KLHL21 suppresses gastric tumourigenesis via maintaining STAT3 signalling equilibrium in stomach homoeostasis.

OBJECTIVE: Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood. DESIGN: An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21-floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms. RESULTS: Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1+ cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy. CONCLUSIONS: Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.

Acute stress during witnessing injustice shifts third-party interventions from punishing the perpetrator to helping the victim.

People tend to intervene in others' injustices by either punishing the transgressor or helping the victim. Injustice events often occur under stressful circumstances. However, how acute stress affects a third party's intervention in injustice events remains open. Here, we show a stress-induced shift in third parties' willingness to engage in help instead of punishment by acting on emotional salience and central-executive and theory-of-mind networks. Acute stress decreased the third party's willingness to punish the violator and the severity of the punishment and increased their willingness to help the victim. Computational modeling revealed a shift in preference of justice recovery from punishment the offender toward help the victim under stress. This finding is consistent with the increased dorsolateral prefrontal engagement observed with higher amygdala activity and greater connectivity with the ventromedial prefrontal cortex in the stress group. A brain connectivity theory-of-mind network predicted stress-induced justice recovery in punishment. Our findings suggest a neurocomputational mechanism of how acute stress reshapes third parties' decisions by reallocating neural resources in emotional, executive, and mentalizing networks to inhibit punishment bias and decrease punishment severity.

Using decision tree to predict non-suicidal self-injury among young adults: the role of depression, childhood maltreatment and recent bullying victimization.

Importance: Non-suicidal self-injury (NSSI) is a significant mental health issue requiring a deeper understanding of its underlying causes, such as childhood maltreatment, adult bullying victimization, and depression. Previous studies have not adequately addressed the cumulative risks of these factors on NSSI among college students. This population-based study investigates these cumulative risk factors.Design, setting, and participants: The cross-sectional study included 63 university's college students with a mean age of 19.6 years (N = 95,833).Main outcomes and measures: Two Chi-Square Automatic Interaction Detection (CHAID) decision tree models were used to classify subgroups based on childhood maltreatment and adult bullying victimization experiences and to investigate their cumulative risks of NSSI. Recursive partitioning algorithms determined each predictor variable's relative importance.Results: The CHAID model accurately predicted NSSI behaviours with an overall accuracy rate of 77.8% for individuals with clinically relevant depressive symptoms and 97.2% for those without. Among depressed individuals, childhood emotional abuse was the strongest NSSI predictor (Chi-Square, 650.747; adjusted P < .001), followed by sexual and physical abuse. For non-depressed individuals, emotional abuse in childhood was the strongest NSSI predictor (Chi-Square, 2084.171; adjusted P < .001), with sexual and verbal bullying in the past year representing the most significant proximal risks.Conclusions and relevance: Emotional abuse during childhood profoundly impacts individuals, increasing the risk of NSSI in both depressed and non-depressed individuals. Clinically relevant depressive symptoms have a moderating effect on the relationship between childhood maltreatment, adult bullying victimization, and NSSI. Identifying these factors can inform targeted interventions to prevent NSSI development among young adults.

Emotional abuse during childhood has a profound impact on individuals, increasing their risk of non-suicidal self-injury (NSSI), regardless of whether they are depressed or non-depressed.Among depressed individuals, childhood emotional abuse emerges as the strongest predictor of NSSI, followed by sexual and physical abuse.In non-depressed individuals, emotional abuse in childhood assumes a similar role as the strongest NSSI predictor, with sexual abuse and verbal bullying in the past year representing the most significant proximal risks.

Children's early signs and developmental trajectories of psychotic-like experiences.

INTRODUCTION: Children who experience persistent psychotic-like experiences (PLEs) are at a higher risk of developing psychotic disorder later in life. The developmental trajectories of PLEs are influenced by various factors. Therefore, it is important to identify early characteristics that can distinguish and predict between different developmental trajectories of PLEs. METHODS: Using PLEs scores from the Adolescent Brain Cognitive Development (ABCD) data across three waves, we categorized participants into five distinct PLEs trajectories groups: persistent group (n = 47), remitting group (n = 185), increasing group (n = 117), remittent group (n = 21), and no PLEs group (n = 4,476). We utilized linear mixed-effect models and generalized linear mixed-effect models to examine the differences in baseline characteristics, including psychological and behavioral problems, suicidality, trauma experiences, developmental milestones, cognitive function, physical health, family income, family history of mental illness, and brain structureamong these PLEs trajectory groups. RESULTS: We found that psychological and behavioral problems (such as DSM-oriented scales/externalizing/ADHD/social/attention/thought problems) assessed by the Child Behavior Checklist (CBCL) were associated with all PLEs groups. The persistent PLEs group had greater ADHD/social/thought problems and suicidal behavior compared to the remitting PLEs group. Comparing with the no PLEs group, poor cognitive function, abnormal brain structure (such as temporal lobe and supramarginal gyrus), more trauma experiences, and lower family income were found in only one of the PLEs groups, but not all PLEs groups. CONCLUSION: The development of PLEs is accompanied by changes in many domains, implying a dynamic and complex developmental process. Given that psychological and behavioral problems can predict the emergence of PLEs at any time and can be regarded as risk factors for persistent PLEs, thereby enabling early precisely interventions, it is important to place greater emphasis on assessing psychological and behavioral problems.

