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Human papillomavirus (HPV) is a significant contributor to the global cancer burden, and its carcinogenic activity is facilitated in part by the HPV early protein 6 (E6), which interacts with the E3-ligase E6AP, also known as UBE3A, to promote degradation of the tumor suppressor, p53. In this study, we present a single-particle cryoEM structure of the full-length E6AP protein in complex with HPV16 E6 (16E6) and p53, determined at a resolution of ~3.3 Å. Our structure reveals extensive protein-protein interactions between 16E6 and E6AP, explaining their picomolar binding affinity. These findings shed light on the molecular basis of the ternary complex, which has been pursued as a potential therapeutic target for HPV-driven cervical, anal, and oropharyngeal cancers over the last two decades. Understanding the structural and mechanistic underpinnings of this complex is crucial for developing effective therapies to combat HPV-induced cancers. Our findings may help to explain why previous attempts to disrupt this complex have failed to generate therapeutic modalities and suggest that current strategies should be reevaluated. HPV’s E6 protein promotes cancer by degrading p53. This study reveals the cryoEM structure of HPV16 E6 in complex with E6AP and p53, highlighting their picomolar affinity and large protein-protein interaction interface.

Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are metalloproteases that mediate IGF bioavailability through cleavage of IGF binding proteins (IGFBPs). Here, we present single-particle cryo-EM structures of the catalytically inactive mutant PAPP-A (E483A) in complex with a peptide from its substrate IGFBP5 (PAPP-A BP5 ) and also in its substrate-free form, by leveraging the power of AlphaFold to generate a high quality predicted model as a starting template. We show that PAPP-A is a flexible trans -dimer that binds IGFBP5 via a 25-amino acid anchor peptide which extends into the metalloprotease active site. This unique IGFBP5 anchor peptide that mediates the specific PAPP-A-IGFBP5 interaction is not found in other PAPP-A substrates. Additionally, we illustrate the critical role of the PAPP-A central domain as it mediates both IGFBP5 recognition and trans -dimerization. We further demonstrate that PAPP-A trans -dimer formation and distal inter-domain interactions are both required for efficient proteolysis of IGFBP4, but dispensable for IGFBP5 cleavage. Together the structural and biochemical studies reveal the mechanism of PAPP-A substrate binding and selectivity. PAPP-A substrate selectivity underlies the tight regulation of IGF signaling. Here, the authors report cryo-EM structures of dimeric PAPP-A in its substrate-free form and in complex with a peptide substrate, which combined with biochemical assays provide a mechanism for PAPP-A substrate binding and selectivity.

The current research tested the hypothesis that individuals engaged in long-term efforts to limit food intake (e.g., individuals with high eating restraint) would have reduced capacity to regulate eating when self-control resources are limited. In the current research, body mass index (BMI) was used as a proxy for eating restraint based on the assumption that individuals with high BMI would have elevated levels of chronic eating restraint. A preliminary study (Study 1) aimed to provide evidence for the assumed relationship between eating restraint and BMI. Participants (N = 72) categorized into high or normal-range BMI groups completed the eating restraint scale. Consistent with the hypothesis, results revealed significantly higher scores on the weight fluctuation and concern for dieting subscales of the restraint scale among participants in the high BMI group compared to the normal-range BMI group. The main study (Study 2) aimed to test the hypothesized interactive effect of BMI and diminished self-control resources on eating behavior. Participants (N = 83) classified as having high or normal-range BMI were randomly allocated to receive a challenging counting task that depleted self-control resources (ego-depletion condition) or a non-depleting control task (no depletion condition). Participants then engaged in a second task in which required tasting and rating tempting cookies and candies. Amount of food consumed during the taste-and-rate task constituted the behavioral dependent measure. Regression analyses revealed a significant interaction effect of these variables on amount of food eaten in the taste-and-rate task. Individuals with high BMI had reduced capacity to regulate eating under conditions of self-control resource depletion as predicted. The interactive effects of BMI and self-control resource depletion on eating behavior were independent of trait self-control. Results extend knowledge of the role of self-control in regulating eating behavior and provide support for a limited-resource model of self-control.

Pregnancy-Associated Plasma Protein A isoforms, PAPP-A and PAPP-A2, are metalloproteases that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor signaling. The structures of homodimeric PAPP-A in complex with IGFBP5 anchor peptide, and inhibitor proteins STC2 and proMBP have been recently reported. Here, we present the single-particle cryo-EM structure of the monomeric, N-terminal LG, MP, and the M1 domains (with the exception of LNR1/2) of human PAPP-A2 to 3.13 Å resolution. Our structure together with functional studies provides insight into a previously reported patient mutation that inactivates PAPP-A2 in a distal region of the protein. Using a combinational approach, we suggest that PAPP-A2 recognizes IGFBP5 in a similar manner as PAPP-A and show that PAPP-A2 cleaves IGFBP5 less efficiently due to differences in the M2 domain. Overall, our studies characterize the cleavage mechanism of IGFBP5 by PAPP-A2 and shed light onto key differences with its paralog PAPP-A. All PAPP-A and PAPP-A2 are two isoforms of pregnancy-associated plasma protein A that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor signaling, however the structure and function of PAPP-A2 remain underexplored. Here, the authors report the cryo-EM structure of PAPP-A2, computational modeling of the PAPP-A2/IGFBP5 complex, and biochemical studies that reveal unique structural features and a lower IGFBP5 cleaving efficiency compared with PAPP-A.

