bluuebunny/crossref_metadata_2025_split huggingface dataset:
Épistémologie et méthodologie de la recherche dans le secteur LANSAD : qu’apporterait une harmonisation des pratiques ?
Authors: Narcy-Combes Jean-Paul , Narcy-Combes Marie-Françoise 
Published: January 2011

Cet article a pour objectif de suggérer des conditions pour que les recherches du secteur aient une plus grande lisibilité tant pour les chercheurs du domaine que pour ceux des autres domaines. Il convient aussi d'accroître notre légitimité scientifique par des pratiques rigoureuses. Une première conséquence est, à la suite d’E. Morin, de réintégrer l'observateur dans son observation et de prendre la mesure des biais que son point de vue et ses options introduisent dans les résultats. Un modèle du cycle de la recherche est présenté ; il prend en compte ce qui précède et une conception « polythéiste » des références aux diverses théories vers lesquelles nous nous tournons. Des implications pratiques sont mises en avant, en particulier en ce qui concerne la rédaction des thèses. Enfin, les relations avec les chercheurs des autres domaines de référence ont été abordées. Il s'agit de trouver la complémentarité des regards et d'éviter toute velléité d'ignorance de leurs critères ou toute tendance à œuvrer dans l'ancillarité.
Human Cord Blood CD4+CD25hi Regulatory T Cells Suppress Prenatally Acquired T Cell Responses toPlasmodium falciparumAntigens
Authors: Mackroth Maria S. , Malhotra Indu , Mungai Peter , Koech Davy , Muchiri Eric , King Christopher L. 
Published: January 2011

AbstractIn malaria endemic regions, a fetus is often exposed in utero to Plasmodium falciparum blood-stage Ags. In some newborns, this can result in the induction of immune suppression. We have previously shown these modulated immune responses to persist postnatally, with a subsequent increase in a child’s susceptibility to infection. To test the hypothesis that this immune suppression is partially mediated by malaria-specific regulatory T cells (Tregs) in utero, cord blood mononuclear cells (CBMC) were obtained from 44 Kenyan newborns of women with and without malaria at delivery. CD4+CD25lo T cells and CD4+CD25hi FOXP3+ cells (Tregs) were enriched from CBMC. Treg frequency and HLA-DR expression on Tregs were significantly greater for Kenyan as compared with North American CBMC (p &lt; 0.01). CBMC/CD4+ T cells cultured with P. falciparum blood-stage Ags induced production of IFN-γ, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25hi cells augmented the Ag-driven IFN-γ production in 69% of subjects with malaria-specific responses and revealed additional Ag-reactive lymphocytes in previously unresponsive individuals (n = 3). Addition of Tregs to CD4+CD25lo cells suppressed spontaneous and malaria Ag-driven production of IFN-γ in a dose-dependent fashion, until production was completely inhibited in most subjects. In contrast, Tregs only partially suppressed malaria-induced Th2 cytokines. IL-10 or TGF-β did not mediate this suppression. Thus, prenatal exposure to malaria blood-stage Ags induces Tregs that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these Tregs postnatally could modify a child’s susceptibility to malaria infection and disease.
Innate Immune Function of the Adherens Junction Protein p120-Catenin in Endothelial Response to Endotoxin
Authors: Wang Yan-lei , Malik Asrar B. , Sun Yu , Hu Sanyuan , Reynolds Albert B. , Minshall Richard D. , Hu Guochang 
Published: January 2011

AbstractSepsis-induced acute lung injury is a common clinical disorder in critically ill patients that is associated with high mortality. In this study, we investigated the role of p120-catenin (p120), a constituent of endothelial adherens junctions, in regulating the innate immune function of lungs. In mice in which acute lung injury was induced by i.p. administration of LPS, we observed a rapid decrease in the expression of p120 in lungs. The p120 protein expression was correlated inversely with severity of inflammation. Suppression of p120 expression in lung endothelial cells in mice using small interfering RNA resulted in high sensitivity to endotoxin and greatly increased the mortality compared with controls. Knockdown of p120 also increased the expression of ICAM-1, neutrophil recruitment, production of cytokines TNF-α and IL-6, pulmonary transvascular protein permeability, and lung water content in response to LPS. We demonstrated that endothelial p120 modulates lung innate immune function by interfering with the association of TLR4 with its adaptor MyD88 to block TLR4 signaling and NF-κB activation in endothelial cells. In conclusion, these studies have uncovered a novel innate immune function of endothelial p120 in downregulating the lung inflammatory response to endotoxin through the suppression of TLR4 signaling.
The Critical Role of IL-1 Receptor-Associated Kinase 4-Mediated NF-κB Activation in Modified Low-Density Lipoprotein-Induced Inflammatory Gene Expression and Atherosclerosis
Authors: Kim Tae Whan , Febbraio Maria , Robinet Peggy , DuGar Brandon , Greene Diane , Cerny Anna , Latz Eicke , Gilmour Raymond , Staschke Kirk , Chisolm Guy , Fox Paul L. , DiCorleto Paul E. , Smith Jonathan D. , Li Xiaoxia 
Published: January 2011

