bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Inducing Autocrine IFN Signaling
Authors: Fang Feng , Ooka Kohtaro , Sun Xiaoyong , Shah Ruchi , Bhattacharyya Swati , Wei Jun , Varga John 
Published: August 2013

Abstract
Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN. Scleroderma patients with progressive skin fibrosis display an IFN-regulated gene signature, implicating TLR3 signaling in the disease. In this study, we show that TLR3 expression was detected on foreskin, adult skin, and lung fibroblasts, and TLR3 levels were significantly elevated in a subset of scleroderma skin biopsies. In explanted skin and lung fibroblasts, the synthetic TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)), a dsRNA analog, caused dose- and time-dependent stimulation of IFN-β production and generation of an IFN-response gene signature that was accompanied by substantial downregulation of collagen and α-smooth muscle actin gene expression. Furthermore, poly(I:C) abrogated TGF-β–induced fibrotic responses and blocked canonical Smad signaling via upregulation of inhibitory Smad7. Surprisingly, the inhibitory effects of poly(I:C) in fibroblasts were independent of TLR3 and were mediated by the cytosolic receptors retinoic acid–inducible gene 1 and melanoma differentiation-associated gene 5, and involved signaling via the IFN receptor. Taken together, these results demonstrate that induction of a fibroblast IFN response gene signature triggered by dsRNA is associated with potent TLR3-independent anti-fibrotic effects. The characteristic IFN response gene signature seen in scleroderma lesions might therefore signify a tissue-autonomous protective attempt to restrict fibroblast activation during injury.
DNA Vaccine that Targets Hemagglutinin to MHC Class II Molecules Rapidly Induces Antibody-Mediated Protection against Influenza
Authors: Grodeland Gunnveig , Mjaaland Siri , Roux Kenneth H. , Fredriksen Agnete Brunsvik , Bogen Bjarne 
Published: August 2013

AbstractNew influenza A viruses with pandemic potential periodically emerge due to viral genomic reassortment. In the face of pandemic threats, production of conventional egg-based vaccines is time consuming and of limited capacity. We have developed in this study a novel DNA vaccine in which viral hemagglutinin (HA) is bivalently targeted to MHC class II (MHC II) molecules on APCs. Following DNA vaccination, transfected cells secreted vaccine proteins that bound MHC II on APCs and initiated adaptive immune responses. A single DNA immunization induced within 8 d protective levels of strain-specific Abs and also cross-reactive T cells. During the Mexican flu pandemic, a targeted DNA vaccine (HA from A/California/07/2009) was generated within 3 wk after the HA sequences were published online. These results suggest that MHC II–targeted DNA vaccines could play a role in situations of pandemic threats. The vaccine principle should be extendable to other infectious diseases.
TLR9 Deficiency Promotes CD73 Expression in T Cells and Diabetes Protection in Nonobese Diabetic Mice
Authors: Tai Ningwen , Wong F. Susan , Wen Li 
Published: August 2013

Abstract
TLR9-deficient (TLR9−/−) NOD mice develop a significantly reduced incidence of diabetes. This study was to investigate the molecular mechanisms of the protective role of TLR9 deficiency. Through gene screening and confirmation by both mRNA and protein expression, we found a significant increase in CD73-expressing immune cells from peripheral lymphoid tissues in TLR9−/− NOD mice. The elevated frequency of CD73-expressing immune cells seemed to be specific for TLR9 deficiency and was MyD88 independent. Moreover, the increased frequency of CD73 expression was limited to the NOD background. Increased frequency of CD73 expression was also associated with lower levels of proinflammatory cytokines and more anti-inflammatory cytokine production in CD4+ T cells in TLR9−/− NOD mice. Purified CD73+CD4+ T cells showed stronger immunosuppressive function in vitro and delayed diabetes development in vivo. The immunosuppression appeared to be mediated by TGF-β. In addition, elevated frequency of CD73-expressing cells was associated with improved β cell function. Our observations were further confirmed by protection from diabetes with similar alterations in CD73 in the NY8.3 TCR NOD mouse model crossed with TLR9−/− mice and by the use of a TLR9 inhibitor in NOD mice. Our novel findings suggest an important immune-regulatory role of CD73 in regulation of diabetes development and may offer a new therapeutic strategy for specific intervention to prevent type 1 diabetes.
Contributions of the Three CYP1 Monooxygenases to Pro-Inflammatory and Inflammation-Resolution Lipid Mediator Pathways
Authors: Divanovic Senad , Dalli Jesmond , Jorge-Nebert Lucia F. , Flick Leah M. , Gálvez-Peralta Marina , Boespflug Nicholas D. , Stankiewicz Traci E. , Fitzgerald Jonathan M. , Somarathna Maheshika , Karp Christopher L. , Serhan Charles N. , Nebert Daniel W. 
Published: August 2013

