Positive Selection Drives cis-regulatory Evolution Across the Threespine Stickleback Y Chromosome.

Allele-specific gene expression evolves rapidly on heteromorphic sex chromosomes. Over time, the accumulation of mutations on the Y chromosome leads to widespread loss of gametolog expression, relative to the X chromosome. It remains unclear if expression evolution on degrading Y chromosomes is primarily driven by mutations that accumulate through processes of selective interference, or if positive selection can also favor the down-regulation of coding regions on the Y chromosome that contain deleterious mutations. Identifying the relative rates of cis-regulatory sequence evolution across Y chromosomes has been challenging due to the limited number of reference assemblies. The threespine stickleback (Gasterosteus aculeatus) Y chromosome is an excellent model to identify how regulatory mutations accumulate on Y chromosomes due to its intermediate state of divergence from the X chromosome. A large number of Y-linked gametologs still exist across 3 differently aged evolutionary strata to test these hypotheses. We found that putative enhancer regions on the Y chromosome exhibited elevated substitution rates and decreased polymorphism when compared to nonfunctional sites, like intergenic regions and synonymous sites. This suggests that many cis-regulatory regions are under positive selection on the Y chromosome. This divergence was correlated with X-biased gametolog expression, indicating the loss of expression from the Y chromosome may be favored by selection. Our findings provide evidence that Y-linked cis-regulatory regions exhibit signs of positive selection quickly after the suppression of recombination and allow comparisons with recent theoretical models that suggest the rapid divergence of regulatory regions may be favored to mask deleterious mutations on the Y chromosome.

The evolution of gene regulation on sex chromosomes.

Sex chromosomes have evolved repeatedly across the tree of life. Most work has focused on the loss of coding regions from sex-limited chromosomes through the accumulation of deleterious mutations. By comparison, less is known about how the regulatory landscape evolves. We review theories of how regulatory landscapes evolve on sex chromosomes and the overall impact they have on gametolog expression. We integrate empirical studies on sex chromosomes with theoretical work to synthesize how regulatory evolution could occur on sex chromosomes. Recent findings have revealed that downregulation of ancestral alleles is probably widespread on Y chromosomes and that regulatory evolution plays a key role in the evolution of sex chromosomes.

The Detection of Environmental Influences on Academic Achievement Appears to Depend on the Analytic Approach.

One long-standing analytic approach in adoption studies is to examine correlations between features of adoptive homes and outcomes of adopted children (hereafter termed 'measured environment correlations') to illuminate environmental influences on those associations. Although results from such studies have almost uniformly suggested modest environmental influences on adopted children's academic achievement, other work has indicated that adopted children's achievement is routinely higher than that of their reared-apart family members, often substantially so. We sought to understand this discrepancy. We examined academic achievement and literacy-promotive features of the home in 424 yoked adoptive/biological families participating in the Early Growth and Development Study (EGDS; i.e., adopted children, adoptive mothers, birth mothers, and biological siblings of the adopted children remaining in the birth homes) using an exhaustive modeling approach. Results indicated that, as anticipated, adopted children scored up to a full standard deviation higher on standardized achievement tests relative to their birth mothers and reared-apart biological siblings. Moreover, these achievement differences were associated with differences in the literacy-promotive features of the adoptive and birth family homes, despite minimal measured environment correlations within adoptive families. A subsequent simulation study highlighted noise in measured environmental variables as an explanation for the decreased utility of measured environment correlations. We conclude that the field's heavy focus on measured environment correlations within adoptive families may have obscured detection of specific environmental effects on youth outcomes, and that future adoption studies should supplement their measured environment analyses with mean differences between reared-apart relatives.

Commentary on 'Grandparental care and child mental health: a systematic review and meta-analysis'.

