bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Viral Protein Tat Can Inhibit the Establishment of HIV-1 Latency
Authors: Donahue Daniel A. , Kuhl Björn D. , Sloan Richard D. , Wainberg Mark A. 
Published: January 2012

ABSTRACT

The establishment of HIV-1 latency can result from limiting levels of transcription initiation or elongation factors, restrictive chromatin modifications, transcriptional interference, and insufficient Tat activity. Since the viral protein Tat can counteract many of these factors, we hypothesized that the presence of exogenous Tat during infection might inhibit the establishment of latency. This was explored using a Jurkat model of latency establishment and reactivation. PCR and reverse transcriptase PCR (RT-PCR) confirmed the latent state in this model and showed evidence of transcriptional interference. To address our hypothesis, cells undergoing infection were first exposed to either purified recombinant Tat or a transactivation-negative mutant. Only the former resulted in a modest inhibition of the establishment of latency. Next, Jurkat cells stably expressing intracellular Tat were used in our latency model to avoid limitations of Tat delivery. Experiments confirmed that intracellular Tat expression did not affect the susceptibility of these cells to viral infection. Eight weeks after infection, Jurkat cells expressing Tat harbored up to 1,700-fold fewer (
P
< 0.01) latent viruses than Jurkat cells that did not express Tat. Additionally, Tat delivered by a second virus was sufficient to reactivate most of the latent population. Our results suggest that inhibition of the establishment of latent infection is theoretically possible. In a hypothetical scenario of therapy that induces viral gene expression during acute infection, activation of viruses which would otherwise have entered latency could occur while concurrent highly active antiretroviral therapy (HAART) would prevent further viral spread, potentially decreasing the size of the established latent reservoir.
Human Metapneumovirus (HMPV) Binding and Infection Are Mediated by Interactions between the HMPV Fusion Protein and Heparan Sulfate
Authors: Chang Andres , Masante Cyril , Buchholz Ursula J. , Dutch Rebecca Ellis 
Published: January 2012

ABSTRACTHuman metapneumovirus (HMPV) is a major worldwide respiratory pathogen that causes acute upper and lower respiratory tract disease. The mechanism by which this virus recognizes and gains access to its target cell is still largely unknown. In this study, we addressed the initial steps in virus binding and infection and found that the first binding partner for HMPV is heparan sulfate (HS). While wild-type CHO-K1 cells are permissive to HMPV infection, mutant cell lines lacking the ability to synthesize glycosaminoglycans (GAGs), specifically, heparan sulfate proteoglycans (HSPGs), were resistant to binding and infection by HMPV. The permissiveness to HMPV infection was also abolished when CHO-K1 cells were treated with heparinases. Importantly, using recombinant HMPV lacking both the G and small hydrophobic (SH) proteins, we report that this first virus-cell binding interaction is driven primarily by the fusion protein (HMPV F) and that this interaction is needed to establish a productive infection. Finally, HMPV binding to cells did not require β1 integrin expression, and RGD-mediated interactions were not essential in promoting HMPV F-mediated cell-to-cell membrane fusion. Cells lacking β1 integrin, however, were less permissive to HMPV infection, indicating that while β1 integrins play an important role in promoting HMPV infection, the interaction between integrins and HMPV occurs after the initial binding of HMPV F to heparan sulfate proteoglycans.
Restricted Replication of Xenotropic Murine Leukemia Virus-Related Virus in Pigtailed Macaques
Authors: Del Prete Gregory Q. , Kearney Mary F. , Spindler Jon , Wiegand Ann , Chertova Elena , Roser James D. , Estes Jacob D. , Hao Xing Pei , Trubey Charles M. , Lara Abigail , Lee KyeongEun , Chaipan Chawaree , Bess Julian W. , Nagashima Kunio , Keele Brandon F. , Macallister Rhonda , Smedley Jeremy , Pathak Vinay K. , KewalRamani Vineet N. , Coffin John M. , Lifson Jeffrey D. 
Published: January 2012

