340 research outputs found
Mutation of the phospholipase C-γ1–binding site of LAT affects both positive and negative thymocyte selection
Linker for activation of T cells (LAT) is a scaffolding adaptor protein that is critical for T cell development and function. A mutation of LAT (Y136F) that disrupts phospholipase C-γ1 activation and subsequent calcium influx causes a partial block in T cell development and leads to a severe lymphoproliferative disease in homozygous knock-in mice. One possible contribution to the fatal disease of LAT Y136F knock-in mice could be from autoreactive T cells generated in these mice because of altered thymocyte selection. To examine the impact of the LAT Y136F mutation on thymocyte positive and negative selection, we bred this mutation onto the HY T cell receptor (TCR) transgenic, recombination activating gene-2 knockout background. Female mice with this genotype showed a severe defect in positive selection, whereas male mice exhibited a phenotype resembling positive selection (i.e., development and survival of CD8(hi) HY TCR-specific T cells) instead of negative selection. These results support the hypothesis that in non-TCR transgenic, LAT Y136F knock-in mice, altered thymocyte selection leads to the survival and proliferation of autoreactive T cells that would otherwise be negatively selected in the thymus
The Four Distal Tyrosines Are Required for LAT-dependent Signaling in FcɛRI-mediated Mast Cell Activation
The linker for activation of T cells (LAT) is an adaptor protein critical for FcɛRI-mediated mast cell activation. LAT is a substrate of the tyrosine kinases activated after TCR and FcɛRI engagement. After phosphorylation of the cytosolic domain of LAT, multiple signaling molecules such as phospholipase C–γ1, Grb2, and Gads associate with phosphorylated LAT via their SH2 domains. The essential role of the four distal tyrosines in TCR-mediated signaling and T cell development has been demonstrated by experiments using LAT-deficient cell lines and genetically modified mice. To investigate the role of these four tyrosines of LAT in FcɛRI-mediated mast cell activation, bone marrow–derived mast cells from LAT-deficient mice were infected with retroviral vectors designed to express wild-type or mutant LAT. Examination of bone marrow–derived mast cells expressing various tyrosine to phenylalanine mutants in LAT demonstrates a differential requirement for these different binding sites. In these studies, assays of biochemical pathways, degranulation, and cytokine and chemokine release were performed. Finally, the role of these tyrosines was also evaluated in vivo using genetically modified animals. Deletion of all four distal tyrosines, and in particular, loss of the primary phospholipase C–γ-binding tyrosine had a significant effect on antigen-induced histamine release
Inactivation of c-Cbl Reverses Neonatal Lethality and T Cell Developmental Arrest of SLP-76–deficient Mice
c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection. To further characterize the function of c-Cbl in T cell development, we analyzed the effect of c-Cbl inactivation in mice deficient in the scaffolding molecule SLP-76. SLP-76–deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage. Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76–deficient mice and partially reversed the T cell development arrest in these mice. SLP-76−/− Cbl−/− mice exhibited marked expansion of polarized T helper type (Th)1 and Th2 cell peripheral CD4+ T cells, lymphoid infiltrates of parenchymal organs, and premature death. This rescue of T cell development is T cell receptor dependent because it does not occur in recombination activating gene 2−/− SLP-76−/− Cbl−/− triple knockout mice. Analysis of the signal transduction properties of SLP-76−/− Cbl−/− T cells reveals a novel SLP-76– and linker for activation of T cells–independent pathway of extracellular signal–regulated kinase activation, which is normally down-regulated by c-Cbl
Seasonal control of Petermann Gletscher ice-shelf melt by the ocean's response to sea-ice cover in Nares Strait
The semi-classical expansion and resurgence in gauge theories: new perturbative, instanton, bion, and renormalon effects
We study the dynamics of four dimensional gauge theories with adjoint
fermions for all gauge groups, both in perturbation theory and
non-perturbatively, by using circle compactification with periodic boundary
conditions for the fermions. There are new gauge phenomena. We show that, to
all orders in perturbation theory, many gauge groups are Higgsed by the gauge
holonomy around the circle to a product of both abelian and nonabelian gauge
group factors. Non-perturbatively there are monopole-instantons with fermion
zero modes and two types of monopole-anti-monopole molecules, called bions. One
type are "magnetic bions" which carry net magnetic charge and induce a mass gap
for gauge fluctuations. Another type are "neutral bions" which are magnetically
neutral, and their understanding requires a generalization of multi-instanton
techniques in quantum mechanics - which we refer to as the
Bogomolny-Zinn-Justin (BZJ) prescription - to compactified field theory. The
BZJ prescription applied to bion-anti-bion topological molecules predicts a
singularity on the positive real axis of the Borel plane (i.e., a divergence
from summing large orders in peturbation theory) which is of order N times
closer to the origin than the leading 4-d BPST instanton-anti-instanton
singularity, where N is the rank of the gauge group. The position of the
bion--anti-bion singularity is thus qualitatively similar to that of the 4-d IR
renormalon singularity, and we conjecture that they are continuously related as
the compactification radius is changed. By making use of transseries and
Ecalle's resurgence theory we argue that a non-perturbative continuum
definition of a class of field theories which admit semi-classical expansions
may be possible.Comment: 112 pages, 7 figures; v2: typos corrected, discussion of
supersymmetric models added at the end of section 8.1, reference adde
The CLIMODE field campaign : observing the cycle of convection and restratification over the Gulf Stream
Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 90 (2009): 1337-1350, doi:10.1175/2009BAMS2706.1.A major oceanographic field experiment is described, which is designed to observe, quantify, and understand the creation and dispersal of weakly stratified fluid known as “mode water” in the region of the Gulf Stream. Formed in the wintertime by convection driven by the most intense air–sea fluxes observed anywhere over the globe, the role of mode waters in the general circulation of the subtropical gyre and its biogeo-chemical cycles is also addressed. The experiment is known as the CLIVAR Mode Water Dynamic Experiment (CLIMODE). Here we review the scientific objectives of the experiment and present some preliminary results.Physical
Oceanography program of NS
Functional Nanoscale Organization of Signaling Molecules Downstream of the T Cell Antigen Receptor
Receptor-regulated cellular signaling often is mediated by formation of transient, heterogeneous protein complexes of undefined structure. We used single and two-color photoactivated localization microscopy to study complexes downstream of the T cell antigen receptor (TCR) in single-molecule detail at the plasma membrane of intact T cells. The kinase ZAP-70 distributed completely with the TCRζ chain and both partially mixed with the adaptor LAT in activated cells, thus showing localized activation of LAT by TCR-coupled ZAP-70. In resting and activated cells, LAT primarily resided in nanoscale clusters as small as dimers whose formation depended on protein-protein and protein-lipid interactions. Surprisingly, the adaptor SLP-76 localized to the periphery of LAT clusters. This nanoscale structure depended on polymerized actin and its disruption affected TCR-dependent cell function. These results extend our understanding of the mechanism of T cell activation and the formation and organization of TCR-mediated signaling complexes, findings also relevant to other receptor systems. © 2011 Elsevier Inc
Integration with the human genome of peptide sequences obtained by high-throughput mass spectrometry
A crucial aim upon the completion of the human genome is the verification and functional annotation of all predicted genes and their protein products. Here we describe the mapping of peptides derived from accurate interpretations of protein tandem mass spectrometry (MS) data to eukaryotic genomes and the generation of an expandable resource for integration of data from many diverse proteomics experiments. Furthermore, we demonstrate that peptide identifications obtained from high-throughput proteomics can be integrated on a large scale with the human genome. This resource could serve as an expandable repository for MS-derived proteome information
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