bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting OX40 Promotes Lung-Resident Memory CD8 T Cell Populations That Protect against Respiratory Poxvirus Infection
Authors: Salek-Ardakani Shahram , Moutaftsi Magdalini , Sette Alessandro , Croft Michael 
Published: June 2011

ABSTRACT
One goal of vaccination is to promote development of mucosal effector cells that can immediately respond to peripheral infection. This is especially important for protection against viruses that enter the host through the respiratory tract. We show that targeting the OX40 costimulatory receptor (CD134) strongly promotes mucosal memory in the CD8 T cell compartment. Systemic injection of an agonist antibody to OX40 strongly enhanced development of polyfunctional effector CD8 T cells that were induced after intraperitoneal infection with a highly virulent strain of vaccinia virus. These cells were located in lymphoid organs and also the lung, and importantly, long-term memory CD8 T cells were maintained in the lung over 1 year. Anti-OX40 also boosted memory development when mice were vaccinated subcutaneously with viral peptide. These CD8 T cells were sufficient to provide protection from lethal respiratory infection with live vaccinia virus independent of CD4 T cells and antibody. Again, the CD8 T cell populations that were induced after secondary infection displayed polyfunctionality and were maintained in the lung for over a year. These data suggest that agonists to the OX40 costimulatory receptor represent potential candidates for incorporation into vaccines for respiratory viruses.
Reconstructing the History of Maize Streak Virus Strain A Dispersal To Reveal Diversification Hot Spots and Its Origin in Southern Africa
Authors: Monjane Adérito L. , Harkins Gordon W. , Martin Darren P. , Lemey Philippe , Lefeuvre Pierre , Shepherd Dionne N. , Oluwafemi Sunday , Simuyandi Michelo , Zinga Innocent , Komba Ephrem K. , Lakoutene Didier P. , Mandakombo Noella , Mboukoulida Joseph , Semballa Silla , Tagne Appolinaire , Tiendrébéogo Fidèle , Erdmann Julia B. , van Antwerpen Tania , Owor Betty E. , Flett Bradley , Ramusi Moses , Windram Oliver P. , Syed Rizwan , Lett Jean-Michel , Briddon Rob W. , Markham Peter G. , Rybicki Edward P. , Varsani Arvind 
Published: June 2011

ABSTRACT
Maize streak virus strain A (MSV-A), the causal agent of maize streak disease, is today one of the most serious biotic threats to African food security. Determining where MSV-A originated and how it spread transcontinentally could yield valuable insights into its historical emergence as a crop pathogen. Similarly, determining where the major extant MSV-A lineages arose could identify geographical hot spots of MSV evolution. Here, we use model-based phylogeographic analyses of 353 fully sequenced MSV-A isolates to reconstruct a plausible history of MSV-A movements over the past 150 years. We show that since the probable emergence of MSV-A in southern Africa around 1863, the virus spread transcontinentally at an average rate of 32.5 km/year (95% highest probability density interval, 15.6 to 51.6 km/year). Using distinctive patterns of nucleotide variation caused by 20 unique intra-MSV-A recombination events, we tentatively classified the MSV-A isolates into 24 easily discernible lineages. Despite many of these lineages displaying distinct geographical distributions, it is apparent that almost all have emerged within the past 4 decades from either southern or east-central Africa. Collectively, our results suggest that regular analysis of MSV-A genomes within these diversification hot spots could be used to monitor the emergence of future MSV-A lineages that could affect maize cultivation in Africa.
p63 Is Necessary for the Activation of Human Papillomavirus Late Viral Functions upon Epithelial Differentiation
Authors: Mighty Kristen K. , Laimins Laimonis A. 
Published: June 2011

