bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection
Authors: Thobakgale Christina F. , Prendergast Andrew , Crawford Hayley , Mkhwanazi Nompumelelo , Ramduth Danni , Reddy Sharon , Molina Claudia , Mncube Zenele , Leslie Alasdair , Prado Julia , Chonco Fundi , Mphatshwe Wendy , Tudor-Williams Gareth , Jeena Prakash , Blanckenberg Natasha , Dong Krista , Kiepiela Photini , Coovadia Hoosen , Ndung'u Thumbi , Walker Bruce D. , Goulder Philip J. R. 
Published: July 2009

ABSTRACT

A broad Gag-specific CD8
+
T-cell response is associated with effective control of adult human immunodeficiency virus (HIV) infection. The association of certain HLA class I molecules, such as HLA-B*57, -B*5801, and -B*8101, with immune control is linked to mutations within Gag epitopes presented by these alleles that allow HIV to evade the immune response but that also reduce viral replicative capacity. Transmission of such viruses containing mutations within Gag epitopes results in lower viral loads in adult recipients. In this study of pediatric infection, we tested the hypothesis that children may tend to progress relatively slowly if either they themselves possess one of the protective HLA-B alleles or the mother possesses one of these alleles, thereby transmitting a low-fitness virus to the child. We analyzed HLA type, CD8
+
T-cell responses, and viral sequence changes for 61 mother-child pairs from Durban, South Africa, who were monitored from birth. Slow progression was significantly associated with the mother or child possessing one of the protective HLA-B alleles, and more significantly so when the protective allele was not shared by mother and child (
P
= 0.007). Slow progressors tended to make CD8
+
T-cell responses to Gag epitopes presented by the protective HLA-B alleles, in contrast to progressors expressing the same alleles (
P
= 0.07; Fisher's exact test). Mothers expressing the protective alleles were significantly more likely to transmit escape variants within the Gag epitopes presented by those alleles than mothers not expressing those alleles (75% versus 21%;
P
= 0.001). Reversion of transmitted escape mutations was observed in all slow-progressing children whose mothers possessed protective HLA-B alleles. These data show that HLA class I alleles influence disease progression in pediatric as well as adult infection, both as a result of the CD8
+
T-cell responses generated in the child and through the transmission of low-fitness viruses by the mother.
Artificial Transmembrane Oncoproteins Smaller than the Bovine Papillomavirus E5 Protein Redefine Sequence Requirements for Activation of the Platelet-Derived Growth Factor β Receptor
Authors: Talbert-Slagle Kristina , Marlatt Sara , Barrera Francisco N. , Khurana Ekta , Oates Joanne , Gerstein Mark , Engelman Donald M. , Dixon Ann M. , DiMaio Daniel 
Published: July 2009

ABSTRACT
The bovine papillomavirus E5 protein (BPV E5) is a 44-amino-acid homodimeric transmembrane protein that binds directly to the transmembrane domain of the platelet-derived growth factor (PDGF) β receptor and induces ligand-independent receptor activation. Three specific features of BPV E5 are considered important for its ability to activate the PDGF β receptor and transform mouse fibroblasts: a pair of C-terminal cysteines, a transmembrane glutamine, and a juxtamembrane aspartic acid. By using a new genetic technique to screen libraries expressing artificial transmembrane proteins for activators of the PDGF β receptor, we isolated much smaller proteins, from 32 to 36 residues, that lack all three of these features yet still dimerize noncovalently, specifically activate the PDGF β receptor via its transmembrane domain, and transform cells efficiently. The primary amino acid sequence of BPV E5 is virtually unrecognizable in some of these proteins, which share as few as seven consecutive amino acids with the viral protein. Thus, small artificial proteins that bear little resemblance to a viral oncoprotein can nevertheless productively interact with the same cellular target. We speculate that similar cellular proteins may exist but have been overlooked due to their small size and hydrophobicity.
Ganglioside GT1b Is a Putative Host Cell Receptor for the Merkel Cell Polyomavirus
Authors: Erickson Kimberly D. , Garcea Robert L. , Tsai Billy 
Published: July 2009

