bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incident Comorbidity Among Patients with Rheumatoid Arthritis Treated or Not with Low-dose Glucocorticoids: A Retrospective Study
Authors: MAZZANTINI MAURIZIO , TALARICO ROSARIA , DOVERI MARICA , CONSENSI ARIANNA , CAZZATO MASSIMILIANO , BAZZICHI LAURA , BOMBARDIERI STEFANO 
Published: September 2010

Objective.To assess the prevalence of comorbidity in a cohort of patients with rheumatoid arthritis (RA), treated or not with low-dose glucocorticoids (GC) and who have been followed for at least 10 years.Methods.This was a retrospective study by review of medical records.Results.We identified 365 patients: 297 (81.3%) were GC users (4–6 mg methylprednisolone daily) and 68 (18.7%) were nonusers. We found that fragility fractures occurred in 18.2% of GC users and in 6.0% of GC nonusers (p < 0.02); arterial hypertension in 32.3% of GC users and in 10.4% of GC nonusers (p < 0.0005); acute myocardial infarction in 13.1% of GC users and in 1.5% of the nonusers (p < 0.01). Prevalence of diabetes mellitus, cataract, and infections was comparable. We divided GC users into groups of different duration of GC therapy: < 2, 2–5, and > 5 years; the mean duration of GC treatment was 1.3 ± 0.5, 3.6 ± 1.1, and 12.1 ± 5.1 years, respectively. GC treatment for > 5 years was associated with significantly higher prevalence of fragility fractures (26.6%; p < 0.001 vs the other groups), arterial hypertension (36.7%; p < 0.0002 vs nonusers and GC users < 2 years), myocardial infarction (16.1%; p < 0.01 vs nonusers), and infections (9.7%; p < 0.005 vs the other groups). GC treatment for 2–5 years was associated with a significantly higher prevalence of arterial hypertension (30.0%; p < 0.01) compared to nonusers.Conclusion.Patients with RA treated with low-dose GC compared to patients never treated with GC show a higher prevalence of fractures, arterial hypertension, myocardial infarction, and serious infections, especially after 5 years of GC treatment. The high prevalence of myocardial infarction and fractures in patients with RA suggests that a more accurate identification of risk factors and prevention measures should be adopted when longterm GC treatment is needed.
La paix du prince. Droit savant et pratiques féodales dans la construction de l'État en Provence (1250-1309)
Authors: Verdon Laure 
Published: September 2010

Résumé Sur la base d’un dossier documentaire constitué d’enquêtes de la seconde moitié du xiii e siècle relatives à des conflits de juridiction en Haute Provence et Provence rhodanienne ainsi que des ordonnances de 1289 et 1294 destinées à mettre fin aux aliénations non contrôlées de biens nobles, cet article reconsidère les relations établies entre le pouvoir souverain et les grands à l’aune de l’application des principes du droit féodal. La question centrale est celle de la paix, telle que définie lors de la diète de Roncaglia (1158), dont les Angevins vont tenter d’appliquer les principes dès leur accession au trône comtal provençal. La paix, qui repose sur le lien de fidélité noué entre puissants, sert de fil rouge à l’analyse qui cerne les origines de ces pratiques dans cette région par un nouveau regard porté sur le corpus des serments de fidélité des xi e et xii e siècle et en suit les évolutions jusqu’au début du xiv e siècle, par une relecture proposée des ordonnances de 1289 et 1294.
Influenza A Virus Protein PB1-F2 Exacerbates IFN-β Expression of Human Respiratory Epithelial Cells
Authors: Le Goffic Ronan , Bouguyon Edwige , Chevalier Christophe , Vidic Jasmina , Da Costa Bruno , Leymarie Olivier , Bourdieu Christiane , Decamps Laure , Dhorne-Pollet Sophie , Delmas Bernard 
Published: September 2010

