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• We examined effects of interparental conflict and children's empathy on their health. • Outcomes were C-reactive protein, Interleukin-6, parent-reported child health. • Greater child empathy was associated with greater inflammation. • Interparental conflict and child empathy interacted to predict child health. • Empathic children may be more likely to experience poorer health in the face of conflict. Interparental conflict is known to negatively impact child well-being, including behavioral and physiological well-being. Children's empathy - that is, vicariously experiencing others' emotions - may increase children's sensitivity to and the biological repercussions of interparental conflict. Although empathy represents a valued trait and is an important part of socioemotional development, its influence on children's physical health is unknown. This study examined whether empathy moderates the association between perceived interparental conflict and both child systemic inflammation and parent-rated overall child health in a sample of children between the ages of seven to nine. Children and their parents participating in the long-term evaluation of the Family Foundations program, a randomized trial of a perinatal preventative intervention, provided data approximately eight years following enrollment into the program. We collected peripheral blood samples via dried blood spots, anthropometric measurements, and child and parent psychosocial questionnaires. Results indicated significant positive main effects of child empathy on both C-reactive protein (CRP; B = 0.26, SE = 0.11, p =.026) and Interleukin-6 (IL-6; B = 0.20, SE = 0.10, p =.045) levels. Further, child affective empathy moderated the associations between perceived interparental conflict and both CRP (B = 0.39, SE = 0.19, p =.050) and parent-reported child health (B = 0.30, SE = 0.13, p =.021), such that greater empathy strengthened the negative associations between interparental conflict and child health. Overall, findings suggests that there may be a biological cost of being more empathic in high-conflict environments and highlight the need for tools to help more empathic children appropriately manage vicarious emotions. [ABSTRACT FROM AUTHOR]

We examined whether participation in adolescent substance use prevention programming can enhance long-term resilience into adulthood such that individuals were better able to cope with adversities during the initial months of the COVID-19 pandemic, yielding benefits for the individuals, their partners/spouses, and children; 197 adults (28–30 years old) who entered the PROSPER randomized trial of substance use prevention programming as 6th graders and subsequently had become parents—and 128 of their partners—participated in two waves of long-term follow-up data collection. Respondents completed questionnaires on substance use, adjustment, parenting quality, and children's mood and behavior problems 15 years after baseline, and again via an online survey in the first three months of the COVID-19 pandemic. Results were mixed, with some indications of better adjustment of PROSPER intervention compared to control participants during the early phase of the pandemic (less increase in alcohol use and less decrease in parenting warmth) and their children (lower levels of externalizing and internalizing problems) but several null results as well (no differences in other substance use behaviors, other parenting measures, or parent depression). Adolescent substance use prevention programs can foster long-term individual and interpersonal resilience factors that allow participants—as well as their children—to adapt and cope with unforeseen periods of acute stress and adversity with less deterioration in health and well-being. [ABSTRACT FROM AUTHOR]

In recognition of the family as central to health, the concept of family, rather than individual, health has been an important area of research and, increasingly, clinical practice. There is a need to leverage existing theories of family health to align with our evolving understanding of Life Course Health Development, including the opportunities and constraints of the family context for promoting lifelong individual and population health. The purpose of this article is to propose an integrative model of family health development within a Life Course Health Development lens to facilitate conceptualization, research, and clinical practice. This model provides an organizing heuristic model for understanding the dynamic interactions between family structures, processes, cognitions, and behaviors across development. Potential applications of this model are discussed. [ABSTRACT FROM AUTHOR]

As the COVID‐19 pandemic has been highly stressful for parents and children, it is clear that strategies that promote long‐term family resilience are needed to protect families in future crises. One such strategy, the Family Foundations program, is focused on promoting supportive coparenting at the transition to parenthood. In a randomized trial, we tested the long‐term intervention effects of Family Foundations on parent, child, and family well‐being one to two months after the imposition of a national shelter‐in‐place public health intervention in 2020. We used regression models to test intervention impact on outcomes reported on by parents in a standard questionnaire format and a series of 8 days of daily reports. We also tested moderation of intervention impact by parent depression and coparenting relationship quality. Relative to control families, intervention families demonstrated significantly lower levels of individual and family problems (general parent hostility, harsh and aggressive parenting, coparenting conflict, sibling relationship conflict, and children's negative mood and behavior problems), and higher levels of positive family relationship quality (positive parenting, couple relationship quality, sibling relations, and family cohesion). For some outcomes, including coparenting conflict, harsh parenting, and child behavior problems, intervention effects were larger for more vulnerable families—that is, families with higher pre‐pandemic levels of parent depression or lower levels of coparenting relationship quality. We conclude that targeted family prevention programming is able to promote healthy parent and child functioning during unforeseen future periods of acute stress. The long‐term benefits of a universal approach to family support at the transition to parenthood indicate the need for greater investment in the dissemination of effective approaches. [ABSTRACT FROM AUTHOR]

To quantify the impact of the COVID‐19 pandemic and public health interventions on parent and child mental health and family relationships, we examined change in individual and family functioning in a sample of parents enrolled in a prevention trial; we examined change before the pandemic (2017–2019) when children were an average of 7 years old to the first months after the imposition of widespread public health interventions in the United States (2020) with paired t tests and HLM models. We examined moderation by parent gender, education, family income, and coparenting conflict. We found large deteriorations from before the pandemic to the first months of the pandemic in child internalizing and externalizing problems and parent depression, and a moderate decline in coparenting quality. Smaller changes were found for parent anxiety and parenting quality. Mothers and families with lower levels of income were at particular risk for deterioration in well‐being. Results indicate a need for widespread family support and intervention to prevent potential family "scarring," that is, prolonged, intertwined individual mental health and family relationship problems. [ABSTRACT FROM AUTHOR]

Just as HIV vaccine science has provided the leading edge of vaccine development innovation, the models of collaborative science pioneered in the HIV vaccine field also represent innovations. Building on this effort, in 2012, the NIH funded two Centers for HIV-AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-IDs) at Duke University and Scripps Research to focus on HIV immunogen design. Keywords: AIDS; HIV; partnership; product development; research; vaccine EN AIDS HIV partnership product development research vaccine 1 4 4 11/24/21 20211102 NES 211102 Forty years since the first report of the disease in the United States now known as HIV/AIDS, an efficacious HIV vaccine remains an elusive goal. [Extracted from the article]