ABSTRACT
The Merkel cell polyomavirus (MCPyV) was identified recently in human Merkel cell carcinomas, an aggressive neuroendocrine skin cancer. Here, we identify a putative host cell receptor for MCPyV. We found that recombinant MCPyV VP1 pentameric capsomeres both hemagglutinated sheep red blood cells and interacted with ganglioside GT1b in a sucrose gradient flotation assay. Structural differences between the analyzed gangliosides suggest that MCPyV VP1 likely interacts with sialic acids on both branches of the GT1b carbohydrate chain. Identification of a potential host cell receptor for MCPyV will aid in the elucidation of its entry mechanism and pathophysiology.
Single-Reaction Genomic Amplification Accelerates Sequencing and Vaccine Production for Classical and Swine Origin Human Influenza A Viruses
Authors: Zhou Bin , Donnelly Matthew E. , Scholes Derek T. , St. George Kirsten , Hatta Masato , Kawaoka Yoshihiro , Wentworth David E. 
Published: July 2009

ABSTRACT
Pandemic influenza A viruses that emerge from animal reservoirs are inevitable. Therefore, rapid genomic analysis and creation of vaccines are vital. We developed a multisegment reverse transcription-PCR (M-RTPCR) approach that simultaneously amplifies eight genomic RNA segments, irrespective of virus subtype. M-RTPCR amplicons can be used for high-throughput sequencing and/or cloned into modified reverse-genetics plasmids via regions of sequence identity. We used these procedures to rescue a contemporary H3N2 virus and a swine origin H1N1 virus directly from human swab specimens. Together, M-RTPCR and the modified reverse-genetics plasmids that we designed streamline the creation of vaccine seed stocks (9 to 12 days).
The Adenovirus E1B 55-Kilodalton and E4 Open Reading Frame 6 Proteins Limit Phosphorylation of eIF2α during the Late Phase of Infection
Authors: Spurgeon Megan E. , Ornelles David A. 
Published: July 2009

ABSTRACT
During a productive infection, species C adenovirus reprograms the host cell to promote viral translation at the expense of cellular translation. The E1B 55-kilodalton (E1B-55K) and E4 open reading frame 6 (E4orf6) proteins are important in this control of gene expression. As part of a ubiquitin-protein ligase, these viral proteins stimulate viral mRNA export, inhibit cellular mRNA export, promote viral gene expression, and direct the degradation of certain host proteins. We report here that the E1B-55K and E4orf6 proteins limited phosphorylation of eIF2α and the activation of the eIF2α kinase PKR. Phospho-eIF2α levels were observed to rise and fall at least twice during infection. The E1B-55K and E4orf6 proteins prevented a third increase at late times of infection. PKR appeared to phosphorylate eIF2α only in the absence of E1B-55K/E4orf6 function. PKR activation and eIF2α phosphorylation was unrelated to the cytoplasmic levels of the adenovirus inhibitor of PKR, VA-I RNA. Nonetheless, expression of a PKR inhibitor, the reovirus double-stranded RNA-binding protein sigma 3, prevented PKR activation and eIF2α phosphorylation. The sigma 3 protein largely corrected the defect in viral late protein synthesis associated with the E1B-55K and E4orf6 mutant viruses without affecting cytoplasmic levels of the late viral mRNA. The ubiquitin-protein ligase activity associated with the E1B-55K/E4orf6 complex was necessary to prevent activation of PKR and phosphorylation of eIF2α. These findings reveal a new contribution of the E1B-55K/E4orf6 complex to viral late protein synthesis and the existence of multiple layers of regulation imposed on eIF2α phosphorylation and PKR activation in adenovirus-infected cells.
Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs
Authors: Böhm Verena , Seckert Christof K. , Simon Christian O. , Thomas Doris , Renzaho Angélique , Gendig Dorothea , Holtappels Rafaela , Reddehase Matthias J. 
Published: July 2009