Abstract
The PB1-F2 protein of the influenza A virus (IAV) contributes to viral pathogenesis by a mechanism that is not well understood. PB1-F2 was shown to modulate apoptosis and to be targeted by the CD8+ T cell response. In this study, we examined the downstream effects of PB1-F2 protein during IAV infection by measuring expression of the cellular genes in response to infection with wild-type WSN/33 and PB1-F2 knockout viruses in human lung epithelial cells. Wild-type virus infection resulted in a significant induction of genes involved in innate immunity. Knocking out the PB1-F2 gene strongly decreased the magnitude of expression of cellular genes implicated in antiviral response and MHC class I Ag presentation, suggesting that PB1-F2 exacerbates innate immune response. Biological network analysis revealed the IFN pathway as a link between PB1-F2 and deregulated genes. Using quantitative RT-PCR and IFN-β gene reporter assay, we determined that PB1-F2 mediates an upregulation of IFN-β expression that is dependent on NF-κB but not on AP-1 and IFN regulatory factor-3 transcription factors. Recombinant viruses knocked out for the PB1-F2 and/or the nonstructural viral protein 1 (the viral antagonist of the IFN response) genes provide further evidence that PB1-F2 increases IFN-β expression and that nonstructural viral protein 1 strongly antagonizes the effect of PB1-F2 on the innate response. Finally, we compared the effect of PB1-F2 variants taken from several IAV strains on IFN-β expression and found that PB1-F2–mediated IFN-β induction is significantly influenced by its amino acid sequence, demonstrating its importance in the host cell response triggered by IAV infection.
Ability of IDO To Attenuate Liver Injury in α-Galactosylceramide–Induced Hepatitis Model
Authors: Ito Hiroyasu , Hoshi Masato , Ohtaki Hirofumi , Taguchi Ayako , Ando Kazuki , Ishikawa Tetsuya , Osawa Yosuke , Hara Akira , Moriwaki Hisataka , Saito Kuniaki , Seishima Mitsuru 
Published: September 2010

Abstract
IDO converts tryptophan to l-kynurenine, and it is noted as a relevant molecule in promoting tolerance and suppressing adaptive immunity. In this study, we examined the effect of IDO in α-galactosylceramide (α-GalCer)–induced hepatitis. The increase in IDO expression in the liver of wild-type (WT) mice administered α-GalCer was confirmed by real-time PCR, Western blotting, and IDO immunohistochemical analysis. The serum alanine aminotransferase levels in IDO-knockout (KO) mice after α-GalCer injection significantly increased compared with those in WT mice. 1-Methyl-d-tryptophan also exacerbated liver injury in this murine hepatitis model. In α-GalCer–induced hepatitis models, TNF-α is critical in the development of liver injury. The mRNA expression and protein level of TNF-α in the liver from IDO-KO mice were more enhanced compared with those in WT mice. The phenotypes of intrahepatic lymphocytes from WT mice and IDO-KO mice treated with α-GalCer were analyzed by flow cytometry, and the numbers of CD49b+ and CD11b+ cells were found to have increased in IDO-KO mice. Moreover, as a result of the increase in the number of NK cells and macrophages in the liver of IDO-KO mice injected with α-GalCer, TNF-α secretion in these mice was greater than that in WT mice. Deficiency of IDO exacerbated liver injury in α-GalCer–induced hepatitis. IDO induced by proinflammatory cytokines may decrease the number of TNF-α–producing immune cells in the liver. Thus, IDO may suppress overactive immune response in the α-GalCer–induced hepatitis model.
Langerhans Cells Serve as Immunoregulatory Cells by Activating NKT Cells
Authors: Fukunaga Atsushi , Khaskhely Noor M. , Ma Ying , Sreevidya Coimbatore S. , Taguchi Kumiko , Nishigori Chikako , Ullrich Stephen E. 
Published: September 2010

Abstract
Ultraviolet exposure alters the morphology and function of epidermal Langerhans cells (LCs), which play a role in UV-induced immune suppression. It is generally believed that UV exposure triggers the migration of immature LCs from the skin to the draining lymph nodes (LNs), where they induce tolerance. However, because most of the previous studies employed in vitro UV-irradiated LCs, the data generated may not adequately reflect what is happening in vivo. In this study, we isolated migrating LCs from the LNs of UV-irradiated mice and studied their function. We found prolonged LC survival in the LNs of UV-irradiated mice. LCs were necessary for UV-induced immune suppression because no immune suppression was observed in LC-deficient mice. Transferring LCs from UV-irradiated mice into normal recipient animals transferred immune suppression and induced tolerance. We found that LCs colocalized with LN NKT cells. No immune suppression was observed when LCs were transferred from UV-irradiated mice into NKT cell-deficient mice. NKT cells isolated from the LNs of UV-irradiated mice secreted significantly more IL-4 than NKT cells isolated from nonirradiated controls. Injecting the wild-type mice with anti–IL-4 blocked the induction of immune suppression. Our findings indicate that UV exposure activates the migration of mature LC to the skin draining LNs, where they induce immune regulation in vivo by activating NKT cells.
Endogenous IL-10 Attenuates Cisplatin Nephrotoxicity: Role of Dendritic Cells
Authors: Tadagavadi Raghu Kempegowda , Reeves William Brian 
Published: September 2010

