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Search Results: 1 - 10 of 201234 matches for " Garry P. Nolan "
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COP9 Signalosome Component JAB1/CSN5 Is Necessary for T Cell Signaling through LFA-1 and HIV-1 Replication
Shigemi M. Kinoshita, Peter O. Krutzik, Garry P. Nolan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0041725
Abstract: To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication. A large library of short peptide aptamers was expressed via retroviral delivery in T cells. Peptides that interfered with T cell activation-dependent processes that might support HIV-1 replication were identified. One of the selected peptides altered signaling, lead to a difference in T cell activation status, and inhibited HIV-1 replication. The target of the peptide was JAB1/CSN5, a component of the signalosome complex. JAB1 expression overcame the inhibition of HIV-1 replication in the presence of peptide and also promoted HIV-1 replication in activated primary CD4+ T cells. This peptide blocked physiological release of JAB1 from the accessory T cell surface protein LFA-1, downstream AP-1 dependent events, NFAT activation, and HIV-1 replication. Thus, genetic selection for intracellular aptamer inhibitors of host cell processes proximal to signals at the immunological synapse of T cells can define unique mechanisms important to HIV-1 replication.
Differential role of ICAM ligands in determination of human memory T cell differentiation
Omar D Perez, Dennis Mitchell, Garry P Nolan
BMC Immunology , 2007, DOI: 10.1186/1471-2172-8-2
Abstract: Signal intensity was dependent on both ICAM ligand and LFA-1 concentration. In the presence of CD3 and CD28 stimulation, ICAM-2 and ICAM-3 decreased TGFβ1 production more than ICAM-1. In long-term differentiation experiments, stimulation with ICAM-3, CD3, and CD28 generated IFNγ producing CD4+CD45RO+CD62L-CD11aBrightCD27- cells that had increased expression of intracellular BCL2, displayed distinct chemokine receptor profiles, and exhibited distinct migratory characteristics. Only CD3/CD28 with ICAM-3 generated CD4+CD45RO+CD62L-CD11aBrightCD27- cells that were functionally responsive to chemotaxis and exhibited higher frequencies of cells that signaled to JNK and ERK1/2 upon stimulation with MIP3α. Furthermore, these reports identify that the LFA-1 receptor, when presented with multiple ligands, can result in distinct T cell differentiation states and suggest that the combinatorial integration of ICAM ligand interactions with LFA-1 have functional consequences for T cell biology.Thus, the ICAM ligands, differentially modulate LFA-1 signaling in T cells and potentiate the development of memory human T cells in vitro. These findings are of importance in a mechanistic understanding of memory cell differentiation and ex vivo generation of memory cell subsets for therapeutic applications.Leukocyte Function Antigen-1 (LFA-1), an αβ heterodimer integrin, is necessary for leukocyte adhesion and migration and is important in the formation of the immunological synapses [1-3]. LFA-1 also has prominent roles in T cell costimulation [4,5] and transendothelial migration [6]. The LFA-1 ligands, intracellular adhesion molecules (ICAMs) -1, -2, and -3, differentially bind to LFA-1 and regulate its adhesion [7-9]. LFA-1 is a mediator of T cell driven inflammatory diseases such as psoriasis[10], rheumatoid arthritis[11], and multiple sclerosis [12], and is a pharmaceutical target for the prevention of the rejection of organ transplantation [13].Peripheral blood lymphocytes (PBLs) prim
Snapin, Positive Regulator of Stimulation- Induced Ca2+ Release through RyR, Is Necessary for HIV-1 Replication in T Cells
Shigemi M. Kinoshita, Amane Kogure, Shizuka Taguchi, Garry P. Nolan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075297
Abstract: To identify critical host factors necessary for human immunodeficiency virus 1 (HIV-1) replication, large libraries of short-peptide-aptamers were expressed retrovirally. The target of one inhibitor peptide, Pep80, identified in this screen was determined to be Snapin, a protein associated with the soluble N-ethyl maleimide sensitive factor adaptor protein receptor (SNARE) complex that is critical for calcium-dependent exocytosis during neurotransmission. Pep80 inhibited Ca2+ release from intracellular stores and blocked downstream signaling by direct interruption of the association between Snapin and an intracellular calcium release channel, the ryanodine receptor (RyR). NFAT signaling was preferentially abolished by Pep80. Expression of Snapin overcame Pep80-mediated inhibition of Ca2+/NFAT signaling and HIV-1 replication. Furthermore, Snapin induced HIV-1 replication in primary CD4+ T cells. Thus, through its interaction with RyR, Snapin is a critical regulator of Ca2+ signaling and T cell activation. Use of the genetically selected intracellular aptamer inhibitors allowed us to define unique mechanisms important to HIV-1 replication and T cell biology.