Abstract
Exciting discoveries related to IL-1R/TLR signaling in the development of atherosclerosis plaque have triggered intense interest in the molecular mechanisms by which innate immune signaling modulates the onset and development of atherosclerosis. Previous studies have clearly shown the definitive role of proinflammatory cytokine IL-1 in the development of atherosclerosis. Recent studies have provided direct evidence supporting a link between innate immunity and atherogenesis. Although it is still controversial about whether infectious pathogens contribute to cardiovascular diseases, direct genetic evidence indicates the importance of IL-1R/TLR signaling in atherogenesis. In this study, we examined the role of IL-1R–associated kinase 4 (IRAK4) kinase activity in modified low-density lipoprotein (LDL)-mediated signaling using bone marrow-derived macrophage as well as an in vivo model of atherosclerosis. First, we found that the IRAK4 kinase activity was required for modified LDL-induced NF-κB activation and expression of a subset of proinflammatory genes but not for the activation of MAPKs in bone marrow-derived macrophage. IRAK4 kinase-inactive knockin (IRAK4KI) mice were bred onto ApoE−/− mice to generate IRAK4KI/ApoE−/− mice. Importantly, the aortic sinus lesion formation was impaired in IRAK4KI/ApoE−/− mice compared with that in ApoE−/− mice. Furthermore, proinflammatory cytokine production was reduced in the aortic sinus region of IRAK4KI/ApoE−/− mice compared with that in ApoE−/− mice. Taken together, our results indicate that the IRAK4 kinase plays an important role in modified LDL-mediated signaling and the development of atherosclerosis, suggesting that pharmacological inhibition of IRAK4 kinase activity might be a feasible approach in the development of antiatherosclerosis drugs.
Conventional Dendritic Cells Mount a Type I IFN Response againstCandidaspp. Requiring Novel Phagosomal TLR7-Mediated IFN-β Signaling
Authors: Bourgeois Christelle , Majer Olivia , Frohner Ingrid E. , Lesiak-Markowicz Iwona , Hildering Kwang-Soo , Glaser Walter , Stockinger Silvia , Decker Thomas , Akira Shizuo , Müller Mathias , Kuchler Karl 
Published: February 2011

AbstractHuman fungal pathogens such as the dimorphic Candida albicans or the yeast-like Candida glabrata can cause systemic candidiasis of high mortality in immunocompromised individuals. Innate immune cells such as dendritic cells and macrophages establish the first line of defense against microbial pathogens and largely determine the outcome of infections. Among other cytokines, they produce type I IFNs (IFNs-I), which are important modulators of the host immune response. Whereas an IFN-I response is a hallmark immune response to bacteria and viruses, a function in fungal pathogenesis has remained unknown. In this study, we demonstrate a novel mechanism mediating a strong IFN-β response in mouse conventional dendritic cells challenged by Candida spp., subsequently orchestrating IFN-α/β receptor 1-dependent intracellular STAT1 activation and IFN regulatory factor (IRF) 7 expression. Interestingly, the initial IFN-β release bypasses the TLR 4 and TLR2, the TLR adaptor Toll/IL-1R domain-containing adapter-inducing IFN-β and the β-glucan/phagocytic receptors dectin-1 and CD11b. Notably, Candida-induced IFN-β release is strongly impaired by Src and Syk family kinase inhibitors and strictly requires completion of phagocytosis as well as phagosomal maturation. Strikingly, TLR7, MyD88, and IRF1 are essential for IFN-β signaling. Furthermore, in a mouse model of disseminated candidiasis we show that IFN-I signaling promotes persistence of C. glabrata in the host. Our data uncover for the first time a pivotal role for endosomal TLR7 signaling in fungal pathogen recognition and highlight the importance of IFNs-I in modulating the host immune response to C. glabrata.
Cutting Edge: Cyclic Polypeptide and Aminoglycoside Antibiotics Trigger IL-1β Secretion by Activating the NLRP3 Inflammasome
Authors: Allam Ramanjaneyulu , Darisipudi Murthy Narayana , Rupanagudi Khader Valli , Lichtnekert Julia , Tschopp Jurg , Anders Hans-Joachim 
Published: January 2011

