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Research reveals a linear association between prevention program dose and outcomes; that is, families receive the most benefits when they attend a sufficient number of program sessions. Ensuring participants receive an effective dose of prevention is a persistent challenge for the widespread implementation of family-centered prevention programs. We investigated factors associated with an effective dose of the Strong African American Families (SAAF) substance use prevention program. Dose-related factors included socioeconomic disadvantage, caregiver depression, family disorganization, youth risk for problem behavior, and community risk. Notably, SAAF includes an ecologically appropriate curriculum and a comprehensive set of engagement procedures, which decrease the influence of these factors on attendance. The sample consisted of 252 African American youth and their caregivers from eight rural counties in South Georgia who had been randomly assigned to receive the SAAF substance use prevention program, a seven-session family skills training program. We operationalized an effective dose of SAAF, per recent research, as attendance in at least 5 of 7 sessions. Logistic structural equation modeling revealed no evidence of the tested factors reducing dose. Family disorganization, however, was associated positively with an effective dose, controlling for all other factors. Families with more disorganization were more likely to receive an effective dose of the program. Findings suggest that ecologically sensitive engagement protocols and curricula may obviate the influence of common risk factors and foster participation among those who most perceive a need for the program.

Food insecurity affects over 11 million youth in the United States and is a complex and understudied form of adversity in adolescence. Food insecurity, particularly during the sensitive period of adolescence, is a considerable psychosocial stressor that may affect neural functioning and behavior. Adolescents exposed to food insecurity may be at a higher risk for impulsive behavior. The associations between food insecurity, neural functioning, and impulsivity have yet to be examined. In addition, the family environment is a core context that may moderate stress-related vulnerabilities. In the present study, I investigated the effects of food insecurity on impulsivity via resting state functional connectivity (rsFC) between the anterior insula (AI) and the middle frontal gyrus (MFG) and evaluated the protective role of family balanced flexibility in the link between food insecurity and neurobiological vulnerabilities in a sample of adolescents. The present study used two waves of data from a study of 142 adolescents. I found that low levels of balanced family flexibility may exacerbate the effect of food insecurity on heightened connectivity between the AI and the MFG. In contrast, high levels of balanced family flexibility partially buffered this link. Increased rsFC between AI and MFG left and left hemispheric nodes predicted an increase in impulsivity. Conditional indirect effects were also found.

Employing a developmental psychopathology framework, we tested the utility of the hormesis model in examining the strengthening of children and youth through limited levels of adversity in relation to internalizing and externalizing outcomes within a brain-by-development context. Analyzing data from the Adolescent Brain and Cognitive Development study ( = 11,878), we formed latent factors of threat, deprivation, and unpredictability. We examined linear and nonlinear associations between adversity dimensions and youth psychopathology symptoms and how change of resting-state functional connectivity (rsFC) in the default mode network (DMN) from Time 1 to Time 5 moderates these associations. A cubic association was found between threat and youth internalizing problems; low-to-moderate family conflict levels reduced these problems. Deprivation also displayed a cubic relation with youth externalizing problems, with moderate deprivation levels associated with fewer problems. Unpredictability linearly increased both problem types. Change in DMN rsFC significantly moderated the cubic link between threat levels and internalizing problems, with declining DMN rsFC levels from Time 1 to Time 5 facilitating hormesis. Hormetic effects peaked earlier, emphasizing the importance of sensitive periods and developmental timing of outcomes related to earlier experiences. Strengthening through limited environmental adversity is crucial for developing human resilience. Understanding this process requires considering both linear and nonlinear adversity-psychopathology associations. Testing individual differences by brain and developmental context will inform preventive intervention programming.

The current study investigates predictors of a full dose of prevention in a trial of the Strong African American Families (SAAF) substance use prevention program. Predictors included socioeconomic disadvantage, caregiver depression, family disorganization, youth vulnerability for problem behavior, and community disadvantage. SAAF includes an ecologically appropriate curriculum and a comprehensive set of engagement procedures. A full dose was operationalized as attendance of at least 5 of 7 sessions. Logistic structural equation modeling (SEM) revealed no evidence of the tested factors predicting an incomplete dose. However, family disorganization was associated positively with dose, controlling for all other factors. Moreover, the interaction of youth vulnerability for problem behavior and community disorder positively predicted dose. Findings may suggest that ecologically sensitive engagement protocols and curricula may obviate the influence of certain barriers to participation. This conclusion requires replication and confirmation with experimental manipulation of engagement protocols.

Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observe that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we find that reductions in glucose-stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARα, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARα agonist, induces expression of mitochondrial targets, improves insulin secretion, and increases the formation of SC-β cells both in vitro and following transplantation. Thus, PPARα-dependent mitochondrial programming promotes the differentiation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D. Here they show that PPARα-dependent mitochondrial programming promotes the differentiation of pluripotent stem cell-derived β cells. Targeting mitochondria has the potential to improve β cell replacement efforts for the treatment of type 1 diabetes.

Activation of innate immune signaling occurs during the progression of immunometabolic diseases, including type 2 diabetes (T2D), yet the impact of innate immune signaling on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for glucose homeostasis and pancreatic β-cell function under basal conditions, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and increases in mitophagy following metabolic stress in both mouse and human islets. Indeed, TRAF6 was critical for the recruitment and function of machinery within both the ubiquitin-mediated (Parkin-dependent) and receptor-mediated (Parkin-independent) mitophagy pathways upon metabolic stress. Intriguingly, the effect of TRAF6 deficiency on glucose homeostasis and mitophagy was fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role for TRAF6 in the cross-regulation of both ubiquitin-and receptor-mediated mitophagy through the restriction of Parkin. Together, we illustrate that β-cells engage innate immune signaling to adaptively respond to a diabetogenic environment.

Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose-stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPAR⍺, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPAR⍺ agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation of SC-β cells both and following transplantation. Thus, PPAR⍺-dependent mitochondrial programming promotes the differentiation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.

Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation and maturation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose- stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARIZ and PPARγ, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARIZ agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation and maturation of SC-β cells both in vitro and following transplantation. Thus, mitochondrial programming promotes the differentiation and maturation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation and maturation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observed that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we found that reductions in glucose- stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARIZ and PPARγ, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARIZ agonist, induced expression of mitochondrial targets, improved insulin secretion, and increased the formation and maturation of SC-β cells both in vitro and following transplantation. Thus, mitochondrial programming promotes the differentiation and maturation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.

Mitochondrial damage is a hallmark of metabolic diseases, including diabetes and metabolic dysfunction-associated steatotic liver disease, yet the consequences of impaired mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity across multiple metabolic tissues. Surprisingly, we demonstrate that defects in the mitochondrial quality control machinery, which we observe in pancreatic β cells of humans with type 2 diabetes, cause reductions of β cell mass due to dedifferentiation, rather than apoptosis. Utilizing transcriptomic profiling, lineage tracing, and assessments of chromatin accessibility, we find that targeted deficiency anywhere in the mitochondrial quality control pathway (e.g., genome integrity, dynamics, or turnover) activate the mitochondrial integrated stress response and promote cellular immaturity in β cells, hepatocytes, and brown adipocytes. Intriguingly, pharmacologic blockade of mitochondrial retrograde signaling in vivo restores β cell mass and identity to ameliorate hyperglycemia following mitochondrial damage. Thus, we observe that a shared mitochondrial retrograde response controls cellular identity across metabolic tissues and may be a promising target to treat or prevent metabolic disorders.