This study explored young children's mental health trajectories during the pandemic (May 2020 to April 2021) as well as associations with family functioning (i.e., cohesion, conflict, chaos, and routines) using data reported by 204 parents (children Mage 5.49; 45% girls, 90% White). Children's internalizing problems decreased early on with the onset of the pandemic, but then leveled off, while no change in externalizing problems was found. Family conflict and chaos were significantly associated with internalizing and externalizing problems at the within‐ and between‐family level, when examined independently. When family‐level factors were evaluated simultaneously, family conflict emerged as a robust risk factor. Intervention efforts, specifically for families experiencing increased conflict, may help support the mental health needs of children. [ABSTRACT FROM AUTHOR]

Ischemic injury triggers a heightened inflammatory response that is essential for tissue repair, but excessive and chronic inflammatory responses contribute to the pathogenesis of ischemic cardiovascular disease. Regulatory T cells (Tregs), a major regulator of self-tolerance and immune suppression, control innate and adaptive immune responses, modulate specific immune cell subsets, prevent excessive inflammation, and participate in tissue repair after ischemia. Herein, we summarize the multiple potential mechanisms by which Tregs exert suppressor functions including modulation of cytokine production, alteration of cell-cell interactions, and disruption of metabolic pathways. Furthermore, we review the role of Tregs implicated in ischemic injury and repair including myocardial, limb, and cerebral ischemia. We conclude with a perspective on the therapeutic opportunities and future challenges of Treg biology in understanding the pathogenesis of ischemic cardiovascular disease states. • Tregs attenuate atherosclerotic development and plaque vulnerability. • Tregs improve acute ischemic myocardial injury, whereas dysfunctional and pro-inflammatory Tregs promote adverse cardiac remodeling in ischemic cardiomyopathy and chronic heart failure. • In a few non-cardiac ischemic injury models, Tregs were found to have stage-specific antithetical effects (promoting) tissue injury. • Clinical studies are underway incorporating the use of Treg-based therapies for myocardial infarction and chronic inflammatory disease states. • Emerging small molecule and biologic-based therapeutics targeting Tregs hold promise for a range of ischemic cardiovascular disease states. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the factor structure and the measurement invariance of the Coparenting Relationship Scale (CRS) across 10 countries based on the seven-factor coparenting model (i.e., Coparenting Agreement, Coparenting Closeness, Exposure to Conflict, Coparenting Support, Endorsement of Partner's Parenting; Division of Labor) proposed by Feinberg (2003). The results of research on coparenting from numerous countries have documented its foundational importance for parent mental health, family relationship quality, child development, and psychopathology. Yet, a cross-country perspective is still lacking. Such a perspective can provide insight into which dimensions of coparenting are universally recognized and which are especially prone to variation. A unique multinational data set, comprised of 15 individual studies collected across 10 countries (Belgium, Brazil, China, Israel, Italy, Japan, Portugal, Switzerland, Turkey, USA) in nine languages was established (N = 9,292; 51.1% mothers). Measurement invariance analyses were conducted. A six-factor structure (original seven factors minus Division of Labor) of the measure was consistent across the different contexts and measurement invariance was achieved at the configural level. There was no support for metric or scalar invariance. These findings provide a basis for the CRS to be used across countries and should inspire future quantitative and qualitative research in cross-country coparenting research to understand what aspects are universal and what aspects of coparenting are linked to specific material, relational, or ideational conditions that underlie high-quality coparenting. [ABSTRACT FROM AUTHOR]

This study explored the use of dynamical systems modeling techniques to evaluate self- and co-regulation of affect in couples' interactions before and after the transition to parenthood, and the impact of the Family Foundations program on these processes. Thirty-four heterosexual couples, randomized to intervention and control conditions, participated in videotaped dyadic interaction tasks at pretest (during pregnancy) and posttest (1 year after birth). Husbands' and wives' positivity and negativity were micro-coded throughout interactions. Individual negativity set-points, self-regulation, and partner co-regulatory processes during interactions were examined using a coupled oscillators model. Regarding self-regulatory processes, men exhibited amplification of negativity at the prenatal assessment that did not change at the postnatal assessment; women demonstrated no significant damping or amplification at pretest and a marginally significant change towards greater amplification at the postnatal assessment. In terms of partner-influenced regulatory dynamics, men's positive behaviors changed from damping to amplifying women's negative behaviors in the control group following the transition to parenthood, but exerted an even stronger damping effect on women's negative behaviors in the intervention group. The study highlights the advantages of dynamic modeling approaches in testing specific hypotheses in the study of self- and co-regulatory couple dynamics and demonstrates the potential of studying dynamic processes to further understanding of developmental and intervention-related change mechanisms. [ABSTRACT FROM AUTHOR]

Despite children's frequent exposure to psychological and physical intimate partner aggression (IPA) and associated long-term consequences, little is known about children's immediate, within-incident reactions to IPA. Additionally, differences in reactions to IPA based on exposure to within-incident "spillover" of aggression across interparental and parent-child dyads have previously remained unexamined. Parents of children age 2.5 years at study commencement (N = 203 from 111 families) reported on incidents of family aggression four times for 1 year. Among select IPA incidents with the child present (n = 163 incidents from 73 families), IPA severity and children's exposure to aggression spillover were uniquely associated with children's expression of greater fear. Moreover, children unexposed to spillover experienced high fear only during relatively severe IPA incidents, whereas spillover-exposed children experienced high fear regardless of IPA severity (supporting observations of fear reactivity in response to low-level threats). Additionally, IPA severity positively predicted, and spillover exposure negatively predicted, children's attempts to make peace or solve the problem for their parents. Further, spillover-exposed children were more likely to withdraw or attempt to make peace during relatively more severe incidents of IPA. Thus, spillover-exposed children may manage their fear during relatively severe IPA incidents by withdrawing and/or engaging in active peacemaking behaviors but not by using other methods that may increase risk of aggression turning toward them. These results extend existing research, illustrate the unique predictive value of within-incident aggression spillover, and provide a foundation for understanding mechanisms through which IPA affects children in a diversity of ways. (PsycINFO Database Record (c) 2019 APA, all rights reserved). [ABSTRACT FROM AUTHOR]

An editorial is presented on the anniversary of the first reported cases of AIDS, the need for a vaccine to prevent human immunodeficiency virus infection remains imperative. Topics include the immunologic markers of protection to guide vaccine development/researchers have predicated large-scale efficacy trials on empirical approaches that seek to identify specific immune responses are correlated with protection and build on the responses that are associated with even modest vaccine efficacy.

