bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Alternative Kaposi's Sarcoma-Associated Herpesvirus Replication Program Triggered by Host Cell Apoptosis
Authors: Prasad Alka , Lu Michael , Lukac David M. , Zeichner Steven L. 
Published: February 2012

ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) is linked to several neoplastic diseases: Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). KSHV replicates actively, via a controlled gene expression program, but can also remain latent. It had been thought that the transition from latent to lytic replication was controlled exclusively by the replication and transcription activator protein RTA (open reading frame 50 [ORF50] gene product). A dominant-negative (DN) ORF50 mutant, ORF50ΔSTAD, blocks gene expression and replication. We produced a PEL cell line derivative containing both latent KSHV genomes and an inducible ORF50ΔSTAD. We unexpectedly found that induction of apoptosis triggered high-level viral replication, even when DN ORF50ΔSTAD was present, suggesting that apoptosis triggers KSHV replication through a distinct RTA-independent pathway. We verified that apoptosis triggers KSHV replication independent of RTA using ORF50 small interfering RNA (siRNA) and also showed that caspase activity is required to trigger KSHV replication. We showed that when apoptosis triggers KSHV replication, the kinetics of late gene expression is accelerated by 12 to 24 h and that virus produced following apoptosis has reduced infectivity. KSHV therefore appears to replicate via two distinct pathways, a conventional pathway requiring RTA, with slower replication kinetics, producing virus with higher infectivity, and an alternative apoptosis-triggered pathway that does not require RTA, has faster replication kinetics, and produces virus with lower infectivity. The existence of a distinct apoptosis-triggered, accelerated replication pathway may have evolutionary advantages for the virus and clinical significance for the treatment of KSHV-associated neoplasms. It also provides further evidence that KSHV can sense and react to its environment.
Posttranslational Modification of Vesicular Stomatitis Virus Glycoprotein, but Not JNK Inhibition, Is the Antiviral Mechanism of SP600125
Authors: Marozin Sabrina , Altomonte Jennifer , Apfel Sibylle , Dinh Phat X. , De Toni Enrico N. , Rizzani Antonia , Nüssler Andreas , Kato Nobuyuki , Schmid Roland M. , Pattnaik Asit K. , Ebert Oliver 
Published: February 2012

ABSTRACTVesicular stomatitis virus (VSV), a negative-sense single-stranded-RNA rhabdovirus, is an extremely promising oncolytic agent for cancer treatment. Since oncolytic virotherapy is moving closer to clinical application, potentially synergistic combinations of oncolytic viruses and molecularly targeted antitumor agents are becoming a meaningful strategy for cancer treatment. Mitogen-activated protein kinase (MAPK) inhibitors have been shown to impair liver cell proliferation and tumor development, suggesting their potential use as therapeutic agents for hepatocellular carcinoma (HCC). In this work, we show that the impairment of MAPKin vitrodid not interfere with the oncolytic properties of VSV in HCC cell lines. Moreover, the administration of MAPK inhibitors did not restore the responsiveness of HCC cells to alpha/beta interferon (IFN-α/β). In contrast to previous reports, we show that JNK inhibition by the inhibitor SP600125 is not responsible for VSV attenuation in HCC cells and that this compound acts by causing a posttranslational modification of the viral glycoprotein.
Kinase Control Prevents HIV-1 Reactivation in Spite of High Levels of Induced NF-κB Activity
Authors: Wolschendorf Frank , Bosque Alberto , Shishido Takao , Duverger Alexandra , Jones Jennifer , Planelles Vicente , Kutsch Olaf 
Published: February 2012

