bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-κB Activation Stimulates Transcription and Replication of Retrovirus XMRV in Human B-Lineage and Prostate Carcinoma Cells
Authors: Sakakibara Shuhei , Sakakibara Kaori , Tosato Giovanna 
Published: January 2011

ABSTRACT
Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus linked to prostate carcinoma and chronic fatigue syndrome. Here we report that NF-κB activation can markedly increase XMRV production. The inflammatory cytokine tumor necrosis factor alpha (TNF-α), which activates NF-κB, significantly augmented viral Gag protein production in XMRV-infected cells. Reporter assays showed that TNF-α and Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1), an intrinsic NF-κB activator, increased long terminal repeat (LTR)-dependent XMRV transcription. We identified two NF-κB binding sites (designated κB-1 and κB-2) in the LTR U3 region of XMRV and demonstrated that both sites bind to the NF-κB component p65/RelA. Mutation of the κB-1 site, but not the κB-2 site, impaired responsiveness to TNF-α and LMP1 in reporter assays. A mutant XMRV with a mutation at the κB-1 site replicated significantly less efficiently than the wild-type XMRV in the prostate carcinoma LNCaP, DU145, and PC-3 cell lines, HEK293 cells, the EBV-immortalized cell line IB4, and the Burkitt's lymphoma cell line BJAB. These results demonstrate that TNF-α and EBV LMP1 enhance XMRV replication in prostate carcinoma and B-lineage cells through the κB-1 site in the XMRV LTR, suggesting that inflammation, EBV infection, and other conditions leading to NF-κB activation may promote XMRV spread in humans.
Transcriptionally Abundant Major Histocompatibility Complex Class I Alleles Are Fundamental to Nonhuman Primate Simian Immunodeficiency Virus-Specific CD8+T Cell Responses
Authors: Budde Melisa L. , Lhost Jennifer J. , Burwitz Benjamin J. , Becker Ericka A. , Burns Charles M. , O'Connor Shelby L. , Karl Julie A. , Wiseman Roger W. , Bimber Benjamin N. , Zhang Guang Lan , Hildebrand William , Brusic Vladimir , O'Connor David H. 
Published: January 2011

ABSTRACTSimian immunodeficiency virus (SIV)-infected macaques are the preferred animal model for human immunodeficiency virus (HIV) vaccines that elicit CD8+T cell responses. Unlike humans, whose CD8+T cell responses are restricted by a maximum of six HLA class I alleles, macaques express up to 20 distinct major histocompatibility complex class I (MHC-I) sequences. Interestingly, only a subset of macaque MHC-I sequences are transcriptionally abundant in peripheral blood lymphocytes. We hypothesized that highly transcribed MHC-I sequences are principally responsible for restricting SIV-specific CD8+T cell responses. To examine this hypothesis, we measured SIV-specific CD8+T cell responses in MHC-I homozygous Mauritian cynomolgus macaques. Each of eight CD8+T cell responses defined by full-proteome gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay were restricted by four of the five transcripts that are transcriptionally abundant (>1% of total MHC-I transcripts in peripheral blood lymphocytes). The five transcriptionally rare transcripts shared by these animals did not restrict any detectable CD8+T cell responses. Further, seven CD8+T cell responses were defined by identifying peptide binding motifs of the three most frequent MHC-I transcripts on the M3 haplotype. Combined, these results suggest that transcriptionally abundant MHC-I transcripts are principally responsible for restricting SIV-specific CD8+T cell responses. Thus, only a subset of the thousands of known MHC-I alleles in macaques should be prioritized for CD8+T cell epitope characterization.
Global Analysis of the Transcriptional Response of Whitefly to
Tomato Yellow Leaf Curl China Virus
Reveals the Relationship of Coevolved Adaptations
Authors: Luan Jun-Bo , Li Jun-Min , Varela Nélia , Wang Yong-Liang , Li Fang-Fang , Bao Yan-Yuan , Zhang Chuan-Xi , Liu Shu-Sheng , Wang Xiao-Wei 
Published: January 2011

