Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions.

Transcription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that androgen receptor (AR) forms condensates through multivalent interactions mediated by its N-terminal intrinsically disordered region (IDR) to orchestrate enhancer assembly in response to androgen signaling. AR IDR can be substituted by IDRs from selective proteins for AR condensation capacity and its function on enhancers. Expansion of the poly(Q) track within AR IDR results in a higher AR condensation propensity as measured by multiple methods, including live-cell single-molecule microscopy. Either weakening or strengthening AR condensation propensity impairs its heterotypic multivalent interactions with other enhancer components and diminishes its transcriptional activity. Our work reveals the requirement of an optimal level of AR condensation in mediating enhancer assembly and suggests that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies.

Positive Youth Development in 2020: Theory, Research, Programs, and the Promotion of Social Justice.

We use Hamilton's (1999) tripartite conception of the positive youth development (PYD) literature - that is, PYD as a theoretical construct, PYD as a frame for program design, and PYD as an instance of specific youth development programs - as a framework for reviewing scholarship involved in the PYD field across the second decade of the 21st century. Advances were made in all three domains and, as well, new issues emerged; chief among them was a focus on the promotion of social justice. We discuss ways in which social justice issues are being addressed within each of these domains and we present a vision for enhancing the PYD-social justice relation in future scholarship involving theory, research, program design, and community-based PYD programs.

The "Haves, Have Some, and Have Nots:" a Latent Profile Analysis of Capacity, Quality, and Implementation in Community-Based Afterschool Programs.

Implementation of evidence-based practices is a critical factor in whether afterschool programs are successful in having a positive impact upon risk reduction and positive youth development. However, important prevention research reveals that contextual and organizational factors can affect implementation (Bradshaw & Pas in School Psychology Review, 40, 530-548, 2011) (Flaspohler et al., in American Journal of Community Psychology, 50(3-4), 271-281, 2012) (Gottfredson et al., Prevention Science, 3, 43-56, 2002) (McIntosh et al., Journal of Positive Behavior Interventions, 18(4), 209-218, 2016) (Payne in Prevention Science, 10, 151-167, 2009). Using a latent profile approach (LPA), this paper examines multiple organizational and neighborhood contextual factors that might affect the degree to which afterschool programs effectively implement evidence-based practices in the context of a cluster-randomized trial of the Paxis Good Behavior Game (PaxGBG). The Interactive Systems Framework (ISF) explores dimensions of capacity that might matter for prevention efforts. As expected, we found that well-resourced and high-quality programs performed well in terms of implementation (the Haves) and, in neighborhood contexts rich in racial-ethnic diversity. Yet, we found that some programs with less physical and material capacity (the Have Nots), demonstrated greater program quality (i.e., supportive adult and peer relationships, engagement, a sense of belonging) and implementation, relative to programs with better capacity (e.g., space, material resources, staffing, and leadership, the Have Somes). While capacity matters, intentional prevention initiatives that seek to promote evidence-based practices are helpful to sites in supporting organizations that might otherwise fail to provide quality programming for youth. This paper addresses a conundrum in prevention science, namely, how to make programming accessible to those who need it with a focus on organizational processes, program quality, and implementation of evidence-based practices.

Racism and preparation for bias within African American families.

Objectives: Exposure to racism experienced by caregivers poses a threat to child developmental outcomes. The current study examines the effects of caregiver-experienced racism on the development of internalizing behaviors for African American children during a sensitive period in their development of racial awareness. Two aspects of caregiver-provided ethnic racial socialization (ERS), cultural socialization and preparation for bias, were assessed as moderators. Supported by prior research, cultural socialization was hypothesized to be protective. Given that research on preparation for bias in early childhood is sparse or inconclusive, no directional hypothesis was formulated for the moderation effect of preparation for bias. Method: A community-recruited, low-income sample of 130 African American caregivers and their children (T3 Mage = 6.20, T4 Mage = 7.17) reported on past-year experiences with racism, ERS practices, and child internalizing behaviors. Path analyses were utilized to assess the influence of caregivers' racist experiences and ERS practices on children's first grade internalizing behaviors after controlling for kindergarten levels. Results: Cultural socialization was not a significant protective factor as hypothesized. However, caregivers' past-year experiences with racism predicted more anxious and sad behaviors in children when caregivers reported using more preparation for bias. Conclusions: The effects of caregivers' racism experiences on their 6-year-old children's internalizing behaviors were contingent on their use of preparation for bias socialization. This study adds to the literature on racism and further elucidates the role preparation for discrimination plays in developmental outcomes for young African American children. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Child Maltreatment and Resilience: The Promotive and Protective Role of Future Orientation.

