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.

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.

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.

[PI3KC2ß: A promising therapeutic target in myotubular myopathy]. / Une cible thérapeutique prometteuse dans la myopathie myotubulaire.

Myotubular myopathy is a rare disease of genetic origin characterized by significant muscle weakness leading to respiratory disorders and for which no treatment exists today. In this paper, we show that inhibition of the activity of the enzyme PI3KC2ß prevents the development of this myopathy in a mouse model of the disease, thus identifying a therapeutic target to treat myotubular myopathy in humans.

Title: Une cible thérapeutique prometteuse dans la myopathie myotubulaire. Abstract: La myopathie myotubulaire est une maladie rare d'origine génétique caractérisée par une importante faiblesse musculaire entraînant des troubles respiratoires et pour laquelle aucun traitement n'existe aujourd'hui. Dans cet article, nous montrons que l'inhibition de l'activité de l'enzyme PI3KC2ß prévient le développement de cette myopathie dans un modèle murin de la maladie, identifiant ainsi une cible thérapeutique pour traiter la myopathie myotubulaire chez l'homme.

Modeling BMI z score lability during childhood as a function of child temperament and genetic risk for obesity.

OBJECTIVE: This study aimed to examine whether child genetic risk for obesity and temperament (i.e., negative affectivity, effortful control) accounted for stability versus lability in children's weight status (BMI z score) over time. METHODS: A total of 561 adopted children (42% female; 56% Caucasian, 13% African American, 11% Latino, and 20% other) and their birth and adoptive parents were followed from birth to age 9 years. The multilevel location-scale model was used to examine whether child genetic risk for obesity and temperament were related to differences in level and lability in child BMI z scores over time. RESULTS: For the full sample, higher levels of child negative affectivity were associated with greater BMI z score lability, whereas higher levels of effortful control and children's mean-level BMI z scores were related to less lability across childhood. Additional analyses examined associations within groups of children with healthy versus overweight/obesity weight statuses. Within the healthy weight status group only, better effortful control was associated with more stable BMI z scores, whereas genetic risk for higher BMI was associated with more labile BMI z scores. CONCLUSIONS: These findings provide insights into factors that can be harnessed to redirect unhealthy trajectories as well as factors that may challenge redirection or maintain a healthy trajectory.

MtrA modulates Mycobacterium tuberculosis cell division in host microenvironments to mediate intrinsic resistance and drug tolerance.

The success of Mycobacterium tuberculosis (Mtb) is largely attributed to its ability to physiologically adapt and withstand diverse localized stresses within host microenvironments. Here, we present a data-driven model (EGRIN 2.0) that captures the dynamic interplay of environmental cues and genome-encoded regulatory programs in Mtb. Analysis of EGRIN 2.0 shows how modulation of the MtrAB two-component signaling system tunes Mtb growth in response to related host microenvironmental cues. Disruption of MtrAB by tunable CRISPR interference confirms that the signaling system regulates multiple peptidoglycan hydrolases, among other targets, that are important for cell division. Further, MtrA decreases the effectiveness of antibiotics by mechanisms of both intrinsic resistance and drug tolerance. Together, the model-enabled dissection of complex MtrA regulation highlights its importance as a drug target and illustrates how EGRIN 2.0 facilitates discovery and mechanistic characterization of Mtb adaptation to specific host microenvironments within the host.

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.

Inactivating the lipid kinase activity of PI3KC2ß is sufficient to rescue myotubular myopathy in mice.

Phosphoinositides (PIs) are membrane lipids that regulate signal transduction and vesicular trafficking. X-linked centronuclear myopathy (XLCNM), also called myotubular myopathy, results from loss-of-function mutations in the MTM1 gene, which encodes the myotubularin phosphatidylinositol 3-phosphate (PtdIns3P) lipid phosphatase. No therapy for this disease is currently available. Previous studies showed that loss of expression of the class II phosphoinositide 3-kinase (PI3K) PI3KC2ß (PI3KC2B) protein improved the phenotypes of an XLCNM mouse model. PI3Ks are well known to have extensive scaffolding functions and the importance of the catalytic activity of this PI3K for rescue remains unclear. Here, using PI3KC2ß kinase-dead mice, we show that the selective inactivation of PI3KC2ß kinase activity is sufficient to fully prevent muscle atrophy and weakness, histopathology, and sarcomere and triad disorganization in Mtm1-knockout mice. This rescue correlates with normalization of PtdIns3P level and mTORC1 activity, a key regulator of protein synthesis and autophagy. Conversely, lack of PI3KC2ß kinase activity did not rescue the histopathology of the BIN1 autosomal CNM mouse model. Overall, these findings support the development of specific PI3KC2ß kinase inhibitors to cure myotubular myopathy.

