Design and Assessment of First-Generation Heterobifunctional PPARα/STING Modulators.

Inflammatory retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD) are prominent causes of blindness in industrialized countries. The complexity of these diseases, involving diverse cell types and pathways that give rise to a multifactorial pathogenesis, complicates drug discovery. As such, therapies exhibiting polypharmacology are expected to improve outcomes through broader disease stage coverage and beneficial spatiotemporal effects. We report herein the first dual modulator of PPARα and STING, two targets tied to disparate pathologies in retinal diseases. Recognizing structural similarities between a reported STING inhibitor SN-013 and our previously described PPARα agonist A229, we designed BH400, which agonizes PPARα (EC50 = 1.2 µM) and inhibits STING (IC50 = 8.1 µM). BH400 demonstrates superior protection over single-target PPARα or STING modulation in microglial and photoreceptor cells. These findings provide compelling evidence for the potential benefit of polypharmacology in common retinal diseases through dual PPARα/STING modulation, motivating further studies.

Correction to "The interpersonal costs of dishonesty: How dishonest behavior reduces individuals' ability to read others' emotions" by Lee et al. (2019).

Reports an error in "The interpersonal costs of dishonesty: How dishonest behavior reduces individuals' ability to read others' emotions" by Julia J. Lee, Ashley E. Hardin, Bidhan Parmar, and Francesca Gino (Journal of Experimental Psychology: General, 2019[Sep], Vol 148[9], 1557-1574). Concerns were raised regarding the findings reported in Study 3 related to data exclusions that may have affected the results. As a result, the findings reported in Study 3 cannot be relied upon. The remaining base of empirical evidence presented in this publication, excluding Study 3, supports the assertion that dishonesty reduces empathic accuracy. The authors (Lee, Hardin, Parmar, & Gino) have requested this correction. (The following abstract of the original article appeared in record 2019-38884-001.) In this research, we examine the unintended consequences of dishonest behavior for one's interpersonal abilities and subsequent ethical behavior. Specifically, we unpack how dishonest conduct can reduce one's generalized empathic accuracy-the ability to accurately read other people's emotional states. In the process, we distinguish these 2 constructs from one another and demonstrate a causal relationship. The effects of dishonesty on empathic accuracy that we found were significant, but modest in size. Across 8 studies (n = 2,588), we find support for (a) a correlational and causal account of dishonest behavior reducing empathic accuracy; (b) an underlying mechanism of reduced relational self-construal (i.e., the tendency to define the self in terms of close relationships); (c) negative downstream consequences of impaired empathic accuracy, in terms of dehumanization and subsequent dishonesty; and (d) a physiological trait (i.e., vagal reactivity) that serves as a boundary condition for the relationship between dishonest behavior and empathic accuracy. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Design, Synthesis, and Structure-Activity Relationships of Biaryl Anilines as Subtype-Selective PPAR-alpha Agonists.

The role of peroxisome proliferator-activated receptor alpha (PPARα) in retinal biology is clarifying, and evidence demonstrates that novel PPARα agonists hold promising therapeutic utility for diseases like diabetic retinopathy and age-related macular degeneration. Herein, we disclose the design and initial structure-activity relationships for a new biaryl aniline PPARα agonistic chemotype. Notably, this series exhibits subtype selectivity for PPARα over other isoforms, a phenomenon postulated to be due to the unique benzoic acid headgroup. This biphenyl aniline series is sensitive to B-ring functionalization but allows isosteric replacement, and provides an opportunity for C-ring extension. From this series, 3g, 6j, and 6d were identified as leads with <90 nM potency in a cell-based luciferase assay cell and exhibited efficacy in various disease-relevant cell contexts, thereby setting the stage for further characterization in more advanced in vitro and in vivo models.

The interpersonal costs of dishonesty: How dishonest behavior reduces individuals' ability to read others' emotions.