Maltreatment is associated with risk for a wide range of socio-emotional and behavioral problems in adolescence. Despite this risk, many maltreated youth adjust well through the process of resilience. Extant research demonstrates that future orientation is linked to reduced risks for maladjustment in adolescence. Few studies, however, have tested the protective and promotive role of future orientation using positive and negative developmental outcomes among maltreated youth. The present study aimed to investigate the promotive and moderating role of future orientation among a longitudinal sample of maltreated and demographically comparable non-maltreated youth (N = 1354, 51.5% female, 53.2% African American). Data collected from Time 1 (Mage = 4.56, SDage = 0.70) to Time 8 (Mage = 18.514, SDage = 0.615) were used. Compared to the non-maltreated youth, maltreated youth showed increased delinquent behaviors and reduced self-esteem. In addition, future orientation significantly predicted higher levels of social competence and attenuated the adverse effects of maltreatment on youth delinquency and substance use. The findings highlight the role of future orientation in the development of resilience among maltreated youth, bearing significant contributions to prevention and intervention programs designed to protect youth against risks linked to child maltreatment and promote their positive development.

Severe Poverty and Growth in Behavioral Self-Regulation: The Mediating Role of Parenting.

This study examined how exposure to severe poverty related to behavioral self-regulation growth during early childhood as mediated by parenting practices. Ethnic differences were tested. Data were collected across 4 waves from 359 low-income African American and Latino families. The frequency of exposure to severe poverty was indicated by how many times family income fell below 50% of the federal poverty line across 4 waves. Behavioral self-regulation was assessed when children were 3½, 6, and 7 years old (Wave 2-4), and parenting was observed when children were age 2½ years old (Wave 1). More frequent exposure to severe poverty was associated with slower behavioral self-regulation growth, and the effect was partially mediated through less sensitive and supportive parenting practices for Latino families. The mediation was not observed for African American families. Targeting the promotion of sensitive and supportive parenting practices may be an effective strategy for accelerating self-regulation development.

Promoting Afterschool Quality and Positive Youth Development: Cluster Randomized Trial of the Pax Good Behavior Game.

This randomized trial tested a strategy originally developed for school settings, the Pax Good Behavior Game (PAX GBG), in the new context of afterschool programs. We examined this approach in afterschool since 70% of all juvenile crime occurs between the hours of 3-6 pm, making afterschool an important setting for prevention and promotion. Dual-career and working families need monitoring and supervision for their children in quality settings that are safe and appropriately structured. While substantial work has identified important features of afterschool programs, increasing attention is being given to how to foster quality. PAX GBG, with its focus on shared norms, cooperative teams, contingent activity rewards, and liberal praise, could potentially enhance not only appropriate structure and supportive relationships, but also youth self-regulation, co-regulation, and socio-emotional development. This study examined the PAX GBG among 76 afterschool programs, serving 811 youth ages 5-12, who were diverse in race-ethnicity, socio-economic status, and geographic locale. Demographically matched pairs of afterschool programs were randomized to PAX GBG or treatment-as-usual. Independent observers conducted ratings of implementation fidelity and program quality across time; along with surveys of children's problem and prosocial behavior. Interaction effects were found using hierarchical linear models such that experimental programs evidencing higher implementation fidelity demonstrated better program quality than controls, (i.e., less harshness, increased appropriate structure, support, and engagement), as well as reduced child-reported hyperactivity and intent-to-treat effects on prosocial behavior. This study demonstrates that best practices fostered by PAX GBG and implemented with fidelity in afterschool result in higher quality contexts for positive youth development.

Ethical Challenges in Promoting the Implementation of Preventive Interventions: Report of the SPR Task Force.

Prevention science researchers and practitioners are increasingly engaged in a wide range of activities and roles to promote evidence-based prevention practices in the community. Ethical concerns invariably arise in these activities and roles that may not be explicitly addressed by university or professional guidelines for ethical conduct. In 2015, the Society for Prevention Research (SPR) Board of Directors commissioned Irwin Sandler and Tom Dishion to organize a series of roundtables and establish a task force to identify salient ethical issues encountered by prevention scientists and community-based practitioners as they collaborate to implement evidence-based prevention practices. This article documents the process and findings of the SPR Ethics Task Force and aims to inform continued efforts to articulate ethical practice. Specifically, the SPR membership and task force identified prevention activities that commonly stemmed from implementation and scale-up efforts. This article presents examples that illustrate typical ethical dilemmas. We present principles and concepts that can be used to frame the discussion of ethical concerns that may be encountered in implementation and scale-up efforts. We summarize value statements that stemmed from our discussion. We also conclude that the field of prevention science in general would benefit from standards and guidelines to promote ethical behavior and social justice in the process of implementing evidence-based prevention practices in community settings. It is our hope that this article serves as an educational resource for students, investigators, and Human Subjects Review Board members regarding some of the complexity of issues of fairness, equality, diversity, and personal rights for implementation of preventive interventions.