Abstract
Sterile inflammation is associated with tissue injury and organ failure. Recent studies indicate that certain endogenous cytokines and immune cells may limit tissue injury by reducing immune-mediated inflammatory responses. Cisplatin is a commonly used anticancer chemotherapeutic agent but causes acute kidney injury and dysfunction. In a recent study, we showed that renal dendritic cells attenuate cisplatin-induced kidney injury by reducing inflammation. In this study, we investigated the effect of endogenous IL-10 and dendritic cell IL-10 in cisplatin-mediated kidney injury. Cisplatin treatment caused increases in renal IL-10R1 expression and STAT3 phosphorylation. In response to cisplatin treatment, IL-10 knockout mice showed more rapid and greater increases in blood urea nitrogen and serum creatinine compared with wild-type mice, indicating that endogenous IL-10 ameliorates kidney injury in cisplatin nephrotoxicity. Renal infiltration of IFN-γ–producing neutrophils was markedly increased in IL-10 knockout mice compared with wild-type mice. However, IFN-γ neutralization had no impact on renal dysfunction, suggesting IFN-γ–independent mechanisms of tissue injury in cisplatin nephrotoxicity. Renal dendritic cells showed high expression of IL-10 in response to cisplatin treatment. We further investigated the effect of dendritic cell-derived IL-10 in cisplatin nephrotoxicity using a conditional cell ablation approach. Mixed bone marrow chimeric mice lacking IL-10 in dendritic cells showed moderately greater renal dysfunction than chimeric mice positive for IL-10 in dendritic cells. These data demonstrate that endogenous IL-10 reduces cisplatin nephrotoxicity and associated inflammation. Moreover, IL-10 produced by dendritic cells themselves accounts for a portion of the protective effect of dendritic cells in cisplatin nephrotoxicity.
OX40 Ligand Regulates Inflammation and Mortality in the Innate Immune Response to Sepsis
Authors: Karulf Matthew , Kelly Ann , Weinberg Andrew D. , Gold Jeffrey A. 
Published: September 2010

Abstract
The initial phase of sepsis is characterized by massive inflammatory cytokine production that contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity. Recent studies described their presence on neutrophils and monocytes, suggesting a potential role in the regulation of cytokine production in innate immunity. The purpose of this study was to determine the role for OX40–OX40 ligand (OX40L) interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on monocytes and neutrophils, with mortality and intensive care unit stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was indicated by improved survival, decreased cytokine production, and a decrease in remote organ damage in OX40L−/− mice. The finding of similar results with an OX40L Ab suggests a potential therapeutic role for OX40L blockade in sepsis. The inability of anti-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensable cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of anti-OX40L Ab in RAG1−/− mice further confirms a T cell-independent role for OX40L stimulation in sepsis. In conclusion, our data provide an in vivo role for the OX40/OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder.
Development of a Nascent Galectin-1 Chimeric Molecule for Studying the Role of Leukocyte Galectin-1 Ligands and Immune Disease Modulation
Authors: Cedeno-Laurent Filiberto , Barthel Steven R. , Opperman Matthew J. , Lee David M. , Clark Rachael A. , Dimitroff Charles J. 
Published: September 2010