ABSTRACTDespite its clinical importance, the molecular biology of HIV-1 latency control is at best partially understood, and the literature remains conflicting. The most recent description that latent HIV-1 is integrated into actively expressed host genes has further confounded the situation. This lack of molecular understanding complicates our efforts to identify therapeutic compounds or strategies that could reactivate latent HIV-1 infection in patients, a prerequisite for the eradication of HIV-1 infection. Currently, many therapeutic development efforts operate under the assumption that a restrictive histone code could govern latent infection and that either dissipation of the histone-based restrictions or NF-κB activation could be sufficient to trigger HIV-1 reactivation. We here present data that suggest an additional, higher level of molecular control. During a high-content drug screening effort, we identified AS601245 as a potent inhibitor of HIV-1 reactivation in latently infected primary T cells and T cell lines. In either system, AS601245 inhibited HIV-1 reactivation despite high levels of induced NF-κB activation. This finding suggests the presence of a gatekeeper kinase activity that controls latent HIV-1 infection even in the presence of high levels of NF-κB activity. Potential therapeutic stimuli that do not target this gatekeeper kinase will likely fail to trigger efficient system-wide HIV-1 reactivation.
Primary Severe Acute Respiratory Syndrome Coronavirus Infection Limits Replication but Not Lung Inflammation upon Homologous Rechallenge
Authors: Clay Candice , Donart Nathan , Fomukong Ndingsa , Knight Jennifer B. , Lei Wanli , Price Lance , Hahn Fletcher , Van Westrienen Jesse , Harrod Kevin S. 
Published: February 2012

ABSTRACT
Our knowledge regarding immune-protective and immunopathogenic events in severe acute respiratory syndrome coronavirus (SARS-CoV) infection is limited, and little is known about the dynamics of the immune response at the primary site of disease. Here, an African green monkey (AGM) model was used to elucidate immune mechanisms that facilitate viral clearance but may also contribute to persistent lung inflammation following SARS-CoV infection. During primary infection, SARS-CoV replicated in the AGM lung for up to 10 days. Interestingly, lung inflammation was more prevalent following viral clearance, as leukocyte numbers peaked at 14 days postinfection (dpi) and remained elevated at 28 dpi compared to those of mock-infected controls. Lung macrophages but not dendritic cells were rapidly activated, and both cell types had high activation marker expression at late infection time points. Lung proinflammatory cytokines were induced at 1 to 14 dpi, but most returned to baseline by 28 dpi except interleukin 12 (IL-12) and gamma interferon. In SARS-CoV homologous rechallenge studies, 11 of the 12 animals were free of replicating virus at day 5 after rechallenge. However, incidence and severity of lung inflammation was not reduced despite the limited viral replication upon rechallenge. Evaluating the role of antibodies in immune protection or potentiation revealed a progressive increase in anti-SARS-CoV antibodies in lung and serum that did not correlate temporally or spatially with enhanced viral replication. This study represents one of the first comprehensive analyses of lung immunity, including changes in leukocyte populations, lung-specific cytokines, and antibody responses following SARS-CoV rechallenge in AGMs.
Induction of the Cellular MicroRNA, Hs_154, by West Nile Virus Contributes to Virus-Mediated Apoptosis through Repression of Antiapoptotic Factors
Authors: Smith Jessica L. , Grey Finn E. , Uhrlaub Jennifer L. , Nikolich-Zugich Janko , Hirsch Alec J. 
Published: February 2012

ABSTRACTMicroRNAs (miRNAs) are a class of noncoding small RNAs that regulate multiple cellular processes, as well as the replication and pathogenesis of many DNA viruses and some RNA viruses. Examination of cellular miRNA profiles in West Nile virus (WNV)-infected HEK293 and SK-N-MC cells revealed increased expression of multiple miRNA species. One of these miRNAs, Hs_154, was significantly induced not only in WNV-infected neuronal cells in culture but also in the central nervous system tissues of infected mice and, upon transfection, caused a significant reduction in viral replication. Analysis of mRNA transcripts enriched through immunoprecipitation of the RNA-induced silencing complex identified several transcripts that contain seed sequence matches to Hs_154 in their 3′ untranslated regions (UTRs). Two of these targets, the CCCTC-binding factor (CTCF) and the epidermal growth factor receptor (EGFR)-coamplified and overexpressed protein (ECOP/VOPP1) proteins display reduced expression in WNV-infected cells, and the 3′ UTRs of these transcripts were sufficient to cause downregulation of expression in infected cells or in cells transfected with Hs_154, findings consistent with miRNA targeting of these transcripts. CTCF and ECOP have been shown to be associated with cell survival, implicating miRNA-directed repression of these targets in WNV-induced cell death. Consistent with this hypothesis, expression of these genes in WNV-infected cells results in a reduction in the number of cells undergoing apoptosis. These observations suggest that induction of Hs_154 expression after WNV infection modulates the apoptotic response to WNV and that cellular miRNA expression can be quickly altered during WNV infection to control aspects of the host response.
A Local, Interactive Network of 3′ RNA Elements Supports Translation and Replication of Turnip Crinkle Virus
Authors: Yuan Xuefeng , Shi Kerong , Simon Anne E. 
Published: February 2012