ABSTRACT

Although xenotropic murine leukemia virus-related virus (XMRV) has been previously linked to prostate cancer and myalgic encephalomyelitis/chronic fatigue syndrome, recent data indicate that results interpreted as evidence of human XMRV infection reflect laboratory contamination rather than authentic
in vivo
infection. Nevertheless, XMRV is a retrovirus of undefined pathogenic potential that is able to replicate in human cells. Here we describe a comprehensive analysis of two male pigtailed macaques (
Macaca nemestrina
) experimentally infected with XMRV. Following intravenous inoculation with >10
10
RNA copy equivalents of XMRV, viral replication was limited and transient, peaking at ≤2,200 viral RNA (vRNA) copies/ml plasma and becoming undetectable by 4 weeks postinfection, though viral DNA (vDNA) in peripheral blood mononuclear cells remained detectable through 119 days of follow-up. Similarly, vRNA was not detectable in lymph nodes by
in situ
hybridization despite detectable vDNA. Sequencing of cell-associated vDNA revealed extensive G-to-A hypermutation, suggestive of APOBEC-mediated viral restriction. Consistent with limited viral replication, we found transient upregulation of type I interferon responses that returned to baseline by 2 weeks postinfection, no detectable cellular immune responses, and limited or no spread to prostate tissue. Antibody responses, including neutralizing antibodies, however, were detectable by 2 weeks postinfection and maintained throughout the study. Both animals were healthy for the duration of follow-up. These findings indicate that XMRV replication and spread were limited in pigtailed macaques, predominantly by APOBEC-mediated hypermutation. Given that human APOBEC proteins restrict XMRV infection
in vitro
, human XMRV infection, if it occurred, would be expected to be characterized by similarly limited viral replication and spread.
Luria-Delbrück Estimation of Turnip Mosaic Virus Mutation Rate
In Vivo
Authors: de la Iglesia Francisca , Martínez Fernando , Hillung Julia , Cuevas José M. , Gerrish Philip J. , Daròs José-Antonio , Elena Santiago F. 
Published: January 2012

ABSTRACT

A potential drawback of recent antiviral therapies based on the transgenic expression of artificial microRNAs is the ease with which viruses may generate escape mutations. Using a variation of the classic Luria-Delbrück fluctuation assay, we estimated that the spontaneous mutation rate in the artificial microRNA (amiR) target of a plant virus was ca. 6 × 10
−5
per replication event.
The Simian Virus 40 Late Viral Protein VP4 Disrupts the Nuclear Envelope for Viral Release
Authors: Giorda Kristina M. , Raghava Smita , Hebert Daniel N. 
Published: January 2012

ABSTRACT
Simian virus 40 (SV40) appears to initiate cell lysis by expressing the late viral protein VP4 at the end of infection to aid in virus dissemination. To investigate the contribution of VP4 to cell lysis, VP4 was expressed in mammalian cells where it was predominantly observed along the nuclear periphery. The integrity of the nuclear envelope was compromised in these cells, resulting in the mislocalization of a soluble nuclear marker. Using assays that involved the cellular expression of VP4 or the treatment of cells with purified VP4, we found that the central hydrophobic domain and a proximal C-terminal nuclear localization signal of VP4 were required for (i) cytolysis associated with prolonged expression; (ii) nuclear envelope accumulation; and (iii) disruption of the nuclear, red blood cell, or host cell membranes. Furthermore, a conserved proline within the hydrophobic domain was required for membrane perforation, suggesting that this residue was crucial for VP4 cytolytic activity. These results indicate that VP4 forms pores in the nuclear membrane leading to lysis and virus release.
The longitudinal prevalence of MRSA in care home residents and the effectiveness of improving infection prevention knowledge and practice on colonisation using a stepped wedge study design
Authors: Horner C , Wilcox M , Barr B , Hall D , Hodgson G , Parnell P , Tompkins D 
Published: January 2012