Stage Dependent Aberrant Regulation of Cytokine-STAT Signaling in Murine Systemic Lupus Erythematosus
Matthew B. Hale, Peter O. Krutzik, Shamsher S. Samra, Janelle M. Crane, Garry P. Nolan
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006756
Abstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease of unknown etiology that involves multiple interacting cell types driven by numerous cytokines and autoimmune epitopes. Although the initiating events leading to SLE pathology are not understood, there is a growing realization that dysregulated cytokine action on immune cells plays an important role in promoting the inflammatory autoimmune state. We applied phospho-specific flow cytometry to characterize the extent to which regulation of cytokine signal transduction through the STAT family of transcription factors is disturbed during the progression of SLE. Using a panel of 10 cytokines thought to have causal roles in the disease, we measured signaling responses at the single-cell level in five immune cell types from the MRLlpr murine model. This generated a highly multiplexed view of how cytokine stimuli are processed by intracellular signaling networks in adaptive and innate immune cells during different stages of SLE pathogenesis. We report that robust changes in cytokine signal transduction occur during the progression of SLE in multiple immune cell subtypes including increased T cell responsiveness to IL-10 and ablation of Stat1 responses to IFNα, IFNγ, IL-6, and IL-21, Stat3 responses to IL-6, Stat5 responses to IL-15, and Stat6 responses to IL-4. We found increased intracellular expression of Suppressor of Cytokine Signaling 1 protein correlated with negative regulation of Stat1 responses to inflammatory cytokines. The results provide evidence of negative feedback regulation opposing inflammatory cytokines that have self-sustaining activities and suggest a cytokine-driven oscillator circuit may drive the periodic disease activity observed in many SLE patients.
Association of Reactive Oxygen Species-Mediated Signal Transduction with In Vitro Apoptosis Sensitivity in Chronic Lymphocytic Leukemia B Cells
Adam L. Palazzo, Erik Evensen, Ying-Wen Huang, Alessandra Cesano, Garry P. Nolan, Wendy J. Fantl
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024592
Abstract: Background Chronic lymphocytic leukemia (CLL) is a B cell malignancy with a variable clinical course and unpredictable response to therapeutic agents. Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in signaling biology in the context of molecular changes occurring in malignancies. In this study SCNP was used to identify proteomic profiles associated with in vitro apoptotic responsiveness of CLL B cells to fludarabine, as a basis for ultimately linking these with clinical outcome. Methodology/Principal Finding SCNP was used to quantify modulated-signaling of B cell receptor (BCR) network proteins and in vitro F-ara-A mediated apoptosis in 23 CLL samples. Of the modulators studied the reactive oxygen species, hydrogen peroxide (H2O2), a known intracellular second messenger and a general tyrosine phosphatase inhibitor stratified CLL samples into two sub-groups based on the percentage of B cells in a CLL sample with increased phosphorylation of BCR network proteins. Separately, in the same patient samples, in vitro exposure to F-ara-A also identified two sub-groups with B cells showing competence or refractoriness to apoptotic induction. Statistical analysis showed that in vitro F-ara-A apoptotic proficiency was highly associated with the proficiency of CLL B cells to undergo H2O2-augmented signaling. Conclusions/Significance This linkage in CLL B cells among the mechanisms governing chemotherapy-induced apoptosis increased signaling of BCR network proteins and a likely role of phosphatase activity suggests a means of stratifying patients for their response to F-ara-A based regimens. Future studies will examine the clinical applicability of these findings and also the utility of this approach in relating mechanism to function of therapeutic agents.
Distinct Patterns of DNA Damage Response and Apoptosis Correlate with Jak/Stat and PI3Kinase Response Profiles in Human Acute Myelogenous Leukemia
David B. Rosen,Santosh Putta,Todd Covey,Ying-Wen Huang,Garry P. Nolan,Alessandra Cesano,Mark D. Minden,Wendy J. Fantl
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012405
Abstract: Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in intracellular signaling responses. Here SCNP was used to characterize Acute Myeloid Leukemia (AML) disease subtypes based on survival, DNA damage response and apoptosis pathways.