The manuscript by Wang et al. contributes mightily to our limited understanding of grandparental care and children's mental health problems. As the authors document, despite the growing number of families worldwide where grandparents serve as the sole primary caregivers or reside with the children's parents to share caregiving responsibilities, and the growing number of studies examining associations between grandparental care and children's mental health-related outcomes, systematic reviews and meta-analyses integrating this literature are missing. There are meta-analyses on relations between grandparental care and such child outcomes as physical health, nutrition and obesity, education, and even resilience, but the extant literature on child outcomes has been limited to more qualitatively oriented reviews and has typically focused on child internalizing and externalizing problems. Thus, the current meta-analysis adds a novel and critically missing quantitative component to our broad understanding of the associations between grandparental care and children's problem behavior. In addition, beyond studies examining children's internalizing and externalizing outcomes, the authors also report on several studies (n = 7) that examine children's positive well-being and overall mental health. Overall, among the 38 studies deemed acceptable for review, the meta-analysis included findings from nearly 345,000 children, with a mean age of 10 years and slightly more female (51%) than male children.

An exploration of the domain specificity of maternal sensitivity among a diverse sample in the infancy period: Unique paths to child outcomes.

Maternal sensitivity during an observed mother-child clean-up task at 18 months and maternal sensitivity during an observed mother-child free-play task at 18 months were tested as independent predictors of child internalizing symptoms, externalizing symptoms, social competence, and language development at 24 months. Participants (n = 292 mothers) were recruited between 2015 and 2017, and were low-income (mean annual income = $19,136) and racially and ethnically diverse (43.8% Black; 44.2% Latinx). Maternal sensitivity during clean-up was a significant predictor of all social-emotional outcomes, and a unique predictor of child internalizing symptoms. Maternal sensitivity during free-play was a unique predictor of child language. Results suggest that context-specific subtypes of maternal sensitivity may differentially relate to early child outcomes.

Enhancing early language and literacy skills for racial/ethnic minority children with low incomes through a randomized clinical trial: The mediating role of cognitively stimulating parent-child interactions.

Parenting is a critical mediator of children's school readiness. In line with this theory of change, data from the randomized clinical trial of Smart Beginnings (tiered Video Interaction Project and Family Check-Up; N = 403, treatment arm n = 201) were used to examine treatment impacts on early language and literacy skills at child age 4 years (nLatinx = 168, nBlack = 198, nMale = 203), as well as indirect impacts through parental support of cognitive stimulation at child age 2 years. Although results did not reveal direct effects on children's early skills, there were significant indirect effects for early literacy (ß = .03, p = .05) and early language (ß = .04, p = .04) via improvements in parental cognitive stimulation. Implications for interventions targeting parenting to improve children's school readiness beginning at birth are discussed.

Disentangling genetic and environmental influences on early language development: The interplay of genetic propensity for negative emotionality and surgency, and parenting behavior effects on early language skills in an adoption study.

Parenting and children's temperament are important influences on language development. However, temperament may reflect prior parenting, and parenting effects may reflect genes common to parents and children. In 561 U.S. adoptees (57% male) and their birth and rearing parents (70% and 92% White, 13% and 4% African American, and 7% and 2% Latinx, respectively), this study demonstrated how genetic propensity for temperament affects language development, and how this relates to parenting. Genetic propensity for negative emotionality inversely predicted language at 27 months (ß = -.15) and evoked greater maternal warmth (ß = .12), whereas propensity for surgency positively predicted language at 4.5 years (ß = .20), especially when warmth was low. Parental warmth (ß = .15) and sensitivity (ß = .19) further contributed to language development, controlling for common gene effects.

Integrating equifinality and multifinality into the of prevention programs in early childhood: The conceptual case for use of tiered models.

Introduced in the context of developmental psychopathology by Cicchetti and Rogosh in the Journal, the current paper incorporates the principles of equifinality and multifinality to support the use of tiered models to prevent the development of emerging child psychopathology and promote school readiness in early childhood. We use the principles of equifinality and multifinality to describe the limitations of applying one intervention model to address all children presenting with different types of risk for early problem behavior. We then describe the potential benefits of applying a tiered model for having impacts at the population level and two initial applications of this approach during early childhood. The first of these tiered models, Smart Beginnings, integrates the use of two evidenced-based preventive interventions, Video Interaction Project, a universal parenting program, and Family Check-Up, a selective parenting program. Building on the strengths of Smart Beginnings, the second trial, The Pittsburgh Study includes Video Interaction Project and Family Check-Up, and other more and less-intensive programs to address the spectrum of challenges facing parents of young children. Findings from these two projects are discussed with their implications for developing tiered models to support children's early development and mental health.

The pernicious role of stress on intergenerational continuity of psychopathology.