Design, synthesis and biological evaluation of renin inhibitors guided by simulated annealing of chemical potential simulations.

We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC50s<100nM) with good oral bioavailability (F>20-58%).

Positive Youth Development Among Diverse Racial-Ethnic Children: Quality Afterschool Contexts as Developmental Assets.

Positive youth development (PYD) deserves more empirical attention, particularly among children of diverse racial-ethnic backgrounds. Given the need among families for monitoring and supervision during out-of-school time, community-based afterschool is a potentially promotive ecological setting. This study explores the quality of afterschool experiences upon PYD. This multimethod study includes over 500 elementary school children in Grades 2-5 (Mage  = 8.80, SD = 1.12). The sample comprises of 49% White, 27% African American, 7% Latino, and 17% mixed race/others with 45% free/reduced lunch eligible children. In multilevel models, independently observed quality across time positively impacted competence, connection, caring for all youth, and cultural values for racial-ethnic minority youth. Afterschool fosters PYD, including sociocultural dimensions, when comprised of appropriately structured, supportive, and engaging interactions.

Introduction to the Special Section of Child Development on Positive Youth Development in Diverse and Global Contexts.

Positive youth development (PYD) research seeks to understand and promote positive aspects of development in young people. In this the special section, focused upon youth from diverse racial-ethnic backgrounds around the globe, we describe the origins and development of the field, identify key and emerging themes, and present the challenges for work in the area in the years ahead. Central to these are elements that are inherent in many of the articles that constitute the section: These include a need to articulate more clearly the role of social and cultural context in positive development, a need to refine the measures and methods used for collecting data, the significance of social identities, and engagement with other fields of study and with policymakers.

Racial-ethnic Identity in Context: Examining Mediation of Neighborhood Factors on Children's Academic Adjustment.

Research consistently shows that neighborhood socio-demographic characteristics and residents' neighborhood perceptions matter for youth well-being, including a positive sense of racial-ethnic identity. Although elementary-school children are likely in the earlier phases of identity formation, the authors examined whether objective and subjective neighborhood characteristics are related to their racial-ethnic identity and, in turn, their academic adjustment. A diverse sample (30.4% African American, 35.2% White, 12.3% Latino, & 22.0% Other) of 227 children in Grades 2 through 5 were surveyed in afterschool programs. Bivariate correlations showed that youth living in disadvantaged neighborhoods reported more barriers due to their race-ethnicity, but these barriers were not related to their sense of academic efficacy. Residing in a disadvantaged neighborhood was unrelated to youth's academic self-efficacy. However, path analyses showed that positive neighborhood perceptions were associated with a stronger sense of race-ethnicity (i.e., affirmation and belonging), which was in turn related to greater academic efficacy. These results suggest that neighborhood connection provides a source of affirmation and value for young children, helping them to understand who they are as part of a racial-ethnic group and helping to foster a sense of future achievement opportunities. This study provides additional evidence that along with other important proximal contexts (e.g., family, school), young children's neighborhood context is important for development. Results are discussed to highlight environmental influences on young children's awareness of race-ethnicity and the implications of the combined impact of neighborhood and racial-ethnic identity on psychosocial adjustment.

Measuring afterschool program quality using setting-level observational approaches.

As the importance of afterschool hours for youth development is widely acknowledged, afterschool settings have recently received increasing attention as an important venue for youth interventions. A range of intervention programs have been in place, generally aiming at positive youth development through enhancing the quality of programs. A growing need has thus arisen for reliable and valid measures of afterschool quality. This study examined the extent to which the two observational tools, i.e., Caregiver Interaction Scales (CIS) and Promising Practices Rating Scales (PPRS), could serve as reliable and valid tools for assessing the various dimensions of afterschool setting quality. The study shows the potential promise of the instruments, on the one hand, and suggests future directions for improvement of measurement design and development of the field, on the other hand. In particular, our findings suggest the importance of addressing the effect of day-to-day fluctuations in observed afterschool quality.