ABSTRACT

The begomoviruses are the largest and most economically important group of plant viruses transmitted exclusively by the whitefly
Bemisia tabaci
in a circulative, persistent manner. The circulation of the viruses within the insect vectors involves complex interactions between virus and vector components; however, the molecular mechanisms of these interactions remain largely unknown. Here we investigated the transcriptional response of the invasive
B. tabaci
Middle East-Asia Minor 1 species to
Tomato yellow leaf curl China virus
(TYLCCNV) using Illumina sequencing technology. Results showed that 1,606 genes involved in 157 biochemical pathways were differentially expressed in the viruliferous whiteflies. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that TYLCCNV can perturb the cell cycle and primary metabolism in the whitefly, which explains the negative effect of this virus on the longevity and fecundity of
B. tabaci
. Our data also demonstrated that TYLCCNV can activate whitefly immune responses, such as autophagy and antimicrobial peptide production, which might lead to a gradual decrease of viral particles within the body of the viruliferous whitefly. Furthermore, PCR results showed that TYLCCNV can invade the ovary and fat body tissues of the whitefly, and Lysotracker and Western blot analyses revealed that the invasion of TYLCCNV induced autophagy in both the ovary and fat body tissues. Surprisingly, TYLCCNV also suppressed the whitefly immune responses by downregulating the expression of genes involved in Toll-like signaling and mitogen-activated protein kinase (MAPK) pathways. Taken together, these results reveal the relationship of coevolved adaptations between begomoviruses and whiteflies and will provide a road map for future investigations into the complex interactions between plant viruses and their insect vectors.
Immunization with Herpes Simplex Virus 2 (HSV-2) Genes plus Inactivated HSV-2 Is Highly Protective against Acute and Recurrent HSV-2 Disease
Authors: Morello Christopher S. , Levinson Michael S. , Kraynyak Kimberly A. , Spector Deborah H. 
Published: January 2011

ABSTRACTTo date, no vaccine that is safe and effective against herpes simplex virus 2 (HSV-2) disease has been licensed. In this study, we evaluated a DNA prime-formalin-inactivated-HSV-2 (FI-HSV2) boost vaccine approach in the guinea pig model of acute and recurrent HSV-2 genital disease. Five groups of guinea pigs were immunized and intravaginally challenged with HSV-2. Two groups were primed with plasmid DNAs encoding the secreted form of glycoprotein D2 (gD2t) together with two genes required for viral replication, either the helicase (UL5) and DNA polymerase (UL30) genes or the single-stranded DNA binding protein (UL29) and primase (UL52) genes. Both DNA-primed groups were boosted with FI-HSV2 formulated with monophosphoryl lipid A (MPL) and alum adjuvants. Two additional groups were primed with the empty backbone plasmid DNA (pVAX). These two groups were boosted with MPL and alum (MPL-alum) together with either formalin-inactivated mock HSV-2 (FI-Mock) or with FI-HSV2. The final group was immunized with gD2t protein in MPL-alum. After challenge, 0/9 animals in the group primed with UL5, UL30, and gD2t DNAs and all 10 animals in the mock-immunized control group (pVAX-FI-Mock) developed primary lesions. All mock controls developed recurrent lesions through day 100 postchallenge. Only 1 guinea pig in the group primed with pVAX DNA and boosted with FI-HSV2 (pVAX-FI-HSV2 group) and 2 guinea pigs in the group primed with UL5, UL30, and gD2t DNAs and boosted with FI-HSV2 (UL5, UL30, gD2t DNA-FI-HSV2 group) developed recurrent lesions. Strikingly, the UL5, UL30, gD2t DNA-FI-HSV2 group showed a 97% reduction in recurrent lesion days compared with the mock controls, had the highest reduction in days with recurrent disease, and contained the lowest mean HSV-2 DNA load in the dorsal root ganglia.
Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors
Authors: Koh Yasuhiro , Matreyek Kenneth A. , Engelman Alan 
Published: January 2011

