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Berglund LJ, Avery DT, Ma CS, Moens L, Deenick EK, Bustamante J, Boisson-Dupuis S, Wong M, Adelstein S, Arkwright PD, Bacchetta R, Bezrodnik L, Dadi H, Roifman CM, Fulcher DA, Ziegler JB, Smart JM, Kobayashi M, Picard C, Durandy A, Cook MC, Casanova JL, Uzel G, Tangye SG
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IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts
BLOOD 2013 DEC 5; 122(24):3940-3950
B-cell responses are guided by the integration of signals through the B-cell receptor (BCR), CD40, and cytokine receptors. The common gamma chain (gamma c)-binding cytokine interleukin (IL)-21 drives humoral immune responses via STAT3-dependent induction of transcription factors required for plasma cell generation. We investigated additional mechanisms by which IL-21/STAT3 signaling modulates human B-cell responses by studying patients with STAT3 mutations. IL-21 strongly induced CD25 (IL-2R alpha) in normal, but not STAT3-deficient, CD40L-stimulated naive B cells. Chromatin immunoprecipitation confirmed IL2RA as a direct target of STAT3. IL-21-induced CD25 expression was also impaired on B cells from patients with IL2RG or IL21R mutations, confirming a requirement for intact IL-21R signaling in this process. IL-2 increased plasmablast generation and immunoglobulin secretion from normal, but not CD25-deficient, naive B cells stimulated with CD40L/IL-21. IL-2 and IL-21 were produced by T follicular helper cells, and neutralizing both cytokines abolished the B-cell helper capacity of these cells. Our results demonstrate that IL-21, via STAT3, sensitizes B cells to the stimulatory effects of IL-2. Thus, IL-2 may play an adjunctive role in IL-21-induced B-cell differentiation. Lack of this secondary effect of IL-21 may amplify the humoral immunodeficiency in patients with mutations in STAT3, IL2RG, or IL21R due to impaired responsiveness to IL-21. (Blood. 2013;122(24):3940-3950)
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Ferbel T, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Miner DC, Petrillo G, 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, Salur S, Schnetzer S, Seitz C, Somalwar S, Stone R, Thomas S, Walker M, Cerizza G, Hollingsworth M, Rose K, Spanier S, Yang ZC, York A, Bouhali O, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Montalvo R, Osipenkov I, Pakhotin Y, Perloff A, Roe J, Safonov A, Sakuma T, 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, Greene S, Gurrola A, Johns W, Maguire C, Mao Y, Melo A, Sharma M, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, 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, Belknap DA, Borrello L, Carlsmith D, Cepeda M, Dasu S, Friis E, Grothe M, Hall-Wilton R, Herndon M, Herve A, Kaadze K, Klabbers P, Klukas J, Lanaro A, Loveless R, Mohapatra A, Mozer MU, Ojalvo I, Pierro GA, Polese G, Ross I, Savin A, Smith WH, Swanson J
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Measurement of the cross section and angular correlations for associated production of a Z boson with b hadrons in pp collisions at root s=7 TeV
JOURNAL OF HIGH ENERGY PHYSICS 2013 DEC 6; ?(12):? Article 039
A study of proton-proton collisions in which two b hadrons are produced in association with a Z boson is reported. The collisions were recorded at a centre-of-mass energy of 7 TeVwith the CMS detector at the LHC, for an integrated luminosity of 5.2 fb(-1). The b hadrons are identified by means of displaced secondary vertices, without the use of reconstructed jets, permitting the study of b-hadron pair production at small angular separation. Differential cross sections are presented as a function of the angular separation of the b hadrons and the Z boson. In addition, inclusive measurements are presented. For both the inclusive and differential studies, different ranges of Z boson momentum are considered, and each measurement is compared to the predictions from different event generators at leading-order and next-to-leading-order accuracy.
