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McNatt MW, Zang T, Bieniasz PD
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Vpu Binds Directly to Tetherin and Displaces It from Nascent Virions
PLOS PATHOGENS 2013 APR; 9(4):? Article e1003299
Tetherin (Bst2/CD317/HM1.24) is an interferon-induced antiviral host protein that inhibits the release of many enveloped viruses by tethering virions to the cell surface. The HIV-1 accessory protein, Vpu, antagonizes Tetherin through a variety of proposed mechanisms, including surface downregulation and degradation. Previous studies have demonstrated that mutation of the transmembrane domains (TMD) of both Vpu and Tetherin affect antagonism, but it is not known whether Vpu and Tetherin bind directly to each other. Here, we use cysteine-scanning mutagenesis coupled with oxidation-induced cross-linking to demonstrate that Vpu and Tetherin TMDs bind directly to each other in the membranes of living cells and to map TMD residues that contact each other. We also reveal a property of Vpu, namely the ability to displace Tetherin from sites of viral assembly, which enables Vpu to exhibit residual Tetherin antagonist activity in the absence of surface downregulation or degradation!
McEwen BS
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Interview with Bruce S. McEwen
TRENDS IN NEUROSCIENCES 2013 APR; 36(4):207-208
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Measurement of associated production of vector bosons and top quark-antiquark pairs in pp collisions at root s=7 TeV
PHYSICAL REVIEW LETTERS 2013 APR 25; 110(17):? Article 172002
The first measurement of vector-boson production associated with a top quark-antiquark pair in proton-proton collisions at root s = 7 TeV is presented. The results are based on a data set corresponding to an integrated luminosity of 5.0 fb(-1), recorded by the CMS detector at the LHC in 2011. The measurement is performed in two independent channels through a trilepton analysis of t (t) over barZ events and a same-sign dilepton analysis of t (t) over barV (V = W or Z) events. In the trilepton channel a direct measurement of the t (t) over barZ cross section sigma(t (t) over barZ) = 0.28(-0.11)(+0.14) (stat)(-0.03)(+0.06) (syst) pb is obtained. In the dilepton channel a measurement of the t (t) over barV cross section yields sigma(t (t) over barV) = 0.43(-0.15)(+0.17) (stat)(-0.07)(+0.09) (syst) pb. These measurements have a significance, respectively, of 3.3 and 3.0 standard deviations from the background hypotheses and are compatible, within uncertainties, with the corresponding next-to-leading order predictions of 0.137(-0.016)(+0.012) and 0.306(-0.053)(+0.031) pb. DOI: 10.1103/PhysRevLett.110.172002
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Barbaro P, Demina R, Eshaq Y, Ferbel T, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Miner DC, Vishnevskiy D, Zielinski M, Bhatti A, Ciesielski R, Demortier L, Goulianos K, Lungu G, Malik S, Mesropian C, Arora S, Barker A, Chou JP, Contreras-Campana C, Contreras-Campana E, Duggan D, Ferencek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Lath A, Panwalkar S, Park M, Patel R, Rekovic V, Robles J, Rose K, Salur S, Schnetzer S, Seitz C, Somalwar S, Stone R, Thomas S, Walker M, Cerizza G, Hollingsworth M, Spanier S, Yang ZC, York A, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Montalvo R, Osipenkov I, Pakhotin Y, Perloff A, Roe J, Safonov A, Sakuma T, Sengupta S, Suarez I, Tatarinov A, Toback D, Akchurin N, Damgov J, Dragoiu C, Dudero PR, Jeong C, Kovitanggoon K, Lee SW, Libeiro T, Volobouev I, Appelt E, Delannoy AG, Florez C, Greene S, Gurrola A, Johns W, Kurt P, Maguire C, Melo A, Sharma M, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, Balazs M, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Lin C, Neu C, Wood J, Gollapinni S, Harr R, Karchin PE, Don CKK, Lamichhane P, Sakharov A, Anderson M, Belknap DA, Borrello L, Carlsmith D, Cepeda M, Dasu S, Friis E, Gray L, Grogg KS, Grothe M, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Klukas J, Lanaro A, Lazaridis C, Loveless R, Mohapatra A, Mozer MU, Ojalvo I, Palmonari F, Pierro GA, Ross I, Savin A, Smith WH, Swanson J
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Measurement of the W+W- and ZZ production cross sections in pp collisions at root s=8 TeV
PHYSICS LETTERS B 2013 APR 25; 721(4-5):190-211
The W+W- and ZZ production cross sections are measured in proton-proton collisions at root s = 8 TeV with the CMS experiment at the LHC in data samples corresponding to an integrated luminosity of up to 5.3 fb(-1). The measurements are performed in the leptonic decay modes W+W- -> l'vl '' v and ZZ -> 2l2l', where l = e, mu and l'(l '') = e, mu, tau. The measured cross sections sigma (pp -> W+W-) =, 69.9 +/- 2.8 (stat.) +/- 5.6 (syst.) 3.1 +/- (lum.) pb and sigma (pp -> ZZ) = 8.4 +/- 1.0 (stat) +/- 0.7 (syst) +/- 0.4 (lum.) pb, for both Z bosons produced in the mass region 60 < m(Z) < 120 GeV, are consistent with standard model predictions. These are the first measurements of the diboson production cross sections at root s = 8 TeV. (C) 2013 CERN. Published by Elsevier B.V. All rights reserved.