ObjectivesTo determine the prevalence and health outcomes of meticillin-resistantStaphylococcus aureus(MRSA) colonisation in elderly care home residents. To measure the effectiveness of improving infection prevention knowledge and practice on MRSA prevalence.SettingCare homes for elderly residents in Leeds, UK.ParticipantsResidents able to give informed consent.DesignA controlled intervention study, using a stepped wedge design, comprising 65 homes divided into three groups. Baseline MRSA prevalence was determined by screening the nares of residents (n=2492). An intervention based upon staff education and training on hand hygiene was delivered at three different times according to group number. Scores for three assessment methods, an audit of hand hygiene facilities, staff hand hygiene observations and an educational questionnaire, were collected before and after the intervention. After each group of homes received the intervention, all participants were screened for MRSA nasal colonisation. In total, four surveys took place between November 2006 and February 2009.ResultsMRSA prevalence was 20%, 19%, 22% and 21% in each survey, respectively. There was a significant improvement in scores for all three assessment methods post-intervention (p≤0.001). The intervention was associated with a small but significant increase in MRSA prevalence (p=0.023). MRSA colonisation was associated with previous and subsequent MRSA infection but was not significantly associated with subsequent hospitalisation or mortality.ConclusionsThe intervention did not result in a decrease in the prevalence of MRSA colonisation in care home residents. Additional measures will be required to reduce endemic MRSA colonisation in care homes.
Does the effect of vitamin A supplements depend on vaccination status? An observational study from Guinea-Bissau
Authors: Fisker Ane B , Aaby Peter , Bale Carlito , Balde Ibraima , Biering-Sørensen Sofie , Agergaard Jane , Martins Cesario , Bibby Bo M , Benn Christine S 
Published: January 2012

ObjectiveVitamin A supplementation (VAS) is estimated to reduce all-cause mortality by 24%. Previous studies indicate that the effect of VAS may vary with vaccination status. The authors evaluated the effect of VAS provided in campaigns on child survival overall and by sex and vaccination status at the time of supplementation.DesignObservational cohort study.Setting and participantsThe study was conducted in the urban study area of the Bandim Health Project in Guinea-Bissau. The authors documented participation or non-participation in two national vitamin A campaigns in December 2007 and July 2008 for children between 6 and 35 months of age. Vaccination status was ascertained by inspection of vaccination cards. All children were followed prospectively.Outcome measuresMortality rates for supplemented and non-supplemented children were compared in Cox models providing mortality rate ratios (MRRs).ResultsThe authors obtained information from 93% of 5567 children in 2007 and 90% of 5799 children in 2008. The VAS coverage was 58% in 2007 and 68% in 2008. Mortality in the supplemented group was 1.5% (44 deaths/2873 person-years) and 1.6% (20 deaths/1260 person-years) in the non-supplemented group (adjusted MRR=0.78 (0.46; 1.34)). The effect was similar in boys and girls. Vaccination cards were seen for 86% in 2007 and 84% in 2008. The effect of VAS in children who had measles vaccine as their last vaccine (2814 children, adjusted MRR=0.34 (0.14; 0.85)) differed from the effect in children who had diphtheria–tetanus–pertussis vaccine as their last vaccine (3680 children, adjusted MRR=1.29 (0.52; 3.22), p=0.04 for interaction).ConclusionThe effect of VAS differed by most recent vaccination, being beneficial after measles vaccine but not after diphtheria–tetanus–pertussis vaccine.
Exposure to bisphosphonates and risk of cancer: a protocol for nested case–control studies using the QResearch primary care database
Authors: Vinogradova Yana , Coupland Carol , Hippisley-Cox Julia 
Published: January 2012

IntroductionBisphosphonates are becoming a common treatment for osteoporosis particularly after discovery of the association between hormone replacement therapy and increased risk of breast cancer. As osteoporosis develops with age, treatment is a long-term intervention. Randomised control trials typically have limited follow-up times, which restricts investigation of the effects of the drugs on risk of primary cancers. A few observational studies have demonstrated a reduced risk of breast cancer and possibly of endometrial cancer in bisphosphonate users. Two epidemiological studies have studied the effect of the drugs on oesophageal cancer but did not reach any definite conclusions. So far, no effects on colorectal and stomach cancer have been shown. This study will investigate the association of bisphosphonates with risks of the 10 most common primary cancers.Methods and analysisA series of nested case–control studies will be based on the general population using records from 660 UK general practices within the QResearch Database. Cases will be patients with primary cancers diagnosed between 1996 and 2011. Each case will be matched by age, sex, practice and calendar year to five controls, who are alive and registered with the practice at the time of diagnosis of the case. Exposure to bisphosphonates will be defined as at least one prescription during the study period. For the most common cancers with substantial numbers of observations, the effect of the duration of the treatment and different types of bisphosphonates will be studied. Conditional logistic regression will be applied to produce ORs adjusted for smoking status, socioeconomic status, ethnicity, cancer-specific co-morbidities and use of other medications.
Addressing geographical variation in the progression of non-communicable diseases in Peru: the CRONICAS cohort study protocol
Authors: Miranda J Jaime , Bernabe-Ortiz Antonio , Smeeth Liam , Gilman Robert H , Checkley William ,   CRONICAS Cohort Study Group
Published: January 2012