Abstract
Clinical use of antibiotics is based on their capacity to inhibit bacterial growth via bacteriostatic or bacteriocidal effects. In this article, we show that the aminoglycoside antibiotic neomycin, the cyclic lipopeptide antibiotic polymyxin B, and the cyclic peptide antibiotics gramicidin and tyrothricin can induce IL-1β secretion in bone marrow dendritic cells and macrophages. LPS priming was required to trigger the transcription and translation of pro–IL-1β but was independent of TNFR or IL-1R signaling. All four antibiotics required the NLRP3 inflammasome, the adaptor ASC, and caspase-1 activation to secrete IL-1β, a process that depended on potassium efflux but was independent of P2X7 receptor. All four antibiotics induced neutrophil influx into the peritoneal cavity of mice, which required NLRP3 only in the case of polymyxin B. Together, certain antibiotics have the potential to directly activate innate immunity of the host.
The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis
Authors: Chouinard François , Lefebvre Julie S. , Navarro Pauline , Bouchard Line , Ferland Claudine , Lalancette-Hébert Mélanie , Marsolais David , Laviolette Michel , Flamand Nicolas 
Published: January 2011

Abstract
Although endocannabinoids are important players in nociception and obesity, their roles as immunomodulators remain elusive. The main endocannabinoids described to date, namely 2-arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA), induce an intriguing profile of pro- and anti-inflammatory effects. This could relate to cell-specific cannabinoid receptor expression and/or the action of endocannabinoid-derived metabolites. Importantly, 2-AG and AEA comprise a molecule of arachidonic acid (AA) in their structure and are hydrolyzed rapidly. We postulated the following: 1) the released AA from endocannabinoid hydrolysis would be metabolized into eicosanoids; and 2) these eicosanoids would mediate some of the effects of endocannabinoids. To confirm these hypotheses, experiments were performed in which freshly isolated human neutrophils were treated with endocannabinoids. Unlike AEA, 2-AG stimulated myeloperoxidase release, kinase activation, and calcium mobilization by neutrophils. Although 2-AG did not induce the migration of neutrophils, it induced the release of a migrating activity for neutrophils. 2-AG also rapidly (1 min) induced a robust biosynthesis of leukotrienes, similar to that observed with AA. The effects of 2-AG were not mimicked nor prevented by cannabinoid receptor agonists or antagonists, respectively. Finally, the blockade of either 2-AG hydrolysis, leukotriene (LT) B4 biosynthesis, or LTB4 receptor 1 activation prevented all the effects of 2-AG on neutrophil functions. In conclusion, we demonstrated that 2-AG potently activates human neutrophils. This is the consequence of 2-AG hydrolysis, de novo LTB4 biosynthesis, and an autocrine activation loop involving LTB4 receptor 1.
Chikungunya Virus Envelope-Specific Human Monoclonal Antibodies with Broad Neutralization Potency
Authors: Warter Lucile , Lee Chia Yin , Thiagarajan Rekha , Grandadam Marc , Lebecque Serge , Lin Raymond T. P. , Bertin-Maghit Sebastien , Ng Lisa F. P. , Abastado Jean-Pierre , Desprès Philippe , Wang Cheng-I , Nardin Alessandra 
Published: January 2011

Abstract
Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics in Africa and Asia. Infection by CHIKV is often characterized by long-lasting, incapacitating arthritis, and some fatal cases have been described among elderly and newborns. Currently, there is no available vaccine or specific treatment against CHIKV. Blood B cells from a donor with history of CHIKV infection were activated, immortalized, amplified, and cloned. Two human mAbs against CHIKV, 5F10 and 8B10, were identified, sequenced, and expressed in recombinant form for characterization. In a plaque reduction neutralization test, 5F10 and 8B10 show mean IC50 of 72 and 46 ng/ml, respectively. Moreover, both mAbs lead to a strong decrease in extracellular spreading of infectious viral particles from infected to uninfected cells. Importantly, the mAbs neutralize different CHIKV isolates from Singapore, Africa, and Indonesia, as well as O’nyong-nyong virus, but do not recognize other alphaviruses tested. Both mAbs are specific for the CHIKV envelope: 5F10 binds to the E2 glycoprotein ectodomain and 8B10 to E1 and/or E2. In conclusion, these two unique human mAbs strongly, broadly, and specifically neutralize CHIKV infection in vitro and might become possible therapeutic tools against CHIKV infection, especially in individuals at risk for severe disease. Importantly, these mAbs will also represent precious tools for future studies on host–pathogen interactions and the rational design of vaccines against CHIKV.
Conformational Melding Permits a Conserved Binding Geometry in TCR Recognition of Foreign and Self Molecular Mimics
Authors: Borbulevych Oleg Y. , Piepenbrink Kurt H. , Baker Brian M. 
Published: February 2011