ABSTRACT
CD8 T cells control cytomegalovirus (CMV) infection in bone marrow transplantation recipients and persist in latently infected lungs as effector memory cells for continuous sensing of reactivated viral gene expression. Here we have addressed the question of whether viral immunoevasins, glycoproteins that specifically interfere with antigen presentation to CD8 T cells, have an impact on viral latency in the murine model. The data show that deletion of immunoevasin genes in murine CMV accelerates the clearance of productive infection during hematopoietic reconstitution and leads to a reduced latent viral genome load, reduced latency-associated viral transcription, and a lower incidence of recurrence in lung explants.
Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication
Authors: Borawski Jason , Troke Philip , Puyang Xiaoling , Gibaja Veronica , Zhao ShanChaun , Mickanin Craig , Leighton-Davies Juliet , Wilson Christopher J. , Myer Vic , CornellaTaracido Ivan , Baryza Jeremy , Tallarico John , Joberty Gerard , Bantscheff Marcus , Schirle Markus , Bouwmeester Tewis , Mathy Joanna E. , Lin Kai , Compton Teresa , Labow Mark , Wiedmann Brigitte , Gaither L. Alex 
Published: July 2009

ABSTRACT
Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection.
ADAR1 Interacts with PKR during Human Immunodeficiency Virus Infection of Lymphocytes and Contributes to Viral Replication
Authors: Clerzius Guerline , Gélinas Jean-François , Daher Aïcha , Bonnet Marion , Meurs Eliane F. , Gatignol Anne 
Published: July 2009

ABSTRACT
The interferon-induced protein kinase RNA activated (PKR) is activated after virus infection. This activation is transient during the human immunodeficiency virus type 1 (HIV-1) infection of lymphocytes, and the protein is not activated at the peak of infection. We observed that interferon-induced adenosine deaminase acting on RNA 1-p150 (ADAR1-p150) and ADAR1-p110 expression increases while the virus replicates actively. Furthermore, both forms of ADAR1 show enhanced interactions with PKR at the peak of HIV infection, suggesting a role for this protein in the regulation of PKR activation. We observed that ADAR1-p150, as previously shown for the TAR RNA binding protein (TRBP), reverses the PKR inhibition of HIV expression and production in HEK 293T cells. This activity requires the Z-DNA binding motif and the three double-stranded RNA binding domains but not the catalytic domain. In astrocytic cells, ADAR1-p150 increased HIV expression and production to an extent similar to that of TRBP. Small interfering RNAs against ADAR1-p150 moderately decreased HIV production. These results indicate that two interferon-induced proteins, ADAR1 and PKR, have antagonistic functions on HIV production. They suggest that ADAR1 and TRBP belong to a multiprotein complex that inhibits PKR during the HIV infection of lymphocytes.
The archaeal origins of the eukaryotic translational system
Authors: Hartman Hyman , Favaretto Paola , Smith Temple F. 
Published: July 2009

Among the 78 eukaryotic ribosomal proteins, eleven are specific to Eukarya, 33 are common only to Archaea and Eukarya and 34 are homologous (at least in part) to those of both Bacteria and Archaea. Several other translational proteins are common only to Eukarya and Archaea (e.g., IF2a, SRP19, etc.), whereas others are shared by the three phyla (e.g., EFTu/EF1A and SRP54).Although this and other analyses strongly support an archaeal origin for a substantial fraction of the eukaryotic translational machinery, especially the ribosomal proteins, there have been numerous unique and ubiquitous additions to the eukaryotic translational system besides the 11 unique eukaryotic ribosomal proteins. These include peptide additions to most of the 67 archaeal homolog proteins, rRNA insertions, the 5.8S RNA and the Alu extension to the SRP RNA. Our comparative analysis of these and other eukaryotic features among the three different cellular phylodomains supports the idea that an archaeal translational system was most likely incorporated by means of endosymbiosis into a host cell that was neither bacterial nor archaeal in any modern sense. Phylogenetic analyses provide support for the timing of this acquisition coinciding with an ancient bottleneck in prokaryotic diversity.
Potentiation of Cannabinoid-Induced Cytotoxicity in Mantle Cell Lymphoma through Modulation of Ceramide Metabolism
Authors: Gustafsson Kristin , Sander Birgitta , Bielawski Jacek , Hannun Yusuf A. , Flygare Jenny 
Published: July 2009

