Coordination and expertise foster legal textualism

Funding Information: ACKNOWLEDGMENTS. This research was supported by the Spanish Ministry of Science and Innovation (PID2020-119791RA-I00; RTI2018-098882-B-I00), the Polish National Science Centre (2020/36/C/HS5/00111; 2017/25/N/HS5/00944), the Swiss National Science Foundation (PZ00P1_179912), and the European Research Council (805498). Publisher Copyright: Copyright © 2022 the Author(s).A cross-cultural survey experiment revealed a dominant tendency to rely on a rule’s letter over its spirit when deciding which behaviors violate the rule. This tendency varied markedly across (k = 15) countries, owing to variation in the impact of moral appraisals on judgments of rule violation. Compared with laypeople, legal experts were more inclined to disregard their moral evaluations of the acts altogether and consequently exhibited stronger textualist tendencies. Finally, we evaluated a plausible mechanism for the emergence of textualism: in a two-player coordination game, incentives to coordinate in the absence of communication reinforced participants’ adherence to rules’ literal meaning. Together, these studies (total n = 5,794) help clarify the origins and allure of textualism, especially in the law. Within heterogeneous communities in which members diverge in their moral appraisals involving a rule’s purpose, the rule’s literal meaning provides a clear focal point—an identifiable point of agreement enabling coordinated interpretation among citizens, lawmakers, and judges.Peer reviewe

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment

Abstract A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD

Roles of Mitochondrial Respiratory Complexes during Infection

International audienceBeyond oxidative phosphorylation (OXPHOS), mitochondria have also immune functions against infection, such as the regulation of cytokine production, the generation of metabolites with antimicrobial proprieties and the regulation of inflammasome-dependent cell death, which seem in turn to be regulated by the metabolic status of the organelle. Although OXPHOS is one of the main metabolic programs altered during infection, the mechanisms by which pathogens impact the mitochondrial electron transport chain (ETC) complexes to alter OXPHOS are not well understood. Similarly, how changes on ETC components affect infection is only starting to be characterized. Herein we summarize and discuss the existing data about the regulation of ETC complexes and super-complexes during infection, in order to shed some light on the mechanisms underlying the regulation of the mitochondrial OXPHOS machinery when intracellular pathogens infect eukaryotic host cells

Lytic cell death induced by melittin bypasses pyroptosis but induces NLRP3 inflammasome activation and IL-1β release

The nucleotide-binding domain and leucine-rich repeat-containing receptor with a pyrin domain 3 (NLRP3) inflammasome is a sensor for different types of infections and alterations of homeostatic parameters, including abnormally high levels of the extracellular nucleotide ATP or crystallization of different metabolites. All NLRP3 activators trigger a similar intracellular pathway, where a decrease in intracellular K+ concentration and permeabilization of plasma membrane are key steps. Cationic amphipathic antimicrobial peptides and peptide toxins permeabilize the plasma membrane. In fact, some of them have been described to activate the NLRP3 inflammasome. Among them, the bee venom antimicrobial toxin peptide melittin is known to elicit an inflammatory reaction via the NLRP3 inflammasome in response to bee venom. Our study found that melittin induces canonical NLRP3 inflammasome activation by plasma membrane permeabilization and a reduction in the intracellular K+ concentration. Following melittin treatment, the apoptosis-associated speck-like protein, an adaptor protein with a caspase recruitment domain (ASC), was necessary to activate caspase-1 and induce IL-1β release. However, cell death induced by melittin prevented the formation of large ASC aggregates, amplification of caspase-1 activation, IL-18 release and execution of pyroptosis. Therefore, melittin-induced activation of the NLRP3 inflammasome results in an attenuated inflammasome response that does not result in caspase-1 dependent cell death.This work was supported by SAF2015-65740-R and Subdirección General de Redes y Centros de Investigación Cooperativa-FEDER, RICET RD12/0018/0007 and RD16/0027/0010. This work was also supported by grants from the European Research Council (ERC-2013-CoG 614578 to PP) and the Instituto Salud Carlos III-Fondo Europeo de Desarrollo Regional (PI13/00174 to PP). FM-S was supported by the Sara Borrell postdoctoral grant from the Instituto Salud Carlos III (CD12/00523