In this research, we examine the unintended consequences of dishonest behavior for one's interpersonal abilities and subsequent ethical behavior. Specifically, we unpack how dishonest conduct can reduce one's generalized empathic accuracy-the ability to accurately read other people's emotional states. In the process, we distinguish these 2 constructs from one another and demonstrate a causal relationship. The effects of dishonesty on empathic accuracy that we found were significant, but modest in size. Across 8 studies (n = 2,588), we find support for (a) a correlational and causal account of dishonest behavior reducing empathic accuracy; (b) an underlying mechanism of reduced relational self-construal (i.e., the tendency to define the self in terms of close relationships); (c) negative downstream consequences of impaired empathic accuracy, in terms of dehumanization and subsequent dishonesty; and (d) a physiological trait (i.e., vagal reactivity) that serves as a boundary condition for the relationship between dishonest behavior and empathic accuracy. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Different physiological reactions when observing lies versus truths: Initial evidence and an intervention to enhance accuracy.

Humans consistently face the challenge of discerning liars from truth-tellers. Hundreds of studies in which observers judge the veracity of laboratory-created lies and truths suggest that this is a difficult task; in this context, lie-detection accuracy is notoriously poor. Challenging these findings and traditional methodologies in lie-detection research, we draw upon the somatic marker hypothesis and research on interoception to find that: (a) people experience physiological reactions indicating increased sympathetic arousal while observing real, high-stakes lies (vs. truths), and (b) attending to these physiological reactions may improve lie-detection accuracy. Consistent with the tipping point framework, participants demonstrated more physiological arousal and vasoconstriction while observing real crime liars versus truth-tellers, but not mock crime liars versus truth-tellers (Experiment 1; N = 48). Experiment 2 replicated this effect in a larger sample of participants (N = 169). Experiment 3 generalized this effect to a novel set of stimuli; participants demonstrated more physiological arousal to game show contestants who lied (vs. told the truth) about their intention to cooperate in a high-stakes economic game (N = 71). In an intervention study (Experiment 4; N = 428), participants were trained to attend to their physiological signals; lie-detection accuracy increased relative to a control condition. Experiment 5 (N = 354) replicated this effect, and the addition of a bogus training condition suggested that increased accuracy was not simply attributable to self-focused attention. Findings highlight the limitations of relying on laboratory-created lies to study human lie-detection and suggest that observers have automatic, physiological reactions to being deceived. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Lay theories of effortful honesty: Does the honesty-effort association justify making a dishonest decision?

Are our moral decisions and actions influenced by our beliefs about how much effort it takes to do the right thing? We hypothesized that the belief that honesty is effortful predicts subsequent dishonest behavior because it facilitates one's ability to justify such actions. In Study 1 (N = 210), we developed an implicit measure of people's beliefs about whether honesty is effortful, and we found that this lay theory predicts dishonesty. In Study 2 (N = 339), we experimentally manipulated individuals' lay theories about honesty and effort and found that an individual's lay theory that honesty is effortful increased subsequent dishonesty. In Study 3, we manipulated (Study 3a; N = 294) and measured (Study 3b; N = 153) lay theories, and then manipulated the strength of situational force that encourages dishonesty, and found that an individual's lay theory influences subsequent dishonesty only in a weak situation, where individuals have more agency to interpret the situation. This research provides novel insights into how our lay theories linking honesty and effort can help us rationalize our dishonesty, independent of whether a particular moral decision requires effort or not. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Polluted Morality: Air Pollution Predicts Criminal Activity and Unethical Behavior.

Air pollution is a serious problem that affects billions of people globally. Although the environmental and health costs of air pollution are well known, the present research investigates its ethical costs. We propose that air pollution can increase criminal and unethical behavior by increasing anxiety. Analyses of a 9-year panel of 9,360 U.S. cities found that air pollution predicted six major categories of crime; these analyses accounted for a comprehensive set of control variables (e.g., city and year fixed effects, population, law enforcement) and survived various robustness checks (e.g., balanced panel, nonparametric bootstrapped standard errors). Three subsequent experiments involving American and Indian participants established the causal effect of psychologically experiencing a polluted (vs. clean) environment on unethical behavior. Consistent with our theoretical perspective, results revealed that anxiety mediated this effect. Air pollution not only corrupts people's health, but also can contaminate their morality.