Abstract
Ceramide levels are elevated in mantle cell lymphoma (MCL) cells following treatment with cannabinoids. Here, we investigated the pathways of ceramide accumulation in the MCL cell line Rec-1 using the stable endocannabinoid analogue R(+)-methanandamide (R-MA). We further interfered with the conversion of ceramide into sphingolipids that promote cell growth. Treatment with R-MA led to increased levels of ceramide species C16, C18, C24, and C24:1 and transcriptional induction of ceramide synthases (CerS) 3 and 6. The effects were attenuated using SR141716A, which has high affinity to cannabinoid receptor 1 (CB1). The CB1-mediated induction of CerS3 and CerS6 mRNA was confirmed using Win-55,212-2. Simultaneous silencing of CerS3 and CerS6 using small interfering RNA abrogated the R-MA-induced accumulation of C16 and C24. Inhibition of either of the enzymes serine palmitoyl transferase, CerS, and dihydroceramide desaturase within the de novo ceramide pathway reversed ceramide accumulation and cell death induced by R-MA treatment. To enhance the cytotoxic effect R-MA, sphingosine kinase-1 and glucosylceramide synthase, enzymes that convert ceramide to the pro-proliferative sphingolipids sphingosine-1-phospate and glucosylceramide, respectively, were inhibited. Suppression of either enzyme using inhibitors or small interfering RNA potentiated the decreased viability, induction of cell death, and ceramide accumulation induced by R-MA treatment. Our findings suggest that R-MA induces cell death in MCL via CB1-mediated up-regulation of the de novo ceramide synthesis pathway. Furthermore, this is the first study were the cytotoxic effect of a cannabinoid is enhanced by modulation of ceramide metabolism. (Mol Cancer Res 2009;7(7):1086–98)
β-Arrestin/Ral Signaling Regulates Lysophosphatidic Acid–Mediated Migration and Invasion of Human Breast Tumor Cells
Authors: Li Timothy T. , Alemayehu Mistre , Aziziyeh Adel I. , Pape Cynthia , Pampillo Macarena , Postovit Lynne-Marie , Mills Gordon B. , Babwah Andy V. , Bhattacharya Moshmi 
Published: July 2009

AbstractThe lipid mediator lysophosphatidic acid (LPA) plays a role in cancer progression and signals via specific G protein–coupled receptors, LPA1-3. LPA has been shown to enhance the metastasis of breast carcinoma cells to bone. However, the mechanisms by which LPA receptors regulate breast cancer cell migration and invasion remain unclear. Breast cancer cell proliferation has been shown to be stimulated by Ral GTPases, a member of the Ras superfamily. Ral activity can be regulated by the multifunctional protein β-arrestin. We now show that HS578T and MDA-MB-231 breast cancer cells and MDA-MB-435 melanoma cells have higher expression of β-arrestin 1 mRNA compared with the nontumorigenic mammary MCF-10A cells. Moreover, we found that the mRNA levels of LPA1, LPA2, β-arrestin 2, and Ral GTPases are elevated in the advanced stages of breast cancer. LPA stimulates the migration and invasion of MDA-MB-231 cells, but not of MCF-10A cells, and this is mediated by pertussis toxin–sensitive G proteins and LPA1. However, ectopic expression of LPA1 in MCF-10A cells caused these cells to acquire an invasive phenotype. Gene knockdown of either β-arrestin or Ral proteins significantly impaired LPA-stimulated migration and invasion. Thus, our data show a novel role for β-arrestin/Ral signaling in mediating LPA-induced breast cancer cell migration and invasion, two important processes in metastasis. (Mol Cancer Res 2009;7(7):1064–77)
DNA Repair and Resistance of Gliomas to Chemotherapy and Radiotherapy
Authors: Frosina Guido 
Published: July 2009

Abstract
The importance of DNA repair as a resistance mechanism in gliomas, the most aggressive form of brain tumor, is a clinically relevant topic. Recent studies show that not all cells are equally malignant in gliomas. Certain subpopulations are particularly prone to drive tumor progression and resist chemo- and radiotherapy. Those cells have been variably named cancer stem cells or cancer-initiating cells or tumor-propagating cells, owing to their possible (but still uncertain) origin from normal stem cells. Although DNA repair reduces the efficacy of chemotherapeutics and ionizing radiation toward bulk gliomas, its contribution to resistance of the rare glioma stem cell subpopulations is less clear. Mechanisms other than DNA repair (in particular low proliferation and activation of the DNA damage checkpoint response) are likely main players of resistance in glioma stem cells and their targeting might yield significant therapeutic gains. (Mol Cancer Res 2009;7(7):989–99)
Arthroscopic Treatment of Multidirectional Shoulder Instability in Athletes
Authors: Baker Champ L. , Mascarenhas Randy , Kline Alex J. , Chhabra Anikar , Pombo Mathew W. , Bradley James P. 
Published: July 2009