ABSTRACT
The late phase of the human papillomavirus (HPV) life cycle is linked to epithelial differentiation, and we investigated the factors that regulate this process. One potential regulator is p63, a member of the p53 family of proteins, which modulates epithelial development, as well as proliferation capability, in stem cells. In this study, we examined the role of p63 in the HPV life cycle using a lentiviral knockdown system for p63. In epithelial cells, the ΔN truncated isoforms of p63 predominate, while the full-length TA isoforms are present at very low levels. Upon the differentiation of normal keratinocytes, p63 levels rapidly decreased while higher levels were retained in HPV-positive cells. Our studies indicate that reducing p63 levels in differentiated HPV-positive cells resulted in the loss of viral genome amplification and late gene expression. p63 regulates the expression of cell cycle regulators, and we determined that cyclin A, cyclin B1, cdk1, and cdc25c were reduced in p63-deficient, HPV-positive keratinocytes, which suggests a possible mechanism of action. In addition, activation of the DNA repair pathway is necessary for genome amplification, and the expression of two members, BRCA2 and RAD51, was altered in the absence of p63 in HPV-positive cells. Our studies indicate that p63 is necessary for the activation of differentiation-dependent HPV late viral functions and provide insights into relevant cellular targets.
Mechanism of Neutralization by the Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01
Authors: Li Yuxing , O'Dell Sijy , Walker Laura M. , Wu Xueling , Guenaga Javier , Feng Yu , Schmidt Stephen D. , McKee Krisha , Louder Mark K. , Ledgerwood Julie E. , Graham Barney S. , Haynes Barton F. , Burton Dennis R. , Wyatt Richard T. , Mascola John R. 
Published: June 2011

ABSTRACT

The structure of VRC01 in complex with the HIV-1 gp120 core reveals that this broadly neutralizing CD4 binding site (CD4bs) antibody partially mimics the interaction of the primary virus receptor, CD4, with gp120. Here, we extended the investigation of the VRC01-gp120 core interaction to the biologically relevant viral spike to better understand the mechanism of VRC01-mediated neutralization and to define viral elements associated with neutralization resistance. In contrast to the interaction of CD4 or the CD4bs monoclonal antibody (MAb) b12 with the HIV-1 envelope glycoprotein (Env), occlusion of the VRC01 epitope by quaternary constraints was not a major factor limiting neutralization. Mutagenesis studies indicated that VRC01 contacts within the gp120 loop D, the CD4 binding loop, and the V5 region were necessary for optimal VRC01 neutralization, as suggested by the crystal structure. In contrast to interactions with the soluble gp120 monomer, VRC01 interaction with the native viral spike did not occur in a CD4-like manner; VRC01 did not induce gp120 shedding from the Env spike or enhance gp41 membrane proximal external region (MPER)-directed antibody binding to the Env spike. Finally, VRC01 did not display significant reactivity with human antigens, boding well for potential
in vivo
applications. The data indicate that VRC01 interacts with gp120 in the context of the functional spike in a manner distinct from that of CD4. It achieves potent neutralization by precisely targeting the CD4bs without requiring alterations of Env spike configuration and by avoiding steric constraints imposed by the quaternary structure of the functional Env spike.
Autocatalytic Activity of the Ubiquitin-Specific Protease Domain of Herpes Simplex Virus 1 VP1-2
Authors: Bolstad M. , Abaitua F. , Crump C. M. , O'Hare P. 
Published: June 2011

ABSTRACT

The herpes simplex virus (HSV) tegument protein VP1-2 is essential for virus entry and assembly. VP1-2 also contains a highly conserved ubiquitin-specific protease (USP) domain within its N-terminal region. Despite conservation of the USP and the demonstration that it can act on artificial substrates such as polyubiquitin chains, identification of the relevance of the USP
in vivo
to levels or function of any substrate remains limited. Here we show that HSV VP1-2 USP can act on itself and is important for stability. VP1-2 N-terminal variants encompassing the core USP domain itself were not affected by mutation of the catalytic cysteine residue (C65). However, extending the N-terminal region resulted in protein species requiring USP activity for accumulation. In this context, C65A mutation resulted in a drastic reduction in protein levels which could be stabilized by proteosomal inhibition or by the presence of normal C65. The functional USP domain could increase abundance of unstable variants, indicating action at least in part, in
trans
. Interestingly, full-length variants containing the inactive USP, although unstable when expressed in isolation, were stabilized by virus infection. The catalytically inactive VP1-2 retained complementation activity of a VP1-2-negative virus. Furthermore, a recombinant virus expressing a C65A mutant VP1-2 exhibited little difference in single-step growth curves and the kinetics and abundance of VP1-2 or a number of test proteins. Despite the absence of a phenotype for these replication parameters, the USP activity of VP1-2 may be required for function, including its own stability, under certain circumstances.
Mammalian Orthoreovirus Escape from Host Translational Shutoff Correlates with Stress Granule Disruption and Is Independent of eIF2α Phosphorylation and PKR
Authors: Qin Qingsong , Carroll Kate , Hastings Craig , Miller Cathy L. 
Published: June 2011

