The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis

Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor interacting protein (RIP) lcinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-gamma in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases

Spatio-temporal dynamics of cod nursery areas in the Baltic Sea

Highlights: • Model output indicates high connectivity between the eastern Baltic cod nursery grounds. • Variability of spatial juvenile distribution patterns affected by flow dynamics. • Trend of simulated occupied juvenile cod habitat have been declining over the last decades. • Condition of juveniles suggests density-dependence due to hypoxia-related decrease in suitable habitat. • Baltic cod recruitment indicator: habitat availability for juvenile settlement as a factor for recruitment. Abstract: In this study the drift of eastern Baltic cod larvae and juveniles spawned within the historical eastern Baltic cod spawning grounds was investigated by detailed drift model simulations for the years 1971–2010, to examine the spatio-temporal dynamics of environmental suitability in the nursery areas of juvenile cod settlement. The results of the long-term model scenario runs, where juvenile cod were treated as simulated passively drifting particles, enabled us to find strong indications for long-term variations of settlement and potentially the reproduction success of the historically important eastern Baltic cod nursery grounds. Only low proportions of juveniles hatched in the Arkona Basin and in the Gotland Basin were able to settle in their respective spawning ground. Ocean currents were either unfavorable for the juveniles to reach suitable habitats or transported the juveniles to nursery grounds of neighboring subdivisions. Juveniles which hatched in the Bornholm Basin were most widely dispersed and showed the highest settlement probability, while the second highest settlement probability and horizontal dispersal was observed for juveniles originating from the Gdansk Deep. In a long-term perspective, wind-driven transport of larvae/juveniles positively affected the settlement success predominately in the Bornholm Basin and in the Bay of Gdansk. The Bornholm Basin has the potential to contribute on average 54% and the Bay of Gdansk 11% to the production of juveniles in the Baltic Sea. Furthermore, transport of juveniles surviving to the age of settlement with origin in the Bornholm Basin contributed on average 13 and 11% to the total settlement in the Arkona Basin and in the Gdansk Deep, respectively. The time-series of the simulated occupied juvenile cod habitat in the Bornholm Basin and in the Gdansk Deep showed a similar declining trend as the Fulton’s K condition factor of demersal 1-group cod, which may confirm the importance of oxygen-dependent habitat availability and its effect on density dependence as a process relevant for recruitment success

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