ABSTRACT

Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a
Betaretrovirus
, a
Gammaretrovirus
, and the
Alpharetrovirus
Rous sarcoma virus (RSV), were susceptible to inhibition by RAL. EVG potently inhibited all lentiviruses and intermediately inhibited
Betaretrovirus
and
Gammaretrovirus
infections yet was basically ineffective against RSV. Substitutions based on HIV type 1 (HIV-1) resistance changes revealed that integrase residue Ser150 contributed significantly to the resistance of RSV. The drugs intermediately inhibited intracisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition.
Reproduction
In Vitro
of a Quasispecies from a Hepatitis C Virus-Infected Patient and Determination of Factors That Influence Selection of a Dominant Species
Authors: Kawaguchi Kazunori , Faulk Kristina , Purcell Robert H. , Emerson Suzanne U. 
Published: January 2011

ABSTRACT

Hepatitis C virus infections proceed to chronicity in the majority of cases. In patients, hepatitis C viruses exist as a dynamic and complex quasispecies. The dominant species at any one time arises in response to host immune pressure and other, incompletely understood factors. It is critical to understand all the mechanisms by which dominance is achieved, but this is difficult to study
in vivo
. Therefore, it would be useful to develop a cell culture system in which naturally occurring quasispecies could be studied. Hepatitis C virus glycoprotein genes E1 and E2 were PCR amplified as a cassette from the plasma of a chronically infected patient and shotgun cloned into a modified 1a/JFH1 infectious cDNA clone. Following transformation of bacteria, plasmids were batch harvested, transcribed, and transfected into Huh7.5 cells to produce a quasispecies of hypervariable region 1 (HVR1) that mimicked that circulating
in vivo
. Serial passage of the quasispecies
in vitro
resulted in replacement of the initially dominant species with a new HVR1 species coexisting with selected growth-enhancing mutations located outside HVR1. Antibody raised against one HVR1 sequence neutralized virus with the homologous HVR1 and cross-neutralized virus with a different sequence. Reciprocal swapping of the HVR1 regions between the two dominating species demonstrated that the HVR1 sequence affects the efficiency of replication and of neutralization by anti-HVR1 but that both processes are strongly influenced by regions outside HVR1.
Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop
Authors: Moore Penny L. , Gray Elin S. , Sheward Daniel , Madiga Maphuti , Ranchobe Nthabeleng , Lai Zhong , Honnen William J. , Nonyane Molati , Tumba Nancy , Hermanus Tandile , Sibeko Sengeziwe , Mlisana Koleka , Abdool Karim Salim S. , Williamson Carolyn , Pinter Abraham , Morris Lynn 
Published: January 2011

ABSTRACT
The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000. CAP256 showed a subtype bias, preferentially neutralizing subtype C and A viruses over subtype B viruses. CAP256 BCN serum targeted a quaternary epitope which included the V1V2 region. Further mapping identified residues F159, N160, L165, R166, D167, K169, and K171 (forming the FN/LRD-K-K motif) in the V2 region as crucial to the CAP256 epitope. However, the fine specificity of the BCN response varied over time and, while consistently dependent on R166 and K169, became gradually less dependent on D167 and K171, possibly contributing to the incremental increase in breadth over 4 years. The presence of an intact FN/LRD-K-K motif in heterologous viruses was associated with sensitivity, although the length of the adjacent V1 loop modulated the degree of sensitivity, with a shorter V1 region significantly associated with higher titers. Repair of the FN/LRD-K-K motif in resistant heterologous viruses conferred sensitivity, with titers sometimes exceeding 1:10,000. Comparison of the CAP256 epitope with that of the PG9/PG16 monoclonal antibodies suggested that these epitopes overlapped, adding to the mounting evidence that this may represent a common neutralization target that should be further investigated as a potential vaccine candidate.
Cytomegalovirus Capsid Protease: Biological Substrates Are Cleaved More Efficiently by Full-Length Enzyme (pUL80a) than by the Catalytic Domain (Assemblin)
Authors: Fernandes Steve M. , Brignole Edward J. , Gibson Wade 
Published: January 2011

