bluuebunny/crossref_metadata_2025_split huggingface dataset:
14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage
Authors: Maksymowych Walter P , van der Heijde Désirée , Allaart Cornelia F , Landewé Robert , Boire Gilles , Tak Paul P , Gui Yuan , Ghahary Aziz , Kilani Ruhangiz , Marotta Anthony 
Published: April 2014

Abstract
Introduction
The aim of this study was to investigate whether 14-3-3η, a specific isoform of a family of proteins regulating processes such as cellular signalling, activates cell-signalling pathways and induces factors known to contribute to the pathophysiology of rheumatoid arthritis (RA). We also investigated whether 14-3-3η is associated with more severe disease in both early and established RA.

Methods
We investigated the effect of 14-3-3η on the activation of RA-relevant signalling cascades and induction of proinflammatory mediators that contribute to the joint damage process. 14-3-3η titres from 33 patients with early RA (mean RA duration = 1.8 months) and from 40 patients with established RA were measured in serum drawn at the 3-year time point of the Behandel Strategieën study. The relationship between 14-3-3η titres and standard clinical variables was investigated by correlation analysis. The association with radiographic damage and radiographic progression over at least a 2-year period was investigated using univariate and multivariate regression analyses.

Results
14-3-3η activated selected members of the mitogen-activated protein kinase (MAPK) family, mainly extracellular regulated kinase 1/2 and c-Jun kinase, but not p38MAPK. Activation by 14-3-3η, using levels spanning the concentration range found in RA patient serum, resulted in the induction of inflammatory transcripts such as interleukin 1 (IL-1) and IL-6 and factors linked to the joint damage process, such as receptor activator of nuclear factor κB ligand and matrix metalloproteinase 1. Serum 14-3-3η correlated significantly with rheumatoid factor (RF) (r = 0.43) and anticitrullinated protein antibodies (ACPAs) (r = 0.31) in the early RA cohort, but not with C-reactive protein (CRP) or the Disease Activity Score in 28 joints in either cohort. Serum 14-3-3η concentrations were significantly higher in patients with radiographically assessed joint damage and in those who had radiographic progression. By multivariate analysis, we show that 14-3-3η complemented markers such as CRP, RF and ACPA in informing RA radiographic status and/or progression.

Conclusions
Extracellular 14-3-3η activates key signalling cascades and induces factors associated with the pathogenesis of RA at concentrations found in patients with RA, and its expression is higher in patients with radiographic damage and RA progression.
Tie Strength, Embeddedness, and Social Influence: A Large-Scale Networked Experiment
Authors: Aral Sinan , Walker Dylan 
Published: April 2014

We leverage the newly emerging business analytical capability to rapidly deploy and iterate large-scale, microlevel, in vivo randomized experiments to understand how social influence in networks impacts consumer demand. Understanding peer influence is critical to estimating product demand and diffusion, creating effective viral marketing, and designing “network interventions” to promote positive social change. But several statistical challenges make it difficult to econometrically identify peer influence in networks. Though some recent studies use experiments to identify influence, they have not investigated the social or structural conditions under which influence is strongest. By randomly manipulating messages sent by adopters of a Facebook application to their 1.3 million peers, we identify the moderating effect of tie strength and structural embeddedness on the strength of peer influence. We find that both embeddedness and tie strength increase influence. However, the amount of physical interaction between friends, measured by coappearance in photos, does not have an effect. This work presents some of the first large-scale in vivo experimental evidence investigating the social and structural moderators of peer influence in networks. The methods and results could enable more effective marketing strategies and social policy built around a new understanding of how social structure and peer influence spread behaviors in society.This paper was accepted by Alok Gupta, special issue on business analytics.
A Strategy to Identify Dominant Point Mutant Modifiers of a Quantitative Trait
Authors: Dove William F , Shedlovsky Alexandra , Clipson Linda , Amos-Landgraf James M , Halberg Richard B , Krentz Kathleen J , Boehm Frederick J , Newton Michael A , Adams David J , Keane Thomas M 
Published: April 2014

