bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electroporation of Synthetic DNA Antigens Offers Protection in Nonhuman Primates Challenged with Highly Pathogenic Avian Influenza Virus
Authors: Laddy Dominick J. , Yan Jian , Khan Amir S. , Andersen Hanne , Cohn Amanda , Greenhouse Jack , Lewis Mark , Manischewitz Jody , King Lisa R. , Golding Hana , Draghia-Akli Ruxandra , Weiner David B. 
Published: February 2009

ABSTRACT
Avian influenza highlights the need for novel vaccination techniques that would allow for the rapid design and production of safe and effective vaccines. An ideal platform would be capable of inducing both protective antibodies and potent cellular immune responses. These potential advantages of DNA vaccines remain unrealized due to a lack of efficacy in large animal studies and in human trials. Questions remain regarding the potential utility of cellular immune responses against influenza virus in primates. In this study, by construct optimization and in vivo electroporation of synthetic DNA-encoded antigens, we observed the induction of cross-reactive cellular and humoral immune responses individually capable of providing protection from influenza virus infection in the rhesus macaque. These studies advance the DNA vaccine field and provide a novel, more tolerable vaccine with broad immunogenicity to avian influenza virus. This approach appears important for further investigation, including studies with humans.
Proteasomal Degradation of the Papillomavirus E2 Protein Is Inhibited by Overexpression of Bromodomain-Containing Protein 4
Authors: Gagnon David , Joubert Simon , Sénéchal Hélène , Fradet-Turcotte Amélie , Torre Sabrina , Archambault Jacques 
Published: February 2009

ABSTRACTThe E2 protein of human papillomavirus (HPV) binds to specific sites in the viral genome to regulate its transcription, replication, and maintenance in infected cells. Like most regulatory proteins, E2 is rapidly turned over. A high-throughput assay was developed to quantify the expression and stability of E2 in vivo, based on its fusion toRenillaluciferase (RLuc). The steady-state levels of Rluc-E2 were quantified by measuring the amounts of associated luciferase activity, and its degradation was measured by monitoring the decrease in enzymatic activity occurring after a block of translation with cycloheximide. Using this assay, the E2 proteins from a low-risk (HPV11) and a high-risk (HPV31) human papillomavirus (HPV) type were found to have short half-lives of 60 min in C33A cervical carcinoma cells and to be ubiquitinated and degraded by the proteasome. Analysis of mutant proteins showed that the instability of E2 is independent of its DNA-binding and transcriptional activities but is encoded within its transactivation domain, the region that binds to the cellular chromatin factor bromodomain-containing protein 4 (Brd4) to regulate viral gene transcription. Overexpression of Brd4, or of its C-terminal E2-interaction domain, was found to increase the steady-state levels and stability of wild-type E2 but not of E2 mutants defective for binding Brd4. These results indicate that the stability of E2 is increased upon complex formation with Brd4 and highlight the value of the luciferase assay for the study of E2 degradation.
Major Coexisting Human Immunodeficiency Virus Type 1envGene Subpopulations in the Peripheral Blood Are Produced by Cells with Similar Turnover Rates and Show Little Evidence of Genetic Compartmentalization
Authors: Ince William L. , Harrington Patrick R. , Schnell Gretja L. , Patel-Chhabra Milloni , Burch Christina L. , Menezes Prema , Price Richard W. , Eron Joseph J. , Swanstrom Ronald I. 
Published: February 2009