Measurements of the pons as a biomarker of progression for pediatric DIPG.

Treatment of pediatric diffuse intrinsic pontine glioma (DIPG) remains challenging, and reliable biomarkers of response are lacking. Radiographic response is a primary endpoint in many investigational studies of brain tumors, but there is no standard method of tumor measurement for DIPG, significant inter-observer variability exists given the invasive nature of these tumors, and tumor measurements are not predictive of outcome. Because DIPGs involve a significant portion of the pons, we evaluated the reliability and prognostic value of one-dimensional (1D) and two-dimensional (2D) pons measurements using anatomical landmarks rather than tumor boundaries. Patients with DIPG (n = 75) were evaluated longitudinally at our institution using MRI. Four readers independently performed 1D and 2D measurements of the pons using FLAIR images. Agreement and inter-reader variability were evaluated using differences among the six reader pairs and the coefficient of variation (CV). Prognostic value of pons measurements was calculated using Cox proportional hazards models, where relative hazard (RH) represents risk of death. Readers evaluated 384 exams. Agreement of readers' 1D and 2D measurements was strong (median difference between reader pairs 3.1 and 5.4%, respectively), with low inter-reader variability (median CV = 3.1% and median CV = 4.8%, respectively). Increases in 1D and 2D pons measurements over time indicated poorer prognosis (RH = 2.29, p = 0.0025 and RH = 1.13, p = 0.0016, respectively), with shorter overall survival. Pons measurements had low inter-reader variability compared to previously reported tumor measurement techniques and correlated with outcome in children with DIPG. Measurements of the pons (as opposed to direct measurements of tumor) are a viable in vivo biomarker for DIPG.

Top-down, bottom-up, and around the jungle gym: a social exchange and networks approach to engaging afterschool programs in implementing evidence-based practices.

This paper uses concepts from social networks and social exchange theories to describe the implementation of evidence-based practices in afterschool programs. The members of the LEGACY Together Afterschool Project team have been involved in conducting collaborative research to migrate a behavioral strategy that has been documented to reduce disruptive behaviors in classroom settings to a new setting-that of afterschool programs. We adapted the Paxis Institute's version of the Good Behavior Game to afterschool settings which differ from in-school settings, including more fluid attendance, multiple age groupings, diverse activities that may take place simultaneously, and differences in staff training and experience (Barrish et al. in J Appl Behav Anal 2(2):119-124, 1969; Embry et al. in The Pax Good Behavior Game. Hazelden, Center City, 2003; Hynes et al. in J Child Serv 4(3):4-20, 2009; Kellam et al. in Drug Alcohol Depend 95:S5-S28, 2008; Tingstrom et al. in Behav Modif 30(2):225-253, 2006). This paper presents the experiences of the three adult groups involved in the implementation process who give first-person accounts of implementation: (1) university-based scientist-practitioners, (2) community partners who trained and provided technical assistance/coaching, and (3) an afterschool program administrator. We introduce here the AIMS model used to frame the implementation process conceptualized by this town-gown collaborative team. AIMS builds upon previous work in implementation science using four phases in which the three collaborators have overlapping roles: approach/engagement, implementation, monitoring, and sustainability. Within all four phases principles of Social Exchange Theory and Social Network Theory are highlighted.

Measuring collective efficacy among children in community-based afterschool programs: exploring pathways toward prevention and positive youth development.

Collective efficacy refers to a perceived sense of connectedness and willingness to intervene among youth, and is a potential aspect of positive youth development (Larson in Am Psychol 55:170-183, 2000; Lerner et al. in Child Dev 71:11-20, 2000; Sampson et al. in Science 277:918-924, 1997). Theoretically, those who feel connected to a group that is empowered to positively influence the behavior of their peers may demonstrate fewer problem behaviors. Few studies, however, have measured the impact of youth perceptions of collective efficacy. As a relatively new child-related research topic, there is much to be learned. One contribution to the foundation of this research agenda begins by evaluating the reliability and validity of a measure of collective efficacy with elementary children attending community-based afterschool programs. This paper describes the internal consistency reliability and various indicators of construct and concurrent validity of the Collective Efficacy Among Children Scale. The measure was found to have high internal consistency reliability. Construct validity was tested using exploratory factor analyses of collective efficacy including the dimensions of willingness to intervene and cohesion found in previous research (Sampson et al. in Science 277:918-924, 1997). Concurrent validity assessed relations between the scale and other measures in theoretically congruent ways. Using Hierarchical Linear Models to account for children's nestedness in after-school programs, connectedness was found to be more related to emotional adjustment, particularly children's prosocial attitudes (caring about others and sharing). Children's perception of the willingness of the group to intervene was found to be related to less problem behavior, (i.e. smoking tobacco, drinking alcohol, vandalism, and stealing). The implications suggest that future research should further explore children's collective efficacy, and ways to foster its development in youth-serving afterschool settings.

