Evaluating (linked) metadata transformations across cultural heritage domains

This paper describes an approach to the evaluation of different aspects in the transformation of existing metadata into Linked data-compliant knowledge bases. At Oslo and Akershus University College of Applied Sciences, in the TORCH project, we are working on three different experimental case studies on extraction and mapping of broadcasting data and the interlinking of these with transformed library data. The case studies are investigating problems of heterogeneity and ambiguity in and between the domains, as well as problems arising in the interlinking process. The proposed approach makes it possible to collaborate on evaluation across different experiments, and to rationalize and streamline the process

The Role of Properdin in Zymosan-and Escherichia coli-Induced Complement Activation

Properdin is well known as an enhancer of the alternative complement amplification loop when C3 is activated, whereas its role as a recognition molecule of exogenous pathogen-associated molecular patterns and initiator of complement activation is less understood. We therefore studied the role of properdin in activation of complement in normal human serum by zymosan and various Escherichia coli strains. In ELISA, microtiter plates coated with zymosan induced efficient complement activation with deposition of C4b and terminal complement complex on the solid phase. Virtually no deposition of C4b or terminal complement complex was observed with mannose-binding lectin (MBL)-deficient serum. Reconstitution with purified MBL showed distinct activation in both readouts. In ELISA, normal human serum-induced deposition of properdin by zymosan was abolished by the C3-inhibiting peptide compstatin. Flow cytometry was used to further explore whether properdin acts as an initial recognition molecule reacting directly with zymosan and three E. coli strains. Experiments reported by other authors were made with EGTA Mg 2+ buffer, permitting autoactivation of C3. We found inhibition by compstatin on these substrates, indicating that properdin deposition depended on initial C3b deposition followed by properdin in a second step. Properdin released from human polymorphonuclear cells stimulated with PMA did not bind to zymosan or E. coli, but when incubated in properdin-depleted serum this form of properdin bound efficiently to both substrates in a strictly C3-dependent manner, as the binding was abolished by compstatin. Collectively, these data indicate that properdin in serum as well as polymorphonuclear-released properdin is unable to bind and initiate direct alternative pathway activation on these substrates

Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin.

Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection in the thymus, resulting in decreased iNKT cell levels and resistance to iNKT cell-mediated inflammatory conditions. Defective antigen presentation and decreased iNKT cells are also observed in ASM-deficient humans with Niemann-Pick disease, and ASM activity in healthy humans correlates with iNKT cell phenotype. Pharmacological ASM administration facilitates antigen presentation and restores the levels of iNKT cells in ASM-deficient mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represents a tight link between cellular sphingolipid metabolism and immunity

Le numérique, aboutissement rêvé du taylorisme ?

Entretien avec Danièle Linhart, réalisé le 15 novembre 2022 par Gabriel Colletis, Raphaëlle Bour, Étienne Fieux, Anne Isla, Julien Pharo, et Maryse Salle

Ornithodoros moubata complement inhibitor (OmCI)—A novel and efficient C5 inhibitor in the pig

Complement and CD14/TLR4 are two important upstream components of innate immunity. Inflammation induced by these danger sensors may be excessive and detrimental in conditions such as sepsis. Inhibition of complement or CD14/TLR4 differentially attenuate experimentally induced inflammation. Combined inhibition has a more pronounced effect, almost abolishing Escherichia coli (E. coli)-induced cytokine release, oxidative burst and expression of the cell-surface marker CD11b in vitro in human studies. We recently showed that an anti-CD14 antibody attenuated proinflammatory cytokines, granulocyte activation and hypercoagulation in E. coli-induced sepsis in vivo in pigs. Combination with a complement inhibitor might enhance the antiinflammatory effect. The aim of the present study was to explore the efficacy in pig of the Ornithodoros moubata complement inhibitor (OmCI) that specifically binds C5 and prevents release of C5a and formation of the terminal complement complex (TCC). Porcine serum and whole blood anticoagulated with lepuridin was incubated with increasing doses of OmCI and activated with E. coli. A pilot study was additionally conducted in vivo in pigs, whereby sepsis was induced by E. coli and the effect of OmCI on the inflammatory response was investigated. Inhibition of complement activity, as evaluated by functional assay of the three initial pathways, was complete at a dose of 2.5 μg OmCI/mL in vitro and 1 mg OmCI/kg in vivo. TCC formation induced by E. coli was abolished in vitro at 5 μg OmCI/mL whole blood, while expression of wCD11R3, the pig analog of human CD11b, was reduced by more than 50% at 5 μg OmCI/mL whole blood. In vivo, OmCI attenuated the increase in IL-8 and TNF-α, and partly protected against the fall in leukocytes seen in the sepsis control group. In conclusion, OmCI efficiently inhibited pig complement activation, showed additional anti-inflammatory effects and is a promising candidate inhibitor for further sepsis studies in vivo