AbstractA central goal in the analysis of complex traits is to identify genes that modify a phenotype. Modifiers of a cancer phenotype may act either intrinsically or extrinsically on the salient cell lineage. Germline point mutagenesis by ethylnitrosourea can provide alleles for a gene of interest that include loss-, gain-, or alteration-of-function. Unlike strain polymorphisms, point mutations with heterozygous quantitative phenotypes are detectable in both essential and nonessential genes and are unlinked from other variants that might confound their identification and analysis. This report analyzes strategies seeking quantitative mutational modifiers of ApcMin in the mouse. To identify a quantitative modifier of a phenotype of interest, a cluster of test progeny is needed. The cluster size can be increased as necessary for statistical significance if the founder is a male whose sperm is cryopreserved. A second critical element in this identification is a mapping panel free of polymorphic modifiers of the phenotype, to enable low-resolution mapping followed by targeted resequencing to identify the causative mutation. Here, we describe the development of a panel of six “isogenic mapping partner lines” for C57BL/6J, carrying single-nucleotide markers introduced by mutagenesis. One such derivative, B6.SNVg, shown to be phenotypically neutral in combination with ApcMin, is an appropriate mapping partner to locate induced mutant modifiers of the ApcMin phenotype. The evolved strategy can complement four current major initiatives in the genetic analysis of complex systems: the Genome-wide Association Study; the Collaborative Cross; the Knockout Mouse Project; and The Cancer Genome Atlas.
Nanoscale Charge Transport Characteristics at Perovskite Interfaces – a Holistic Perspective
Authors: Kraya Ramsey , Kraya Laura 
Published: April 2014

ABSTRACTHere we investigate how charge transport properties scale down to the nanoscale regime, comparing the properties to standard semiconductor materials and providing a perspective on what it means to device manufacturing. Strontium titanate - the prototypical oxide material - has been widely studied for applications in thermoelectrics, nanoelectronics, catalysis, and other uses. We investigated how charge transport is effected at interfaces to strontium titanate under a wide range of conditions - by varying contact size, interface shape, dopant concentration, surface structures and in various combinations and relate the results to experiments utilizing standard semiconducting materials such as silicon and gallium arsenide. Also, the results of the analysis has wide ranging implications, especially for ferroelectric perovskite materials and serves as the basis for understanding and controlling switching effects - both polarization and oxygen migration based switching.
Calcul économique et incertitude socio-politique : une procédure d’évaluation des projets publics
Authors: Kast Robert , Luchini Stéphane 
Published: April 2014

Public Contract Bidding : Fixed-Price Contracts Amended by Change Orders or Incentive Contracts ?
French procurement contracts are usually awarded by fixed-price contracts. However, fixed prices can be raised by change orders that occur after the contract is signed. The authors develop a model of this procedure that gives an explanation for low-ball bidding strategies and cost overruns. Then the authors show that this procedure can yield an expected price lower than the optimal linear incentive contract of McAfee and McMillan (1986).
Modification of the Amino Terminus of a Class II Epitope Confers Resistance to Degradation by CD13 on Dendritic Cells and Enhances Presentation to T Cells
Authors: Dong Xin , An Bing , Salvucci Kierstead Lisa , Storkus Walter J. , Amoscato Andrew A. , Salter Russell D. 
Published: April 2014

AbstractDendritic cells and human B cell lines were compared for ability to present synthetic peptides corresponding to residues 145–159 and 188–203 of human Ig κ-chains to peptide-specific mouse T cell hybridomas restricted by HLA-DR4Dw4. B cell lines presented both peptides, but dendritic cells could only efficiently present the latter epitope. In this paper, we show that dendritic cells degrade the 145–159 peptide, removing four residues from the amino terminus. Binding of the peptide to the class II restriction element is not required for this process. The degradation product is resistant to further cleavage, accumulates in the culture supernatant, and does not bind to HLA-DR4Dw4 or stimulate T cell reactivity. Cleavage can be blocked with bestatin, but not with other protease inhibitors tested, or by a mAb directed against aminopeptidase N (CD13). Addition of an acetyl group to the amino terminus of peptide 145–159 also blocks degradation, and allows dendritic cells to present the peptide to specific T cells with greatly increased efficiency. These results demonstrate that CD13 on dendritic cells is able to selectively and efficiently degrade exogenously provided peptide Ags, in a process that can be blocked by addition of an acetyl group to the amino terminus of the peptide. Modification of the amino terminus of peptide epitopes susceptible to degradation may prove to be useful as a general strategy for enhancing their immunogenicity.
Cutting Edge: Heat Shock Protein (HSP) 60 Activates the Innate Immune Response: CD14 Is an Essential Receptor for HSP60 Activation of Mononuclear Cells
Authors: Kol Amir , Lichtman Andrew H. , Finberg Robert W. , Libby Peter , Kurt-Jones Evelyn A. 
Published: April 2014