The transition to parenthood is a common yet stressful experience faced by many young and midlife adults, and the risk of cardiometabolic conditions also begins to rise at this time. Consequently, parenthood represents an opportune time to intervene with adults to support their psychological and physical health. We examined whether the benefits of the Family Foundations program, a perinatal preventative intervention promoting positive coparenting, extend beyond documented mental health and family relationship outcomes to better cardiometabolic risk factors among parents. We analyzed data from 183 couples (n = 366 participants) who, eight years prior, were randomly assigned to the 9-session perinatal preventative intervention program or a control condition. We collected dried blood spots to measure C-reactive protein (CRP), interleukin-6 (IL-6), and cholesterol; parents also reported on their self-rated health. Randomization to the intervention condition was associated with lower cholesterol (B=−.081, p =.049). Among parents who demonstrated more negative communication styles at pretest (during pregnancy), the intervention was further associated with better self-rated health (B=.181, p =.018). Participation in the intervention program was also marginally associated with lower CRP (B=−.261, p =.077), particularly among mothers (B=−.428, p =.076). These findings indicate that coparenting-focused interventions, such as Family Foundations, can lead to benefits beyond psychosocial and behavioral outcomes, and suggest that Family Foundations may improve parents' longer-term physical health, with potentially more benefits among couples who demonstrated more negative communication styles during pregnancy. • Long-term effects of Family Foundations, a coparenting intervention, were examined. • Outcomes were C-reactive protein, Interleukin-6, cholesterol, self-reported health. • Parents in the intervention group had better health at follow-up. • Parents with more negative communication styles at baseline may benefit more. • Even purely psychosocial interventions can impact physical health. [ABSTRACT FROM AUTHOR]

Study of fathers has gained significant traction over recent decades. However, the experience for men over the transition to parenthood remains focused on high‐socioeconomic and socially advantaged fathers. Researchers have yet to thoroughly investigate how fathers may uniquely experience this transition period with a history of childhood maltreatment, given that childhood abuse is known to impact several components of development and relationship functioning into adulthood. The current study endeavored to fill this gap by evaluating the associations between fathers' childhood experiences of physical and emotional abuse and their relationship functioning over the transition to parenthood in terms of both the couple relationship and social adjustment in relationships with others. Using data from 399 fathers who participated in a randomized control trial during pregnancy, the results from stepwise regressions indicate fathers with a history of emotional abuse experience particular declines in their external relationships (reductions in social support and increases in social stress) from prenatal (Wave 1) to postpartum (Wave 2) reports. However, no significant association emerged between fathers' history of maltreatment and their relationship functioning with their partners. These results underscore the importance of investigating the impact of different types of abuse on men in fatherhood. Moreover, we emphasize the need to study further fathers' social adjustment over the transition to parenthood beyond the couple relationship and broad social support to address the needs of men with a history of maltreatment in their new role as fathers. [ABSTRACT FROM AUTHOR]

The transition to parenthood is a stressful period for most parents as individuals and as couples, with variability in parent mental health and couple relationship functioning linked to children's long-term emotional, mental health, and academic outcomes. Few couple-focused prevention programs targeting this period have been shown to be effective. The purpose of this study was to test the short-term efficacy of a brief, universal, transition-to-parenthood intervention (Family Foundations) and report the results of this randomized trial at 10 months postpartum. This was a randomized controlled trial; 399 couples expecting their first child were randomly assigned to intervention or control conditions after pretest. Intervention couples received a manualized nine-session (five prenatal and four postnatal classes) psychoeducational program delivered in small groups. Intent-to-treat analyses indicated that intervention couples demonstrated better posttest levels than control couples on more than two thirds of measures of coparenting, parent mental health, parenting, child adjustment, and family violence. Program effects on family violence were particularly large. Of eight outcome variables that did not demonstrate main effects, seven showed moderated intervention impact; such that, intervention couples at higher levels of risk during pregnancy showed better outcomes than control couples at similar levels of risk. These findings replicate a prior smaller study of Family Foundations, indicating that the Family Foundations approach to supporting couples making the transition to parenthood can have broad impact for parents, family relationships, and children's adjustment. Program effects are consistent and benefit all families, with particularly notable effects for families at elevated prenatal risk. [ABSTRACT FROM AUTHOR]

This study examined longitudinal change in coparenting support and conflict for married parents during their child's adolescence, and the links between financial, work, and community factors and coparenting support and conflict. We utilized an ecological perspective, drawing on five waves of data from 635 dual-earner families with adolescents (M = 11.29, SD = .48 years old at Time 1). Applying a multilevel modeling approach and using reports from mothers and fathers we examined: (a) change in coparenting support and conflict over six years; (b) correlated change in contextual factors (financial strain, work hours and satisfaction, and community cohesion) with change in coparenting; and (c) differences in associations for mothers versus fathers. Findings revealed a decline over six years in perceptions of partner coparenting support for mothers and fathers, but no significant change in perceived coparenting conflict. Changes in financial strain, work characteristics, and community cohesion were associated with change in coparenting support and conflict in expected directions; interactions by parent gender suggest that mothers' reports of coparenting quality are more closely linked to some contextual influences than fathers' reports. Discussion centers on the implications of social contexts for coparenting at a critical period in youth development. (PsycINFO Database Record [ABSTRACT FROM AUTHOR]

Although interparental conflict (IPC) has been linked directly and indirectly (via adolescents' appraisals) with a wide range of adolescent outcomes, little is known about the implications of IPC and related adolescent threat appraisals for substance use. Drawing on the cognitive-contextual framework, we test competing hypotheses about how IPC may impact adolescent substance use outcomes, specifically testing whether (a) threat appraisals are directly related to escalation in alcohol and tobacco use over adolescence, or (b) threat appraisals are indirectly associated with substance use through their impact on adolescent internalizing problems. Family data from 768 2-caregiver families were analyzed for this study. Adolescents (53% female) were followed on 7 occasions starting in the fall of 6th grade (mean age = 11.3 years) through the spring of 11th grade. IPC and family demographic data were collected from parents. Youth provided data on their appraisals of conflict, internalizing problems, and substance use. Using longitudinal growth curve models, findings supported threat appraisals as a direct risk factor for escalating cigarette use, but not escalating alcohol use, during adolescence. In the alcohol trajectory model, IPC was a direct predictor of increases in alcohol use over time. These findings indicate that high levels of threat appraisals are a specific and direct risk for greater increases in cigarette use over the course of adolescence and that IPC confers risk for increasing rates of alcohol use over adolescence. (PsycINFO Database Record [ABSTRACT FROM AUTHOR]