Ornithodoros moubata complement inhibitor (OmCI)—A novel and efficient C5 inhibitor in the pig

Complement and CD14/TLR4 are two important upstream components of innate immunity. Inflammation induced by these danger sensors may be excessive and detrimental in conditions such as sepsis. Inhibition of complement or CD14/TLR4 differentially attenuate experimentally induced inflammation. Combined inhibition has a more pronounced effect, almost abolishing Escherichia coli (E. coli)-induced cytokine release, oxidative burst and expression of the cell-surface marker CD11b in vitro in human studies. We recently showed that an anti-CD14 antibody attenuated proinflammatory cytokines, granulocyte activation and hypercoagulation in E. coli-induced sepsis in vivo in pigs. Combination with a complement inhibitor might enhance the antiinflammatory effect. The aim of the present study was to explore the efficacy in pig of the Ornithodoros moubata complement inhibitor (OmCI) that specifically binds C5 and prevents release of C5a and formation of the terminal complement complex (TCC). Porcine serum and whole blood anticoagulated with lepuridin was incubated with increasing doses of OmCI and activated with E. coli. A pilot study was additionally conducted in vivo in pigs, whereby sepsis was induced by E. coli and the effect of OmCI on the inflammatory response was investigated. Inhibition of complement activity, as evaluated by functional assay of the three initial pathways, was complete at a dose of 2.5 μg OmCI/mL in vitro and 1 mg OmCI/kg in vivo. TCC formation induced by E. coli was abolished in vitro at 5 μg OmCI/mL whole blood, while expression of wCD11R3, the pig analog of human CD11b, was reduced by more than 50% at 5 μg OmCI/mL whole blood. In vivo, OmCI attenuated the increase in IL-8 and TNF-α, and partly protected against the fall in leukocytes seen in the sepsis control group. In conclusion, OmCI efficiently inhibited pig complement activation, showed additional anti-inflammatory effects and is a promising candidate inhibitor for further sepsis studies in vivo

The anti-inflammatory effect of combined complement and CD14 inhibition is preserved during escalating bacterial load

Combined inhibition of complement and CD14 is known to attenuate bacterial-induced inflammation, but the dependency of the bacterial load on this effect is unknown. Thus, we investigated whether the effect of such combined inhibition on Escherichia coli- and Staphylococcus aureus-induced inflammation was preserved during increasing bacterial concentrations. Human whole blood was preincubated with anti-CD14, eculizumab (C5-inhibitor) or compstatin (C3-inhibitor), or combinations thereof. Then heat-inactivated bacteria were added at final concentrations of 5 × 104−1 × 108/ml (E. coli) or 5 × 107−4 × 108/ml (S. aureus). Inflammatory markers were measured using enzyme-linked immunosorbent assay (ELISA), multiplex technology and flow cytometry. Combined inhibition of complement and CD14 significantly (P < 0.05) reduced E. coli-induced interleukin (IL)-6 by 40–92% at all bacterial concentrations. IL-1β, IL-8 and macrophage inflammatory protein (MIP)-1α were significantly (P < 0.05) inhibited by 53–100%, and the effect was lost only at the highest bacterial concentration. Tumour necrosis factor (TNF) and MIP-1β were significantly (P < 0.05) reduced by 80–97% at the lowest bacterial concentration. Monocyte and granulocyte CD11b were significantly (P < 0.05) reduced by 63–91% at all bacterial doses. Lactoferrin was significantly (P < 0.05) attenuated to the level of background activity at the lowest bacterial concentration. Similar effects were observed for S. aureus, but the attenuation was, in general, less pronounced. Compared to E. coli, much higher concentrations of S. aureus were required to induce the same cytokine responses. This study demonstrates generally preserved effects of combined complement and CD14 inhibition on Gram-negative and Gram-positive bacterial-induced inflammation during escalating bacterial load. The implications of these findings for future therapy of sepsis are discussed