AbstractHeat shock proteins (HSP), highly conserved across species, are generally viewed as intracellular proteins thought to serve protective functions against infection and cellular stress. Recently, we have reported the surprising finding that human and chlamydial HSP60, both present in human atheroma, can activate vascular cells and macrophages. However, the transmembrane signaling pathways by which extracellular HSP60 may activate cells remains unclear. CD14, the monocyte receptor for LPS, binds numerous microbial products and can mediate activation of monocytes/macrophages and endothelial cells, thus promoting the innate immune response. We show here that human HSP60 activates human PBMC and monocyte-derived macrophages through CD14 signaling and p38 mitogen-activated protein kinase, sharing this pathway with bacterial LPS. These findings provide further insight into the molecular mechanisms by which extracellular HSP may participate in atherosclerosis and other inflammatory disorders by activating the innate immune system.
A Critical Role for B7/CD28 Costimulation in Experimental Autoimmune Encephalomyelitis: A Comparative Study Using Costimulatory Molecule-Deficient Mice and Monoclonal Antibody Blockade
Authors: Girvin Ann M. , Dal Canto Mauro C. , Rhee Lesley , Salomon Benoît , Sharpe Arlene , Bluestone Jeffrey A. , Miller Stephen D. 
Published: April 2014

AbstractThe B7/CD28 pathway provides critical costimulatory signals required for complete T cell activation and has served as a potential target for immunotherapeutic strategies designed to regulate autoimmune diseases. This study was designed to examine the roles of CD28 and its individual ligands, B7-1 and B7-2, in experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the CNS. EAE induction in CD28- or B7-deficient nonobese diabetic (NOD) mice was compared with the effects of B7/CD28 blockade using Abs in wild-type NOD mice. Disease severity was significantly reduced in CD28-deficient as well as anti-B7-1/B7-2-treated NOD mice. B7-2 appeared to play the more dominant role as there was a moderate decrease in disease incidence and severity in B7-2-deficient animals. EAE resistance was not due to the lack of effective priming of the myelin peptide-specific T cells in vivo. T cells isolated from CD28-deficient animals produced equivalent amounts of IFN-γ and TNF-α in response to the immunogen, proteolipid protein 56–70. In fact, IFN-γ and TNF-α production by Ag-specific T cells was enhanced in both the B7-1 and B7-2-deficient NOD mice. In contrast, peptide-specific delayed-type hypersensitivity responses in these animals were significantly decreased, suggesting a critical role for CD28 costimulation in in vivo trafficking and systemic immunity. Collectively, these results support a critical role for CD28 costimulation in EAE induction.
Dendritic Cells Genetically Engineered to Express Fas Ligand Induce Donor-Specific Hyporesponsiveness and Prolong Allograft Survival
Authors: Min Wei-Ping , Gorczynski Reginald , Huang Xu-Yan , Kushida Michelle , Kim Peter , Obataki Masayuki , Lei Ji , Suri Rakesh M. , Cattral Mark S. 
Published: April 2014