In their chapter, Jinal Bhiman and Penny Moore4 describe how existing global virology and immunology networks built for HIV vaccine research proved extremely important in response to the SARS-CoV-2 pandemic. One of the great successes of the SARS-CoV-2 pandemic responses has been the rapid development of vaccines to protect against infection. Alexandra Sette and Shane Crotty2 then consider in detail immunological memory to SARS-CoV-2 infection and COVID-19 vaccines. [Extracted from the article]

Despite substantial rates of parent to child aggression (PCA) and intimate partner aggression (IPA) co-occurrence within families, the co-occurrence of PCA and IPA within incidents of aggression has not previously been examined. To do so, we developed the Children, Intimate Relationships, and Conflictual Life Events (CIRCLE) interview to simultaneously measure incidents of psychological and physical PCA and IPA. The CIRCLE interview was administered quarterly for approximately 1 year to 109 women and 94 men from 111 couples with a first born child approximately 32 months of age at study initiation. Demonstrating the CIRCLE interview's ability to yield new knowledge about the nature of family aggression, we describe the frequency of aggressive incidents, the average number of aggressive behaviors within incidents, the daily occurrence of multiple aggressive incidents, and rates of within-incident PCA and IPA co-occurrence. With the exception of men's physical IPA, aggression scores derived from the CIRCLE interview exhibited a relatively high degree of interpartner reporting concordance, as well as structural validity and convergent validity with common aggression measures. Aggression reports via repeated testing were not influenced by social desirability or attempts to avoid aggression. Participants who perceived enhanced memory for aggression as a function of study participation reported increasing PCA and IPA frequencies over time. In the prediction of child conduct and emotional problems, the CIRCLE interview demonstrated predictive validity and incremental validity over traditional aggression measures. For the first time, within-incident co-occurrence of PCA and IPA was documented and shown to uniquely impact child outcomes. (PsycINFO Database Record [ABSTRACT FROM AUTHOR]

In this review, we focus on the emerging role of microRNAs, non-coding RNAs that regulate gene expression and signaling pathways, in dysfunctional adipose tissue. We highlight current paradigms of microRNAs involved in adipose differentiation and function in depots such as white, brown, and beige adipose tissues and potential implications of microRNA dysregulation in human disease such as obesity, inflammation, microvasculature dysfunction, and related cardiovascular diseases. We highlight accumulating studies indicating that adipocyte-derived microRNAs may not only serve as biomarkers of cardiometabolic disease, but also may directly regulate gene expression of other tissues. Finally, we discuss the future prospects, challenges, and emerging strategies for microRNA delivery and targeting for therapeutic applications in cardiovascular disease states associated with adipocyte dysfunction. [ABSTRACT FROM AUTHOR]

Objective: Although maternal stress, anxiety, and depression have been linked to negative birth outcomes, few studies have investigated preventive interventions targeting maternal mental health as a means of reducing such problems. This randomized controlled study examines whether Family Foundations (FF)-a transition to parenthood program for couples focused on promoting coparenting quality, with previously documented impact on maternal stress, depression, and anxiety-can buffer the negative effects of maternal mental health problems. Methods: To assess the effects of FF, we used a randomized block design with a sample of 259 expectant mothers assigned to FF or a control condition and analyzed using propensity score models. We examine two-way interactions of condition (intervention vs. control) with maternal mental health problems (financial stress, depression, and anxiety) on birth outcomes (birth weight, days in hospital for mothers and infants). For birth weight, we assess whether intervention effects depend on length of gestation by including a third interaction term. Results: FF buffered ( p < 0.05) the negative impact of maternal mental health problems on birth weight and both mother and infant length of post-partum hospital stay. For birth weight, assignment to FF was associated with higher birth weight for infants born before term. Conclusions: These results demonstrate that a psycho-educational program for couples focused on enhancing mutual coparental support, with preventive effects on maternal mental health, can reduce incidence of birth problems among women at elevated risk. Such improvements in birth outcomes could translate into substantial reductions in public and personal healthcare costs. Future work should assess mediating mechanisms of intervention impact and cost-benefit ratio of the intervention. Clinical trials registration: The Family Foundations follow-up intervention study is currently registered with . The study identifier is NCT01907412. [ABSTRACT FROM AUTHOR]

Existing research demonstrated large deteriorations in parent, child, and family well‐being within 2 months after the onset of the COVID‐19 pandemic. Yet, little is known about the trajectories of families' adjustment in the following months, including what risk factors are associated with changes in families' adjustment. The current study examined (1) change in the parent, child, and family well‐being over time; (2) associations of pandemic‐related stressors, financial and social distancing‐associated stress, with well‐being between and within families; and (3) the role of local COVID‐19 prevalence, prior participation in family‐focused prevention, and parent gender. From April 2020 to January 2021, 393 parents from 235 families reported five times on parent mental health, child behavior problems, family relationships, and pandemic‐related stressors. Findings indicate that, across all domains of well‐being, there was either little change across the 8 months or a small degree of recovery followed by a shift to further deterioration. On average, parents experiencing greater pandemic‐related stressors also reported poorer functioning in all domains; monthly fluctuations in pandemic‐related stressors were also associated with fluctuations in parent mental health and child behavior problems. In some domains, the links between pandemic‐related stressors and parent and child well‐being were stronger among families living in areas with overall higher COVID‐19 prevalence rates. Parents' experiences during the pandemic did not differ systematically across prior intervention participation or parent gender. Taken together, findings suggest a need for supportive interventions to help families navigate extended periods of crisis. [ABSTRACT FROM AUTHOR]

Community coalitions have been promoted as a strategy to help overcome challenges to the dissemination and implementation of evidence-based prevention programs. This paper explores the characteristics of coalitions that enable the provision of implementation support for prevention programs in general and for the implementation of evidence-based prevention programs with fidelity. Longitudinal cross-lagged panel models were used to study 74 Communities That Care (CTC) coalitions in Pennsylvania. These analyses provide evidence of a unidirectional influence of coalition functioning on the provision of implementation support. Coalition member knowledge of the CTC model best predicted the coalition's provision of support for evidence-based program implementation with fidelity. Implications for developing and testing innovative methods for delivering training and technical assistance to enhance coalition member knowledge are discussed. [ABSTRACT FROM AUTHOR]