AbstractGalectin-1 (Gal-1), a β-galactoside–binding lectin, plays a profound role in modulating adaptive immune responses by altering the phenotype and fate of T cells. Experimental data showing recombinant Gal-1 (rGal-1) efficacy on T cell viability and cytokine production, nevertheless, is controversial due to the necessity of using stabilizing chemicals to help retain Gal-1 structure and function. To address this drawback, we developed a mouse Gal-1 human Ig chimera (Gal-1hFc) that did not need chemical stabilization for Gal-1 ligand recognition, apoptosis induction, and cytokine modulation in a variety of leukocyte models. At high concentrations, Gal-1hFc induced apoptosis in Gal-1 ligand+ Th1 and Th17 cells, leukemic cells, and granulocytes from synovial fluids of patients with rheumatoid arthritis. Importantly, at low, more physiologic concentrations, Gal-1hFc retained its homodimeric form without losing functionality. Not only did Gal-1hFc–binding trigger IL-10 and Th2 cytokine expression in activated T cells, but members of the CD28 family and several other immunomodulatory molecules were upregulated. In a mouse model of contact hypersensitivity, we found that a non-Fc receptor-binding isoform of Gal-1hFc, Gal-1hFc2, alleviated T cell-dependent inflammation by increasing IL-4+, IL-10+, TGF-β+, and CD25high/FoxP3+ T cells, and by decreasing IFN-γ+ and IL-17+ T cells. Moreover, in human skin-resident T cell cultures, Gal-1hFc diminished IL-17+ T cells and increased IL-4+ and IL-10+ T cells. Gal-1hFc will not only be a useful new tool for investigating the role of Gal-1 ligands in leukocyte death and cytokine stimulation, but for studying how Gal-1–Gal-1 ligand binding shapes the intensity of immune responses.
IL-21 Deficiency Influences CD8 T Cell Quality and Recall Responses following an Acute Viral Infection
Authors: Yi John S. , Ingram Jennifer T. , Zajac Allan J. 
Published: September 2010

Abstract
CD4 T cells are principal producers of IL-21 and are often required for optimal CD8 T cell responses. Therefore, we investigated the importance of IL-21 in determining the phenotypic attributes, functional quality, and maintenance of antiviral CD8 T cells following acute infection with the prototypic mouse pathogen lymphocytic choriomeningitis virus. Previous reports have documented an obligatory role for IL-21 in sustaining CD8 T cell responses during chronic infections. Here we show that the requirements for IL-21 are less stringent following acute infections; however, in the absence of IL-21, the capacity of CD8 T cells to attain the polyfunctional trait of IL-2 production is consistently reduced during both the effector and memory phases. This is further supported by in vitro studies showing that the addition of IL-21 promotes the differentiation of IL-2–producing CD8 T cells. Although the generation of memory CD8 T cells, which are capable of mounting protective recall responses, proceeds independently of IL-21, we demonstrate that IL-21 does function to support secondary responses, especially under competitive conditions. Collectively, these studies highlight the potential roles of IL-21 in determining the quality of CD8 T cell responses postinfection.
Thrombospondin-1 Derived from APCs Regulates Their Capacity for Allosensitization
Authors: Saban Daniel R. , Bock Felix , Chauhan Sunil K. , Masli Sharmila , Dana Reza 
Published: September 2010

Abstract
Thrombospondin (TSP)-1 is a matricellular glycoprotein with immunoregulatory properties, which include inhibition of APC function. We show in transplantation that TSP-1 inhibits T cell allosensitization and consequently suppresses immune rejection. This was revealed by comparing wild-type (WT) versus TSP-1 null allografts in corneal transplantation, as the cornea is a rich source of TSP-1. Compared with only 50% of rejected WT allografts, nearly all TSP-1 null allografts succumbed to rejection. This effect was reflected by donor-derived APCs, which exhibited a distinctively greater capacity for allosensitization in transplanted hosts. Corroborated in MLRs, greater proliferation levels and robust IFN-γ (but not IL-10)–positive T cells resulted from stimulation by TSP-1 null APCs relative to WT ones. Moreover, enhanced expression of MHC class II and B7 maturation markers were detected on TSP-1 null APCs during inflammation. Increased expression of CCR7 was further matched by enhanced lymph node migration of TSP-1 null APCs posttransplantation. We therefore conclude that APC-derived TSP-1 suppresses their capacity to allosensitize T cells, and this regulation stems from their resistance to taking on a mature form. Future strategies targeting APCs for TSP-1 upregulation may thus be effective in promoting allograft survival.
Lunatic Fringe Enhances Competition for Delta-Like Notch Ligands but Does Not Overcome Defective Pre-TCR Signaling during Thymocyte β-Selection In Vivo
Authors: Visan Ioana , Yuan Julie S. , Liu Ying , Stanley Pamela , Guidos Cynthia J. 
Published: September 2010