AbstractMolecular mimicry between foreign and self Ags is a mechanism of TCR cross-reactivity and is thought to contribute to the development of autoimmunity. The αβ TCR A6 recognizes the foreign Ag Tax from the human T cell leukemia virus-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease human T cell leukemia virus-1–associated myelopathy/tropical spastic paraparesis, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found in our study that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics and that in contrast with other recent structures of TCRs with self Ags, A6 engages the HuD Ag with the same traditional binding mode used to engage Tax. Although peptide and MHC conformational changes are needed for recognition of HuD but not Tax and the difference of a single hydroxyl triggers an altered TCR loop conformation, TCR affinity toward HuD is still within the range believed to result in negative selection. Probing further, we found that the HuD–HLA-A2 complex is only weakly stable. Overall, these findings help clarify how molecular mimicry can drive self/nonself cross-reactivity and illustrate how low peptide-MHC stability can permit the survival of T cells expressing self-reactive TCRs that nonetheless bind with a traditional binding mode.
CX3CR1+ Lung Mononuclear Phagocytes Spatially Confined to the Interstitium Produce TNF-α and IL-6 and Promote Cigarette Smoke-Induced Emphysema
Authors: Xiong Zeyu , Leme Adriana S. , Ray Prabir , Shapiro Steven D. , Lee Janet S. 
Published: January 2011

Abstract
Increased numbers of macrophages are found in the lungs of smokers and those with chronic obstructive pulmonary disease. Experimental evidence shows the central role of macrophages in elaboration of inflammatory mediators such as TNF-α and the progression toward cigarette smoke-induced emphysema. We investigated the role of CX3CR1 in recruitment of mononuclear phagocytes, inflammatory cytokine responses, and tissue destruction in the lungs after cigarette smoke exposure. Using mice in which egfp is expressed at the locus of the cx3cr1 gene, we show that alveolar macrophages increased transmembrane ligand CX3CL1 expression and soluble CX3CL1 was detectable in the airspaces, but cx3cr1GFP/GFP and cx3cr1GFP/+ mice failed to show recruitment of CX3CR1+ cells into the airspaces with cigarette smoke. In contrast, cigarette smoke increased the accumulation of CX3CR1+CD11b+ mononuclear phagocytes that were spatially confined to the lung interstitium and heterogenous in their expression of CD11c, MHC class II, and autofluorescent property. Although an intact CX3CL1–CX3CR1 pathway amplified the percentage of CX3CR1+CD11b+ mononuclear phagocytes in the lungs, it was not essential for recruitment. Rather, functional CX3CR1 was required for a subset of tissue-bound mononuclear phagocytes to produce TNF-α and IL-6 in response to cigarette smoke, and the absence of functional CX3CR1 protected mice from developing tissue-destructive emphysema. Thus, CX3CR1+ “tissue resident” mononuclear phagocytes initiate an innate immune response to cigarette smoke by producing TNF-α and IL-6 and are capable of promoting emphysema.
Cutting Edge: Tubulin α Functions as an Adaptor in NFAT–Importin β Interaction
Authors: Ishiguro Kazuhiro , Ando Takafumi , Maeda Osamu , Watanabe Osamu , Goto Hidemi 
Published: January 2011

Abstract
Upon T cell stimulation, NFAT is dephosphorylated by calcineurin, leading to nuclear translocation via NFAT–importin β interaction. Whereas the process of NFAT dephosphorylation has been well researched, the molecular mechanism of NFAT–importin β interaction remains unknown. In contrast to NF-κB and STAT, no importin α family members have been reported as adaptor proteins for NFAT. Our study shows that tubulin α, but not tubulin β, binds to the N-terminal region of NFAT containing the regulatory and Rel homology domains. Importin β interacts with the NFAT–tubulin α complex rather than NFAT or tubulin α alone, resulting in cotranslocation of NFAT and tubulin α into the nucleus. Furthermore, the interaction is suppressed by acetate-induced tubulin α acetylation at lysine 40. In conclusion, tubulin α functions as an adaptor in NFAT–importin β interaction, and this function is regulated by acetate-induced acetylation.
Cutting Edge: Persistently Open Chromatin at Effector Gene Loci in Resting Memory CD8+ T Cells Independent of Transcriptional Status
Authors: Zediak Valerie P. , Johnnidis Jonathan B. , Wherry E. John , Berger Shelley L. 
Published: January 2011