Development and Psychopathology has been a premier resource for understanding stressful childhood experiences and the intergenerational continuity of psychopathology. Building on that tradition, we examined the unique and joint influences of maternal stress on children's effortful control (age 7) and externalizing behavior (age 11) as transmitted via genetics, the prenatal environment, and the postnatal environment. The sample included N = 561 adopted children and their biological and adoptive parents. Path models identified a direct effect of biological mother life stress on children's effortful control (ß = -.08) and an indirect effect of her life stress on child externalizing behavior via effortful control (ß = .52), but no main or indirect effects of biological parent psychopathology, prenatal stress, or adoptive mother adverse childhood experiences (ACES). Adoptive mother ACES amplified the association between biological mother life stress and child effortful control (ß = -.08), externalizing behavior (ß = 1.41), and the indirect effect via effortful control, strengthening associations when adoptive mothers reported average or high ACES during their own childhoods. Results suggest that novel study designs are needed to enhance the understanding of how life stress gets "under the skin" to affect psychopathology in the offspring of adults who have experienced stress.

Unique influences of pregnancy and anticipated parenting on cigarette smoking: results and implications of a within-person, between-pregnancy study.

Not all pregnant individuals want to become parents and "parenting intention" can also vary within individuals during different pregnancies. Nevertheless, the potential impact of parenting intention on health-related behavior during pregnancy has been heavily underexplored. In this study, we employed a within-person between pregnancy design to estimate the effect of parenting-specific influences on smoking, separate from pregnancy-specific and individual-level influences. We quantified within-mother differences in smoking during pregnancies of infants they reared (n = 84) versus pregnancies of infants they placed for adoption at birth (n = 65) using multivariate mixed-effects Poisson regression models. Mean cigarettes/day declined as the pregnancy progressed regardless of whether infants were reared or placed. However, participants smoked fewer cigarettes/day during reared pregnancies. Relative to "adopted" pregnancies, smoking during "reared" pregnancies was lower by 24%, 41%, and 54% in first (95% CI 0.64-0.90; p = 0.001), second (95% CI 0.48-0.72; p < 0.001), and third trimesters (95% CI 0.36-0.59; p < 0.001), respectively, independent of between-pregnancy differences in maternal age, fetal sex, parity, and pregnancy complications. Female sex and nulliparity were protective. Parenting intention was associated with a protective effect on pregnancy smoking independent of pregnancy-specific influences and individual characteristics. Failure to consider the impact of parenting intention on health-related behavior during pregnancy could perpetuate an unrealistic expectation to "do what's best for the baby" and stigmatize women with unintended or unwanted pregnancies.

Adolescent Developmental Pathways Among Depression, Conduct Problems, and Rejection: Integrative Data Analysis Across Three Samples.

OBJECTIVE: The current study investigated sex differences in longitudinal associations among youth depression, conduct problems, and peer rejection from ages 11 to 16. We hypothesized that girls would follow the irritable depression model, which posits that depression leads to conduct problems, and that peer rejection would mediate this relationship. We hypothesized that boys would follow the cumulative failure model, which suggests that conduct problems predict future depression, mediated by peer rejection. METHOD: We used integrative data analysis to combine three datasets, creating an aggregate sample of 2,322 adolescents, 58.4% of an ethnic minority group, and 51.3% boys. Using random-intercept cross-lagged panel modeling with data from ages 11-16, we conducted a nested model comparison. RESULTS: Results indicated that a model which allowed paths to differ by sex demonstrated better model fit than a constrained model. While depression, conduct problems, and peer rejection were relatively stable over time and had correlated random intercepts, there were few crossover paths between these domains for either sex. When the strengths of individual crossover pathways were compared based on sex, only the path from conduct problems at age 13 to depression at age 14 was significantly different, with this path being stronger for girls. CONCLUSIONS: These results suggest that stable, between-person effects largely drive relationships between depression, conduct problems, and peer rejection during adolescence, whereas there are few transactional, within-person pathways between these domains. This pattern of findings demonstrates the utility of random intercept cross-lagged panel modeling for disentangling between- and within-person effects.

Cascading Influences of Caregiver Experiences of Discrimination and Adolescent Antisocial Behavior.