Abstract
All three cytochrome P450 1 (CYP1) monooxygenases are believed to participate in lipid mediator biosynthesis and/or their local inactivation; however, distinct metabolic steps are unknown. We used multiple-reaction monitoring and liquid chromatography-UV coupled with tandem mass spectrometry–based lipid-mediator metabololipidomics to identify and quantify three lipid-mediator metabolomes in basal peritoneal and zymosan-stimulated inflammatory exudates, comparing Cyp1a1/1a2/1b1(−/−) C57BL/6J-background triple-knockout mice with C57BL/6J wild-type mice. Significant differences between untreated triple-knockout and wild-type mice were not found for peritoneal cell number or type or for basal CYP1 activities involving 11 identified metabolic steps. Following zymosan-initiated inflammation, 18 lipid mediators were identified, including members of the eicosanoids and specialized proresolving mediators (i.e., resolvins and protectins). Compared with wild-type mice, Cyp1 triple-knockout mice exhibited increased neutrophil recruitment in zymosan-treated peritoneal exudates. Zymosan stimulation was associated with eight statistically significantly altered metabolic steps: increased arachidonic acid–derived leukotriene B4 (LTB4) and decreased 5S-hydroxyeicosatetraenoic acid; decreased docosahexaenoic acid–derived neuroprotectin D1/protectin D1, 17S-hydroxydocosahexaenoic acid, and 14S-hydroxydocosahexaenoic acid; and decreased eicosapentaenoic acid–derived 18R-hydroxyeicosapentaenoic acid (HEPE), 15S-HEPE, and 12S-HEPE. In neutrophils analyzed ex vivo, elevated LTB4 levels were shown to parallel increased neutrophil numbers, and 20-hydroxy–LTB4 formation was found to be deficient in Cyp1 triple-knockout mice. Together, these results demonstrate novel contributions of CYP1 enzymes to the local metabolite profile of lipid mediators that regulate neutrophilic inflammation.
Negative Regulation of Nmi on Virus-Triggered Type I IFN Production by Targeting IRF7
Authors: Wang Jie , Yang Bo , Hu Yu , Zheng Yuhan , Zhou Haiyan , Wang Yanming , Ma Yonglei , Mao Kairui , Yang Leilei , Lin Guomei , Ji Yongyong , Wu Xiaodong , Sun Bing 
Published: August 2013

Abstract
Viral infection causes host cells to produce type I IFNs, which play a critical role in viral clearance. IFN regulatory factor (IRF) 7 is the master regulator of type I IFN-dependent immune responses. In this article, we report that N-Myc and STATs interactor (Nmi), a Sendai virus–inducible protein, interacted with IRF7 and inhibited virus-triggered type I IFN production. The overexpression of Nmi inhibited the Sendai virus–triggered induction of type I IFNs, whereas the knockdown of Nmi promoted IFN production. Furthermore, the enhanced production of IFNs resulting from Nmi knockdown was sufficient to protect cells from infection by vesicular stomatitis virus. In addition, Nmi was found to promote the K48-linked ubiquitination of IRF7 and the proteasome-dependent degradation of this protein. Finally, an impairment of antiviral responses is also detectable in Nmi-transgenic mice. These findings suggest that Nmi is a negative regulator of the virus-triggered induction of type I IFNs that targets IRF7.
Dendritic Cell Reprogramming by Endogenously Produced Lactic Acid
Authors: Nasi Aikaterini , Fekete Tünde , Krishnamurthy Akilan , Snowden Stuart , Rajnavölgyi Eva , Catrina Anca I. , Wheelock Craig E. , Vivar Nancy , Rethi Bence 
Published: August 2013