This study is a longitudinal investigation of the Promoting School-community-university Partnerships to Enhance Resilience (PROSPER) partnership model designed to evaluate the level of sustainability funding by community prevention teams, including which factors impact teams' generation of sustainable funding. Community teams were responsible for choosing, implementing with quality, and sustaining evidence-based programs (EBPs) intended to reduce substance misuse and promote positive youth and family development. Fourteen US rural communities and small towns were studied. Data were collected from PROSPER community team members ( N = 164) and prevention coordinators ( N = 10) over a 5-year period. Global and specific aspects of team functioning were assessed over six waves. Outcome measures were the total funds (cash and in-kind) raised to implement prevention programs. All 14 community teams were sustained for the first 5 years. However, there was substantial variability in the amount of funds raised, and these differences were predicted by earlier and concurrent team functioning and by team sustainability planning. Given the sufficient infrastructure and ongoing technical assistance provided by the PROSPER partnership model, local sustainability of EBPs is achievable. [ABSTRACT FROM AUTHOR]

Although maternal stress and depression have been linked to adverse birth outcomes (ABOs), few studies have investigated preventive interventions targeting maternal mental health as a means of reducing ABOs. This randomized controlled study examines the impact of Family Foundations (FF)-a transition to parenthood program for couples focused on promoting coparenting quality, with previously documented impact on maternal stress and depression-on ABOs. We also examine whether intervention buffers birth outcomes from the negative effect of elevated salivary cortisol levels. We use intent-to-treat analyses to assess the main effects of the FF intervention on ABOs (prematurity, birth weight, pregnancy complications, Cesarean section, and days in hospital for mothers and infants) among 148 expectant mothers. We also test the interaction of cortisol with intervention condition status in predicting ABOs. FF participation was associated with reduced risk of C-section (OR .357, p < 0.05, 95 % CI 0.149, 0.862), but did not have main effects on other ABOs. FF significantly buffered ( p < 0.05) the negative impact of maternal cortisol on birth weight, gestational age, and days in hospital for infants; that is, among women with relatively higher levels of prenatal cortisol, the intervention reduced ABOs. These results demonstrate that a psycho-educational program for couples reduces incidence of ABOs among higher risk women. Future work should test whether reduced maternal stress and depression mediate these intervention effects. [ABSTRACT FROM AUTHOR]

This study examines long-term effects of a transition to parenthood program, Family Foundations, designed to enhance child outcomes through a strategic focus on supporting the coparenting relationship. Roughly 5 to 7 years after baseline (pregnancy), parent and teacher reports of internalizing and externalizing problems and school adjustment were collected by mail for 98 children born to couples enrolled in the randomized trial. Teachers reported significantly lower levels of internalizing problems among children in the intervention group compared with children in the control group and, consistent with prior findings at age 3, lower levels of externalizing problems for boys in the intervention group. Baseline level of observed couple negative communication moderated intervention effects for parent and teacher report of child adjustment and teacher report of school adjustment and adaptation. Effect sizes ranged from 0.40 to 0.98. Results indicate that relatively brief preventive programs for couples at the transition to parenthood have the capacity to promote long-term positive benefits for children's adjustment. Although we attended to missing data issues in several ways, high levels of attrition in this long-term follow-up study is a cause for caution. [ABSTRACT FROM AUTHOR]

Long-term studies evaluating threat appraisals as an intervening variable linking interparental conflict (IPC) and internalizing problems are lacking, as are longitudinal studies evaluating the role of the broader family context in these models. Guided by the cognitive-contextual framework, this study followed 225 adolescents (53% females) and their families from age 11 into young adulthood (age 19.6) to evaluate the long-term implications of IPC and threat appraisals for young adult internalizing symptoms. First, a long-term mediation model revealed that increases in IPC from age 11 to 14 (but not initial levels) best accounted for adolescent threat appraisals at age 14. In turn, threat appraisals mediated the association between IPC and young adult (age 19.6) internalizing problems. Second, the family climate—defined as high levels of cohesion and organization—moderated the relation between IPC and threat appraisals. Adolescents in families that experienced declines in positive family climate and increasing IPC had the highest threat appraisals; however, families that maintained (or increased in) positive family climate were protective against increasing IPC. Interestingly, the combination of decreasing IPC and decreasing positive family climate corresponded with the lowest threat appraisals in the sample, contrary to expectations. This finding seems consistent with a family disengagement perspective which may be less threatening to adolescents but may confer risk for other problem outcomes. This study underscores the importance of IPC and threat appraisals during adolescence, and offers new insights into the role of the family climate in protecting against escalating IPC for young adult internalizing risk. [ABSTRACT FROM AUTHOR]

Drug-eluting stents have emerged as potent weapons in the treatment of patients with symptomatic coronary artery disease by reducing restenosis rates; however, a significant clinical consequence of these stents is delayed reendothelialization, which may increase the risk of late stent thrombosis. In this issue of the JCI, Santulli and colleagues generated an adenovirus that expresses the cyclin-dependent kinase inhibitor p27Kip1 (p27) and bears four tandem copies of target sequences for the endothelial cell-enriched microRNA (miRNA) miR-126-3p (Ad-p27-126TS) in an attempt to specifically reduce proliferation of vascular smooth muscle cells, but not endothelial cells. Indeed, delivery of Ad-p27-126TS to balloon-injured arteries in rats not only induced faster and more complete reendothelialization, but also effectively improved neointimal hyperplasia, hypercoagulability, and vasoreactivity. Collectively, these findings provide a cogent foundation for the potential therapeutic use of miRNA-facilitated gene delivery strategies to heal vessel wall injury. [ABSTRACT FROM AUTHOR]

Abstract: This paper examines how an adolescent's position relative to cohesive friendship groups in the school-wide social network is associated with alcohol, tobacco, and marijuana use. We extend prior research in this area by refining the categories of group positions, using more extensive friendship information, applying newer analytic methods to identify friendship groups, and making strategic use of control variables to clarify the meaning of differences among group positions. We report secondary analyses of 6th through 9th grade data from the PROSPER study, which include approximately 9500 adolescents each year from 27 school districts and 368 school grade cohort friendship networks. We find that core members of friendship groups were more likely to drink than isolates and liaisons, especially in light of their positive social integration in school, family, and religious contexts. Isolates were more likely to use cigarettes than core members, even controlling for all other factors. Finally, liaisons were more likely to use marijuana than core members. [Copyright &y& Elsevier]

