidomide, a “lead compound” of IMiD immunomodulatory drugs in bone marrow (BM) endothelial cells (EC) of patients with multiple myeloma (MM) in active phase (MMEC).Experimental Design: The antiangiogenic effect in vivo was studied using the chorioallantoic membrane (CAM) assay. Functional studies in vitro (angiogenesis, “wound” healing and chemotaxis, cell viability, adhesion, and apoptosis) were conducted in both primary MMECs and ECs of patients with monoclonal gammopathies (MGUS) of undetermined significance (MGEC) or healthy human umbilical vein endothelial cells (HUVEC). Real-time reverse transcriptase PCR, Western blotting, and differential proteomic analysis were used to correlate morphologic and biological EC features with the lenalidomide effects at the gene and protein levels.Results: Lenalidomide exerted a relevant antiangiogenic effect in vivo at 1.75 μmol/L, a dose reached in interstitial fluids of patients treated with 25 mg/d. In vitro, lenalidomide inhibited angiogenesis and migration of MMECs, but not of MGECs or control HUVECs, and had no effect on MMEC viability, apoptosis, or fibronectin- and vitronectin-mediated adhesion. Lenalidomide-treated MMECs showed changes in VEGF/VEGFR2 signaling pathway and several proteins controlling EC motility, cytoskeleton remodeling, and energy metabolism pathways.Conclusions: This study provides information on the molecular mechanisms associated with the antimigratory and antiangiogenic effects of lenalidomide in primary MMECs, thus giving new avenues for effective endothelium-targeted therapies in MM. Clin Cancer Res; 17(7); 1935–46. ©2011 AACR.
Gender differences in mental health literacy among Chinese-speaking Australians in Melbourne, Australia
Authors: Wong Daniel Fu Keung , Lam Angus Yuk Kit , Poon Ada , Chow Amy Yin Man 
Published: February 2011

Objective: This study attempted to understand gender differences in knowledge of mental illness, preference for professional help, and medications and treatment methods among Australians of Chinese-speaking background. Methods: This study adopted a cluster convenience sampling method in which subjects were taken from the four major areas in cosmopolitan Melbourne where most Chinese people are living. A total of 200 Chinese-speaking Australians participated in the study. They were presented with two vignettes describing an individual with acute depression or acute schizophrenia and then questions were asked to assess their understanding of the conditions, preference for professional help, medications and treatment methods. Results: More female than male respondents could correctly identify the conditions in the two vignettes. Female participants also perceived medications to be relatively more harmful than their male counterparts. In contrast, there were significantly more males than females who adhered to traditional views on the causation of mental illness; had significantly higher percentages of endorsement of ‘deal with it alone’; believed ‘traditional Chinese medical doctor’ and ‘Chinese herbal medicines’ to be helpful to the person in the schizophrenia vignette; and significantly endorsed ‘psychiatric ward’, ‘electro-convulsive treatment’, ‘changing fungshui’ and ‘traditional Chinese worship’ to be helpful for the persons in both vignettes. A combination of factors, which included age, duration of migration and traditional Chinese cultural values, were put forward to explain the above differences. Conclusions: Campaigns to improve the mental health literacy of Chinese-speaking Australians must take into account the gender differences between male and female Chinese-speaking Australians so that culturally relevant and gender-specific education programmes can be developed.
Comorbidity of anxiety and depressive disorders: A comparative population study in Western and non-Western inhabitants in the Netherlands
Authors: Schrier Agnes C. , de Wit Matty A.S. , Coupé Veerle M.H. , Fassaert Thijs , Verhoeff Arnoud P. , Kupka Ralph W. , Dekker Jack , Beekman Aartjan T.F. 
Published: February 2011

Background: Overlap of depressive and anxiety symptoms is supposedly more common in non-Western populations. This can lead to diagnostic uncertainity and undertreatment. Aims: The aim of this study was to assess cross-cultural differences regarding the comorbidity of anxiety and depressive disorders in a comparative population study. Methods: In a random urban population sample, stratified for descent, in Amsterdam, the Netherlands, diagnostic interviews were held by bilingual interviewers. Diagnoses of anxiety and depressive disorders, based on the Composite International Diagnostic Interview, were obtained for 307 native Dutch subjects, 205 Turkish-Dutch subjects and 186 Moroccan-Dutch subjects. Results: The prevalence rate of comorbid anxiety and depressive disorders was higher in Turkish-Dutch (9.8 %) and Moroccan-Dutch (3.8%) subjects compared to native Dutch subjects (2.3%). However, this could be explained by differences in baseline prevalence rate and level of severity of the separate disorders. The onset order of anxiety disorders and depressive disorders was comparable in each ethnic group. Conclusions: The high prevalence rate of comorbid anxiety and depressive diorders in non-Western immigrants in the Netherlands necessitates assesssment and treatment of both disorders. There was no indication of a – culturally influenced – stronger overlap between anxiety and depressive disorders in non-Western immigrants in the Netherlands.