Background There are few reports in the literature detailing the arthroscopic treatment of multidirectional instability of the shoulder. Hypothesis Arthroscopic management of symptomatic multidirectional instability in an athletic population can successfully return athletes to sports with a high rate of success as determined by patient-reported outcome measures. Study Design Case series; Level of evidence, 4. Methods Forty patients (43 shoulders) with multidirectional instability of the shoulder were treated via arthroscopic means and were evaluated at a mean of 33.5 months postoperatively. The mean patient age was 19.1 years (range, 14-39). There were 24 male patients and 16 female patients. Patients were evaluated with the American Shoulder and Elbow Surgeons and Western Ontario Shoulder Instability scoring systems. Stability, strength, and range of motion were also evaluated with patient-reported scales. Results The mean American Shoulder and Elbow Surgeons score postoperatively was 91.4 of 100 (range, 59.9-100). The mean Western Ontario Shoulder Instability postoperative percentage score was 91.1 of 100 (range, 72.9-100). Ninety-one percent of patients had full or satisfactory range of motion, 98% had normal or slightly decreased strength, and 86% were able to return to their sport with little or no limitation. Conclusion Arthroscopic methods can provide an effective treatment for symptomatic multidirectional instability in an athletic population.
The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function
Authors: Lee John J. , Rauter Ingrid , Garibyan Lilit , Ozcan Esra , Sannikova Tatyana , Dillon Stacey R. , Cruz Anthony C. , Siegel Richard M. , Bram Richard , Jabara Haifa , Geha Raif S. 
Published: July 2009

AbstractTNFRSF13B, which encodes TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor), is mutated in 10% of patients with common variable immune deficiency (CVID). One of the 2 most common TACI mutations in CVID, A181E, introduces a negative charge into the transmembrane domain. To define the consequence of the A181E mutation on TACI function, we studied the effect of its murine equivalent, mTACI A144E, on TACI signaling in transfected cells and on TACI function in transgenic mice. The mTACI A144E mutant, like its human TACI A181E counterpart, was expressed on the surface of 293T transfectants and was able to bind ligand, but exhibited impaired constitutive and ligand-induced NFκB signaling. In addition, constitutive and ligand-induced clustering of the intracellular domain was deficient for A144E as measured by fluorescence resonance energy transfer. Transgenic mice expressing the A144E mutant on TACI−/− background had low serum IgA levels and significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll. B cells from A144E transgenic mice were impaired in their capacity to proliferate and secrete IgG1 and IgA in response to TACI ligation. These results suggest that mTACI A144E mutation and its human counterpart, A181E, disrupt TACI signaling and impair TACI-dependent B-cell functions.
Safety and immunologic effects of IL-15 administration in nonhuman primates
Authors: Berger Carolina , Berger Michael , Hackman Robert C. , Gough Michael , Elliott Carole , Jensen Michael C. , Riddell Stanley R. 
Published: July 2009

AbstractThe administration of cytokines that modulate endogenous or transferred T-cell immunity could improve current approaches to clinical immunotherapy. Interleukin-2 (IL-2) is used most commonly for this purpose, but causes systemic toxicity and preferentially drives the expansion of CD4+CD25+Foxp3+ regulatory T cells, which can inhibit antitumor immunity. IL-15 belongs to the γc cytokine family and possesses similar properties to IL-2, including the ability to induce T-cell proliferation. Whereas IL-2 promotes apoptosis and limits the survival of CD8+ memory T cells, IL-15 is required for the establishment and maintenance of CD8+ T-cell memory. However, limited data are available to guide the clinical use of IL-15. Here, we demonstrate in nonhuman primates that IL-15 administration expands memory CD8+ and CD4+ T cells, and natural killer (NK) cells in the peripheral blood, with minimal increases in CD4+CD25+Foxp3+ regulatory T cells. Daily administration of IL-15 resulted in persistently elevated plasma IL-15 levels and transient toxicity. Intermittent administration of IL-15 allowed clearance of IL-15 between doses and was safe for more than 3 weeks. These findings demonstrate that IL-15 has profound immunomodulatory properties distinct from those described for IL-2, and suggest that intermittent administration of IL-15 should be considered in clinical studies.