Association between sports-related concussions and the risk of self-injury thoughts and behaviors: Who, and under what circumstances?

BACKGROUND: Understanding the association between sport-related concussions and the risk of suicidal and non-suicidal self-injury thoughts and behaviors (SITBs), including non-suicidal self-injury (NSSI), suicidal ideation (SI), suicidal plan (SP), and suicidal attempt (SA), is crucial for suicide prevention. We aimed to identify the circumstances in which individuals with or without a concussion are vulnerable to SITBs. METHODS: The cross-sectional study included 85,469 students from 63 Chinese university with a mean age of 19.6 years. Firstly, propensity score matching, and inverse probability of treatment weighting (IPTW) were used to match the concussion and non-concussion group based on a range of biological, social, and psychological factors. Subsequently, multivariable logistic regression and a decision tree algorithm were employed to evaluate the interaction and cumulative impact of these risk factors and concussion on the probability of SITBs. RESULTS: In the unmatched sample, concussion exposures were associated with all SITBs, with NSSI (OR, 1.41), SI (OR, 1.10), SP (OR, 1.23), and SA (OR, 1.28). However, the matched and weighted sample only had a significant association with NSSI and SI. The decision tree model revealed that, in the unmatched sample, among individuals without depressive symptoms or childhood emotional abuse, the risk of concussion on SITBs increased from 45.5 % to 65.2 % (χ2, 9.370; adjusted P = .002) after experiencing sexual abuse and verbal bullying. In the matched sample, the risk increased from 46.2 % to 64.6 % (χ2, 6.848; adjusted P = .009). CONCLUSION: Our study revealed that individuals who suffered concussions exhibited a significantly higher risk of SITBs.

Indocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial.

Indocyanine green (ICG) fluorescence imaging-guided lymphadenectomy has been demonstrated to be effective in increasing the number of lymph nodes (LNs) retrieved in laparoscopic gastrectomy for gastric cancer (GC). Previously, we reported the primary outcomes and short-term secondary outcomes of a phase 3, open-label, randomized clinical trial (NCT03050879) investigating the use of ICG for image-guided lymphadenectomy in patients with potentially resectable GC. Patients were randomly (1:1 ratio) assigned to either the ICG or non-ICG group. The primary outcome was the number of LNs retrieved and has been reported. Here, we report the primary outcome and long-term secondary outcomes including three-year overall survival (OS), three-year disease-free survival (DFS), and recurrence patterns. The per-protocol analysis set population is used for all analyses (258 patients, ICG [n = 129] vs. non-ICG group [n = 129]). The mean total LNs retrieved in the ICG group significantly exceeds that in the non-ICG group (50.5 ± 15.9 vs 42.0 ± 10.3, P < 0.001). Both OS and DFS in the ICG group are significantly better than that in the non-ICG group (log-rank P = 0.015; log-rank P = 0.012, respectively). There is a difference in the overall recurrence rates between the ICG and non-ICG groups (17.8% vs 31.0%). Compared with conventional lymphadenectomy, ICG guided laparoscopic lymphadenectomy is safe and effective in prolonging survival among patients with resectable GC.

Loss of ATOH1 in Pit Cell Drives Stemness and Progression of Gastric Adenocarcinoma by Activating AKT/mTOR Signaling through GAS1.