Brophy TM, Coller BS, Ahamed J
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Identification of the Thiol Isomerase-binding Peptide, Mastoparan, as a Novel Inhibitor of Shear-induced Transforming Growth Factor beta 1 (TGF-beta 1) Activation
JOURNAL OF BIOLOGICAL CHEMISTRY 2013 APR 12; 288(15):10628-10639
TGF-beta 1 is a disulfide-bonded homodimeric protein produced by platelets and other cells that plays a role in many physiologic and pathologic processes. TGF-beta 1 is secreted as an inactive large latent complex (LLC) comprised of TGF-beta 1, latency-associated peptide, and latent TGF-beta binding protein 1. We previously demonstrated that shear force can activate LLC and that thiol-disulfide exchange contributes to the process. We have now investigated the role of thiol isomerases in the activation of LLC in platelet releasates (PR) and recombinant LLC. The wasp venom peptide mastoparan, which inhibits the chaperone activity of PDI, inhibited stirring-and shear-induced activation of latent TGF-beta 1 by 90 and 75% respectively. To identify the proteins that bind to mastoparan either directly or indirectly, PR were chromatographed on a mastoparan affinity column. Latent TGF-beta binding protein 1, latency-associated peptide, TGF-beta 1, clusterin, von Willebrand factor,!
de Diego RP, Mulvey C, Crawford M, Trotter MWB, Lorenzo L, Sancho-Shimizu V, Abel L, Zhang SY, Casanova JL, Godovac-Zimmermann J
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The proteome of Toll-like receptor 3-stimulated human immortalized fibroblasts: Implications for susceptibility to herpes simplex virus encephalitis
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2013 APR; 131(4):1157-1166
Background: Inborn errors in Toll-like receptor 3 (TLR3)-IFN type I and III pathways have been implicated in susceptibility to herpes simplex virus encephalitis (HSE) in children, but most patients studied do not carry mutations in any of the genes presently associated with HSE susceptibility. Moreover, many patients do not display any TLR3-IFN-related fibroblastic phenotype. Objective: To study other signaling pathways downstream of TLR3 and/or other independent pathways that may contribute to HSE susceptibility. Methods: We used the stable isotope labeling of amino acids in cell culture proteomics methodology to measure changes in the human immortalized fibroblast proteome after TLR3 activation. Results: Cells from healthy controls were compared with cells from a patient with a known genetic etiology of HSE (UNC-93B(-/-)) and also to cells from an HSE patient with an unknown gene defect. Consistent with known variation in susceptibility of individuals to viral infections, substantial variation in the response level of different healthy controls was observed, but common functional networks could be identified, including upregulation of superoxide dismutase 2. The 2 patients with HSE studied show clear differences in functional response networks when compared with healthy controls and also when compared with each other. Conclusions: The present study delineates a number of novel proteins, TLR3-related pathways, and cellular phenotypes that may help elucidate the genetic basis of childhood HSE. Furthermore, our results reveal superoxide dismutase 2 as a potential therapeutic target for amelioration of the neurologic sequelae caused by HSE. (J Allergy Clin Immunol 2013;131:1157-66.)