BackgroundThe rise in non-communicable diseases in developing countries has gained increased attention. Given that around 80% of deaths related to non-communicable diseases occur in low- and middle-income countries, there is a need for local knowledge to address such problems. Longitudinal studies can provide valuable information about disease burden of non-communicable diseases in Latin America to inform both public health and clinical settings.MethodsThe CRONICAS cohort is a longitudinal study performed in three Peruvian settings that differ by degree of urbanisation, level of outdoor and indoor pollution and altitude. The author sought to enrol an age- and sex-stratified random sample of 1000 participants at each site. Study procedures include questionnaires on socio-demographics and well-known risk factors for cardiopulmonary disease, blood draw, anthropometry and body composition, blood pressure and spirometry before and after bronchodilators. All participants will be visited at baseline, at 20 and 40 months. A random sample of 100 households at each site will be assessed for 24 h particulate matter concentration. Primary outcomes include prevalence of risk factors for cardiopulmonary diseases, changes in blood pressure and blood glucose over time and decline in lung function.DiscussionThere is an urgent need to characterise the prevalence and burden of non-communicable diseases in low- and middle-income countries. Peru is a middle-income country currently undergoing a rapid epidemiological transition. This longitudinal study will provide valuable information on cardiopulmonary outcomes in three different settings and will provide a platform to address potential interventions that are locally relevant or applicable to other similar settings in Latin America.
The effect of MELatOnin on Depression, anxietY, cognitive function and sleep disturbances in patients with breast cancer. The MELODY trial: protocol for a randomised, placebo-controlled, double-blinded trial
Authors: Hansen Melissa Voigt , Madsen Michael Tvilling , Hageman Ida , Rasmussen Lars Simon , Bokmand Susanne , Rosenberg Jacob , Gögenur Ismail 
Published: January 2012

IntroductionBreast cancer represents about one-third of all cancer diagnoses and accounts for about 15% of cancer deaths in women. Many of these patients experience depression, anxiety, sleep disturbances and cognitive dysfunction. This may adversely affect quality of life and also contribute to morbidity and mortality. Melatonin is a regulatory circadian hormone having, among others, a hypnotic and an antidepressive effect. It has very low toxicity and very few adverse effects compared with the more commonly used antidepressants and hypnotics.Methods and analysisThe objective of this double-blind, randomised, placebo-controlled trial is to investigate whether treatment with oral melatonin has a prophylactic or ameliorating effect on depressive symptoms, anxiety, sleep disturbances and cognitive dysfunction in women with breast cancer. Furthermore, the authors will examine whether a specific clock-gene, PER3, is correlated with an increased risk of depressive symptoms, sleep disturbances or cognitive dysfunction. The MELODY trial is a prospective double-blinded, randomised, placebo-controlled trial in which the authors intend to include 260 patients. The primary outcome is depressive symptoms measured by the Major Depression Inventory. The secondary outcomes are anxiety measured by a Visual Analogue Scale, total sleep time, sleep efficiency, sleep latency and periods awake measured by actigraphy and changes in cognitive function measured by a neuropsychological test battery. Tertiary outcomes are fatigue, pain, well-being and sleep quality/quantity measured by Visual Analogue Scale and sleep diary and sleepiness measured by the Karolinska Sleepiness Scale. The PER3 genotype is also to be determined in blood samples.
Effects of an intravenous bolus of alfaxalone versus propofol on intraocular pressure in sheep
Authors: Torres M‐D. , Andaluz A. , García F. , Fresno L. , Moll X. 
Published: January 2012