Gastric cancer stem cells (GCSCs) are self-renewing tumor cells that govern chemoresistance in gastric adenocarcinoma (GAC), whereas their regulatory mechanisms remain elusive. Here, the study aims to elucidate the role of ATOH1 in the maintenance of GCSCs. The preclinical model and GAC sample analysis indicate that ATOH1 deficiency is correlated with poor GAC prognosis and chemoresistance. ScRNA-seq reveals that ATOH1 is downregulated in the pit cells of GAC compared with those in paracarcinoma samples. Lineage tracing reveals that Atoh1 deletion strongly confers pit cell stemness. ATOH1 depletion significantly accelerates cancer stemness and chemoresistance in Tff1-CreERT2; Rosa26Tdtomato and Tff1-CreERT2; Apcfl/fl ; p53fl/fl (TcPP) mouse models and organoids. ATOH1 deficiency downregulates growth arrest-specific protein 1 (GAS1) by suppressing GAS1 promoter transcription. GAS1 forms a complex with RET, which inhibits Tyr1062 phosphorylation, and consequently activates the RET/AKT/mTOR signaling pathway by ATOH1 deficiency. Combining chemotherapy with drugs targeting AKT/mTOR signaling can overcome ATOH1 deficiency-induced chemoresistance. Moreover, it is confirmed that abnormal DNA hypermethylation induces ATOH1 deficiency. Taken together, the results demonstrate that ATOH1 loss promotes cancer stemness through the ATOH1/GAS1/RET/AKT/mTOR signaling pathway in GAC, thus providing a potential therapeutic strategy for AKT/mTOR inhibitors in GAC patients with ATOH1 deficiency.

Radiomics signature for prediction of long-term survival and recurrence patterns in patients with gastric cancer after radical gastrectomy: A multicenter study.

Background: This study aimed to develop and validate a radiomics score to predict the long-term survival and patterns of recurrence of gastric cancer (GC). Methods: A total of 513 patients who underwent radical gastrectomy for GC after curative resection between 2008 and 2016 at two institutions were analyzed. A radiomics score was generated using the least absolute shrinkage and selection operator Cox regression model on 327 patients and was validated in 186 patients. A nomogram consisting of the radiomics score and clinicopathological factors was created and compared with the tumor-lymph node-metastasis (TNM) staging system. Model performance was assessed using calibration, discrimination, and clinical usefulness. Results: The radiomics score was established based on five selected features. A higher score was significantly associated with poorer recurrence-free survival (RFS) and overall survival (OS) rates, both in the training and validation cohorts (P < 0.05). Multivariate analysis demonstrated that the radiomics score was an independent prognostic factor for both RFS and OS (P < 0.05). A nomogram incorporating the radiomics score had a significantly better prognostic value than the TNM system alone. Moreover, a high score was significantly associated with an increased risk of distant recurrence, a medium score was significantly associated with an increased risk of peritoneal recurrence, and a low score was significantly associated with an increased risk of locoregional recurrence, in the entire cohort (P < 0.05). Conclusions: The newly proposed radiomics score may be a powerful predictor of long-term outcomes and recurrence patterns of GC. Further studies are warranted to confirm these findings.

Cortisol awakening response and testosterone jointly affect adolescents' theory of mind.

Adolescence is a critical period for the maturation of neurobiological processes and hormone secretion. Recent studies on the dual-hormone hypothesis have indicated that basal cortisol and testosterone jointly affect dominant and aggressive behavior among adolescents and adults. Whether this hypothesis applies to prosocial-related understanding of others' mental states remains unclear. The present study investigated associations between basal testosterone, basal cortisol (and cortisol awakening response [CAR]), and the cognitive/affective theory of mind (ToM) in 243 adolescents (67.9 % male, aged 14 to 17 years, Mage = 16.09, standard deviation = 0.62). Cognitive ToM (cToM) and affective ToM (aToM) were assessed with a cartoon story reasoning task: In the cToM condition, participants viewed a comic strip story and needed to predict what would happen based on a character's intentions, and in the aToM condition, they viewed a comic strip of two characters interacting and needed to think about what would make the protagonist feel better. The results showed that basal testosterone and basal cortisol did not interact with each other to affect the performance of ToM, either in terms of ToM accuracy or response speed. However, under the condition of low CAR, testosterone is associated with the fast performance of cToM, although the interaction of testosterone and CAR occurred only in female adolescents. Overall, our data provide new evidence for the dual-hormone hypothesis and further extend the hypothesis to social understanding.

An immunosuppressive scoring system to predict recurrence and assist in decision regarding postoperative adjuvant treatment in gastric cancer.