Behavioral and emotional problems are common in early childhood and put children at risk for developing more serious problems. This study tested the mediating mechanisms through which a universal coparenting intervention implemented during the transition to parenthood led to reduced child adjustment problems at age 3 and explored child gender as a potential moderator. One hundred sixty-nine heterosexual couples expecting their first child were randomly assigned to a control condition or Family Foundations, a series of eight classes that targeted the coparenting relationship. Data were collected through videotaped triadic mother-father-child interaction tasks when the child was 1 and 3 years of age. Separate longitudinal path analyses for mothers and fathers tested coparenting competition and positivity as mediators of program effects on child adjustment problems. Significant mediated effects for coparenting competition were found for fathers with both sons and daughters and for mothers with sons but not for mothers with daughters. These effects accounted for between 39 and 55 % of the intervention's impact on child adjustment problems. Coparenting positivity did not mediate program effects. These results support the use of a prevention approach to reduce coparenting competition and enhance child adjustment and provide information that can be used to refine theory. [ABSTRACT FROM AUTHOR]

The study examines whether anxiety or chronic relationship stress alter the way that couple conflict affects cortisol levels for women and men during the transition to parenthood. Saliva samples, assayed for cortisol, were collected before and after couple interaction from 128 heterosexual couples expecting their first child. Confirming prior research, expectant mothers had higher cortisol levels than their spouses, and gestational age was linked to women's cortisol level. Negativity during couple interaction was associated with greater cortisol reactivity for men, but not women. Tests of moderation indicated little relation between negativity and cortisol recovery for individuals with a low level of anxiety or little history of chronic arguing with the partner. However, among individuals with elevated levels of either of these two factors, negativity was linked to less cortisol recovery for men, but more cortisol recovery for women. Consistent results were also found for the relation between low warmth in the couple interaction and both reactivity and recovery for men and women high in anxiety. Future research should examine whether pregnancy is responsible for these different gender patterns, or whether the inhibition of negativity is stressful for women with high levels of risk. [ABSTRACT FROM AUTHOR]

To test the assumption embedded in state-of-the-art, community assessment and decision-making regarding prevention of underage drinking: that there is minimal variation in the way that risk and protective factors (RPF) are associated with underage drinking across communities. Three large datasets provided the same measures of adolescent alcohol use and RPFs. Multilevel ordered-logistic regression models were carried out separately for each dataset and separately for males and females in 8th and 10th grades, testing random slopes for each RPF index. Predicted school-level coefficients were derived from these models, representing the association between RPFs and alcohol use. The variation in associations between RPFs and alcohol use across schools was greatest for antisocial peer risk and community protection; the lowest variation across schools was found for family cohesion and individual antisocial behavior. Ranges in predicted coefficients indicate large differences across schools for many RPFs. Bivariate correlations indicated that school-level associations vary across RPFs in expected directions. Policy makers should recognize that the magnitude of associations between RPFs and adolescent alcohol use vary considerably across communities, and that such variability is greater for certain RPFs than others. These findings have implications for policies regarding how prevention resources are targeted within and across communities. [ABSTRACT FROM AUTHOR]

Objectives. We examined the independent and combined influence of major risk and protective factors on youths' alcohol use. Methods. Five large data sets provided similar measures of alcohol use and risk or protective factors. We carried out analyses within each data set, separately for boys and girls in 8th and 10th grades. We included interaction and curvilinear predictive terms in final models if results were robust across data sets. We combined results using meta-analytic techniques. Results. Individual, family, and peer risk factors and a community protective factor moderately predicted youths' alcohol use. Family and school protective factors did not predict alcohol use when combined with other factors. Youths' antisocial attitudes were more strongly associated with alcohol use for those also reporting higher levels of peer or community risk. For certain risk factors, the association with alcohol use varied across different risk levels. Conclusions. Efforts toward reducing youths' alcohol use should be based on robust estimates of the relative influence of risk and protective factors across adolescent environment domains. Public health advocates should focus on context (e.g., community factors) as a strategy for curbing underage alcohol use. [ABSTRACT FROM AUTHOR]

Objective: Although studies have demonstrated that an adolescent's parents and friends both influence adolescent substance use, it is not known whether the parenting experienced by one's friends also affects one's own use. Drawing on conceptions of shared parenting and the tenets of coercion theory, we investigated the extent to which three domains of parenting behaviors (parental knowledge, inductive reasoning, and consistent discipline) influenced the alcohol, cigarette, and marijuana use of not only their own adolescent children but also of members of their adolescents' friendship groups. Method: Analyses of friendship nominations within each of two successive ninth-grade cohorts in 27 Iowa and Pennsylvania schools (N = 7,439 students, 53.6% female) were used to identify 897 friendship groups. Hierarchical logistic regression models were used to examine prospective associations between 9th-grade friendship group-level parenting behaviors and adolescent self-reported alcohol, cigarette, and marijuana use in 10th grade. Results: Adolescent substance use in 10th grade was significantly related to parenting behaviors of friends' parents, after controlling for adolescents' reports of their own substance use and their own parents' behaviors at the 9th grade level. These associations were particularly strong for parents' knowledge about their children and use of inconsistent discipline strategies. Significant interaction effects indicated that these relationships were strongest when adolescents received positive parenting at home. Some, but not all, of the main effects of friends' parents' parenting became nonsignificant after friends' substance use in ninth grade was included in the model. Conclusions: The findings suggest that the parenting style in adolescents' friends' homes plays an important role in determining adolescent substance use. Implications of the joint contribution of parents and peers for prevention and intervention are discussed. [ABSTRACT FROM AUTHOR]

Sibling relationships are an important context for development, but are often ignored in research and preventive interventions with youth and families. In childhood and adolescence, siblings spend considerable time together, and siblings' characteristics and sibling dynamics substantially influence developmental trajectories and outcomes. This paper reviews research on sibling relationships in childhood and adolescence, focusing on sibling dynamics as part of the family system and sibling influences on adjustment problems, including internalizing and externalizing behaviors and substance use. We present a theoretical model that describes three key pathways of sibling influence: one that extends through siblings' experiences with peers and school, and two that operate largely through family relationships. We then describe the few existing preventive interventions that target sibling relationships and discuss the potential utility of integrating siblings into child and family programs. [ABSTRACT FROM AUTHOR]

To promote an effective approach to prevention, the community diagnosis model helps communities systematically assess and prioritize risk factors to guide the selection of preventive interventions. This increasingly widely used model relies primarily on individual-level research that links risk and protective factors to substance use outcomes. I discuss common assumptions in the translation of such research concerning the definition of risk factor elevation; the equivalence, independence, and stability of relations between risk factors and problem behaviors; and community differences in risk factors and risk factor-problem behavior relations. Exploring these assumptions could improve understanding of the relations of risk factors and substance use within and across communities and enhance the efficacy of the community diagnosis model. This approach can also be applied to other areas of public health where individual and community levels of risk and outcomes intersect. [ABSTRACT FROM AUTHOR]