We investigated the role of three beliefs in predicting teachers’ motivating style toward students—namely, how effective, how normative, and how easy-to-implement autonomy-supportive and controlling teaching were each believed to be. We further examined national collectivism–individualism as a predictor of individual teachers’ motivating style and beliefs about motivating style, as we expected that a collectivistic perspective would tend teachers toward the controlling style and toward positive beliefs about that style. Participants were 815 full-time PreK-12 public school teachers from eight different nations that varied in collectivism–individualism. All three teacher beliefs explained independent and substantial variance in teachers’ self-described motivating styles. Believed effectiveness was a particularly strong predictor of self-described motivating style. Collectivism–individualism predicted which teachers were most likely to self-describe a controlling motivating style, and a mediation analysis showed that teachers in collectivistic nations self-described a controlling style because they believed it to be culturally normative classroom practice. These findings enhance the literature on the antecedents of teachers’ motivating styles by showing that teacher beliefs strongly predict motivating style, and that culture informs one of these beliefs—namely, normalcy.

Whether playing video games with prosocial content has an influence on empathy among players remains contentious in the research literature. Some evidence suggests playing cooperatively with other gamers enhances empathy, but data have not conclusively linked prosocial content with empathy. Further, mechanisms of this potential relationship are unclear, and little work has been conducted on how cognitive skills, such as fluid reasoning, may mediate this relationship. The current study examines these relationships with a large sample of 3034 youth (27.2% female, Mage = 11.2; range 8–17 at time 1) in Singapore. Data were considered longitudinally across two years in three waves. Ultimately, no evidence emerged that prosocial content in video games had any impact on empathy related outcomes, nor was fluid reasoning a mediator variable for any relationship. However, variables such as social competence and depression and anxiety symptoms were highly related to empathy measures. This evidence adds to the growing debate in the field that video games may not dramatically alter, whether positively or negatively, the development of emotional and behavioral outcomes for youth.

The aim of the present study was to test the validity of the Brief Self-Control Scale (BSCS; Tangney, Baumeister and Boone 2004) including its dimensional structure based on competing one- and two-factor models, discriminant validity from the conceptually-related self-discipline construct, invariance across multiple samples from different national groups, and predictive validity with respect to health-related behaviors. Samples of undergraduate students (total N = 1282) from four national groups completed the brief self-control scale, the self-discipline scale from the NEO-PI-R, and self-report measures of binge drinking, exercise, and healthy eating. Confirmatory factor analytic models supported a two-factor structure of self-control encompassing restraint and non-impulsivity components. The model exhibited good fit in all samples and invariance of factor loadings in multi-sample analysis. The restraint and non-impulsivity components exhibited discriminant validity and were also distinct from self-discipline. Structural equation models revealed that non-impulsivity predicted binge drinking in three of the samples, and restraint predicted exercise in two samples, with no role for self-discipline. Results point to a multi-dimensional structure for trait self-control consistent with previous theory separating impulsive- and control-related components.

The purpose of this study was to identify student clusters with homogenous profiles in perceptions of task- and ego-involving, autonomy, and social relatedness supporting motivational climate in school physical education. Additionally, we investigated whether different motivational climate groups differed in their enjoyment in PE. Participants of the study were 2 594 girls and 1 803 boys, aged 14-15 years. Students responded to questionnaires assessing their perception of motivational climate and enjoyment in physical education. Latent profile analyses produced a five-cluster solution labeled 1) 'low autonomy, relatedness, task, and moderate ego climate' group', 2) 'low autonomy, relatedness, and high task and ego climate, 3) 'moderate autonomy, relatedness, task and ego climate' group 4) 'high autonomy, relatedness, task, and moderate ego climate' group, and 5) 'high relatedness and task but moderate autonomy and ego climate' group. Analyses of variance showed that students in clusters 4 and 5 perceived the highest level of enjoyment whereas students in cluster 1 experienced the lowest level of enjoyment. The results showed that the students' perceptions of various motivational climates created differential levels of enjoyment in PE classes. Verf.-Referat.

The issue of whether video games with aggressive or violent content (henceforth aggressive video games) contribute to aggressive behavior in youth remains an issue of significant debate. One issue that has been raised is that some studies may inadvertently inflate effect sizes by use of questionable researcher practices and unstandardized assessments of predictors and outcomes, or lack of proper theory-driven controls. In the current article, a large sample of 3034 youth (72.8% male Mage = 11.2) in Singapore were assessed for links between aggressive game play and seven aggression or prosocial outcomes 2 years later. Theoretically relevant controls for prior aggression, poor impulse control, gender and family involvement were used. Effect sizes were compared to six nonsense outcomes specifically chosen to be theoretically unrelated to aggressive game play. The use of nonsense outcomes allows for a comparison of effect sizes between theoretically relevant and irrelevant outcomes, to help assess whether any statistically significant outcomes may be spurious in large datasets. Preregistration was employed to reduce questionable researcher practices. Results indicate that aggressive video games were unrelated to any of the outcomes using the study criteria for significance. It would take 27 h/day of M-rated game play to produce clinically noticeable changes in aggression. Effect sizes for aggression/prosocial outcomes were little different than for nonsense outcomes. Evidence from this study does not support the conclusion that aggressive video games are a predictor of later aggression or reduced prosocial behavior in youth.