Inhibition of the immune microenvironment is the main cause of tumor recurrence after surgery in patients with gastric cancer (GC). In this study, immunohistochemistry and multiple immunofluorescence staining were used to evaluate immunosuppressive indicators and immune biomarkers in 825 patients with gastric cancer from three centers. We constructed an immunosuppressive recurrence score (IRS) using LASSO Cox regression based on the expression of six immunosuppressive indicators and found that the IRS and IRS-based nomogram were significantly accurate and reliable in predicting recurrence. Moreover, an elevated IRS was associated with locoregional recurrence and postoperative adjuvant chemotherapy failure. Furthermore, an increase in IRS indicated inhibition of the antitumor effect of CD8+ tumor-infiltrating lymphocytes in the invasive margin. Thus, we propose that the IRS can predict the recurrence outcome of patients with GC by distinguishing the immunosuppressive status, which is helpful in the selection of individualized adjuvant treatment plans.

m6A methylation mediates LHPP acetylation as a tumour aerobic glycolysis suppressor to improve the prognosis of gastric cancer.

LHPP, a histidine phosphatase, has been implicated in tumour progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Here, we obtained GC tissues and corresponding normal tissues from 48 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. The results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein levels. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. Together, our findings suggest that LHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.

Help or punishment: acute stress moderates basal testosterone's association with prosocial behavior.

The gonadal hormone testosterone is well-recognized to facilitate various behaviors for obtaining social status. A good reputation (i.e. competitive, generous, and trustworthy) is of crucial importance for acquiring high social status. It is unclear which type of reputation is preferred by individuals under the influence of testosterone. Given that the recent dual-hormone hypothesis emphasizes the modulating effect of stress (cortisol) on the influence of testosterone, it would be intriguing to test the role of stress-induced cortisol in testosterone-related reputation seeking. To test this hypothesis, we induced acute stress in 93 participants with cold pressor test (CPT) paradigm (vs. control condition), and then they were instructed to play a third-party intervention game, in which they made decisions as an uninvolved, outside the third party to punish a violator, help a victim, or do nothing. Salivary samples were obtained to assess participants' testosterone and cortisol levels. We split the testosterone concentration by median to low endogenous testosterone (LT) and high endogenous testosterone (HT). We found that HT individuals' prosocial preferences did not affect by acute stress. They were more likely to choose punishment than helping under both stress and control conditions. In contrast, individuals with low testosterone were more inclined to help than punish under control conditions. Interestingly, acute stress brought behavior patterns of LT individuals closer to those of HT individuals, that is, they reduced their helping behavior and increased the intensity of punishments. In this preliminary study on the preference inducement of testosterone for different types of prosocial behaviors, we discuss the physiological mechanism of the relationship between testosterone and reputation and the implications of these results for the dual-hormone hypothesis.HIGHLIGHTSLow testosterone (LT) individuals were more inclined to help than punish.High testosterone (HT) individuals were more inclined to punish than help.The HT individuals' preferences for prosocial types were not affected by acute stress.Acute stress brought the behavior patterns of LT individuals closer to those of HT individuals.

The peroxisome proliferator-activated receptor agonist rosiglitazone specifically represses tumour metastatic potential in chromatin inaccessibility-mediated FABP4-deficient gastric cancer.

Background: Efforts to prevent recurrence in gastric cancer (GC) patients are limited by current incomplete understanding of the pathological mechanisms. The present study aimed to identify novel tumour metastasis-associated genes and investigate potential value of these genes in clinical diagnosis and therapy. Methods: RNA sequencing was performed to identify differentially expressed genes related to GC metastasis. The expression and prognostic significance of fatty acid binding protein 4 (FABP4) were evaluated in two independent cohorts of GC patients. Chromatin immunoprecipitation sequencing, diverse mouse models and assays for transposase-accessible chromatin with high-throughput sequencing were used to investigate the roles and mechanisms of action of FABP4. Results: The results of the present multicentre study confirmed an association between a decrease in the expression of FABP4 and poor outcomes in GC patients. FABP4 inhibited GC metastasis but did not influence tumour growth in vitro and in vivo. Mechanistically, FABP4 binding with peroxisome proliferator-activated receptor γ (PPAR-γ) facilitated the translocation of PPAR-γ to the nucleus. FABP4 depletion suppressed PPAR-γ-mediated transcription of cell adhesion molecule 3 (CADM3), which preferentially governed GC metastasis. Notably, the PPAR-γ agonist rosiglitazone reversed the metastatic properties of FABP4-deficient GC cells in vitro and demonstrated viable therapeutic potential in multiple mouse models. For GC patients with diabetes, low FABP4 portends better prognosis than high FABP4 after receipt of rosiglitazone treatment. Additionally, chromatin inaccessibility induced by HDAC1 reduced FABP4 expression at the epigenetic level. Conclusions: Our findings suggest that chromatin inaccessibility orchestrates a reduction in FABP4 expression, which inhibits CADM3 transcription via PPAR-γ, thereby resulting in GC metastasis. The antidiabetic drug rosiglitazone restores PPAR-γ/CADM3 activation in FABP4-deficient GC and thus has promising therapeutic potential.