Abstract: We explored how parent gender, infant temperament, and coparenting dynamics worked together to shape mothers’ and fathers’ depressive symptoms, stress, and parental efficacy during early parenthood. We were interested in the coparenting relationship as a context that shapes how parents respond to their infant''s temperamental qualities. Participants were 139 couples who had recently given birth to their first child. Parent reports of temperament were collected when the infant was 4–8 months old and reports of coparenting and parent adjustment were collected at 13 months. Two-level random intercept models revealed interactions between temperament and coparenting, highlighting the family system as a context for how men and women adapt to their parenting role. There was little evidence for mother–father differences in these associations. [Copyright &y& Elsevier]

Despite advances in understanding the role that several physiological systems play in the occurrence of general violence, little progress has been made toward understanding biological correlates of intimate partner violence (IPV). We explored involvement of one physiological system, the hypothalamic-pituitary-adrenal (HPA) axis. Among 137 heterosexual couples expecting a first child, baseline level of HPA activity-assessed via salivary cortisol collected before a couple conflict discussion-was linked to both men's and women's violence perpetration. HPA reactivity to the conflict bout did not show an independent association with IPV. However, persisting elevation in men's, and down-regulation in women's, HPA activity during a further recovery period was linked to men's violence perpetration. Aggr. Behav. 37:492-502, 2011. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This study investigated the ability of a psychosocial prevention program implemented through childbirth education programs to enhance the coparental and couple relationship, parental mental health, the parent-child relationship, and child outcomes. A sample of 169 heterosexual, adult couples expecting their first child was randomized to intervention and control conditions. The intervention families participated in Family Foundations, a series of eight classes delivered before and after birth, which was designed as a universal prevention program (i.e., applicable to all couples, not just those at high risk). Intent-to-treat analyses utilizing data collected from child age 6 months through 3 years indicated significant program effects on parental stress and self-efficacy, coparenting, harsh parenting, and children's emotional adjustment among all families, and maternal depression among cohabiting couples. Among families of boys, program effects were found for child behavior problems and couple relationship quality. These results indicate that a universal prevention approach at the transition to parenthood focused on enhancing family relationships can have a significant and substantial positive impact on parent and child well-being. [ABSTRACT FROM AUTHOR]

This study examines how aspects of coalition functioning predict a coalition’s ability to promote high-quality implementation of evidence-based programs (EBPs). The study involved 62 Communities That Care (CTC) coalitions in Pennsylvania measured annually from 2003 to 2007. Findings indicate that the communities with higher levels of poverty and longer existing coalitions are related to lower support for high-quality EBP implementation. Several aspects of coalition functioning—including higher levels of funding; leadership strength; board efficiency; strong internal and external relationships; and fidelity to the CTC model—significantly predicted support for high-quality EBP implementation. Earlier measurements of coalition functioning (2003–2004 and 2005–2006) predicted EBP implementation (2007) more strongly than concurrent coalition assessments (2007). The discussion focuses on how coalitions and technical assistance providers can improve coalition support for the implementation of EBPs. [ABSTRACT FROM AUTHOR]

Despite the public health burden of adolescent substance use, delinquency, and other problem behavior, few comprehensive models of disseminating evidence-based prevention programs to communities have demonstrated positive youth outcomes at a population level, capacity to maintain program fidelity, and sustainability. We examined whether the Communities That Care (CTC; Hawkins and Catalano ) model had a positive impact on risk/protective factors and academic and behavioral outcomes among adolescents in a quasi-experimental effectiveness study. We conducted a longitudinal study of CTC in Pennsylvania utilizing biannual surveillance data collected through anonymous in-school student surveys. We utilized multilevel models to examine CTC impact on change in risk/protective factors, grades, delinquency, and substance use over time. Youth in CTC communities demonstrated less growth in delinquency, but not substance use, than youth in non-CTC communities. Levels of risk factors increased more slowly, and protective factors and academic performance decreased more slowly, among CTC community grade-cohorts that were exposed to evidence-based, universal prevention programs than comparison grade cohorts. Community coalitions can affect adolescent risk and protective behaviors at a population level when evidence-based programs are utilized. CTC represents an effective model for disseminating such programs. [ABSTRACT FROM AUTHOR]

This study used data from a sample of 6th to 12th grade students ( N = 48,641, 51% female), nested in 192 schools, to determine if the influence of family-based protective factors varied across different school contexts. Hierarchical logistic regression models were used to examine the effects of individual-level family protective factors, relative to school-level aggregates of the same factors, on recent (past 30 days) use of cigarettes, alcohol, and marijuana. Cross-level interactions indicated that the effect of the student’s level of family protection, relative to other students in their school, differed depending on the aggregated school level of family protection. The results suggested that the benefit of belonging to a well-functioning family was more influential for students attending schools characterized by higher-than-average aggregated levels of protection compared to students attending schools of lower-than-average protection. Thus, family-level factors offered less protection for students in relatively high-risk school contexts. These results were consistent with a protective–reactive interaction and suggest that a thorough understanding of adolescent substance use must consider the complex interplay among adolescents, their families, and their social environments. [ABSTRACT FROM AUTHOR]

This study investigated whether a psycho-educational program with modest dosage (eight sessions), delivered in a universal framework through childbirth education programs and targeting the coparenting relationship would have a positive impact on observed family interaction and child behavior at 6-month follow-up (child age 1 year). One hundred sixty-nine couples, randomized to intervention and control conditions, participated in videotaped family observation tasks at pretest (during pregnancy) and at child age 1 year (2003–2007). Coparenting, parenting, couple relationship, and child self-regulatory behaviors were coded by teams of raters. Intent-to-treat analyses of program effects controlled for age, education, and social desirability. Evidence of significant ( p < 0.05) program effects at follow-up emerged in all four domains. Effect sizes ranged from 0.28 to 1.01. Targeting the coparenting relationship at the transition to parenthood represents an effective, non-stigmatizing means of promoting parenting quality and child adjustment. [ABSTRACT FROM AUTHOR]