OBJECTIVE: Although a growing body of work has found that parents' experiences of racial and socioeconomic (SES) based discrimination are directly related to their children's behavior problems , more work is needed to understand possible pathways by which these factors are related and to identify potential targets for prevention and/or intervention. METHOD: Using a large (N = 572), longitudinal sample of low-income families from diverse racial backgrounds, the current study explored whether caregivers' experiences of racial and SES discrimination during their children's middle childhood (i.e. ages 7.5-9.5) predicted youth-reported antisocial behavior during adolescence and potential factors mediating these associations (e.g. caregiver depressive symptoms and positive parenting practices). RESULTS: We found that higher levels of caregiver experiences of discrimination at child ages 7.5-9.5 predicted higher levels of caregiver depressive symptoms at child age 10.5, which were related to lower levels of caregiver endorsement of positive parenting practices at child age 14.5, which in turn, predicted higher levels of youth-reported antisocial behavior at age 16. CONCLUSION: The findings highlight the adverse effects of racism and discrimination in American society. Second, the findings underscore the need to develop interventions which mitigate racism and discrimination among perpetrators and alleviate depressive symptoms among caregivers.

Comparison of trueness and repeatability of facial prosthesis design using a 3D morphable model approach, traditional computer-aided design methods, and conventional manual sculpting techniques.

STATEMENT OF PROBLEM: Manually sculpting a wax pattern of a facial prosthesis is a time-, skill-, and resource-intensive process. Computer-aided design (CAD) methods have been proposed as a substitute for manual sculpting, but these techniques can still require high technical or artistic abilities. Three-dimensional morphable models (3DMMs) could semi-automate facial prosthesis CAD. Systematic comparisons of different design approaches are needed. PURPOSE: The purpose of this study was to compare the trueness and repeatability of replacing facial features with 3 methods of facial prosthesis design involving 3DMM, traditional CAD, and conventional manual sculpting techniques. MATERIAL AND METHODS: Fifteen participants without facial defects were scanned with a structured light scanner. The facial meshes were manipulated to generate artificial orbital, nasal, or combined defects. Three methods of facial prosthesis design were compared for the 15 participants and repeated to produce 5 of each design for 2 participants. For the 3DMM approach, the Leeds face model informed the designs in a statistically meaningful way. For the traditional CAD methods, designs were created by using mirroring techniques or from a nose model database. For the conventional manual sculpting techniques, wax patterns were manually created on 3D printed full face baseplates. For analysis, the unedited facial feature was the standard. The unsigned distance was calculated from each of the several thousand vertices on the unedited facial feature to the closest point on the external surface of the prosthesis prototype. The mean absolute error was calculated, and a Friedman test was performed (α=.05). RESULTS: The median mean absolute error was 1.13 mm for the 3DMM group, 1.54 mm for the traditional CAD group, and 1.49 mm for the manual sculpting group, with no statistically significant differences among groups (P=.549). Boxplots showed substantial differences in the distribution of mean absolute error among groups, with the 3DMM group showing the greatest consistency. The 3DMM approach produced repeat designs with the lowest coefficient of variation. CONCLUSIONS: The 3DMM approach shows potential as a semi-automated method of CAD. Further clinical research is planned to explore the 3DMM approach in a feasibility trial.

Promoting Cognitive Stimulation in Parents Across Infancy and Toddlerhood: A Randomized Clinical Trial.