Exploration of Tumor Biopsy Gene Signatures to Understand the Role of the Tumor Microenvironment in Outcomes to Lisocabtagene Maraleucel.

In the TRANSCEND NHL 001 study, 53% of patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with lisocabtagene maraleucel (liso-cel) achieved a complete response (CR). To determine characteristics of patients who did and did not achieve a CR, we examined the tumor biology and microenvironment from lymph node tumor biopsies. LBCL biopsies from liso-cel-treated patients were taken pretreatment and ∼11 days posttreatment for RNA sequencing (RNA-seq) and multiplex immunofluorescence (mIF). We analyzed gene expression data from pretreatment biopsies (N = 78) to identify gene sets enriched in patients who achieved a CR to those with progressive disease. Pretreatment biopsies from month-3 CR patients displayed higher expression levels of T-cell and stroma-associated genes, and lower expression of cell-cycle genes. To interpret whether LBCL samples were "follicular lymphoma (FL)-like," we constructed an independent gene expression signature and found that patients with a higher "FL-like" gene expression score had longer progression-free survival (PFS). Cell of origin was not associated with response or PFS, but double-hit gene expression was associated with shorter PFS. The day 11 posttreatment samples (RNA-seq, N = 73; mIF, N = 53) had higher levels of chimeric antigen receptor (CAR) T-cell densities and CAR gene expression, general immune infiltration, and immune activation in patients with CR. Further, the majority of T cells in the day 11 samples were endogenous. Gene expression signatures in liso-cel-treated patients with LBCL can inform the development of combination therapies and next-generation CAR T-cell therapies.

Tamoxifen improves muscle structure and function of Bin1- and Dnm2-related centronuclear myopathies.

Congenital myopathies define a genetically heterogeneous group of disorders associated with severe muscle weakness, for which no therapies are currently available. Here we investigated the repurposing of tamoxifen in mouse models of mild or severe forms of centronuclear myopathies due to mutations in BIN1 (encoding amphiphysin 2) or DNM2 (encoding dynamin 2), respectively. Exposure to a tamoxifen-enriched diet from 3 weeks of age resulted in significant improvement in muscle contractility without increase in fibre size in both models, underlying an increase in the capacity of the muscle fibres to produce more force. In addition, the histological alterations were fully rescued in the BIN1-centronuclear myopathies mouse model. To assess the mechanism of the rescue, transcriptome analyses and targeted protein studies were performed. Although tamoxifen is known to modulate the transcriptional activity of the oestrogen receptors, correction of the disease transcriptomic signature was marginal on tamoxifen treatment. Conversely, tamoxifen lowered the abnormal increase in dynamin 2 protein level in both centronuclear myopathies models. Of note, it was previously reported that dynamin 2 increase is a main pathological cause of centronuclear myopathies. The Akt/mTOR muscle hypertrophic pathway and protein markers of the ubiquitin-proteasome system (the E3 ubiquitin ligase cullin 3) and autophagy (p62) were increased in both models of centronuclear myopathies. Normalization of dynamin 2 level mainly correlated with the normalization of cullin 3 protein level on tamoxifen treatment, supporting the idea that the ubiquitin-proteasome system is a main target for the tamoxifen effect in the amelioration of these diseases. Overall, our data suggest that tamoxifen antagonizes disease development probably through dynamin 2 level regulation. In conclusion, the beneficial effect of tamoxifen on muscle function supports the suggestion that tamoxifen may serve as a common therapy for several autosomal forms of centronuclear myopathies.

Perceptions of racism in a children's psychiatric inpatient unit: A qualitative study of entrenching and uprooting factors.