Abstract
The demand for controlling T cell responses via dendritic cell (DC) vaccines initiated a quest for reliable and feasible DC modulatory strategies that would facilitate cytotoxicity against tumors or tolerance in autoimmunity. We studied endogenous mechanisms in developing monocyte-derived DCs (MoDCs) that can induce inflammatory or suppressor programs during differentiation, and we identified a powerful autocrine pathway that, in a cell concentration–dependent manner, strongly interferes with inflammatory DC differentiation. MoDCs developing at low cell culture density have superior ability to produce inflammatory cytokines, to induce Th1 polarization, and to migrate toward the lymphoid tissue chemokine CCL19. On the contrary, MoDCs originated from dense cultures produce IL-10 but no inflammatory cytokines upon activation. DCs from high-density cultures maintained more differentiation plasticity and can develop to osteoclasts. The cell concentration–dependent pathway was independent of peroxisome proliferator–activated receptor γ (PPARγ), a known endogenous regulator of MoDC differentiation. Instead, it acted through lactic acid, which accumulated in dense cultures and induced an early and long-lasting reprogramming of MoDC differentiation. Our results suggest that the lactic acid–mediated inhibitory pathway could be efficiently manipulated in developing MoDCs to influence the immunogenicity of DC vaccines.
CTLA4Ig Inhibits Effector T Cells through Regulatory T Cells and TGF-β
Authors: Deppong Christine M. , Bricker Traci L. , Rannals Brandy D. , Van Rooijen Nico , Hsieh Chyi-Song , Green Jonathan M. 
Published: August 2013

Abstract
The CD28 costimulatory receptor is a critical regulator of T cell function, making it an attractive therapeutic target for the treatment of immune-mediated diseases. CTLA4Ig, now approved for use in humans, prevents naive T cell activation by binding to B7 proteins and blocking engagement of CD28. However, CTLA4Ig suppresses inflammation even if administered when disease is established, suggesting alternative mechanisms. We identified a novel, CD28-independent mechanism by which CTLA4Ig inhibits activated T cells. We show that in vitro, CTLA4Ig synergizes with NO from bone marrow–derived macrophages to inhibit T cell proliferation. Depletion of regulatory T cells (Tregs) or interference with TGF-β signaling abrogated the inhibitory effect of CTLA4Ig. Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells. Furthermore, CTLA4Ig was ineffective in SMAD3-deficient mice, supporting a requirement for TGF-β signaling. Thus, in addition to preventing naive T cells from being fully activated, CTLA4Ig can turn off already activated effector T cells by an NO/regulatory T cell/TGF-β–dependent pathway. This mechanism is similar to cell-extrinsic effects of endogenous CTLA4 and may be particularly important in the ability of CTLA4Ig to treat chronic inflammatory disease.
Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56dim NK Cells
Authors: Hagberg Niklas , Theorell Jakob , Schlums Heinrich , Eloranta Maija-Leena , Bryceson Yenan T. , Rönnblom Lars 
Published: August 2013

AbstractPatients with systemic lupus erythematosus (SLE) display an activated type I IFN system due to unceasing IFN-α release from plasmacytoid dendritic cells (pDCs) stimulated by nucleic acid–containing immune complexes (ICs). NK cells strongly promote the IFN-α production by pDCs; therefore, we investigated surface molecules that could be involved in the pDC–NK cell cross-talk. In human PBMCs stimulated with RNA-containing ICs (RNA-ICs), the expression of the signaling lymphocyte activation molecule (SLAM) family receptors CD319 and CD229 on pDCs and CD319 on CD56dim NK cells was selectively increased. Upregulation of CD319 and CD229 on RNA-IC–stimulated pDCs was induced by NK cells or cytokines (e.g., GM-CSF, IL-3). IFN-α–producing pDCs displayed a higher expression of SLAM molecules compared with IFN-α− pDCs. With regard to signaling downstream of SLAM receptors, pDCs expressed SHIP-1, SHP-1, SHP-2, and CSK but lacked SLAM-associated protein (SAP) and Ewing’s sarcoma-activated transcript 2 (EAT2), indicating that these receptors may act as inhibitory receptors on pDCs. Furthermore, pDCs from patients with SLE had decreased expression of CD319 on pDCs and CD229 on CD56dim NK cells, but RNA-IC stimulation increased CD319 and CD229 expression. In conclusion, this study reveals that the expression of the SLAM receptors CD319 and CD229 is regulated on pDCs and NK cells by lupus ICs and that the expression of these receptors is specifically altered in SLE. These results, together with the observed genetic association between the SLAM locus and SLE, suggest a role for CD319 and CD229 in the SLE disease process.
B Cell–Intrinsic and –Extrinsic Regulation of Antibody Responses by PARP14, an Intracellular (ADP-Ribosyl)Transferase
Authors: Cho Sung Hoon , Raybuck Ariel , Wei Mei , Erickson John , Nam Ki Taek , Cox Reagan G. , Trochtenberg Alyssa , Thomas James W. , Williams John , Boothby Mark 
Published: August 2013