ABSTRACT

In response to mammalian orthoreovirus (MRV) infection, cells initiate a stress response that includes eIF2α phosphorylation and protein synthesis inhibition. We have previously shown that early in infection, MRV activation of eIF2α phosphorylation results in the formation of cellular stress granules (SGs). In this work, we show that as infection proceeds, MRV disrupts SGs despite sustained levels of phosphorylated eIF2α and, further, interferes with the induction of SGs by other stress inducers. MRV interference with SG formation occurs downstream of eIF2α phosphorylation, suggesting the virus uncouples the cellular stress signaling machinery from SG formation. We additionally examined mRNA translation in the presence of SGs induced by eIF2α phosphorylation-dependent and -independent mechanisms. We found that irrespective of eIF2α phosphorylation status, the presence of SGs in cells correlated with inhibition of viral and cellular translation. In contrast, MRV disruption of SGs correlated with the release of viral mRNAs from translational inhibition, even in the presence of phosphorylated eIF2α. Viral mRNAs were also translated in the presence of phosphorylated eIF2α in PKR
−/−
cells. These results suggest that MRV escape from host cell translational shutoff correlates with virus-induced SG disruption and occurs in the presence of phosphorylated eIF2α in a PKR-independent manner.
Replacement of Previously Circulating Respiratory Syncytial Virus Subtype B Strains with the BA Genotype in South Africa
Authors: van Niekerk Stephanie , Venter Marietjie 
Published: June 2011

ABSTRACT

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in infants, the immunocompromised, and the elderly in both developed and developing countries. Reinfections are common, and G protein variability is one mechanism to overcome herd immunity. This is illustrated by the appearance of the BA genotype with a 60-nucleotide duplication dominating the subtype B genotypes in epidemics worldwide. To investigate the evolution of subtype B in South Africa since 2002, the genetic variability of the G protein was analyzed in all recent strains isolated over 4 years (2006 to 2009) in South African hospitals. Bayesian analysis revealed a replacement of all subtype B genotypes previously identified in South Africa with the BA genotype since 2006, while subtype A genotypes identified in previous years are still circulating. Compared to BA strains from other countries, the evolutionary rate of the South African BA genotype was shown to be 2.305 × 10
−3
nucleotide substitutions/site/year and drift was evident. The most recent common ancestor (MRCA) of the South African BA viruses was determined to date back to 1996. All South African BA isolates clustered with the BA-IV subgenotype, and the appearance of new subgenotypes within this branch may occur if drift continues. Sequencing of the complete G protein of selected South African strains revealed an additional 6-nucleotide deletion. Acquisition of the 60-nucleotide duplication appeared to have improved the fitness of this virus, and more recent subtype B strains may need to be included in experimental vaccines to evaluate their efficacy in the current setting of evolved circulating strains.
Host Factors in Enterovirus 71 Replication
Authors: Shih Shin-Ru , Stollar Victor , Li Mei-Ling 
Published: June 2011

ABSTRACT
Enterovirus 71 (EV71) infections continue to remain an important public health problem around the world, especially in the Asia-Pacific region. There is a significant mortality rate following such infections, and there is neither any proven therapy nor a vaccine for EV71. This has spurred much fundamental research into the replication of the virus. In this review, we discuss recent work identifying host cell factors which regulate the synthesis of EV71 RNA and proteins. Three of these proteins, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), far-upstream element-binding protein 2 (FBP2), and FBP1 are nuclear proteins which in EV71-infected cells are relocalized to the cytoplasm, and they influence EV71 internal ribosome entry site (IRES) activity. hnRNP A1 stimulates IRES activity but can be replaced by hnRNP A2. FBP2 is a negative regulatory factor with respect to EV71 IRES activity, whereas FBP1 has the opposite effect. Two other proteins, hnRNP K and reticulon 3, are required for the efficient synthesis of viral RNA. The cleavage stimulation factor 64K subunit (CstF-64) is a host protein that is involved in the 3′ polyadenylation of cellular pre-mRNAs, and recent work suggests that in EV71-infected cells, it may be cleaved by the EV71 3C protease. Such a cleavage would impair the processing of pre-mRNA to mature mRNAs. Host cell proteins play an important role in the replication of EV71, but much work remains to be done in order to understand how they act.
Prion Disease Detection, PMCA Kinetics, and IgG in Urine from Sheep Naturally/Experimentally Infected with Scrapie and Deer with Preclinical/Clinical Chronic Wasting Disease
Authors: Rubenstein Richard , Chang Binggong , Gray Perry , Piltch Martin , Bulgin Marie S. , Sorensen-Melson Sharon , Miller Michael W. 
Published: June 2011