Molecular imaging of pediatric brain tumors: comparison of tumor metabolism using ¹8F-FDG-PET and MRSI.

Magnetic resonance spectroscopic imaging (MRSI) and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) are non-invasive imaging techniques routinely used to evaluate tumor malignancy in adults with brain tumors. We compared the metabolic activity of pediatric brain tumors using FDG-PET and MRSI. Children (n = 37) diagnosed with a primary brain tumor underwent FDG-PET and MRSI within two weeks of each other. Tumor metabolism was classified as inactive, active or highly active using the maximum choline:N-acetyl-asparate (Cho:NAA) on MRSI and the highest tumor uptake on FDG-PET. A voxel-wise comparison was used to evaluate the area with the greatest abnormal metabolism. Agreement between methods was assessed using the percent agreement and the kappa statistic (κ). Pediatric brain tumors were metabolically heterogeneous on FDG-PET and MRSI studies. Active tumor metabolism was observed more frequently using MRSI compared to FDG-PET, and agreement in tumor classification was weak (κ = 0.16, p = 0.12), with 42 % agreement (95 % CI = 25-61 %). Voxel-wise comparison for identifying the area of greatest metabolic activity showed overlap in the majority (62 %) of studies, though exact agreement between techniques was low (29.4 %, 95 % CI = 15.1-47.5 %). These results indicate that FDG-PET and MRSI detect similar but not always identical regions of tumor activity, and there is little agreement in the degree of tumor metabolic activity between the two techniques.

Discovery of novel aminoquinazolin-7-yl 6,7-dihydro-indol-4-ones as potent, selective inhibitors of heat shock protein 90.

A novel class of Hsp90 inhibitors, structurally distinct from previously reported scaffolds, was developed from rational design and optimization of a compound library screen hit. These aminoquinazoline derivatives, represented by compound 15 (SNX-6833) or 1-(2-amino-4-methylquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one, selectively bind to Hsp90 and inhibit its cellular activities at concentrations as low as single digit nanomolar.

Advances in bridging research and practice: introduction to the second special issue on the interactive system framework for dissemination and implementation.

The need for new ways to bridge the gap between research and practice is clear; the use of evidence-based prevention programs and implementation with fidelity in practice are strikingly limited. The Interactive Systems Framework for Dissemination and Implementation (ISF) was created to help bridge research and practice by specifying the systems and processes required to support dissemination and implementation of evidence-based programs, processes, practices, and policies. The ISF identifies three key systems necessary for this process which include the Synthesis and Translation System, the Support System, and the Delivery System. The ISF was featured in a special issue of the American Journal of Community Psychology in 2008. This special issue extends that work by including both researchers who have applied an ISF lens to aspects of their current work and researchers who have proactively applied the ISF in a process that goes across the various systems of the ISF, i.e., Synthesis and Translation, Support, and Delivery. Content areas include: children's mental health, teen pregnancy prevention, HIV prevention, violence prevention, heart disease and stroke prevention, breast cancer prevention, and substance abuse prevention. In this introductory article, we provide a brief description of the history of the ISF and a summary of the articles in the special issue.

Using the interactive systems framework in understanding the relation between general program capacity and implementation in afterschool settings.

The present study uses the Interactive Systems Framework (ISF) to understand how general capacity influences the implementation of prevention programs in afterschool settings. Eight afterschool sites received the Good Behavior Game (GBG) intervention, a program designed to foster supportive behavioral management and positive youth behavior. In line with the Prevention Support System component of ISF, the intervention afterschool staff were trained and received weekly on-site support from coaches in implementing the GBG. It was found that GBG implementation scores were greatest in afterschool programs that rated high on both organizational- and community-levels of general capacity; high scores on only one level of general capacity resulted in lower implementation scores. Thus, afterschool sites that were more organized, maintained adequate facilities, and developed strong linkages to individuals or organizations in the community scored highest in implementation fidelity and quality. This study highlights the importance of considering interactions among multiple levels of general capacity in efforts to promote evidence-based practices in afterschool settings. Caution should be taken in generalizing findings due to the small sample in this study.