ABSTRACT

We compared the full-length capsid maturational protease (pPR, pUL80a) of human cytomegalovirus with its proteolytic domain (assemblin) for the ability to cleave two biological substrates, and we found that pPR is more efficient with both. Affinity-purified, refolded enzymes and substrates were combined under defined reaction conditions, and cleavage was monitored and quantified following staining of the resulting electrophoretically separated fragments. The enzymes were stabilized against self-cleavage by a single point mutation in each cleavage site (ICRMT-pPR and IC-assemblin). The substrates were pPR itself, inactivated by replacing its catalytic nucleophile (S132A-pPR), and the sequence-related assembly protein precursor (pAP, pUL80.5). Our results showed that (i) ICRMT-pPR is 5- to 10-fold more efficient than assemblin for all cleavages measured (i.e., the M site of pAP and the M, R, and I sites of S132A-pPR). (ii) Cleavage of substrate S132A-pPR proceeded M>R>I for both enzymes. (iii) Na
2
SO
4
reduced M- and R-site cleavage efficiency by ICRMT-pPR, in contrast to its enhancing effect for both enzymes on I site and small peptide cleavage. (iv) Disrupting oligomerization of either the pPR enzyme or substrate by mutating Leu382 in the amino-conserved domain reduced cleavage efficiency two- to fourfold. (v) Finally, ICRMT-pPR mutants that include the amino-conserved domain, but terminate with Pro481 or Tyr469, retain the enzymatic characteristics that distinguish pPR from assemblin. These findings show that the scaffolding portion of pPR increases its enzymatic activity on biologically relevant protein substrates and provide an additional link between the structure of this essential viral enzyme and its biological mechanism.
Fatalities in swimming pools with lifeguards: USA, 2000–2008
Authors: Pelletier Andrew R , Gilchrist Julie 
Published: January 2011

BackgroundPools with lifeguards are often perceived to represent a safe environment for swimming.ObjectivesTo examine how often fatalities occurred in pools with lifeguards and what factors were common in these incidents.DesignCase series.SettingUSA.SubjectsA case was defined as a death in a swimming pool with at least one lifeguard that occurred in the USA from 2000 to 2008. Potential cases were identified from media accounts using Lexis-Nexis and ProQuest databases. Supplemental information was obtained through internet based searches and review of death certificates.ResultsA total of 140 deaths from 37 states were identified. Of decedents, 109 (78%) were children and 93 (66%) were males. African Americans accounted for 44% of deaths among those of known race. 104 (74%) fatalities occurred during May through August; 85 (61%) deaths occurred in outdoor pools. Sites for fatal incidents included 53 (38%) municipal pools, 21 (15%) community organisations, and 20 (14%) schools. The median swimmer to lifeguard ratio was 13:1. Decedents were initially identified in the pool twice as often by non-lifeguards (eg, other swimmers or bystanders) as by lifeguards.ConclusionsDeaths in pools with lifeguards are uncommon, but do occur. Groups most affected include children, males, and African Americans. While lifeguards provide an important layer of protection at swimming pools, they alone cannot prevent all drownings. Additional safety measures are needed.
Smoke-free households with children and decreasing rates of paediatric clinical encounters for otitis media in the United States
Authors: Alpert Hillel R , Behm Ilan , Connolly Gregory N , Kabir Zubair 
Published: January 2011

ObjectiveTemporal trends in paediatric encounters for otitis media (OM) were last characterised and observed to be steadily increasing from 1975 to the mid-1990s. The present study uses an ecological design to quantify trends in paediatric encounters for OM concurrent with a period of decline of an important risk factor, secondhand smoke (SHS) exposure among children.Patients and methodsAnnual paediatric ambulatory visit and hospital discharge rates for children ≤6 years with OM as primary diagnosis were computed with nationally representative data for 1993–2006. Percentages of households with children ≤6 years and no-smoking rules were computed using Tobacco Use Supplement to the Current Population Survey data. Average annual percentage changes were determined for covariate-adjusted rates of paediatric encounters for OM using joinpoint analysis.ResultsWhile percentages of homes with children and no-smoking rules increased by 89% from 45.5% in 1993 to 86.1% in 2006, average annual covariate-adjusted paediatric encounters for OM decreased by 4.6% (95% CI 4.5% to 4.8%) for ambulatory visits and by 9.8% (95% CI 9.1% to 10.6%) for hospital discharges. Coverage by 7-valent pneumococcal conjugate vaccination (PCV7) increased since 2002, while little variation occurred in other potentially associated risk factors.ConclusionsPaediatric encounter rates for OM decreased steadily over a 13-year period reversing a previously reported long-term increasing trend reported. Reduced SHS exposure, PCV7 coverage since 2002 and other factors may have contributed to the decline. Further research is needed to provide direct estimates of paediatric encounter rates in exposed and unexposed populations for causal inference.
A Germline Variant in the Interferon Regulatory Factor 4 Gene as a Novel Skin Cancer Risk Locus
Authors: Han Jiali , Qureshi Abrar A. , Nan Hongmei , Zhang Jiangwen , Song Yiqing , Guo Qun , Hunter David J. 
Published: January 2011