A Novel Method for Detection of Phosphorylation in Single Cells by Surface Enhanced Raman Scattering (SERS) using Composite Organic-Inorganic Nanoparticles (COINs)
Catherine M. Shachaf, Sailaja V. Elchuri, Ai Leen Koh, Jing Zhu, Lienchi N. Nguyen, Dennis J. Mitchell, Jingwu Zhang, Kenneth B. Swartz, Lei Sun, Selena Chan, Robert Sinclair, Garry P. Nolan
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005206
Abstract: Background Detection of single cell epitopes has been a mainstay of immunophenotyping for over three decades, primarily using fluorescence techniques for quantitation. Fluorescence has broad overlapping spectra, limiting multiplexing abilities. Methodology/Principal Findings To expand upon current detection systems, we developed a novel method for multi-color immuno-detection in single cells using “Composite Organic-Inorganic Nanoparticles” (COINs) Raman nanoparticles. COINs are Surface-Enhanced Raman Scattering (SERS) nanoparticles, with unique Raman spectra. To measure Raman spectra in single cells, we constructed an automated, compact, low noise and sensitive Raman microscopy device (Integrated Raman BioAnalyzer). Using this technology, we detected proteins expressed on the surface in single cells that distinguish T-cells among human blood cells. Finally, we measured intracellular phosphorylation of Stat1 (Y701) and Stat6 (Y641), with results comparable to flow cytometry. Conclusions/Significance Thus, we have demonstrated the practicality of applying COIN nanoparticles for measuring intracellular phosphorylation, offering new possibilities to expand on the current fluorescent technology used for immunoassays in single cells.
Joint Modeling and Registration of Cell Populations in Cohorts of High-Dimensional Flow Cytometric Data
Saumyadipta Pyne, Sharon X. Lee, Kui Wang, Jonathan Irish, Pablo Tamayo, Marc-Danie Nazaire, Tarn Duong, Shu-Kay Ng, David Hafler, Ronald Levy, Garry P. Nolan, Jill Mesirov, Geoffrey J. McLachlan
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100334
Abstract: In biomedical applications, an experimenter encounters different potential sources of variation in data such as individual samples, multiple experimental conditions, and multivariate responses of a panel of markers such as from a signaling network. In multiparametric cytometry, which is often used for analyzing patient samples, such issues are critical. While computational methods can identify cell populations in individual samples, without the ability to automatically match them across samples, it is difficult to compare and characterize the populations in typical experiments, such as those responding to various stimulations or distinctive of particular patients or time-points, especially when there are many samples. Joint Clustering and Matching (JCM) is a multi-level framework for simultaneous modeling and registration of populations across a cohort. JCM models every population with a robust multivariate probability distribution. Simultaneously, JCM fits a random-effects model to construct an overall batch template – used for registering populations across samples, and classifying new samples. By tackling systems-level variation, JCM supports practical biomedical applications involving large cohorts. Software for fitting the JCM models have been implemented in an R package EMMIX-JCM, available from http://www.maths.uq.edu.au/~gjm/mix_soft?/EMMIX-JCM/.
EGRET Observations of Gamma Rays from Point Sources with Galactic Latitude +10(degrees) < b < +40(degrees)
P. L. Nolan
Physics , 1995, DOI: 10.1086/176872
Abstract: The EGRET instrument aboard the Compton Gamma Ray Observatory (CGRO) has completed the first all-sky survey in high-energy gamma rays and has repeatedly viewed selected portions of the sky. Analysis of the region with galactic latitude $+10\arcdeg < b < +40\arcdeg$ indicates the presence of nineteen point sources, including nine which can be identified as active galactic nuclei, some of which have been reported previously, as well as ten other sources with no definite counterparts. Using the combined exposures from Phase 1 and Phase 2 of the CGRO viewing program, the spectra, time variability, and positions of all detected sources in this region are determined. It is tentatively suggested that one of the unidentified sources might be associated with the radio galaxy Centaurus A.
Models for generalized spherical and related distributions
John P Nolan
Statistics , 2015,
Abstract: A flexible model is developed for multivariate generalized spherical distributions, i.e. ones with level sets that are star shaped. To work in dimension above 2 requires tools from computational geometry and multivariate numerical integration. In order to simulate from these star shaped contours, an algorithm to simulate from general tessellations has been developed that has applications in other situations. These techniques are implemented in an R package gensphere.
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