AbstractPolarization of an immune response toward tolerance or immunity is dictated by the interactions between T cells and dendritic cells (DC), which in turn are modulated by the expression of distinct cell surface molecules, and the cytokine milieu in which these interactions are taking place. Genetic modification of DC with genes coding for specific immunoregulatory cell surface molecules and cytokines offers the potential of inhibiting immune responses by selectively targeting Ag-specific T cells. In this study, the immunomodulatory effects of transfecting murine bone marrow-derived DC with Fas ligand (FasL) were investigated. In this study, we show that FasL transfection of DC markedly augmented their capacity to induce apoptosis of Fas+ cells. FasL-transfected DC inhibited allogeneic MLR in vitro, and induced hyporesponsiveness to alloantigen in vivo. The induction of hyporesponsiveness was Ag specific and was dependent on the interaction between FasL on DC and Fas on T cells. Finally, we show that transfusion of FasL-DC significantly prolonged the survival of fully MHC-mismatched vascularized cardiac allografts. Our findings suggest that DC transduced with FasL may facilitate the development of Ag-specific unresponsiveness for the prevention of organ rejection. Moreover, they highlight the potential of genetically engineering DC to express other genes that affect immune responses.
Bacterial Proteins Can Be Processed by Macrophages in a Transporter Associated with Antigen Processing-Independent, Cysteine Protease-Dependent Manner for Presentation by MHC Class I Molecules
Authors: Campbell Daniel J. , Serwold Thomas , Shastri Nilabh 
Published: April 2014

AbstractMHC class I molecules present peptides derived primarily from endogenously synthesized proteins on the cell surface as ligands for CD8+ T cells. However, CD8+ T cell responses to extracellular bacteria, virus-infected, or tumor cells can also be elicited because certain professional APC can generate peptide/MHC class I (MHC-I) complexes from exogenous sources. Whether the peptide/MHC-I complexes are generated because the exogenous proteins enter the classical cytosolic, TAP-dependent MHC-I processing pathway or an alternate pathway is controversial. Here we analyze the generation of peptide/MHC-I complexes from recombinant Escherichia coli as an exogenous Ag source that could be delivered to the phagosomes or directly into the cytosol. We show that peritoneal and bone marrow macrophages generate peptide/MHC-I complexes by the classical as well as an alternate, but relatively less efficient, TAP-independent pathway. Using a novel method to detect proteolytic intermediates we show that the generation of the optimal MHC-I binding peptide in the alternate pathway requires cysteine as well as other protease(s). This alternate TAP-independent pathway also operates in vivo and provides a potential mechanism for eliciting CD8+ T cell responses to exogenous Ags.
Cutting Edge: Lack of Peripheral B Cells and Severe Agammaglobulinemia in Mice Simultaneously Lacking Bruton’s Tyrosine Kinase and the B Cell-Specific Transcriptional Coactivator OBF-1
Authors: Schubart Daniel B. , Rolink Antonius , Schubart Karin , Matthias Patrick 
Published: April 2014

Abstract
OBF-1 is a B cell-restricted transcriptional coactivator that is recruited to octamer-containing promoters by interacting with the POU domain of Oct-1 or Oct-2. We have shown earlier that mice lacking OBF-1 were dramatically impaired in their ability to mount humoral immune responses and did not develop germinal centers in the spleen; however, they had a largely normal B cell development in the bone marrow. In this study, we demonstrate that OBF-1-deficient mice also have an early defect in B cell development and show that OBF-1−/− immature B cells are greatly impaired at the transition from the bone marrow to the spleen. In addition, when the OBF-1 mutation is combined to a mutation in the gene encoding Bruton’s tyrosine kinase, a striking phenotype is observed. These double-deficient animals lack peripheral B cells and have virtually no serum Igs, thus closely resembling human X chromosome-linked agammaglobulinemia.
Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas
Authors: Nugent C. Thomas , Morgan David J. , Biggs Judith A. , Ko Alice , Pilip Ingrid M. , Pamer Eric G. , Sherman Linda A. 
Published: April 2014