ABSTRACT

Prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders. Low levels of infectious agent and limited, infrequent success of disease transmissibility and PrP
Sc
detection have been reported with urine from experimentally infected clinical cervids and rodents. We report the detection of prion disease-associated seeding activity (PASA) in urine from naturally and orally infected sheep with clinical scrapie agent and orally infected preclinical and infected white-tailed deer with clinical chronic wasting disease (CWD). This is the first report on PASA detection of PrP
Sc
from the urine of naturally or preclinical prion-diseased ovine or cervids. Detection was achieved by using the surround optical fiber immunoassay (SOFIA) to measure the products of limited serial protein misfolding cyclic amplification (sPMCA). Conversion of PrP
C
to PrP
Sc
was not influenced by the presence of poly(A) during sPMCA or by the homogeneity of the PrP genotypes between the PrP
C
source and urine donor animals. Analysis of the sPMCA-SOFIA data resembled a linear, rather than an exponential, course. Compared to uninfected animals, there was a 2- to 4-log increase of proteinase K-sensitive, light chain immunoglobulin G (IgG) fragments in scrapie-infected sheep but not in infected CWD-infected deer. The higher-than-normal range of IgG levels found in the naturally and experimentally infected clinical scrapie-infected sheep were independent of their genotypes. Although analysis of urine samples throughout the course of infection would be necessary to determine the usefulness of altered IgG levels as a disease biomarker, detection of PrP
Sc
from PASA in urine points to its potential value for antemortem diagnosis of prion diseases.
Stenting of acute and subacute intracranial vertebrobasilar arterial occlusive lesions
Authors: Kansara Amit , Pandey Paritosh , Tiwari Ambooj , Rayes Mahmoud , Narayanan Sandra , Xavier Andrew R 
Published: June 2011

Background and objectiveThe outcome of failed recanalization in patients with acutely symptomatic intracranial vertebrobasilar (VB) artery occlusive disease is poor. This paper reports the recanalization rate and safety of VB artery stenting in acutely symptomatic patients presenting >8 h after onset of symptoms.MethodsA retrospective review of a prospectively maintained database of stent-supported endovascular treatment of intracranial circulation was carried out to identify patients with VB artery occlusive disease who were acutely revascularized >8 h after symptom onset.ResultsOf 12 patients (mean age 61 years), nine had acute stroke and three had recurrent transient ischemic attacks. The median time to intervention was 59 h (range 8–80). The median National Institute of Health Stroke Scale score was 11.5 (range 1–40). Angiography showed thrombolysis in myocardial infarction (TIMI) 0 flow in six patients and TIMI 1 flow in the other six. Stents were placed in the basilar artery in six and at the VB junction in the other six. Mechanical and/or intra-arterial thrombolysis was used in three patients before stenting. Nine patients had self-expanding stents and three had balloon-expandable stents. The recanalization rate was 100%. Procedure-related and 3-month mortality was zero. Two patients had asymptomatic intracranial hemorrhage. At 3-month follow-up a favorable outcome with a modified Rankin score ≤2 was achieved in eight. A follow-up angiogram in eight patients showed mild re-stenosis in three.ConclusionStent-supported VB artery revascularization can be a viable option with an acceptable safety profile in acute VB occlusion or unstable intracranial atherosclerotic arterial disease (ICAD) in carefully selected patients.
Patterns of ‘leakage’ in the utilisation of clinical guidelines: a systematic review
Authors: Mickan Sharon , Burls Amanda , Glasziou Paul 
Published: June 2011

ABSTRACT

Background
Research evidence is insufficient to change physicians' behaviour. In 1996, Pathman developed a four step model: that physicians need to be aware of, agree with, adopt, and adhere to guidelines.

Objective
To review evidence in different settings on the patterns of ‘leakage’ in the utilisation of clinical guidelines using Pathman’s awareness-to-adherence model.

Methods
A systematic review was conducted in June 2010. Primary studies were included if they reported on rates of awareness and agreement and adoption and/or adherence.