ABSTRACT

The majority of the 3′ untranslated region (UTR) of
Turnip crinkle virus
(TCV) was previously identified as forming a highly interactive structure with a ribosome-binding tRNA-shaped structure (TSS) acting as a scaffold and undergoing a widespread conformational shift upon binding to RNA-dependent RNA polymerase (RdRp). Tertiary interactions in the region were explored by identifying two highly detrimental mutations within and adjacent to a hairpin H4 upstream of the TSS that reduce translation
in vivo
and cause identical structural changes in the loop of the 3′ terminal hairpin Pr. Second-site changes that compensate for defects in translation/accumulation and reverse the structural differences in the Pr loop were found in the Pr stem, as well as in a specific stem within the TSS and within the capsid protein (CP) coding region, suggesting that the second-site changes were correcting a conformational defect and not restoring specific base pairing. The RdRp-mediated conformational shift extended upstream through this CP open reading frame (ORF) region after bypassing much of an intervening, largely unstructured region, supporting a connection between 3′ elements and coding region elements. These data suggest that the Pr loop, TSS, and H4 are central elements in the regulation of translation and replication in TCV and allow for development of an RNA interactome that maps the higher-order structure of a postulated RNA domain within the 3′ region of a plus-strand RNA virus.
Single-Dose Immunization with Virus Replicon Particles Confers Rapid Robust Protection against Rift Valley Fever Virus Challenge
Authors: Dodd Kimberly A. , Bird Brian H. , Metcalfe Maureen G. , Nichol Stuart T. , Albariño César G. 
Published: February 2012

ABSTRACT

Rift Valley fever virus (RVFV) causes outbreaks of severe disease in people and livestock throughout Africa and the Arabian Peninsula. The potential for RVFV introduction outside the area of endemicity highlights the need for fast-acting, safe, and efficacious vaccines. Here, we demonstrate a robust system for the reverse genetics generation of a RVF virus replicon particle (VRP
RVF
) vaccine candidate. Using a mouse model, we show that VRP
RVF
immunization provides the optimal balance of safety and single-dose robust efficacy. VRP
RVF
can actively synthesize viral RNA and proteins but lacks structural glycoprotein genes, preventing spread within immunized individuals and reducing the risk of vaccine-induced pathogenicity. VRP
RVF
proved to be completely safe following intracranial inoculation of suckling mice, a stringent test of vaccine safety. Single-dose subcutaneous immunization with VRP
RVF
, although it is highly attenuated, completely protected mice against a virulent RVFV challenge dose which was 100,000-fold greater than the 50% lethal dose (LD
50
). Robust protection from lethal challenge was observed by 24 h postvaccination, with 100% protection induced in as little as 96 h. We show that a single subcutaneous VRP
RVF
immunization initiated a systemic antiviral state followed by an enhanced adaptive response. These data contrast sharply with the much-reduced survivability and immune responses observed among animals immunized with nonreplicating viral particles, indicating that replication, even if confined to the initially infected cells, contributes substantially to protective efficacy at early and late time points postimmunization. These data demonstrate that replicon vaccines successfully bridge the gap between safety and efficacy and provide insights into the kinetics of antiviral protection from RVFV infection.
Cohort profile: Ho Chi Minh City Youth Cohort—changes in diet, physical activity, sedentary behaviour and relationship with overweight/obesity in adolescents
Authors: Trang Nguyen Hoang Hanh Doan , Hong Tang Kim , Dibley Michael John 
Published: February 2012

