Cyclooxygenase-2 contributes to the selective induction of cell death by the endocannabinoid 2-arachidonoyl glycerol in hepatic stellate cells.

in Biochemical and biophysical research communications (2016), 470(3), 678-84

The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular ... [more ▼]

The endogenous cannabinoid 2-arachidonoyl glycerol (2-AG) is an anti-fibrotic lipid mediator that induces apoptosis in hepatic stellate cells (HSCs), but not in hepatocytes. However, the exact molecular mechanisms of this selective induction of HSC death are still unresolved. Interestingly, the inducible isoform of cyclooxygenase, COX-2, can metabolize 2-AG to pro-apoptotic prostaglandin glycerol esters (PG-GEs). We analyzed the roles of COX-2 and endocannabinoid-derived PG-GEs in the differential susceptibility of primary activated HSCs and hepatocytes toward 2-AG-induced cell death. HSCs displayed significant COX-2 expression in contrast to hepatocytes. Similar to 2-AG, treatment of HSCs with PGD2-GE dose-dependently induced cell death independently from cannabinoid receptors that was accompanied by PARP- and caspase 3-cleavage. In contrast to 2-AG, PGD2-GE failed to induce significant ROS formation in HSCs, and depletion of membrane cholesterol did not rescue HSCs from PGD2-GE-induced apoptosis. These findings indicate differential engagement of initial intracellular signaling pathways by 2-AG and its COX-2-derived metabolite PGD2-GE, but similar final cell death pathways. Other PG-GEs, such as PGE2-or PGF2alpha-GE did not induce apoptosis in HSCs. Primary rat hepatocytes were mainly resistant against 2-AG- and PGD2-GE-induced apoptosis. HSCs, but not hepatocytes were able to metabolize 2-AG to PGD2-GE. As a proof of principle, HSCs from COX-2(-/-) mice lacked PDG2-GE production after 2-AG treatment. Accordingly, COX-2(-/-) HSCs were resistant against 2-AG-induced apoptosis. In conclusion, the divergent expression of COX-2 in HSCs and hepatocytes contributes to the different susceptibility of these cell types towards 2-AG-induced cell death due to the generation of pro-apoptotic PGD2-GE by COX-2 in HSCs. Modulation of COX-2-driven metabolization of 2-AG may provide a novel physiological concept allowing the specific targeting of HSCs in liver fibrosis. [less ▲]

SOFIA: An Automated Security Oracle for Black-Box Testing of SQL-Injection Vulnerabilities

in Proceedings of the 31th IEEE/ACM International Conference on Automated Software Engineering (2016)

Security testing is a pivotal activity in engineering secure software. It consists of two phases: generating attack inputs to test the system, and assessing whether test executions expose any ... [more ▼]

Security testing is a pivotal activity in engineering secure software. It consists of two phases: generating attack inputs to test the system, and assessing whether test executions expose any vulnerabilities. The latter phase is known as the security oracle problem. In this work, we present SOFIA, a Security Oracle for SQL-Injection Vulnerabilities. SOFIA is programming-language and source-code independent, and can be used with various attack generation tools. Moreover, because it does not rely on known attacks for learning, SOFIA is meant to also detect types of \sqli attacks that might be unknown at learning time. The oracle challenge is recast as a one-class classification problem where we learn to characterise legitimate SQL statements to accurately distinguish them from \sqli attack statements. We have carried out an experimental validation on six applications, among which two are large and widely-used. SOFIA was used to detect real \sqli vulnerabilities with inputs generated by three attack generation tools. The obtained results show that SOFIA is computationally fast and achieves a recall rate of 100\% (i.e., missing no attacks) with a low false positive rate (0.6\%). [less ▲]

Systems proteomics of liver mitochondria function.

in Science (2016), 352(6291), 0189

Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across ... [more ▼]

Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein's activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics--a combination moving us forward in complex trait analysis. [less ▲]

Spiel und Erkenntnis in der Grundschule: Theorie - Empirie - Konzepte

Book published by Kohlhammer (2016)

Während der Kindergarten eine selbstverständliche Domäne des kindlichen Spiels darstellt, ist die Bedeutung des Spiels in der Grundschule als produktives Element der Didaktik des Unterrichts bis heute ... [more ▼]

Während der Kindergarten eine selbstverständliche Domäne des kindlichen Spiels darstellt, ist die Bedeutung des Spiels in der Grundschule als produktives Element der Didaktik des Unterrichts bis heute kaum ins Blickfeld getreten. Das Buch fragt nach der Bedeutung des Spiels in der Schule und nach Spielformen, die sich produktiv im Unterricht einsetzen lassen. Es führt dafür das theoretische Wissen über die Struktur des Spiels mit dem Wissen um die kindliche Erkenntnistätigkeit im Rahmen einer qualitativ-empirischen Studie zusammen und entwickelt Grundsätze der Unterrichtsgestaltung in der Grundschule, um Elemente des Spielens und Erkennens im Unterricht zu verknüpfen. [less ▲]

Phase separation in NiCrN coatings induced by N2addition in the gasphase: A way to generate magnetic thin films by reactive sputtering ofa non-magnetic NiCr target

in Applied Surface Science (2016), 389

On quantizable odd Lie bialgebras

in Letters in Mathematical Physics (2016), 106(9), 1199-1215

The notion of a quantizable odd Lie bialgebra is introduced. A minimal resolution of the properad governing such Lie bialgebras is constructed.

Cognitive inequalities in later life: Cross-country differences in the education-cognition gradient

in Gerontologist (2016), 56(S3), 428-429

Mobilising meaning: multimodality, translocation, technology and heritage

in Thyssen, Geert; Priem, Karin (Eds.) Modes and Meaning: Displays of Evidence in Education (2016)

Malaise in the Western Middle Classes

E-print/Working paper (2016)

Malaise in the Western Middle Classes

in UNESCO (Ed.) World Social Science Report 2016. Challenging Inequalities: Pathways to a Just World (2016)