OBJECTIVE: To test the impact of the fully integrated Smart Beginnings model on parental support of cognitive stimulation from 6 to 24 months across infancy and toddlerhood. STUDY DESIGN: This was a single-blind, 2-site randomized clinical trial of the Smart Beginnings intervention. Enrollment took place at birth in postpartum units of hospitals in New York City and Pittsburgh, Pennsylvania, with a consecutive sample of 403 mother-infant dyads. Smart Beginnings combines a Video Interaction Project-14-session universal primary prevention program delivered in the pediatric clinic at the time of well-child visits birth-36 months-with potential for Family Check-Up-3-4 sessions targeted secondary prevention home-visiting program. The principal outcome was parental support of cognitive stimulation assessed via parent survey and video-recorded observations of parent-child interactions. Ordinary least squares and mixed effects regressions were conducted. RESULTS: Families were mostly Black/African-American (50%) or Latinx (42%); all were Medicaid eligible (100%). Smart Beginnings significantly promoted cognitive stimulation during infancy and toddlerhood for most survey outcomes across time, including StimQ common total (effect size [ES] = 0.25, P = .01) and READ Quantity (ES = .19, P = .04) and Quality (ES = .30, P = .001). For the observations, the impact of Smart Beginnings varied by time, with significant impacts at 6 (ES = 0.37-.40, P < .001) and 24 (ES = 0.27-.30, P < .001) months, but not 18 months. CONCLUSIONS: Smart Beginnings positively promotes cognitive stimulation from infancy through toddlerhood using the integrated model. This study adds to the body of research showing preventive interventions in pediatric primary care and home visiting can support early relational health including parental support of cognitive stimulation. TRIAL REGISTRATION: NCT02459327.

Systemic Inflammation Contributes to the Association Between Childhood Socioeconomic Disadvantage and Midlife Cardiometabolic Risk.

BACKGROUND: Childhood socioeconomic disadvantage is associated with increased risk for chronic inflammation and cardiometabolic disease at midlife. PURPOSE: As it is presently unknown whether inflammation mediates the relationship between childhood socioeconomic status (SES) and adulthood cardiometabolic risk, we investigated associations between retrospectively reported childhood SES, circulating levels of inflammatory markers, and a latent construct of cardiometabolic risk in midlife adults. METHODS: Participants were 1,359 healthy adults aged 30-54 (Adult Health and Behavior I&II; 52% women, 17% Black) who retrospectively reported childhood SES (parental education, occupational grade). Measures included plasma interleukin (IL)-6, C-reactive protein (CRP), and cardiometabolic risk factors. Structural equation modeling was conducted, with cardiometabolic risk modeled as a second-order latent variable with adiposity, blood lipids, glucose control, and blood pressure as first-order components. RESULTS: Lower childhood SES was associated with greater risk for cardiometabolic disease at midlife (ß = -0.08, CI[-0.04, -0.01], p = .01) in models adjusted for demographics, but this association was attenuated in models that adjusted for adulthood SES and health behaviors. In fully-adjusted models, the relationship between lower childhood SES and adult cardiometabolic risk was partially explained by higher circulating levels of CRP (ß = -0.05, CI[-0.02, -0.01], p = .001), but not by IL-6. In an exploratory model, lower adulthood SES was also found to independently contribute to the association between childhood SES and adult cardiometabolic risk (ß = -0.02, CI[-0.01, -0.001], p = .02). CONCLUSIONS: The current study provides initial evidence that systemic inflammation may contribute to childhood socioeconomic disparities in cardiometabolic risk in midlife. Future work would benefit from prospective investigation of these relationships.

Developmental trajectories of behavioral inhibition from infancy to age seven: The role of genetic and environmental risk for psychopathology.

The present study leveraged data from a longitudinal adoption study of 361 families recruited between 2003 and 2010 in the United States. We investigated how psychopathology symptoms in birth parents (BP; Mage  = 24.1 years; 50.5-62.9% completed high school) and adoptive parents (AP; Mage  = 37.8 years; 80.9% completed college; 94% mother-father couples) influenced children's behavioral inhibition (BI) trajectories. We used latent growth models of observed BI at 18 and 27 months, and 4.5 and 7 years in a sample of adopted children (Female = 42%, White = 57%, Black = 11%, Multi-racial = 21%, Latinx = 9%). BI generally decreased over time, yet there was substantial variability in these trajectories. Neither BP nor AP psychopathology symptoms independently predicted systematic differences in BI trajectories. Instead, we found that AP internalizing symptoms moderated the effects of BP psychopathology on trajectories of BI, indicating a gene by environment interaction.

How pubertal timing and self-regulation predict adolescent sexual activity in resource-poor environments.