ABSTRACTA distinctive feature of chronic human immunodeficiency virus type 1 (HIV-1) infection is the presence of multiple coexisting genetic variants, or subpopulations, that comprise the HIV-1 population detected in the peripheral blood. Analysis of HIV-1 RNA decay dynamics during the initiation of highly active antiretroviral therapy (HAART) has been a valuable tool for modeling the life span of infected cells that produce the bulk HIV-1 population. However, different HIV-1 target cells may have different turnover rates, and it is not clear whether the bulk HIV-1 RNA decay rate actually represents a composite of the decay rates of viral subpopulations compartmentalized in different cellular subsets with different life spans. Using heteroduplex tracking assays targeting the highly variable V3 or V4-V5 regions of the HIV-1envgene in eight subjects, we found that all detectable coexisting HIV-1 variants in the peripheral blood generally decayed at similar rates during the initiation of HAART, suggesting that all of the variants were produced by cells with similar life spans. Furthermore, single genome amplification and coreceptor phenotyping revealed that in two subjects coexisting HIV-1 variants with distinct CXCR4 or CCR5 coreceptor phenotypes decayed with similar rates. Also, in nine additional subjects, recombination and a lack of genetic compartmentalization between X4 and R5 variants were observed, suggesting an overlap in host cell range. Our results suggest that the HIV-1envsubpopulations detectable in the peripheral blood are produced by cells with similar life spans and are not genetically isolated within particular cell types.
Essential Role for either
TRS1
or
IRS1
in Human Cytomegalovirus Replication
Authors: Marshall Emily E. , Bierle Craig J. , Brune Wolfram , Geballe Adam P. 
Published: February 2009

ABSTRACT

Viral infections often produce double-stranded RNA (dsRNA), which in turn triggers potent antiviral responses, including the global repression of protein synthesis mediated by protein kinase R (PKR) and 2′-5′ oligoadenylate synthetase (OAS). As a consequence, many viruses have evolved genes, such as those encoding dsRNA-binding proteins, which counteract these pathways. Human cytomegalovirus (HCMV) encodes two related proteins, pTRS1 and pIRS1, which bind dsRNA and can prevent activation of the PKR and OAS pathways. HCMV mutants lacking either
IRS1
or
TRS1
replicate at least moderately well in cell culture. However, as we demonstrate in the present study, an HCMV mutant lacking both
IRS1
and
TRS1
(HCMV[ΔI/ΔT]) has a severe replication defect. Infection with HCMV[ΔI/ΔT] results in a profound inhibition of overall and viral protein synthesis, as well as increased phosphorylation of eukaryotic initiation factor 2α (eIF2α). The vaccinia virus
E3L
gene can substitute for
IRS1
or
TRS1
, enabling HCMV replication. Despite the accumulation of dsRNA in HCMV-infected cells, the OAS pathway remains inactive, even in HCMV[ΔI/ΔT]-infected cells. These results suggest that PKR-mediated phosphorylation of eIF2α is the dominant dsRNA-activated pathway responsible for inhibition of protein synthesis and HCMV replication in the absence of both
IRS1
and
TRS1
and that the requirement for evasion of the PKR pathway likely explains the necessity for
IRS1
or
TRS1
for productive infection.
Role of Sialic Acid Binding Specificity of the 1918 Influenza Virus Hemagglutinin Protein in Virulence and Pathogenesis for Mice
Authors: Qi Li , Kash John C. , Dugan Vivien G. , Wang Ruixue , Jin Guozhong , Cunningham Robert E. , Taubenberger Jeffery K. 
Published: February 2009

ABSTRACT
The 1918 influenza pandemic caused more than 40 million deaths and likely resulted from the introduction and adaptation of a novel avian-like virus. Influenza A virus hemagglutinins are important in host switching and virulence. Avian-adapted influenza virus hemagglutinins bind sialic acid receptors linked via α2-3 glycosidic bonds, while human-adapted hemagglutinins bind α2-6 receptors. Sequence analysis of 1918 isolates showed hemagglutinin genes with α2-6 or mixed α2-6/α2-3 binding. To characterize the role of the sialic acid binding specificity of the 1918 hemagglutinin, we evaluated in mice chimeric influenza viruses expressing wild-type and mutant hemagglutinin genes from avian and 1918 strains with differing receptor specificities. Viruses expressing 1918 hemagglutinin possessing either α2-6, α2-3, or α2-3/α2-6 sialic acid specificity were fatal to mice, with similar pathology and cellular tropism. Changing α2-3 to α2-6 binding specificity did not increase the lethality of an avian-adapted hemagglutinin. Thus, the 1918 hemagglutinin contains murine virulence determinants independent of receptor binding specificity.
Secular trends in aerobic fitness performance in 13–18-year-old adolescents from 1976 to 2001
Authors: Huotari P R T , Nupponen H , Laakso L , Kujala U M 
Published: February 2009