AbstractThe capacity to achieve sufficient concentrations of Ag-specific Ab of the appropriate isotypes is a critical component of immunity that requires efficient differentiation and interactions of Ag-specific B and Th cells along with dendritic cells. Numerous bacterial toxins catalyze mono(ADP-ribosyl)ation of mammalian proteins to influence cell physiology and adaptive immunity. However, little is known about biological functions of intracellular mammalian mono(ADP-ribosyl)transferases, such as any ability to regulate Ab responses. poly-(ADP-ribose) polymerase 14 (PARP14), an intracellular protein highly expressed in lymphoid cells, binds to STAT6 and encodes a catalytic domain with mammalian mono(ADP-ribosyl)transferase activity. In this article, we show that recall IgA as well as the STAT6-dependent IgE Ab responses are impaired in PARP14-deficient mice. Whereas PARP14 regulation of IgE involved a B cell–intrinsic process, the predominant impact on IgA was B cell extrinsic. Of note, PARP14 deficiency reduced the levels of Th17 cells and CD103+ DCs, which are implicated in IgA regulation. PARP14 enhanced the expression of RORα, Runx1, and Smad3 after T cell activation, and, importantly, its catalytic activity of PARP14 promoted Th17 differentiation. Collectively, the findings show that PARP14 influences the class distribution, affinity repertoire, and recall capacity of Ab responses in mice, as well as provide direct evidence of the requirement for protein mono-ADP-ribosylation in Th cell differentiation.
CD4+CD25+Foxp3+ Regulatory T Cells Promote Th17 Responses and Genital Tract Inflammation upon Intracellular Chlamydia muridarum Infection
Authors: Moore-Connors Jessica M. , Fraser Robert , Halperin Scott A. , Wang Jun 
Published: August 2013

Abstract
The functional role of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in host responses to intracellular bacterial infection was investigated in an in vitro coculturing system and a murine model of Chlamydia muridarum genital tract infection. Remarkably, C. muridarum infection subverted the immune suppressive role of CD4+CD25+Foxp3+ Tregs; instead of hampering immune responses, Tregs not only promoted Th17 differentiation from conventional CD4+ T cells but also themselves converted into proinflammatory Th17 cells in both in vitro and in vivo settings. Anti-CD25 mAb PC61 treatment to deplete ∼50% of pre-existing Tregs prior to C. muridarum genital tract infection markedly reduced the frequency and the total number of Th17 but not Th1 CD4+ cells at both immune induction and memory phases. Most importantly, Treg-depleted mice displayed significantly attenuated inflammation, neutrophil infiltration, and reduced severity of oviduct pathology upon C. muridarum genital infection. To our knowledge, this is the first report demonstrating that the level of pre-existing CD4+CD25+Foxp3+ Tregs in Chlamydia-infected hosts has a major impact on the development Chlamydia-associated diseases.
Global DNA Methylation Remodeling Accompanies CD8 T Cell Effector Function
Authors: Scharer Christopher D. , Barwick Benjamin G. , Youngblood Benjamin A. , Ahmed Rafi , Boss Jeremy M. 
Published: August 2013

Abstract
The differentiation of CD8 T cells in response to acute infection results in the acquisition of hallmark phenotypic effector functions; however, the epigenetic mechanisms that program this differentiation process on a genome-wide scale are largely unknown. In this article, we report the DNA methylomes of Ag-specific naive and day-8 effector CD8 T cells following acute lymphocytic choriomeningitis virus infection. During effector CD8 T cell differentiation, DNA methylation was remodeled such that changes in DNA methylation at gene promoter regions correlated negatively with gene expression. Importantly, differentially methylated regions were enriched at cis-elements, including enhancers active in naive T cells. Differentially methylated regions were associated with cell type–specific transcription factor binding sites, and these transcription factors clustered into modules that define networks targeted by epigenetic regulation and control of effector CD8 T cell function. Changes in the DNA methylation profile following CD8 T cell activation revealed numerous cellular processes, cis-elements, and transcription factor networks targeted by DNA methylation. Together, the results demonstrated that DNA methylation remodeling accompanies the acquisition of the CD8 T cell effector phenotype and repression of the naive cell state. Therefore, these data provide the framework for an epigenetic mechanism that is required for effector CD8 T cell differentiation and adaptive immune responses.
Artiste, animateur culturel ou médiateur culturel ?
Authors: Hotte Lucie 
Published: August 2013

