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Abstract The evolution of cooperation through indirect reciprocity is a pivotal mechanism for sustaining large-scale societies. Because third parties return cooperative behaviour in indirect reciprocity, reputations that assess and share these third parties’ behaviour play an essential role. Studies on indirect reciprocity have predominantly focused on the costs associated with cooperative behaviour, overlooking the costs tied to the mechanisms underpinning reputation sharing. Here, we explore the robustness of social norms necessary to secure the stability of indirect reciprocity, considering both the costs of reputation and the resilience against perfect defectors. Firstly, our results replicate that only eight social norms, known as the ‘leading eight,’ can establish a cooperative regime. Secondly, we reveal the robustness of these norms against reputation costs and perfect defectors. Our analysis identifies four norms that exhibit resilience in the presence of defectors due to their neutral stance on justified defection and another four that demonstrate robustness against reputation costs through their negative evaluation of unjustified cooperation. The study underscores the need to further research how reputational information is shared within societies to promote cooperation in diverse and complex environments.

Abstract Exploring the evolutionary mechanisms of cooperation in societies where reputational consensus cannot be assumed, as in divided societies, is important for understanding the basic principles of human behavior in modern societies. Indirect reciprocity provides a major explanatory mechanism, but most studies have focused on how donors, i.e., one who decides whether to donate (cooperate or help) to a recipient or do nothing, are assessed. It is natural to think that there is no consensus among assessors in our society, and there is no reason to update only donor assessments when updating assessments. We constructed an agent-based model that enables updating of both donors’ and recipients’ images. Our exhaustive simulations showed that the well analyzed assessment rules updating donors’ images are only second best to an assessment rule updating bad images in most likely for maintaining cooperative regimes. Such a social norm that prioritizes a positive assessment is considered tolerant, which is also consistent with previous studies arguing that tolerant evaluation is important in private-assessment schemes.

Abstract Mucin overproduction is a common feature of chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and exacerbates their underlying respiratory condition. Surfactant protein D (SP-D) protects against airway diseases through modulation of immune reactions, but whether it also exerts direct effects on airway epithelial cells has remained unclear. Therefore, we sought to investigate the inhibitory role of SP-D on mucin production in airway epithelial cells. We prepared air–liquid interface (ALI) cultures of human primary bronchial epithelial cells (HBECs), which recapitulated a well-differentiated human airway epithelium. Benzo(a)pyrene (BaP), a key toxicant in cigarette smoke, induced mucin 5AC (MUC5AC) production in ALI-cultured HBECs, airway secretory cell lines, and airway epithelia of mice. Then, the protective effects of SP-D against the BaP-induced mucin overproduction were examined. BaP increased MUC5AC production in ALI cultures of HBECs, and this effect was attenuated by SP-D. SP-D also suppressed the BaP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and MUC5AC expression in NCI-H292 goblet-like cells, but not in NCI-H441 club-like cells. Signal regulatory protein α (SIRPα) was found to be expressed in HBECs and NCI-H292 cells but absent in NCI-H441 cells. In NCI-H292 cells, SP-D activated SH2 domain-containing tyrosine phosphatase-1 (SHP-1), downstream of SIRPα, and knockdown of SIRPα abolished the suppressive effects of SP-D on BaP-induced ERK phosphorylation and MUC5AC production. Consistent with these in vitro findings, intratracheal instillation of SP-D prevented the BaP-induced phosphorylation of ERK and Muc5ac expression in airway epithelial cells in a mouse model. SP-D acts directly on airway epithelial cells to inhibit mucin secretion through ligation of SIRPα and SHP-1-mediated dephosphorylation of ERK. Targeting of SIRPα is therefore a potential new therapeutic approach to suppression of mucin hypersecretion in chronic airway diseases such as COPD and asthma.

Abstract The liver is an essential organ for regulating innate and acquired immunity. We hypothesized that the pre-treatment hepatic function affects the clinical outcome of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). We analyzed 140 patients with NSCLC who received ICIs. We investigated the association between pre-treatment liver function, assessed using the albumin–bilirubin (ALBI) grade, and clinical outcomes in univariate, multivariate, and propensity score matching analyses. Patients were divided into four grades according to pre-treatment liver function. Eighty-eight patients had good hepatic reserve (ALBI grade 1 or 2a), whereas 52 patients had poor hepatic reserve (ALBI grade 2b or 3). In the univariate Kaplan–Meier analysis, the ALBI grade 1, 2a group had a significantly prolonged progression-free survival (PFS, 5.3 versus 2.5 months, p = 0.0019) and overall survival (OS, 19.6 vs. 6.2 months, p = 0.0002). These results were consistent, regardless of whether the analysis was performed in patients with a performance status of 0 or 1 at pre-treatment (N = 124) or in those selected using propensity score matching (N = 76). In the multivariate analysis, pre-treatment ALBI grade was an independent prognostic factor for both PFS (hazard ratio [HR] 0.57, 95% confidence interval [95% CI] 0.38–0.86, p = 0.007) and OS (HR 0.45, 95% CI 0.29–0.72, p = 0.001). Our results suggest that pre-treatment hepatic function assessed by ALBI grade could be an essential biomarker for predicting the efficacy of treatment with ICIs in NSCLC.

Abstract Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

Abstract Despite intensive studies on the evolution of cooperation in spatial public goods games, there have been few investigations into locality effects in interaction games, adaptation, and punishment. Here we analyze locality effects using an agent-based model of a regular graph. Our simulation shows that a situation containing a local game, local punishment, and global adaptation leads to the most robustly cooperative regime. Further, we show an interesting feature in local punishment. Previous studies showed that a local game and global adaptation are likely to generate cooperation. However, they did not consider punishment. We show that if local punishment is introduced in spatial public goods games, a situation satisfying either local game or local adaptation is likely to generate cooperation. We thus propose two principles. One is if interactions in games can be restricted locally, it is likely to generate cooperation independent of the interaction situations on punishment and adaptation. The other is if the games must be played globally, a cooperative regime requires both local punishment and local adaptation.

Abstract Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10–1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06–0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.

Abstract Reputation-based cooperation is often observed in modern society. People gain several types of information by assessing others. Among these, the most important information is the actions of people and those of their recipients. However, almost all studies assume that people consider all of the information they receive. This assumption is extreme, and people engaging in reputation-based cooperation may not pay attention to some information, i.e., they may display selective inattention. We demonstrate that subjects’ decision-making in relation to cooperative action depends on the content of the information they receive about their recipients. Our results show that subjects either consider or ignore information depending on the content of that information. When their recipients had cooperated previously, subjects cooperated without considering the information they received. When the recipients had played before with those who had bad reputations, subjects did not use that information, regardless of whether it was disclosed proactively. In other cases, subjects considered information on both the previous actions of recipients and those of the recipients’ own recipients. We found that subjects did not always use the information to make decisions, although they willingly received information about their recipients. This supports the proposition that selective inattention occurs in reputation-based cooperation.