Brumbaugh CC, Kothuri R, Marci C, Siefert C, Pfaff DD
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Physiological Correlates of the Big 5: Autonomic Responses to Video Presentations
APPLIED PSYCHOPHYSIOLOGY AND BIOFEEDBACK 2013 DEC; 38(4):293-301
Personality's link to emotional experience has been demonstrated, but specific biological responses to emotion as a function of personality have not been well-established. Here, the association between personality and physiological responses (heart rate, skin conductance, and respiration) to emotional videos was assessed. One-hundred sixty-nine participants self-reported on their Big 5 personality traits and underwent ambulatory monitoring as they watched four brief video clips from primetime television content showing scenes containing violence, fear, sadness, and tension. Generally, the negatively-toned emotional scenes provoked increases in skin conductance response and declines in heart rate. We found that physiological outcomes depended on the particular emotional scene and on personality, most notably Extraversion and Neuroticism. Extraversion, and to a lesser degree, Neuroticism, were associated with increases in autonomic arousal responses to the scenes. Gender also interacted with personality to predict responses, such that women who scored higher on measures of Extraversion, Neuroticism, and Conscientious tended to show more physiological arousal than men. Overall, the emotional scenes evoked increases in arousal and more controlled attention. The findings are discussed in context of the limited capacity model and shed light on how personality and gender affect physiological reactions to emotional experiences in everyday life.
Palmerini T, Tomasi L, Barozzi C, Della Riva D, Mariani A, Taglieri N, Leone O, Ceccarelli C, De Servi S, Branzi A, Genereux P, Stone GW, Ahamed J
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Detection of Tissue Factor Antigen and Coagulation Activity in Coronary Artery Thrombi Isolated from Patients with ST-Segment Elevation Acute Myocardial Infarction
PLOS ONE 2013 DEC 11; 8(12):? Article e81501
Introduction: Although ruptured atherosclerotic plaques have been extensively analyzed, the composition of thrombi causing arterial occlusion in patients with ST-segment elevation acute myocardial infarction has been less thoroughly investigated. We sought to investigate whether coagulant active tissue factor can be retrieved in thrombi of patients with STEMI undergoing primary percutaneous coronary intervention. Methods: Nineteen patients with ST-segment elevation acute myocardial infarction referred for primary percutaneous coronary intervention were enrolled in this study. Coronary thrombi aspirated from coronary arteries were routinely processed for paraffin embedding and histological evaluation (4 patients) or immediately snap frozen for evaluation of tissue factor activity using a modified aPTT test (15 patients). Immunoprecipitation followed by immunoblotting was also performed in 12 patients. Results: Thrombi aspirated from coronary arteries showed large and irregular areas of tissue factor staining within platelet aggregates, and in close contact with inflammatory cells. Some platelet aggregates stained positive for tissue factor, whereas others did not. Monocytes consistently stained strongly for tissue factor, neutrophils had a more variable and irregular tissue factor staining, and red blood cells did not demonstrate staining for tissue factor. Median clotting time of plasma samples containing homogenized thrombi incubated with a monoclonal antibody that specifically inhibits tissue factor-mediated coagulation activity (mAb 5G9) were significantly longer than their respective controls (88.9 seconds versus 76.5 seconds, respectively; p<0.001). Tissue factor was also identified by immunoprecipitation in 10 patients, with significant variability among band intensities. Conclusions: Active tissue factor is present in coronary artery thrombi of patients with ST-segment elevation acute myocardial infarction, suggesting that it contributes to activate the coagulation cascade ensuing in coronary thrombosis.
Domingos AI, Sordillo A, Dietrich MO, Liu ZW, Tellez LA, Vaynshteyn J, Ferreira JG, Ekstrand MI, Horvath TL, de Araujo IE, Friedman JM
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Hypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugar
ELIFE 2013 DEC 31; 2(?):? Article e01462
Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners owing to their post-ingestive rewarding effect, which elevates striatal dopamine (DA) release. While the post-ingestive rewarding effect, which artificial sweeteners do not have, signals the nutrient value of sugar and influences food preference, the neural circuitry that mediates the rewarding effect of glucose is unknown. In this study, we show that optogenetic activation of melanin-concentrating hormone (MCH) neurons during intake of the artificial sweetener sucralose increases striatal dopamine levels and inverts the normal preference for sucrose vs sucralose. Conversely, animals with ablation of MCH neurons no longer prefer sucrose to sucralose and show reduced striatal DA release upon sucrose ingestion. We further show that MCH neurons project to reward areas and are required for the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5(-/-) mice. These studies identify an essential component of the neural pathways linking nutrient sensing and food reward.