Niikura K, Zhou Y, Ho A, Kreek MJ
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PROOPIOMELANOCORTIN (POMC) EXPRESSION AND CONDITIONED PLACE AVERSION DURING PROTRACTED WITHDRAWAL FROM CHRONIC INTERMITTENT ESCALATING-DOSE HEROIN IN POMC-EGFP PROMOTER TRANSGENIC MICE
NEUROSCIENCE 2013 APR 16; 236(?):220-232
In heroin-dependent individuals, the drive to avoid or ameliorate the negative affective/emotional state associated with the discontinuation of heroin contributes to the chronic relapsing nature of the disease. Here, we investigate changes in proopiomelanocortin (POMC) expression at three time points across an extended period of heroin withdrawal in a clinically relevant rodent model of addiction using conditioned place aversion (CPA) in POMC-EGFP (POMC-enhanced green fluorescent protein) bacterial artificial chromosome (BAC) transgenic mice. Neurons expressing POMC-EGFP were found in the medial nucleus of the amygdala (MeA), basomedial amygdala (BMA) and dentate gyrus of hippocampus (DG), as well as the arcuate nucleus of hypothalamus (ARC). Heroin-treated mice displayed robust CPA after acute spontaneous withdrawal (12 h), which persisted across the extended (14 days) withdrawal period. After 12-h withdrawal, heroin-treated mice showed lower signal intensity of POMC-EGF!
Lowry ER, Kruyer A, Norris EH, Cederroth CR, Strickland S
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THE GLUK4 KAINATE RECEPTOR SUBUNIT REGULATES MEMORY, MOOD, AND EXCITOTOXIC NEURODEGENERATION
NEUROSCIENCE 2013 APR 3; 235(?):215-225
Though the GluK4 kainate receptor subunit shows limited homology and a restricted expression pattern relative to other kainate receptor subunits, its ablation results in distinct behavioral and molecular phenotypes. GluK4 knockout mice demonstrated impairments in memory acquisition and recall in a Morris water maze test, suggesting a previously unreported role for kainate receptors in spatial memory. GluK4 knockout mice also showed marked hyperactivity and impaired pre-pulse inhibition, thereby mirroring two of the hallmark endophenotypes of patients with schizophrenia and bipolar disorder. Furthermore, we found that GluK4 is a key mediator of excitotoxic neurodegeneration: GluK4 knockout mice showed robust neuroprotection in the CA3 region of the hippocampus following intrahippocampal injection of kainate and widespread neuroprotection throughout the hippocampus following hypoxia-ischemia. Biochemical analysis of kainate- or sham-treated wild-type and GluK4 knockout hipp!
Kosten TR, Domingo CB, Hamon SC, Nielsen DA
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DBH gene as predictor of response in a cocaine vaccine clinical trial
NEUROSCIENCE LETTERS 2013 APR 29; 541(?):29-33
We examined a pharmacogenetic association of the dopamine beta-hydroxylase (DBH) gene with a response to an anti-cocaine vaccine that was tested in a recent clinical trial. This gene is associated with cocaine-induced paranoia, which has a slower onset than the euphoria from cocaine. The vaccine reduced euphoria by slowing the entry of cocaine into the brain, but it may not reduce aversive symptoms like paranoia. A 16-week Phase IIb randomized double-blind placebo-controlled trial of 114 cocaine and opioid dependent subjects who received five vaccinations over the first 12 weeks was examined. We genotyped 71 subjects for the rs1611115 (-1021C>T) variant of the DBH gene and compared vaccine to placebo subjects on cocaine-free urines. Using repeated measures analysis of variance, corrected for population structure, vaccine pharmacotherapy reduced cocaine positive urines significantly based on DBH genotype. Patients with the low D beta H level genotype dropped from 77% to 51!
Dale JB, Fischetti VA, Carapetis JR, Steer AC, Sow S, Kumar R, Mayosi BM, Rubin FA, Mulholland K, Hombach JM, Schodel F, Henao-Restrepo AM
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Group A streptococcal vaccines: Paving a path for accelerated development
VACCINE 2013 APR 18; 31(?):B216-B222
Group A streptococci (GAS) are important causes of morbidity and mortality worldwide. These organisms cause a wide spectrum of disease, ranging from uncomplicated sore throat to invasive, life-threatening infections, as well as immune complications such as acute rheumatic fever (ARF), rheumatic heart disease (RHD) and acute post-streptococcal glomerulonephritis (APSGN). Vaccine prevention of GAS infections and their immunological complications has been a goal of researchers for decades. Several vaccine candidates against GAS infection are in various stages of pre-clinical and clinical development, including M protein-based vaccines (N-terminal vaccine candidates and M protein conserved region vaccines), and non-M protein vaccine candidates representing conserved GAS antigens. Some of the obstacles to GAS vaccine development are related to the complexity of the global epidemiology of GAS infections, the limitation in the criteria for selection of antigens to include in com!