Studies found support for a link between pubertal timing and self-regulation in low-resource environments. This link could potentially explain a link between pubertal timing and early risk behavior. This study builds on this body of research by examining the mediated effect of pubertal timing on sexual activity through self-regulation in 728 adolescents and their families in a group with poor resources and a group with adequate resources. Income-to-Needs (ITN) was measured at age 7.5 to establish two groups (low-ITN and Medium/High-ITN). Pubertal timing was measured at age 10.5, self-regulation was assessed at age 14 and operationalized with effortful control, and sexual activity was assessed at age 16. Structural equation modeling was employed to test the hypothesized model in both groups. The link between pubertal timing and sexual activity mediated by effortful control was only significant in the low-ITN group. Specifically, more advanced pubertal maturity was associated with lower levels of adolescents' effortful control, which in turn was associated with more sexual activity at age 16. Findings were partially replicated with a drug use index replacing sexual activity. This study shows a different operating link from pubertal timing to effortful control and subsequent risk behavior in resource-poor environments. Implications are discussed.

Impacts of a tiered intervention on child internalizing and externalizing behavior in the context of maternal depression.

Greater maternal depressive symptoms are consistently associated with higher levels of behavioral difficulties in children, emerging in early childhood and with long-lasting consequences for children's development. Interventions promoting early relational health have been shown to have benefits for children's behavior; however, these impacts are not always realized in the context of maternal depression. This study examined whether tiered programs could address this limitation by focusing on both parenting, through universal primary prevention, and psychosocial stressors and parent mental health, through tailored secondary prevention. Analysis of a randomized controlled trial (RCT) of the Smart Beginnings (SB) intervention was conducted to determine whether SB attenuated the association between maternal depression and early childhood internalizing and externalizing behaviors. Maternal depression significantly predicted both internalizing and externalizing behaviors in linear regression models. Further, there was a significant interaction between maternal depression and treatment group, such that among mothers with higher depressive symptoms, the SB treatment attenuated the magnitude of the association between depression and child behavior. Findings suggest that while parenting support is important for all families, it may be particularly critical for those with higher levels of depression and underscores the need to consider multidimensional family processes in both research and clinical practice.

Disrupting Maternal Transmission of Depression: Using Integrative Data Analysis (IDA) to Examine Indirect Effects of the Family Check-Up (FCU) Across Three Randomized Trials.

Maternal depression is a well-established risk factor for the development of depression in offspring. As such, reducing maternal depression may be key to effective prevention efforts to reduce offspring's depression. Based on the broad risk represented by maternal depression, examining cross-over effects of parent-focused interventions on maternal depression is important. The present study examined improvements in maternal depression as a mediator of the long-term effects of the Family Check-Up (FCU) prevention program on youth depression across three randomized controlled trials. The FCU is a family-focused intervention originally designed to reduce youth problem behaviors, particularly conduct problems and substance use, but has also been found to have cross-over effects on other youth problem behaviors, including internalizing symptoms. We utilized integrative data analysis that allows for powerful tests of prevention effects across trials, specifically moderated nonlinear factor analysis, to integrate data across three trials: one trial initiated in early childhood and two in early adolescence. Using a latent growth modeling approach, we first examined direct effects of the FCU on changes in maternal depression. Then we examined the mediating effect of maternal depression on changes in both parent and youth reports of youth depression. A significant intervention effect on maternal depression was observed across the three trials, with the FCU predicting improvements in maternal depression. In turn, such improvements predicted a reduction in the growth in both parent and youth reports of youth depressive symptoms across 10 years post baseline. These results demonstrate the utility in addressing cross-over effects of family-focused interventions in reducing the long-term development of depression in youth through mediating pathways.

Long-term Effects of the Family Check-Up on Suicidality in Childhood and Adolescence: Integrative Data Analysis of Three Randomized Trials.

This study employed integrative data analysis techniques to examine the long-term effects of the family check-up (FCU) on changes in youth suicide risk using three randomized prevention trials, including one trial initiated in early childhood and two initiated in early adolescence. Data were harmonized across studies using moderated nonlinear factor analysis, and intervention effects were tested using an autoregressive latent trajectory model examining changes in suicide risk across long-term follow-up. Across trials, significant long-term effects of the FCU on reductions in suicide risk were observed, although differences between intervention and control group trajectories declined over time. No moderation of intervention effects was observed by youth gender or race/ethnicity or across samples. While results offer further support for the benefits of the FCU for suicide risk reduction, they also suggest that such effects may wane over time, underscoring the need for continued development of the FCU to enhance longer-term durability of effects on suicide-related behaviors.