Clinical implications of Indocyanine Green Fluorescence Imaging-Guided laparoscopic lymphadenectomy for patients with gastric cancer: A cohort study from two randomized, controlled trials using individual patient data.

BACKGROUND: The value of indocyanine green (ICG) fluorescence imaging in tracing metastatic lymph nodes (LNs) has rarely been reported. We aimed to evaluate the clinical implications of fluorescence imaging-guided lymphadenectomy and the sensitivity of fluorescent lymphography to detect metastatic LN stations in gastric cancer (GC). MATERIALS AND METHODS: This analysis pooled data from two randomized controlled trials (FUGES-012 and FUGES-019 studies) on laparoscopic ICG tracer-guided lymphadenectomy for GC between November 2018 and October 2020. Patients who received ICG injection using either the intraoperative subserosal or preoperative submucosal approaches 1 day before surgery and underwent fluorescence imaging-guided lymphadenectomy were defined as the ICG group. Patients who underwent conventional lymphadenectomy without ICG injection and intraoperative imaging were defined as the non-ICG group. RESULTS: Among 514 enrolled patients, the ICG and non-ICG groups included 385 and 129, respectively. A significantly higher mean number of LNs was retrieved in the ICG group than in the non-ICG group (49.9 vs. 42.0, P < 0.001). The ICG group showed a lower LN noncompliance rate than that in the non-ICG group (31.9% vs. 57.4%, P < 0.001). The sensitivity of fluorescence imaging for detecting all metastatic LN stations was 86.8%. The negative predictive value was 92.2% for nonfluorescent stations. For detecting all metastatic stations, subgroup analysis revealed 97.7%, 91.7%, 86.2%, and 84.3% sensitivities for pT1, pT2, pT3, and pT4a tumors, respectively. Regardless of gastrectomy type, the diagnostic accuracy for detecting all metastatic stations in the D1+ and D2 stations for cT1-cT2 disease reached 100%. CONCLUSION: ICG fluorescence imaging, using either the subserosal or submucosal approaches, assisted in the thorough dissection of potentially metastatic LNs, as recommended for individualized laparoscopic lymphadenectomy for GC.

Acute psychosocial stress increases third-party helping but not punishing behavior.

Despite extensive research on the effects of stress on the brain and behaviors, there is a debate whether stress promotes prosocial behaviors, especially acute stress due to intricate costly punishment in the ultimatum game. Therefore, the present study introduced an irrelevant third party to examine how acute stress and the triggered cortisol influence third parties' punishing and helping behaviors as more convincing altruistic behaviors. The 65 participants were exposed to a psychosocial stressor (n = 33) or a control condition (n = 32). Afterwards, two third-party intervention tasks (a token allocation task and criminal scenario judgment task) were completed, during which the participants, as an "irrelevant" third party, could choose whether to sacrifice their own interests to help the victim or punish the transgressor. Participants' affective states, heart rate, and salivary cortisol were repeatedly measured throughout the experiment. Results showed that acute stress can lead to more third-party helping behaviors but not more punishing behaviors. Specifically, participants under stress tended to transfer more monetary units to the victim in the token allocation task than the control-group participants, and they tended to help the victim in the scenario task. In contrast, there was no significant difference in punishing behavior between the stressed and control participants. These findings reveal that acute psychosocial stress triggers the "tend and befriend" response, which might reflect the prosocial intuition under acute stress.

Self-Punishment Promotes Forgiveness in the Direct and Indirect Reciprocity Contexts.

Most previous studies regarding self-punishment have focused on the correlation between moral emotion and self-punishment. Only a few studies have attempted to understand self-punishment from the perspective of seeking forgiveness, and no study has yet directly tested whether wrongdoers' self-punishment promotes others to forgive the wrongdoers. In three studies, the participants judged the wrongdoers' self-punishment behaviors following an unfair allocation and reported the extent to which they forgave the wrongdoers. The results demonstrated that self-punishment did promote forgiveness in both the direct (Studies 1 and 2) and indirect reciprocity (Study 3) contexts. Consistent with costly signaling theory, the costlier the self-punishment was, the stronger the effect it had on forgiveness. Moreover, communicative self-punishment had a better effect than silent self-punishment when the cost was relatively high in the direct-reciprocity studies. These findings can guide us regarding how to address a damaged relationship via self-punishment when compensation is not feasible or acceptable.