Considerable evidence suggests that modifiable risk factors for adverse pregnancy outcomes such as preterm birth and low birthweight include obesity, sedentary behavior, and infections. There is a growing consensus that the preconceptional and interconceptional periods may be an ideal time for preventive intervention targeting these risk factors; enhancing health before pregnancy would subsequently reduce the risk for poor pregnancy outcomes. This paper provides an overview of the development of a health behavior intervention, Strong Healthy Women, that aims to improve women’s preconceptional and interconceptional health. We describe the rationale, delivery, and targeted outcomes of the program, as well as the design of an ongoing trial currently testing program efficacy. The content areas are also discussed and include pregnancy-conception, stress, physical activity, nutrition, infection, sources of smoke in the home, and substance use. This intervention protocol may offer researchers and healthcare professionals a framework for designing other programs aiming to improve women’s preconceptional health. [ABSTRACT FROM AUTHOR]

Background: After many years in which evaluations had generally not found the coalition approach to be effective, the community-coalition approach has recently been shown to produce a public health impact if best practices are utilized. The next challenge is to foster sustainability among coalitions in order to achieve long-term public health outcomes. This study examined the level of and predictors of sustainability among Communities That Care (CTC) sites in Pennsylvania. Methods: Board functioning and the funding of 110 CTC sites were assessed through the reports of board members, staff, and technical-assistance providers from 2003 through 2006; data were analyzed in 2007. Results: Ninety percent of CTC coalitions continued after the 3-year initial funding period, with 3%–8% of sites terminating each year thereafter. Approximately two thirds of CTC sites continued to operate 4 years after the termination of the original 3-year implementation grant. Many of the sites attracted funding at a level equivalent to or greater than the initial grant. Overall coalition functioning, as reported by either board members or technical-assistance providers, along with planning for sustainability, predicted both survival and post-launch funding. Conclusions: Evidence suggests that board functioning predicts survival, at least in part independently of its influence on funding; and that planning for sustainability predicts sustainability, at least in part independently of overall coalition functioning. [Copyright &y& Elsevier]

This study investigated the ability of a theoretically driven, psychosocial prevention program implemented through childbirth education programs to enhance the coparental relationship, parental mental health, the parent-child relationship, and infant emotional and physiological regulation. A sample of 169 heterosexual, adult couples who were expecting their 1st child was randomized to intervention and control conditions. The intervention families participated in Family Foundations, a series of 8 classes, delivered before and after birth, that was designed as a universal prevention program (i.e., it was applicable to all couples, not just those at high risk). Intent-to-treat analyses indicated significant program effects on coparental support, maternal depression and anxiety, distress in the parent-child relationship, and several indicators of infant regulation. Intervention effects were not moderated by income, but greater positive impact of the program was found for lower educated parents and for families with a father who reported higher levels of insecure attachment in close relationships. These findings support the view that coparenting is a potentially malleable intervention target that may influence family relationships as well as parent and child well-being. [ABSTRACT FROM AUTHOR]

Monocyte differentiation involves the participation of lineage-restricted transcription factors, although the mechanisms by which this process occurs are incompletely defined. Within the hematopoietic system, members of the Kruppel-like family of factors (KLFs) play essential roles in erythrocyte and T lymphocyte development. Here we show that KLF4/GKLF is expressed in a monocyte-restricted and stage-specific pattern during myelopoiesis and functions to promote monocyte differentiation. Overexpression of KLF4 in HL-60 cells confers the characteristics of mature monocytes. Conversely, KLF4 knockdown blocked phorbol ester-induced monocyte differentiation. Forced expression of KLF4 in primary common myeloid progenitors (CMPs) or hematopoietic stem cells (HSCs) induced exclusive monocyte differentiation in clonogenic assays, whereas KLF4 deficiency inhibited monocyte but increased granulocyte differentiation. Mechanistic studies demonstrate that KLF4 is a target gene of PU.1. Consistently, KLF4 can rescue PU.1−/− fetal liver cells along the monocytic lineage and can activate the monocytic-specific CD14 promoter. Thus, KLF4 is a critical regulator in the transcriptional network controlling monocyte differentiation. [ABSTRACT FROM AUTHOR]

This study investigated the family context of adolescent sibling similarity and differentiation in maladjustment (antisocial behavior and depression) by examining negativity in different subsystems. Two hypotheses were proposed: (1) Parental and sibling negativity tends to diffuse through the family system, especially because of the high level of reciprocity in sibling relationships, leading to sibling similarity; and (2) interparental (coparenting) conflict disrupts cohesive functioning and thereby motivates and facilitates sibling differentiation and niche picking. To control for the effects of similar genes between siblings, the authors used behavioral genetic models with a genetically informed sample of 720 two-parent families, each with at least 2 adolescent siblings. Results for the differences in shared environmental influences across groups high and low in each of the domains of family negativity provided partial support for the hypotheses. The results further understanding of influences on individual differences and support a theory of how parent-child and interparental relationships intersect with sibling relationship dynamics. [ABSTRACT FROM AUTHOR]

Activation of macrophages is important in chronic inflammatory disease states such as atherosclerosis. Proinflammatory cytokines such as interferon-γ (IFN-γ), lipopolysaccharide (LPS), or tumor necrosis factor-α can promote macrophage activation. Conversely, anti-inflammatory factors such as transforming growth factor-β1 (TGF-β1) can decrease proinflammatory activation. The molecular mediators regulating the balance of these opposing effectors remain incompletely understood. Herein, we identify Kruppel-like factor 4 (KLF4) as being markedly induced in response to IFN-γ, LPS, or tumor necrosis factor-α and decreased by TGF-β1 in macrophages. Overexpression of KLF4 in J774a macrophages induced the macrophage activation marker inducible nitric-oxide synthase and inhibited the TGF-β1 and Smad3 target gene plasminogen activator inhibitor-1 (PAl-1). Conversely, KLF4 knockdown markedly attenuated the ability of IFN-γ, LPS, or IFN-γ plus LPS to induce the iNOS promoter, whereas it augmented macrophage responsiveness to TGF-β1 and Smad3 signaling. The KLF4 induction of the iNOS promoter is mediated by two KLF DNA-binding sites at -95 and -212 bp, and mutation of these sites diminished induction by IFN-γ and LPS. We further provide evidence that KLF4 interacts with the NF-κB family member p65 (RelA) to cooperatively induce the iNOS promoter. In contrast, KLF4 inhibited the TGF-β1/Smad3 induction of the PAl-1 promoter independent of KLF4 DNA binding through a novel antagonistic competition with Smad3 for the C terminus of the coactivator p300/CBP. These findings support an important role for KLF4 as a regulator of key signaling pathways that control macrophage activation. [ABSTRACT FROM AUTHOR]