Ornithodoros moubata complement inhibitor is an equally effective C5 inhibitor in pigs and humans

Experimental evidence suggests that C inhibition and more particularly combined inhibition of C and the TLR coreceptor CD14 may be of therapeutic benefit in sepsis and other inflammatory conditions. A barrier to the testing and further development of many inhibitors is that their activity is species specific. Pig is a relevant species for experimental models of human disease, and this study undertakes a comprehensive comparison of the inhibitory efficacy of the C5 inhibitor Ornithodoros moubata C inhibitor (OmCI) in human and porcine whole blood ex vivo models of Escherichia coli-induced sepsis. The effect of OmCI on complement activity in pigs undergoing E. coli sepsis was also examined. Porcine and human serum, and whole blood anticoagulated with lepirudin, was incubated with E. coli and the effect of OmCI investigated. The ex vivo results were virtually identical in pig and human. OmCI completely ablated the activity of all three C pathways at 0.64 μM. E. coli-induced C activation and expression of CD11b (wCD11R3 in the pig), was abolished ex vivo at 0.32 μM OmCI. Combining anti-CD14 and OmCI reduced the formation of IL-8 and TNF-α more potently than the single inhibitors. OmCI also efficiently bound E. coli-induced leukotriene B4 in pig and human plasma. In support of our ex vivo findings, in vivo the activity of all C pathways was inhibited at 0.6 mg OmCI/kg pig. In conclusion, OmCI efficiently inhibited pig and human C activation, has accompanying anti-inflammatory effects and is a promising candidate inhibitor for further in vivo studies of sepsis

Organ inflammation in porcine Escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and CD14.

Sepsis is an infection-induced systemic inflammatory syndrome, potentially causing organ failure. We previously showed attenuating effects on inflammation, thrombogenicity and haemodynamics by inhibiting the Toll-like receptor co-factor CD14 and complement factor C5 in a porcine Escherichia coli-induced sepsis model. The present study explored the effect on organ inflammation in these pigs. Tissue samples were examined from the combined treatment group (n = 8), the positive (n = 8) and negative (n = 6) control groups after 4h of sepsis. Inflammatory biomarkers were measured using ELISA, multiplex and qPCR analysis. Combined inhibition of C5 and CD14 markedly attenuated IL-1β by 31-66% (P < 0.05) and IL-6 by 54-96% (P < 0.01) in liver, kidney, lung and spleen; IL-8 by 65-100% in kidney, lung, spleen, and heart (P < 0.05) and MCP-1 by 46-69% in liver, kidney, spleen and heart (P < 0.05). Combined inhibition significantly attenuated tissue factor mRNA upregulation in spleen (P < 0.05) and IP-10 mRNA upregulation in four out of five organs. Finally, C5aR mRNA downregulation was prevented in heart and kidney (P < 0.05). Combined inhibition of C5 and CD14 thus markedly attenuated inflammatory responses in all organs examined. The anti-inflammatory effects observed in lung and heart may explain the delayed haemodynamic disturbances observed in septic pigs receiving combined inhibition of C5 and CD14