ObjectiveTo analyse the secular trends in aerobic fitness performance and some of its determinants (body mass index (BMI) and leisure time physical activity (LTPA)) in adolescents.DesignCross-sectional population-based studies in 1976 and 2001 in Finland. A stratified random sample of Finnish 13–18-year-old adolescents was studied in 1976 (n = 717; 384 boys and 333 girls) and in 2001 (n = 558; 305 boys and 253 girls). The main outcome measure was aerobic fitness, estimated with a 2000 m (for boys) and 1500 m (for girls) running test; the weight and height of participants were also measured. Self-reported weekly frequency of LTPA of at least 30 min duration and regularity of participation in organised sport were obtained by questionnaire. Identical methods were used in 1976 and 2001.ResultsRunning time was longer in 2001 compared to 1976 in boys (56 s, Cohen d = 0.46, medium effect size; p<0.001) and girls (29 s, d = 0.32, small; p<0.01). BMI and participation in LTPA explained more of the variance in aerobic fitness in 2001 than in 1976 in boys and girls.ConclusionsAerobic fitness of school-aged children deteriorated between the measurement points. BMI and organised LTPA were better associated with aerobic fitness in 2001 than in 1976. An increase in overweight and obesity was associated with the decrease in aerobic fitness. Although the importance of organised LTPA to fitness increased, it is possible that the decrease in overall physical activity between 1976 and 2001 contributed most to the decrease in the level of aerobic fitness.
The effectiveness of vocationally oriented multidisciplinary intervention on sickness absence and early retirement among employees at risk: an observational study
Authors: Suoyrjö H , Oksanen T , Hinkka K , Kivimäki M , Klaukka T , Pentti J , Vahtera J 
Published: February 2009

Objective:To study the effect of a preventive vocationally oriented intervention on rates of sickness absence and disability pension in employees considered to be at risk of future work disability.Design:An observational register-based study of public sector employees.Subjects:2236 intervention programme participants and 8944 matched controls were followed up for 8 years.Methods:Multidisciplinary intervention was carried out at rehabilitation institutions. Data on demographics and sickness absences were obtained from employers’ records and information about health at baseline, participation in the intervention and subsequent disability pension from national registers.Results:Before the intervention participants had 17% more annual sick leave days and a 23% higher rate of absence spells lasting >21 days than controls. In the intervention year and 3 subsequent years, the sickness absence rate among participants reduced to that observed among controls but thereafter increased to the pre-intervention level (p for curvilinear trend <0.001 for absence days and 0.03 for absence spells). The association between the intervention and future disability pension was non-proportional among participants. Compared to controls, risk among participants was lower in the first 4 years of follow-up but thereafter returned to the previous higher level. The temporary decline in sickness absence attributable to the intervention totalled 6673 absence days per 1000 employees and the cumulative reduction in disability was 56.4 years. These direct health benefits may not fully cover the costs of the intervention.Conclusion:The risk of work disability can be temporarily reduced in employees at risk by means of a vocationally oriented multidisciplinary intervention programme.
Open source marketing: Camel cigarette brand marketing in the “Web 2.0” world
Authors: Freeman B , Chapman S 
Published: February 2009

Background:The international trend towards comprehensive bans on tobacco advertising has seen the tobacco industry become increasingly innovative in its approach to marketing. Further fuelling this innovation is the rapid evolution and accessibility of web-based technology. The internet, as a relatively unregulated marketing environment, provides many opportunities for tobacco companies to pursue their promotional ambitions.Methods:In this paper, “open source marketing” is considered as a vehicle that has been appropriated by the tobacco industry, through a case study of efforts to design the packaging for the Camel Signature Blends range of cigarettes. Four sources are used to explore this case study including a marketing literature search, a web-based content search via the Google search engine, interviews with advertising trade informants and an analysis of the Camel brand website.Results:RJ Reynolds (RJR) has proven to be particularly innovative in designing cigarette packaging. RJR engaged with thousands of consumers through their Camel brand website to design four new cigarette flavours and packages. While the Camel Signature Blends packaging designs were subsequently modified for the retail market due to problems arising with their cartoon-like imagery, important lessons arise on how the internet blurs the line between marketing and market research.Conclusions:Open source marketing has the potential to exploit advertising ban loopholes and stretch legal definitions in order to generate positive word of mouth about tobacco products. There are also lessons in the open source marketing movement for more effective tobacco control measures including interactive social marketing campaigns and requiring plain packaging of tobacco products.
Impact on the Australian Quitline of new graphic cigarette pack warnings including the Quitline number: Figure 1
Authors: Miller C L , Hill D J , Quester P G , Hiller J E 
Published: February 2009