AbstractAs a result of expression of the influenza hemagglutinin (HA) in the pancreatic islets, the repertoire of HA-specific CD8+ T lymphocytes in InsHA transgenic mice (D2 mice expressing the HA transgene under control of the rat insulin promoter) is comprised of cells that are less responsive to cognate Ag than are HA-specific CD8+ T lymphocytes from conventional mice. Previous studies of tolerance induction involving TCR transgenic T lymphocytes suggested that a variety of different mechanisms can reduce avidity for Ag, including altered cell surface expression of molecules involved in Ag recognition and a deficiency in signaling through the TCR complex. To determine which, if any, of these mechanisms pertain to CD8+ T lymphocytes within a conventional repertoire, HA-specific CD8+ T lymphocytes from B10.D2 mice and B10.D2 InsHA transgenic mice were compared with respect to expression of cell surface molecules, TCR gene utilization, binding of tetrameric KdHA complexes, lytic mechanisms, and diabetogenic potential. No evidence was found for reduced expression of TCR or CD8 by InsHA-derived CTL, nor was there evidence for a defect in triggering lytic activity. However, avidity differences between CD8+ clones correlated with their ability to bind KdHA tetramers. These results argue that most of the KdHA-specific T lymphocytes in InsHA mice are not intrinsically different from KdHA-specific T lymphocytes isolated from conventional animals. They simply express TCRs that are less avid in their binding to KdHA.
Surface Expression of the IFN-γR2 Chain Is Regulated by Intracellular Trafficking in Human T Lymphocytes
Authors: Rigamonti Laura , Ariotti Silvia , Losana Giuliana , Gradini Roberto , Russo Matteo A. , Jouanguy Emmanuelle , Casanova Jean-Laurent , Forni Guido , Novelli Francesco 
Published: April 2014

AbstractThe surface and cytoplasmic expressions of the transducing chain (IFN-γR2) of the heterodimeric IFN-γ receptor on human T lymphocytes have been investigated. We show that its surface expression is low, whereas high cytoplasmic levels are found in both resting and PHA-activated T lymphocytes. This low expression does not prevent activated T cells from responding to IFN-γ, because it induces IFN-regulatory factor 1 expression. Low surface IFN-γR2 expression appears to be due to recycling between cytoplasmic stores and the cell surface, which does not depend on signals mediated by endogenous IFN-γ, because IFN-γR2 surface expression is low, and its internalization is equally observed in patients with inherited IFN-γR1 gene deficiency and in healthy donors. Moreover, IFN-γR2 internalization in T lymphoblasts from healthy donors was not affected by the presence of anti-IFN-γ-neutralizing or anti-IFN-γR1-blocking mAb. In conclusion, these data illustrate a new mechanism whereby human T cells limit the surface expression of IFN-γR2 in a ligand-independent manner.
Activated and Memory CD8+ T Cells Can Be Distinguished by Their Cytokine Profiles and Phenotypic Markers
Authors: Slifka Mark K. , Whitton J. Lindsay 
Published: April 2014

AbstractDissecting the mechanisms of T cell-mediated immunity requires the identification of functional characteristics and surface markers that distinguish between activated and memory T lymphocytes. In this study, we compared the rates of cytokine production by virus-specific primary and memory CD8+ T cells directly ex vivo. Ag-specific IFN-γ and TNF-α production by both primary and long-term memory T cells was observed in ≤60 min after peptide stimulation. Although the on-rate kinetics of cytokine production were nearly identical, activated T cells produced more IFN-γ, but less TNF-α, than memory T cells. Ag-specific cytokine synthesis was not a constitutive process and terminated immediately following disruption of contact with peptide-coated cells, demonstrating that continuous antigenic stimulation was required by both T cell populations to maintain steady-state cytokine production. Upon re-exposure to Ag, activated T cells resumed cytokine production whereas only a subpopulation of memory T cells reinitiated cytokine synthesis. Analysis of cytokine profiles and levels of CD8, LFA-1, and CTLA-4 together revealed a pattern of expression that clearly distinguished in vivo-activated T cells from memory T cells. Surprisingly, CTLA-4 expression was highest at the early stages of the immune response but fell to background levels soon after viral clearance. This study is the first to show that memory T cells have the same Ag-specific on/off regulation of cytokine production as activated T cells and demonstrates that memory T cells can be clearly discriminated from activated T cells directly ex vivo by their cytokine profiles and the differential expression of three well-characterized T cell markers.