The objective of this prospective study was to determine the effects of a single intravenous bolus of alfaxalone in 2‐hydroxypropyl‐β‐cyclodextrin and propofol on the intraocular pressure (IOP) in sheep. Ten Ripollesa sheep with a bodyweight of 48.5 (6.8) kg (mean [sd]) were used in the study. Twenty‐four hours before the experimental procedure, a complete ophthalmic examination was performed in all animals. The day of the study, intravenous alfaxalone (2 mg/kg) or propofol (6 mg/kg) was randomly administered in a cross‐over design, with a washout period of two weeks. Measurements of IOP, globe position and pupil size were obtained at basal time, before induction (time 0) and at two, five, 10, 15, 20, 30, 45, 60, 90 and 120 minutes after drug administration. Occasional side effects and time to standing were also noted. Intravenous administration of alfaxalone and propofol in sheep resulted in no alteration of IOP. Nevertheless, a decrease in the pupil size was observed in both groups. This present study shows that alfaxalone and propofol, administrated as a single intravenous bolus, are good options for maintaining IOP during anaesthesia in sheep, although marked miosis was observed after administration.
PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma
Authors: Huang Lin , Nakai Yuji , Kuwahara Iku , Matsumoto Ken 
Published: January 2012

Abstract
Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) with the transcription factor FLI-1. However, expression of the EWS/FLI-1 chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that additional events are required. Here, we report the identification of the Akt substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40 expression by binding the 3′ untranslated region in PRAS40 mRNA. ESFT cell proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased cell proliferation elicited by EWS knockdown. In support of a pathologic role for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the development of ESFT and might therefore represent a novel therapeutic target in this aggressive disease. Cancer Res; 72(5); 1260–9. ©2012 AACR.
Kaposi Sarcoma Herpesvirus Promotes Endothelial-to-Mesenchymal Transition through Notch-Dependent Signaling
Authors: Gasperini Paola , Espigol-Frigole Georgina , McCormick Peter J. , Salvucci Ombretta , Maric Dragan , Uldrick Thomas S. , Polizzotto Mark N. , Yarchoan Robert , Tosato Giovanna 
Published: January 2012

Abstract
Endothelial-to-mesenchymal transition (EndMT) is now widely considered a pivotal contributor to cancer progression. In this study, we show that the Kaposi's sarcoma (KS)–associated herpesvirus (KSHV) is a sufficient cause of EndMT, potentially helping to explain the aggressiveness of KS that occurs commonly in AIDS patients. Upon KSHV infection, primary dermal microvascular endothelial cells lost expression of endothelial markers and acquired expression of mesenchymal markers, displaying new invasive and migratory properties along with increased survival. KSHV activated Notch-induced transcription factors Slug and ZEB1, and canonical Notch signaling was required for KSHV-induced EndMT. In contrast, KSHV did not utilize the TGFβ signaling pathway, which has also been linked to EndMT. Within KS lesions, KSHV-infected spindle cells displayed features compatible with KSHV-induced EndMT including a complex phenotype of endothelial and mesenchymal properties, Notch activity, and nuclear ZEB1 expression. Our results show that KSHV engages the EndMT program to increase the invasiveness and survival of infected endothelial cells, traits that likely contribute to viral persistence and malignant progression. One important implication of our findings is that therapeutic approaches to disrupt the Notch pathway may offer novel approaches for KS treatment. Cancer Res; 72(5); 1157–69. ©2012 AACR.
The 14-3-3σ Tumor Suppressor Has Multiple Functions in ErbB2-Induced Breast Cancer
Authors: Hynes Nancy E. , Smirnova Tatiana 
Published: January 2012

Abstract
Ling and colleagues demonstrated that loss of the conditional 14-3-3σ allele results in accelerated HER2/ERBB2-driven mammary tumorigenesis and metastasis. This study underscores the role of 14-3-3σ as a potent tumor suppressor in ERBB2-driven tumor initiation and progression. Cancer Discovery; 2(1); 19–22. ©2012 AACR.
Commentary on Ling et al., p. 68.