Background:In March 2006, Australia introduced graphic pictorial warnings on cigarette packets. For the first time, packs include the Quitline number.Objective:To measure the combined effect of graphic cigarette pack warnings and printing the Quitline number on packs on calls to the Australian Quitline service.Methods:Calls to the Australian Quitline were monitored over 4 years, 2 years before and after the new packets were introduced.Results:There were twice as many calls to the Quitline in 2006 (the year of introduction), as there were in each of the preceding 2 years. The observed increase in calls exceeds that explained by the accompanying television advertising alone. While call volume tapered back in 2007, it remained at a level higher than before the introduction of new packets. No change was observed in the proportion of first time callers.Conclusion:Introducing graphic cigarette packet warnings and the Quitline number on cigarette packets boosts demand for Quitline services, with likely flow on effects to cessation.
Identification of MCAM/CD146 as the Target Antigen of a Human Monoclonal Antibody that Recognizes Both Epithelioid and Sarcomatoid Types of Mesothelioma
Authors: Bidlingmaier Scott , He Jiang , Wang Yong , An Feng , Feng Jinjin , Barbone Dario , Gao Dongwei , Franc Ben , Broaddus V. Courtney , Liu Bin 
Published: February 2009

Abstract
The prognosis for patients diagnosed with mesothelioma is generally poor, and currently available treatments are usually ineffective. Therapies that specifically target tumor cells hold much promise for the treatment of cancers that are resistant to current approaches. We have previously selected phage antibody display libraries on mesothelioma cell lines to identify a panel of internalizing human single chain (scFv) antibodies that target mesothelioma-associated, clinically represented cell surface antigens and further exploited the internalizing function of these scFvs to specifically deliver lethal doses of liposome-encapsulated small molecule drugs to both epithelioid and sarcomatous subtypes of mesothelioma cells. Here, we report the identification of MCAM/MUC18/CD146 as the surface antigen bound by one of the mesothelioma-targeting scFvs using a novel cloning strategy based on yeast surface human proteome display. Immunohistochemical analysis of mesothelioma tissue microarrays confirmed that MCAM is widely expressed by both epithelioid and sarcomatous types of mesothelioma tumor cells in situ but not by normal mesothelial cells. In addition, quantum dot-labeled anti-MCAM scFv targets primary meosthelioma cells in tumor fragment spheroids cultured ex vivo. As the first step in evaluating the therapeutic potential of MCAM-targeting antibodies, we performed single-photon emission computed tomography studies using the anti-MCAM scFv and found that it recognizes mesothelioma organotypic xenografts in vivo. The combination of phage antibody library selection on tumor cells and rapid target antigen identification by screening the yeast surface-displayed human proteome could be a powerful method for mapping the targetable tumor cell surface epitope space. [Cancer Res 2009;69(4):1570–7]
Protein Kinase Cβ Is an Effective Target for Chemoprevention of Colon Cancer
Authors: Fields Alan P. , Calcagno Shelly R. , Krishna Murli , Rak Sofija , Leitges Michael , Murray Nicole R. 
Published: February 2009

Abstract
Colon cancer develops over a period of 10 to 15 years, providing a window of opportunity for chemoprevention and early intervention. However, few molecular targets for effective colon cancer chemoprevention have been characterized and validated. Protein kinase CβII (PKCβII) plays a requisite role in the initiation of colon carcinogenesis in a preclinical mouse model by promoting proliferation and increased β-catenin accumulation. In this study, we test the hypothesis that PKCβII is an effective target for colon cancer chemoprevention using enzastaurin (LY317615), a PKCβ-selective inhibitor, in a mouse model of colon carcinogenesis. We find that enzastaurin potently reduces azoxymethane-induced colon tumor initiation and progression by inhibiting PKCβII-mediated tumor cell proliferation and β-catenin accumulation. Biochemically, enzastaurin reduces expression of the PKCβII- and β-catenin/T-cell factor–regulated genes PKCβII, cyclooxygenase II, and vascular endothelial growth factor, three genes implicated in colon carcinogenesis. Our results show that enzastaurin is an effective chemopreventive agent in a mouse model of sporadic colon cancer that significantly reduces both tumor initiation and progression by inhibiting expression of proproliferative genes. Thus, PKCβII is an important target for colon cancer chemoprevention and the PKCβ-selective inhibitor enzastaurin may represent an effective chemopreventive agent in patients at high risk for colon cancer. [Cancer Res 2009;69(4):1643–50]
Mother and Toddler Activity in the Zone of Proximal Development for Pretend Play as a Predictor of Higher Child IQ
Authors: Morrissey Anne-Marie , Brown P. Margaret 
Published: February 2009