Cet article étudie l’évolution du rôle dévolu aux artistes dans le contexte de communautés francophones minoritaires du Canada. Il cerne deux moments. Le premier correspond aux années 1970 et à la prise de parole engagée des artistes. Durant cette période, ils endossent volontiers le rôle d’animateur culturel que les élites et les gouvernements souhaitent les voir jouer. Le deuxième moment correspond à la popularisation du terme « médiateur culturel » durant les 1990. Ce terme apparaît cependant dans un contexte où les artistes francophones minoritaires refusent de voir leur art mis au service d’une cause, comme le révèle leur discours.
Cinq représentations savantes de la francophonie des Amériques – réflexions autour d’un ouvrage récent
Authors: Belliveau Joel 
Published: August 2013

L’expression « francophonie d’Amérique » renvoie-t-elle à quelque chose de réel ? Existe-t-il des bases communes entre les divers milieux ou communautés francophones et d’héritage français du continent ? Telle est la question à laquelle ce texte tente de répondre, et ce, par le biais d’une « recension des idées » qui circulent à cet égard dans de diverses disciplines des sciences humaines. Cinq représentations distinctes de l’Amérique « franco » sont mises en lumière. En cours de route, les francophonies du continent sont examinées à l’aune des logiques du nationalisme, des réseaux, du communautarisme et du métissage.
Understanding safety climate in small automobile collision repair shops
Authors: Parker David L. , Brosseau Lisa M. , Bejan Anca , Skan Maryellen , Xi Min 
Published: August 2013

AbstractBackgroundIn the United States, approximately 236,000 people work in 37,600 auto collision‐repair businesses. Workers in the collision‐repair industry may be exposed to a wide range of physical and chemical hazards.MethodsThis manuscript examines the relationship of safety climate as reported by collision repair shop workers and owners to: (1) an independent business safety assessment, and (2) employee self‐reported work practices. The study was conducted in the Twin Cities metropolitan area.ResultsA total of 199 workers from 49 collision shops completed a survey of self‐reported work practices and safety climate. Surveys were completed by an owner or manager in all but three shops. In general, self‐reported work practices were poor. Workers' scores on safety climate were uniformly lower than those of owners. For workers, there was no correlation between how well the business scored on an independent audit of business safety practices and the safety climate measures they reported. For owners, however, there was a positive correlation between safety climate scores and the business safety assessment. For workers, safety rules and procedures were associated with improved work practices for those engaged in both painting‐related and body technician‐related activities.ConclusionsThe enforcement of safety rules and procedures emerged as a strong factor positively affecting self‐reported work practices. These findings identify a simple, cost effective path to reducing hazards in small workplaces. Am. J. Ind. Med. 57:78–86, 2014. © 2013 Wiley Periodicals, Inc.
Increased cardiovascular mortality and suicide after methyl chloride exposure
Authors: Rafnsson Vilhjalmur , Kristbjornsdottir Adalbjorg 
Published: August 2013

AbstractObjectivesMethyl chloride leakage from a refrigerator occurred on board an Icelandic fishing vessel in 1963. Many of the crew members were hospitalized due to various neurological symptoms and signs. The aim was to study long‐term mortality.MethodsThis is a cohort study. Five referents were selected from registries of deckhands and officers matched to each crew member according to age and occupation. Follow‐up was through record linkage of personal identifiers with the nation‐wide mortality registry. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated in Cox proportional hazards model.ResultsThe intoxicated crew was composed of 20 deckhands and 7 officers; the reference group counted 100 deckhands and 35 officers. Follow‐up to the end of 2010; 14 of the exposed deckhands and 6 of the officers had died, versus 49 deckhands and 26 officers among the reference group. For all cardiovascular events, the HR was 2.06 (95% CI 1.02–4.15), for acute coronary heart disease, the HR was 3.12 (95% CI 1.11–8.78), for cerebrovascular diseases, the HR was 5.35 (1.18–24.35), and for suicide, the HR was 13.76 (1.18–160.07).ConclusionsFollow‐up showed increased mortality due to cardiovascular diseases after 47 years. The suicide cases had developed severe depression after the methyl chloride intoxication that was related to the exposure. The use of the personal identifiers and the population registries strengthen the study. Detailed information on risk factors for chronic diseases is lacking in this study; however, the matching by occupation renders some similarity to the groups compared in the study. Am. J. Ind. Med. 57:108–113, 2014. © 2013 Wiley Periodicals, Inc.