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Measurement of the prompt J/psi and psi(2S) polarizations in pp collisions at root s=7 TeV
PHYSICS LETTERS B 2013 DEC 18; 727(4-5):381-402
The polarizations of prompt J/psi and psi(2S) mesons are measured in proton-proton collisions at root s = 7 TeV, using a dimuon data sample collected by the CMS experiment at the LHC, corresponding to an integrated luminosity of 4.9 fb(-1). The prompt J/psi and psi(2S) polarization parameters lambda, lambda, and lambda, as well as the frame-invariant quantity (lambda) over bar. are measured from the dimuon decay angular distributions in three different polarization frames. The J/psi results are obtained in the transverse momentum range 14 < P-T < 70 GeV, in the rapidity intervals |y| < 0.6 and 0.6 < |y| < 1.2. The corresponding psi(2S) results cover 14 < PT < 50 GeV and include a third rapidity bin, 1.2 < |y| < 1.5. No evidence of large polarizations is seen in these kinematic regions, which extend much beyond those previously explored. (C) 2013 CERN. Published by Elsevier B.V. All rights reserved.
Wang CQF, Akalu YT, Suarez-Farinas M, Gonzalez J, Mitsui H, Lowes MA, Orlow SJ, Manga P, Krueger JG
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IL-17 and TNF Synergistically Modulate Cytokine Expression while Suppressing Melanogenesis: Potential Relevance to Psoriasis
JOURNAL OF INVESTIGATIVE DERMATOLOGY 2013 DEC; 133(12):2741-2752
Inflammation-associated pigmentation changes are extremely common, but the etiology underlying this clinical observation remains elusive. Particularly, it is unclear how the myriad of cytokines known to be involved in inflammatory skin processes affect epidermal melanocytes. We sought to determine how IL-17 and tumor necrosis factor (TNF) influence normal human melanocytes, as these two cytokines have been implicated in various skin diseases. IL-17 and TNF jointly stimulated broad inductions of cytokines, including melanoma mitogens CXCL1 and IL-8. Moreover, IL-17 and TNF synergistically inhibited pigmentation-related signaling and melanin production, and induced keratinocyte production of beta-defensin 3, an antagonist for melanocortin 1 receptor. When analyzing psoriasis lesions that are known to overexpress IL-17 and TNF, we observed an increase in melanocyte number and a simultaneous decrease in pigmentation signaling. Furthermore, therapeutic neutralization of TNF and IL-17 with mAbs resulted in a rapid recovery of pigment gene expression in psoriasis lesions. These results demonstrate that IL-17 and TNF can affect both the growth and pigment production of melanocytes, which may contribute to the pigmentation changes associated with psoriasis. These findings may allow the development of novel therapeutics for pigmentary disorders and bring new insights into the immune milieu surrounding melanocytes and related neoplasms.
Niepel M, Molloy KR, Williams R, Farr JC, Meinema AC, Vecchietti N, Cristea IM, Chait BT, Rout MP, Strambio-De-Castillia C
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The nuclear basket proteins Mlp1p and Mlp2p are part of a dynamic interactome including Esc1p and the proteasome
MOLECULAR BIOLOGY OF THE CELL 2013 DEC 15; 24(24):3920-3938
The basket of the nuclear pore complex (NPC) is generally depicted as a discrete structure of eight protein filaments that protrude into the nucleoplasm and converge in a ring distal to the NPC. We show that the yeast proteins Mlp1p and Mlp2p are necessary components of the nuclear basket and that they also embed the NPC within a dynamic protein network, whose extended interactome includes the spindle organizer, silencing factors, the proteasome, and key components of messenger ribonucleoproteins (mRNPs). Ultrastructural observations indicate that the basket reduces chromatin crowding around the central transporter of the NPC and might function as a docking site for mRNP during nuclear export. In addition, we show that the Mlps contribute to NPC positioning, nuclear stability, and nuclear envelope morphology. Our results suggest that the Mlps are multifunctional proteins linking the nuclear transport channel to multiple macromolecular complexes involved in the regulation of gene expression and chromatin maintenance.