This study investigated the pretend play of mother—toddler dyads in relation to later child IQ. Twenty-one toddlers were videotaped in monthly play sessions with their mothers, from age 8 to 17 months, and later assessed at 5 years of age on the Stanford-Binet IV. Children's and mothers' pretend play levels and frequencies were measured using Brown's (1997) Pretend Play Observation Scale. Dyadic play activity was analyzed using the conceptual frameworks of scaffolding and Vygotsky's Zone of Proximal Development (ZPD). Toddlers later assessed as having higher IQ demonstrated more rapid learning in the ZPD for pretend play and experienced earlier maternal transfer of responsibility for play. These findings support other evidence on the differential early development of high ability or gifted children and the role of caregiver interactions in that development. Putting the Research to Use: This study provides evidence that gifted children show differential development, in this case more rapid learning, from the first year of life. It also demonstrates how responsive parental interactions can support this advanced development. For family and professional caregivers, the findings imply that optimum caregiving for the young gifted child involves interactions that are both responsive to individual potential and appropriately challenging. In regard to the methodological challenges of researching early giftedness, the study demonstrated that the constructs of the ZPD and scaffolding were useful frameworks for investigating early gifted development and caregiver influences on that development. Pretend play activity was also shown to be an effective measure and a useful context for the study of gifted development in infants and toddlers. It would be valuable for future researchers in this area to utilize similar approaches that are grounded in the unique developmental characteristics of young children, and that aim to account for the interactive contexts that are so important in children's lives. The field of gifted education, in general, would also benefit from an increased awareness and exploration of the role of play in the development of intellect, imagination and creativity.
Profoundly Gifted Girls and Autism Spectrum Disorder
Authors: Assouline Susan G. , Nicpon Megan Foley , Doobay Alissa 
Published: February 2009

A case study of the psychometric characteristics of two profoundly gifted girls, one with autism spectrum disorder (ASD) and the other without ASD, is used to describe the nuances and subtleties most relevant in understanding the relationship between extreme giftedness and social difficulties. Through the presentation of the results from psychoeducational and psychosocial assessments, we demonstrate how data from a comprehensive evaluation can distinguish between the manifestation of extreme giftedness and concomitant social impairment indicative of ASD. Comparison of the assessment results highlights the relevance of cognitive and achievement information as well as the need for specific measures to diagnosis ASD. The girls demonstrated virtually identically superior cognitive and achievement performances. However, an in-depth analysis of additional measures, especially those specific to ASD, indicates that information about adaptive behavior and executive functioning can reveal important distinctions that are helpful in understanding the need for unique interventions specific to ASD. Putting the Research to Use: Previous literature reviews about profoundly gifted students with social impairments have cautioned against misdiagnosis (Webb et al., 2005) of psychological disorders. These psychologists posit that social impairments are primarily the result of social-emotional vulnerability associated with very high IQs. Further, they argue that concomitant social difficulties are characteristics of giftedness, not indicators of a disability. We compared two profoundly gifted girls, each with social difficulties, who are virtually identical in their cognitive and achievement profiles. Our comparison reveal the importance of basing conclusions about social impairments on comprehensive assessments that use measures uniquely designed to distinguish between “difficulty” and “disability.” We demonstrate that although “misdiagnosis” is a possibility with profoundly gifted children, the greater risk is “missed” diagnosis, which precludes the opportunity for appropriate intervention. In today's atmosphere of “anti-testing” it is important to advocate for a comprehensive assessment with the necessary measures to understand the degree of social impairment.