Pan-caspase inhibition during normothermic machine perfusion of discarded livers mitigates ex situ innate immune responses.

Access to liver transplantation is limited by a significant organ shortage. The recent introduction of machine perfusion technology allows surgeons to monitor and assess ex situ liver function prior to transplantation. However, many donated organs are of inadequate quality for transplant, though opportunities exist to rehabilitate organ function with adjunct therapeutics during normothermic machine perfusion. In this preclinical study, we targeted the apoptosis pathway as a potential method of improving hepatocellular function. Treatment of discarded human livers during normothermic perfusion with an irreversible pan-caspase inhibitor, emricasan, resulted in significant mitigation of innate immune and pro-inflammatory responses at both the transcriptional and protein level. This was evidenced by significantly decreased circulating levels of the pro-inflammatory cytokines, interleukin-6, interleukin-8, and interferon-gamma, compared to control livers. Compared to emricasan-treated livers, untreated livers demonstrated transcriptional changes notable for enrichment in pathways involved in innate immunity, leukocyte migration, and cytokine-mediated signaling. Targeting of unregulated apoptosis may represent a viable therapeutic intervention for immunomodulation during machine perfusion.

Activation of autophagy during normothermic machine perfusion of discarded livers is associated with improved hepatocellular function.

Liver transplantation is hampered by a severe shortage of donor organs. Normothermic machine perfusion (NMP) of donor livers allows dynamic preservation in addition to viability assessment before transplantation. Little is known about the injury and repair mechanisms induced during NMP. To investigate these mechanisms, we examined gene and protein expression changes in a cohort of discarded human livers, stratified by hepatocellular function, during NMP. Six human livers acquired through donation after circulatory death (DCD) underwent 12 h of NMP. Of the six livers, three met predefined criteria for adequate hepatocellular function. We applied transcriptomic profiling and protein analysis to evaluate temporal changes in gene expression during NMP between functional and nonfunctional livers. Principal component analysis segregated the two groups and distinguished the various perfusion time points. Transcriptomic analysis of biopsies from functional livers indicated robust activation of innate immunity after 3 h of NMP followed by enrichment of prorepair and prosurvival mechanisms. Nonfunctional livers demonstrated delayed and persistent enrichment of markers of innate immunity. Functional livers demonstrated effective induction of autophagy, a cellular repair and homeostasis pathway, in contrast to nonfunctional livers. In conclusion, NMP of discarded DCD human livers results in innate immune-mediated injury, while also activating autophagy, a presumed mechanism for support of cellular repair. More pronounced activation of autophagy was seen in livers that demonstrated adequate hepatocellular function.NEW & NOTEWORTHY We demonstrate that ischemia-reperfusion injury occurs in all livers during NMP, though there are notable differences in gene expression between functional and nonfunctional livers. We further demonstrate that activation of the liver's repair and homeostasis mechanisms through autophagy plays a vital role in the graft's response to injury and may impact liver function. These findings indicate that liver autophagy might be a key therapeutic target for rehabilitating the function of severely injured or untransplantable livers.

Kea show no evidence of inequity aversion.

It has been suggested that inequity aversion is a mechanism that evolved in humans to maximize the pay-offs from engaging in cooperative tasks and to foster long-term cooperative relationships between unrelated individuals. In support of this, evidence of inequity aversion in nonhuman animals has typically been found in species that, like humans, live in complex social groups and demonstrate cooperative behaviours. We examined inequity aversion in the kea (Nestor notabilis), which lives in social groups but does not appear to demonstrate wild cooperative behaviours, using a classic token exchange paradigm. We compared the number of successful exchanges and the number of abandoned trials in each condition and found no evidence of an aversion to inequitable outcomes when there was a difference between reward quality or working effort required between actor and partner. We also found no evidence of inequity aversion when the subject received no reward while their partner received a low-value reward.

Keas Perform Similarly to Chimpanzees and Elephants when Solving Collaborative Tasks.

Cooperation between individuals is one of the defining features of our species. While other animals, such as chimpanzees, elephants, coral trout and rooks also exhibit cooperative behaviours, it is not clear if they think about cooperation in the same way as humans do. In this study we presented the kea, a parrot endemic to New Zealand, with a series of tasks designed to assess cooperative cognition. We found that keas were capable of working together, even when they had to wait for their partner for up to 65 seconds. The keas also waited for a partner only when a partner was actually needed to gain food. This is the first demonstration that any non-human animal can wait for over a minute for a cooperative partner, and the first conclusive evidence that any bird species can successful track when a cooperative partner is required, and when not. The keas did not attend to whether their partner could actually access the apparatus themselves, which may have been due to issues with task demands, but one kea did show a clear preference for working together with other individuals, rather than alone. This preference has been shown to be present in humans but absent in chimpanzees. Together these results provide the first evidence that a bird species can perform at a similar level to chimpanzees and elephants across a range of collaborative tasks. This raises the possibility that aspects of the cooperative cognition seen in the primate lineage have evolved convergently in birds.