ObjectivesThe Ho Chi Minh Youth cohort study aimed to assess the change in nutritional status; indicators of adiposity; diet; physical activity and sedentary behaviours; home, neighbourhood and school microenvironments and their complex relationships in adolescents in urban areas of Ho Chi Minh City.DesignProspective 5-year cohort.SettingSystematic random sampling was used to select 18 schools in urban districts.ParticipantsChildren were followed up over 5 years with an assessment in each year. Consent, from both adolescents and their parents, was required. At baseline, 759 students were recruited into the cohort, and of these students, 740 remained in the cohort for the first round, 712 for the second round, 630 for the third round and 585 for the last round of follow-up.Primary and secondary outcome measuresAnthropometric measurements were taken using established guidelines. Six main groups of exposure factors including dietary intake and behaviours, physical activity and sedentary behaviours, family social and physical environment, school environment, socioeconomic status and parental characteristics were measured.ResultsRetention rate was high (77%). Within 5-year period, the prevalence of combined overweight and obesity using International Obesity Task Force cut-off values increased from 14.2% to 21.8%. Time spent on physical activity decreased significantly in the 5-year period from 87 to 50 min/day. Time spent on sedentary behaviours increased in the 5-year period from 512 to 600 min/day.ConclusionsThe complete data analysis of this cohort study will allow a full exploration of the role of environmental and lifestyle behaviours on adolescent overweight and obesity and also identify the factors most strongly associated with excess weight gain and the appearance of overweight and obesity in different age groups of adolescents from this large city in Vietnam.
Unequal access to ART: exploratory results from rural and urban case studies of ART use
Authors: Cleary Susan May , Birch Stephen , Moshabela Mosa , Schneider Helen 
Published: February 2012

IntroductionSouth Africa has the world's largest antiretroviral treatment (ART) programme. While services in the public sector are free at the point of use, little is known about overall access barriers. This paper explores these barriers from the perspective of ART users enrolled in services in two rural and two urban settings.MethodsUsing a comprehensive framework of access, interviews were conducted with over 1200 ART users to assess barriers along three dimensions: availability, affordability and acceptability. Summary statistics were computed and comparisons of access barriers between sites were explored using multivariate linear and logistic regressions.ResultsWhile availability access barriers in rural settings were found to be mitigated through a more decentralised model of service provision in one site, affordability barriers were considerably higher in rural versus urban settings. 50% of respondents incurred catastrophic healthcare expenditure and 36% borrowed money to cover these expenses in one rural site. On acceptability, rural users were less likely to report feeling respected by health workers. Stigma was reported to be lowest in the two sites with the most decentralised services and the highest coverage of those in need.ConclusionsWhile results suggest inequitable access to ART for rural relative to urban users, nurse-led services offered through primary healthcare facilities mitigated these barriers in one rural site. This is an important finding given current policy emphasis on decentralised and nurse-led ART in South Africa. This study is one of the first to present comprehensive evidence on access barriers to assist in the design of policy solutions.
Prevention of mother-to-child transmission of HIV: assessing the accuracy of routinely collected data on maternal antiretroviral prophylaxis coverage in Kenya
Authors: Ferguson Laura , Grant Alison D , Ong'ech John O , Vusha Sophie , Watson-Jones Deborah , Ross David A 
Published: February 2012

ObjectiveTo explore the accuracy of routinely collected prevention of mother-to-child transmission of HIV (PMTCT) coverage data in Kenya.MethodsIn case studies at two government hospitals, the authors reviewed national reporting guidelines, interviewed nurses and undertook a retrospective analysis of routine hospital data from antenatal care, maternity and HIV services from January 2009 to June 2010. Each woman attending these services was given a unique study number to enable analysis of her recorded use of PMTCT services across different hospital visits. These data were compared with the hospitals' monthly PMTCT reports to the district.ResultsWhere a woman made more than one visit, PMTCT drug provision could be reported multiple times for the same woman, and women known to be HIV positive prior to pregnancy were omitted from the denominator of PMTCT coverage calculations. Practices for reporting data on maternal PMTCT prophylaxis provision varied in the two hospitals. According to the study data, using the hospital registers and accounting for multiple visits by the same woman, 642 women were known to have HIV and 412 (64%) were given maternal PMTCT prophylaxis. According to the monthly reports, 430 women were diagnosed as having HIV in pregnancy-related services and 538 (125%) were given maternal PMTCT prophylaxis.ConclusionsIf replicated elsewhere, these reporting practices could lead to overestimation of national PMTCT coverage. Simple yet accurate routine data collection systems are needed to monitor PMTCT coverage accurately and to highlight where changes need to be made so as to ensure that infants are born HIV free.
BIFURCATION ANALYSIS ON AN HIV-1 MODEL WITH CONSTANT INJECTION OF RECOMBINANT
Authors: YU PEI , ZOU XINGFU 
Published: February 2012