Abstract
Notch1 activation by Delta-like (DL) Notch ligands is essential to induce T cell commitment and to suppress B cell development from thymus-seeding progenitors. Thymus-seeding progenitor competition for DL4 is critically regulated by Lunatic Fringe (Lfng), which glycosylates epidermal growth factor repeats in the Notch1 extracellular domain to enhance binding avidity for DL ligands. Notch1 activation is also essential for the process of β-selection, which drives TCRβ+ CD4/CD8 double-negative 3 (DN3) precursors to proliferate and generate a large pool of CD4/CD8 double-positive thymocytes. We have used several genetic approaches to determine the importance of Lfng–Notch1 interactions in regulating competition of preselection and postselection DN3 thymocytes for DL ligands in vivo. Surprisingly, although Lfng overexpression enhanced DL4 binding by preselection DN3a thymocytes, it did not confer them with a competitive advantage in mixed chimeras. In contrast, Lfng overexpression enhanced competition of post–β-selection DN3b precursors for DL ligands. Lfng modification of O-fucose in the Notch1 ligand-binding domain contributed to but was not solely responsible for the developmental effects of Lfng overexpression. Although previous studies have suggested that pre–TCR-deficient DN3 thymocytes compete poorly for DL ligands, Lfng overexpression did not fully restore double-positive thymocyte pools from DN3b cells with pre-TCR signaling defects. Thus, pre-TCR and Notch signaling have largely nonoverlapping functions in β-selection. Collectively, our data reveal that Lfng enhances DN3b precursor competition for intrathymic DL ligands to maximize Notch-induced clonal expansion during the earliest stage of β-selection.
TLR Agonists That Induce IFN-β Abrogate Resident Macrophage Suppression of T Cells
Authors: Hamilton Melisa J. , Antignano Frann , von Rossum Anna , Boucher Jean-Luc , Bennewith Kevin L. , Krystal Gerald 
Published: September 2010

Abstract
Resident tissue macrophages (Mϕs) continually survey the microenvironment, ingesting Ags and presenting them on their surface for recognition by T cells. Because these Ags can be either host cell- or pathogen-derived, Mϕs must be able to distinguish whether a particular Ag should provoke an immune response or be tolerated. However, the mechanisms that determine whether Mϕs promote or inhibit T cell activation are not well understood. To investigate this, we first determined the mechanism by which murine resident peritoneal Mϕs suppress in vitro T cell proliferation in the absence of pathogens and then explored the effects of different pathogen-derived molecules on Mϕ immunosuppression. Our results suggest that, in response to IFN-γ, which is secreted by TCR-activated T cells, resident peritoneal Mϕs acquire immunosuppressive properties that are mediated by NO. However, pretreatment of Mϕs with LPS or dsRNA, but not CpG or peptidoglycan, eliminates their suppressive properties, in part via the induction of autocrine-acting IFN-β. These results suggest TLR agonists that activate TRIF, and consequently induce IFN-β, but not those that exclusively signal through MyD88, abrogate the immunosuppressive properties of Mϕs, and thus promote T cell expansion and elimination of invading microorganisms.
Numerical Resolution Near t = 0 of Nonlinear Evolution Equations in the Presence of Corner Singularities in Space Dimension 1
Authors: Chen Qingshan , Qin Zhen , Temam Roger 
Published: September 2010

AbstractThe incompatibilities between the initial and boundary data will cause singularities at the time-space corners, which in turn adversely affect the accuracy of the numerical schemes used to compute the solutions. We study the corner singularity issue for nonlinear evolution equations in 1D, and propose two remedy procedures that effectively recover much of the accuracy of the numerical scheme in use. Applications of the remedy procedures to the 1D viscous Burgers equation, and to the 1D nonlinear reaction-diffusion equation are presented. The remedy procedures are applicable to other nonlinear diffusion equations as well.
Variance-Based Global Sensitivity Analysis via Sparse-Grid Interpolation and Cubature
Authors: Buzzard Gregery T. , Xiu Dongbin 
Published: September 2010

AbstractThe stochastic collocation method using sparse grids has become a popular choice for performing stochastic computations in high dimensional (random) parameter space. In addition to providing highly accurate stochastic solutions, the sparse grid collocation results naturally contain sensitivity information with respect to the input random parameters. In this paper, we use the sparse grid interpolation and cubature methods of Smolyak together with combinatorial analysis to give a computationally efficient method for computing the global sensitivity values of Sobol’. This method allows for approximation of all main effect and total effect values from evaluation of f on a single set of sparse grids. We discuss convergence of this method, apply it to several test cases and compare to existing methods. As a result which may be of independent interest, we recover an explicit formula for evaluating a Lagrange basis interpolating polynomial associated with the Chebyshev extrema. This allows one to manipulate the sparse grid collocation results in a highly efficient manner.