Abstract
Genome-wide association studies on pigmentary phenotypes provide a pool of candidate genetic markers for skin cancer risk. The SNPs identified from a genome-wide association study of natural hair color were assessed for associations with the risk of three types of skin cancer simultaneously in a nested case-control study within the Nurses' Health Study [218 melanoma, 285 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 870 common controls]. Along with two known pigmentation loci, MC1R and OCA2, the IRF4 rs12203592 T allele was associated with an increased risk of each type of skin cancer (P value, 6.6 × 10−4 for melanoma, 7.0 × 10−7 for SCC, and 0.04 for BCC). This association was further replicated in additional samples (190 melanoma, 252 SCC, and 634 common controls). The P value in the replication set was 0.03 for melanoma and 4.2 × 10−3 for SCC. The risk of BCC was replicated in an independent set of 213 cases and 718 controls (P value, 0.02). The combined results showed that the association with SCC reached the genome-wide significance level [odds ratio (OR) for additive model = 1.61, 95%CI, 1.36–1.91, P = 3.2 × 10−8]. The OR was 1.49 for melanoma (95%CI, 1.23–1.80; P = 4.5 × 10−5), and 1.32 for BCC (95%CI, 1.11–1.57; P = 1.6×10−3). Given that the T allele was shown previously to be associated with increased expression of IRF4 locus, further studies are warranted to elucidate the role of the IRF4 gene in human pigmentation and skin cancer development. Cancer Res; 71(5); 1533–9. ©2011 AACR.
Paradoxical Relationship between Chromosomal Instability and Survival Outcome in Cancer
Authors: Birkbak Nicolai J. , Eklund Aron C. , Li Qiyuan , McClelland Sarah E. , Endesfelder David , Tan Patrick , Tan Iain B. , Richardson Andrea L. , Szallasi Zoltan , Swanton Charles 
Published: January 2011

Abstract
Chromosomal instability (CIN) is associated with poor prognosis in human cancer. However, in certain animal tumor models elevated CIN negatively impacts upon organism fitness, and is poorly tolerated by cancer cells. To better understand this seemingly contradictory relationship between CIN and cancer cell biological fitness and its relationship with clinical outcome, we applied the CIN70 expression signature, which correlates with DNA-based measures of structural chromosomal complexity and numerical CIN in vivo, to gene expression profiles of 2,125 breast tumors from 13 published cohorts. Tumors with extreme CIN, defined as the highest quartile CIN70 score, were predominantly of the estrogen receptor negative (ER−), basal-like phenotype and displayed the highest chromosomal structural complexity and chromosomal numerical instability. We found that the extreme CIN/ER− tumors were associated with improved prognosis relative to tumors with intermediate CIN70 scores in the third quartile. We also observed this paradoxical relationship between CIN and prognosis in ovarian, gastric, and non–small cell lung cancer, with poorest outcome in tumors with intermediate, rather than extreme, CIN70 scores. These results suggest a nonmonotonic relationship between gene signature expression and HR for survival outcome, which may explain the difficulties encountered in the identification of prognostic expression signatures in ER− breast cancer. Furthermore, the data are consistent with the intolerance of excessive CIN in carcinomas and provide a plausible strategy to define distinct prognostic patient cohorts with ER− breast cancer. Inclusion of a surrogate measurement of CIN may improve cancer risk stratification and future therapeutic approaches. Cancer Res; 71(10); 3447–52. ©2011 AACR.