This paper is a continuation of our previous work on an HIV-1 therapy model of fighting a virus with another virus [Jiang et al., 2009]. The work in [Jiang et al., 2009] investigated cascading bifurcations between equilibrium solutions, as well as Hopf bifurcation from a double-infected equilibrium solution. In this paper, we propose a modification of the model in [Revilla & Garcia-Ramos, 2003; Jiang et al., 2009] by adding a constant η to the recombinant virus equation, which accounts for the treatment of constant injection of recombinants. We study the dynamics of the new model and find that η plays an important role in the therapy. Unlike the previous model without injection of recombinant, which has three equilibrium solutions, this new model can only allow two biologically meaningful equilibrium solutions.It is shown that there is [Formula: see text] depending on η, such that the HIV free equilibrium solution [Formula: see text] is globally asymptotically stable when the basic reproduction ratio, [Formula: see text]; [Formula: see text] becomes unstable when [Formula: see text]. In the latter case, there occurs the double-infection equilibrium solution, [Formula: see text], which is stable when [Formula: see text] for some [Formula: see text] larger than [Formula: see text], and loses its stability when [Formula: see text] passes the critical value [Formula: see text] and bifurcates into a family of limit cycles through Hopf bifurcation. Our results show that appropriate injection rate can help eliminate the HIV virus in the sense that the HIV free equilibrium can be made globally asymptotically stable by choosing η > 0 sufficiently large. This is in contrast to the conclusion for the case with η = 0 in which, the recombinants do not help eliminate the HIV virus but only help reduce the HIV load in the long term sense.
Impaired Cognitive Function and Hippocampal Neurogenesis following Cancer Chemotherapy
Authors: Christie Lori-Ann , Acharya Munjal M. , Parihar Vipan K. , Nguyen Anna , Martirosian Vahan , Limoli Charles L. 
Published: February 2012

Abstract
Purpose: A substantial proportion of breast cancer survivors report significant, long-lasting impairments in cognitive function, often referred to as “chemobrain.” Advances in detection and treatment mean that many more patients are surviving long-term following diagnosis of invasive breast cancer. Thus, it is important to define the types, extent, and persistence of cognitive impairments following treatment with cytotoxic cancer drugs.
Experimental Design: We examined the effects of chronic treatment with two agents commonly used in patients with breast cancer, cyclophosphamide and doxorubicin (Adriamycin). Athymic nude rats were given 50 mg/kg cyclophosphamide, 2 mg/kg doxorubicin, or saline injections once per week for 4 weeks. A novel place recognition task and contextual and cued fear conditioning were used to characterize learning and memory ability. Immunofluorescence staining for immature and mature neurons and activated microglia was used to assess changes in neurogenesis and neuroinflammation.
Results: Cyclophosphamide- and doxorubicin-treated rats showed significantly impaired performance on the novel place recognition task and the contextual fear conditioning task compared with untreated controls, suggesting disrupted hippocampal-based memory function. Chemotherapy-treated animals showed a significant decline in neurogenesis [80%–90% drop in bromodeoxyuridine (BrdUrd)-labeled cells expressing NeuN]. Activated microglia (ED1-positive) were found after cyclophosphamide but not doxorubicin treatment.
Conclusions: Our results show that chronic treatment with either of two commonly used chemotherapeutic agents impairs cognitive ability and suggest that strategies to prevent or repair disrupted hippocampal neurogenesis may be effective in ameliorating this serious side effect in cancer survivors. Clin Cancer Res; 18(7); 1954–65. ©2012 AACR.