Results
11 primary studies were identified, reporting on 29 recommendations. Descriptive analyses of patterns and causes of leakage were tabulated and graphed. Leakage was progressive across all four steps. Median adherence from all recommendations was 34%, suggesting that potential benefits for patients from health research may be lost. There was considerable variation across different types of guidelines. Recommendations for drug interventions, vaccination and health promotion activities showed high rates of awareness. Leakage was most pronounced between adoption and adherence for drug recommendations and between awareness and agreement for medical management recommendations. Barriers were reported differentially for all steps of the model.

Conclusion
Leakage from research publication to guideline utilisation occurs in a wide variety of clinical settings and at all steps of the awareness-to-adherence pathway. This review confirms that clinical guidelines are insufficient to implement research and suggests there may be different factors influencing clinicians at each step of this pathway. Recommendations to improve guideline adherence need to be tailored to each step.
Maximal T Cell–Mediated Antitumor Responses Rely upon CCR5 Expression in Both CD4+ and CD8+ T Cells
Authors: González-Martín Alicia , Gómez Lucio , Lustgarten Joseph , Mira Emilia , Mañes Santos 
Published: June 2011

Abstract
Immune responses against cancer rely upon leukocyte trafficking patterns that are coordinated by chemokines. CCR5, the receptor for chemotactic chemokines MIP1alpha, MIP1beta, and RANTES (CCL3, CCL4, CCL5), exerts major regulatory effects on CD4+- and CD8+ T cell-mediated immunity. Although CCR5 and its ligands participate in the response to various pathogens, its relevance to tumoral immune control has been debated. Here, we report that CCR5 has a specific, ligand-dependent role in optimizing antitumor responses. In adoptive transfer studies, efficient tumor rejection required CCR5 expression by both CD4+ and CD8+ T cells. CCR5 activation in CD4+ cells resulted in CD40L upregulation, leading to full maturation of antigen-presenting cells and enhanced CD8+ T-cell crosspriming and tumor infiltration. CCR5 reduced chemical-induced fibrosarcoma incidence and growth, but did not affect the onset or progression of spontaneous breast cancers in tolerogenic Tg(MMTV-neu) mice. However, CCR5 was required for TLR9-mediated reactivation of antineu responses in these mice. Our results indicate that CCR5 boosts T-cell responses to tumors by modulating helper-dependent CD8+ T-cell activation. Cancer Res; 71(16); 5455–66. ©2011 AACR.
Anchors, mermaids, shower-curtain seaweeds and fish-shaped fish: The texture of poetic agency
Authors: Wijland Roel 
Published: June 2011

This article defines and theoretically positions the alternative conceptualization of poetic agency. In its aesthetic singularity it aims to humbly resonate with Arcadian explorations of commodities as poetic objects (Benjamin, 1999). It proposes a reconnaissance of poetics that challenges and complements the prevalent mapping of consumer agency in narrative structures. In order to holistically express practical encounters in situ (Allen, 2002) the inquiry explores the liminal texture of meaning-making. The positioning of poetic agency in a culturally particularist model of consumer experience (Sherry Jr, 2000) is suspended between the four notions of narrativity, performativity, liminality and materiality, and evoked in four separate poems. The article finishes its ethno-poetic journey with a purposefully written poem that illuminates theory and method of poetic agency in a fresh context.
Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia
Authors: Alford Kate A. , Reinhardt Katarina , Garnett Catherine , Norton Alice , Böhmer Katarina , von Neuhoff Christine , Kolenova Alexandra , Marchi Emanuele , Klusmann Jan-Henning , Roberts Irene , Hasle Henrik , Reinhardt Dirk , Vyas Paresh 
Published: June 2011

Abstract
Children with Down syndrome (DS) up to the age of 4 years are at a 150-fold excess risk of developing myeloid leukemia (ML-DS). Approximately 4%-5% of newborns with DS develop transient myeloproliferative disorder (TMD). Blast cell structure and immunophenotype are similar in TMD and ML-DS. A mutation in the hematopoietic transcription factor GATA1 is present in almost all cases. Here, we show that simple techniques detect GATA1 mutations in the largest series of TMD (n = 134; 88%) and ML-DS (n = 103; 85%) cases tested. Furthermore, no significant difference in the mutational spectrum between the 2 disorders was seen. Thus, the type of GATA1 sequence mutation is not a reliable tool and is not prognostic of which patients with TMD are probable to develop ML-DS.