Nielsen DA, Hamon SC, Kosten TR
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The kappa-opioid receptor gene as a predictor of response in a cocaine vaccine clinical trial
PSYCHIATRIC GENETICS 2013 DEC; 23(6):225-232
ObjectivesWe examined the pharmacogenetic association between a variant in the -opioid receptor (OPRK1) gene and the response to treatment with a cocaine vaccine tested in a recent clinical trial (October 2003 to April 2005). This gene has a protective allele for opioid addiction that may act by the inhibiting dopamine activation associated with reinforcement.MethodsSixty-nine DNA samples were obtained from 114 cocaine-dependent and opioid-dependent patients who were enrolled in a 16-week phase IIb randomized double-blind placebo-controlled trial and received five vaccinations over the first 12 weeks. We genotyped 66 of these patients for the rs6473797 variant of the OPRK1 gene and compared vaccine patients with placebo patients in terms of cocaine-free urines over time.ResultsUsing repeated measures analysis of variance corrected for population structure, it was seen that vaccine pharmacotherapy reduced cocaine-positive urines significantly on the basis of the OPRK1 genotype. Among patients treated with the cocaine vaccine, those who were homozygous for the protective A allele of rs6473797 had the proportion of positive urines drop from 78 to 51% on using the vaccine (point-wise P<0.0001, experiment-wise P<0.005), whereas the positive urines of individuals carrying the nonprotective, risk G allele dropped from 82 to 77%. Strong treatment by single nucleotide polymorphism interactions reflected a lower baseline and significant reduction for placebo patients with the risk G allele (P<0.00001).ConclusionThis study indicates that a patient's OPRK1 genotype could be used to identify a subset of individuals for whom vaccine treatment may be an effective pharmacotherapy for cocaine dependence.
Dahan R, Gebe JA, Preisinger A, James EA, Tendler M, Nepom GT, Reiter Y
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Antigen-specific immunomodulation for type 1 diabetes by novel recombinant antibodies directed against diabetes-associates auto-reactive T cell epitope
JOURNAL OF AUTOIMMUNITY 2013 DEC; 47(?):83-93
The trimolecular complex composed of autoreactive T-cell receptor, MHC class II, and an autoantigenic peptide plays a central role in the activation of pathogenic Islet-specific CD4+ T cells in type 1 diabetes (T1D). We isolated and characterized novel antibodies against autoreactive T-cell epitopes associated with T1D. Our antibodies mimic the specificity of the T-cell receptor (TCR), while binding MHC class II/peptide complexes in an autoantigen peptide specific, MHC-restricted manner. The isolated TCR-like antibodies were directed against the minimal T-cell epitope GAD-555-567 in the context of the HLA-DR4-diabetic-associated molecule. A representative high-affinity TCR-like antibody clone (G3H8) enabled the detection of intra- and extra-cellular DR4/GAD-555-567 complexes in antigen presenting cells. 1561M single mutation at the central position (P5) of the GAD-555-567 peptide abolished the binding of G3H8 to the DR4/GAD complex, demonstrating its high fine TCR-like specificity. The G3H8 TCR-like antibody significantly inhibited GAD-555-567 specific, DR4 restricted T-cell response in vitro and in vivo in HLA-DR4 transgenic mice. Our findings constitute a proof-of-concept for the utility of TCR-like antibodies as antigen-specific immunomodulation agents for regulating pathogenic T-cells and suggest that TCR-like antibodies targeting autoreactive MHC class II epitopes are valuable research tools that enable studies related to antigen presentation as well as novel therapeutic agents that may be used to modulate autoimmune disorders such as T1D. (C) 2013 Elsevier Ltd. All rights reserved.