Abstract
Memory CD8+ T cells are characterized by more rapid and robust effector function upon infection compared with naive T cells, but factors governing effector gene responsiveness are incompletely understood. We sought to understand transcriptional control of the effector genes IFN-γ (Ifng), granzyme B (Gzmb), and perforin 1 (Prf1) in murine memory CD8+ T cells by characterizing their transcriptional profiles and chromatin states during lymphocytic choriomeningitis virus infection. Each effector gene has a distinct transcriptional profile in resting memory cells and following restimulation. Primary infection leads to reduced nucleosomal density near the transcription start sites and reduced H3K27 methylation throughout the Ifng and Gzmb loci, and these chromatin changes persist in the memory phase. Despite similarities in chromatin at the memory stage, PolII recruitment and continuous transcription occur at the Ifng locus but not the Gzmb locus. We propose that these chromatin changes poise effector genes for rapid upregulation, but are insufficient for PolII recruitment and transcription.
Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring
Authors: Hsieh Christine , Chang Anthony , Brandt Daniel , Guttikonda Riteesha , Utset Tammy O. , Clark Marcus R. 
Published: January 2011

AbstractObjectiveIn lupus nephritis, glomerular injury correlates poorly with progression to renal failure. While the tubulointerstitium is also commonly involved, the importance of such involvement is not well defined. Therefore, we developed a simple method to assess the prognostic utility of measuring tubulointerstitial inflammation (TI).MethodsSixty‐eight systemic lupus erythematosus patients with lupus nephritis were enrolled. Tubulointerstitial lymphocytic infiltrates were quantitated both by anti‐CD45 antibody staining and standard histochemical staining. Followup data were obtained and survival analysis was carried out to determine which histologic features were predictive of subsequent renal failure.ResultsBy CD45 staining, TI was a common pathologic finding, with 72% of biopsies having moderate or severe involvement. The extent of TI correlated with serum creatinine, but not with double‐stranded DNA antibodies, serum C3, or glomerular inflammation. TI severity, but not glomerular injury, identified patients at greater risk for renal failure (P = 0.02). A high National Institutes of Health (NIH) chronicity index also identified patients at risk for renal failure. However, when the glomerular and tubulointerstitial subcomponents of the NIH chronicity index were separated in a bivariate model, only tubulointerstitial chronicity provided prognostic information (hazard ratio [HR] 2.2, 95% confidence interval [95% CI] 1.3–3.6; P = 0.002 versus HR 1.0, 95% CI 0.7–1.5; P = 0.97 for glomerular chronicity).ConclusionTI identifies lupus nephritis patients at greatest risk for progression to renal failure. The immunologic mechanisms underlying TI may provide novel targets for therapeutic intervention.
Multilayer Systems for Cutting Tools: On the Relationship between Coating Design, Surface Processing, and Residual Stress
Authors: Klaus Manuela , Genzel Christoph 
Published: January 2011

AbstractCutting tools made of cemented carbide (WC/Co) are coated by chemical vapor deposition with Al2O3 and TiC1−xNx (x = 0 … 1) or combinations of these materials to improve wear resistance. Due to the high deposition temperature > 800 °C and the differences in the thermal expansion coefficients the as grown coating systems show unfavorable tensile residual stresses. To generate beneficial compressive residual stresses which improve the toughness behavior of the tools, mechanical post‐treatment processing like dry or wet blasting is introduced after coating deposition. By variation of the blasting parameters as well as of the coating design and the structural coating properties, it is possible to tailor the residual stresses with respect to both amount and depth distribution. In the present study we demonstrate by the example of Al2O3/TiCN coating systems on WC cutting inserts that an efficient assessment of this “residual stress engineering” step is possible by employing X‐ray methods which allow for nondestructive, phase selective, and depth resolved materials characterization. In order to be sensitive in different depth zones below the surface, low energy angle‐dispersive diffraction and high energy white beam synchrotron diffraction were applied to analyze the residual stress state within the coatings and in the interfacial substrate region, respectively.