WHAT IS KNOWN ON THE SUBJECT?: The impacts of racism on health are well documented and are greater for mental than for general health. Mental health professionals are well positioned to help dismantle racism and structural barriers compromising optimal patient care. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: We describe a systematic and orderly way to identify factors that contribute to entrenching racism as the status quo or that help to uproot it. By incorporating a racial equity lens, we can better understand daily racism and inform the optimal antiracist actions most relevant to an inpatient psychiatric setting. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Our two-domain/six-theme model may serve as a rubric for individuals to engage in structured self-reflection, for organizations in auditing or programmatic evaluation, or as scaffolding for difficult but frequently elided conversations. The unique strengths of a mental health environment can be harnessed toward the elimination of racism and racist practices in clinical care and in the workplace ABSTRACT: INTRODUCTION: It is well documented that racism plays a role in health care access and outcomes. However, discussions about racism in the inpatient psychiatric workplace are generally avoided. To address this gap, we incorporated a racial equity perspective into a qualitative study to better understand daily racism, its impact on patients and staff, and to inform optimal antiracist actions most relevant to inpatient psychiatric settings. AIM/QUESTION: We sought to identify factors that may contribute to or deter from racism to inform interventions to sustain a psychologically supportive environment for patients and staff. METHODS: We conducted semistructured interviews using a purposive sample of 22 individuals in an acute child psychiatric inpatient service. We analysed transcripts using thematic analysis guided by a constructivist grounded theory conceptual framework. RESULTS: We identified two countervailing processes: (1) Entrenching-factors that sustain or increase racism: Predisposing, Precipitating, and Perpetuating and (2) Uprooting-factors that rectify or reduce racism: Preventing, Punctuating, and Prohibiting. We organized each of the elements into a '6P' model along a temporal sequence around sentinel racist events. For each of the six components we describe: Contributing Factors, Emotional Reactions, and Behavioural Responses as reported by participants. IMPLICATIONS FOR PRACTICE: Identifying factors that entrench or uproot racism can inform specific steps to improve the care of all children and families on an inpatient child psychiatry unit. The two-domain/six-theme model we developed can serve as a rubric for individuals or milieu-based inpatient settings serving patients of any age to engage in structured self-reflection, auditing, program evaluation, or as scaffolding for difficult but frequently elided conversations.

Family interactions in toddlerhood influence social competence in preschool age: Accounting for genetic and prenatal influences.

Identification of early promotive and risk factors for social competence is important for fostering children's successful social development; particularly given social competence is essential for children's later academic and psychological well-being. While research suggests that the early parent-child relationship, genetics, and prenatal influences are associated with social competence, there is less research considering how these factors may operate together to shape children's social competence in early childhood. Using a genetically informed sample from the Early Growth and Development Study (N = 561), we examined multiple levels of influence (i.e., genetic, prenatal, parenting, and child characteristics) on children's social competence at 4.5 years old. Results from structural equation models showed adoptive mother overreactivity at 18 months was positively associated with child dysregulation at 27 months, which, in turn, was associated with lower levels of social competence at 4.5 years. Also, child reactivity at 18 months was independently associated with higher levels of adoptive mother overreactivity at 27 months, which, in turn, was associated with lower levels of social competence at 4.5 years. Finally, we found an evocative effect on adoptive fathers' overreactivity at 18 months such that prenatal birth mother distress was negatively associated with adoptive fathers' overreactivity at 18 months. Overall, this study found evidence for genetic influences, and bidirectional associations between parent and child in toddlerhood that are related to lower levels of social competence when children were 4.5 years old. We also found that the prenatal environment was associated with parenting, but not with child behavior directly. This study's ability to simultaneously examine multiple domains of influence helps provide a more comprehensive picture of important mechanisms and developmental periods for children's early social competence.

Zn2+ inhibits spatial memory and hippocampal place cell representation through high-affinity binding to the NMDA receptor GluN2A subunit.

A subset of glutamatergic neurons in the forebrain uses labile Zn2+ as a co-transmitter alongside glutamate. Synaptic Zn2+ plays a key role in learning and memory processes, but its mechanisms of action remain poorly understood. Here, we used a knock-in (KI) mouse line carrying a point mutation at the GluN2A Zn2+ binding site that selectively eliminates zinc inhibition of NMDA receptors. Ablation of Zn2+-GluN2A binding improves spatial memory retention and contextual fear memory formation. Electrophysiological recording of hippocampal neurons in the CA1 area revealed a greater proportion of place cells and substantial place field remapping in KI mice compared to wildtype littermates. Persistent place cell remapping was also seen in KI mice upon repeated testing suggesting an enhanced ability to maintain a distinct representation across multiple overlapping experiences. Together, these findings reveal an original molecular mechanism through which synaptic Zn2+ negatively modulates spatial cognition by dampening GluN2A-containing NMDA receptor signaling.

Developmental profiles of child behavior problems from 18 months to 8 years: The protective effects of structured parenting vary by genetic risk.

Some children are more affected by specific family environments than others, as a function of differences in their genetic make-up. However, longitudinal studies of genetic moderation of parenting effects during early childhood have not been conducted. We examined developmental profiles of child behavior problems between 18 months and age 8 in a longitudinal parent-offspring sample of 361 adopted children. In toddlerhood (18 months), observed structured parenting indexed parental guidance in service of task goals. Biological parent psychopathology served as an index of genetic influences on children's behavior problems. Four profiles of child behavior problems were identified: low stable (11%), average stable (50%), higher stable (29%), and high increasing (11%). A multinominal logistic regression analysis indicated a genetically moderated effect of structured parenting, such that for children whose biological mother had higher psychopathology, the odds of the child being in the low stable group increased as structured parenting increased. Conversely, for children whose biological mother had lower psychopathology, the odds of being in the low stable group was reduced when structured parenting increased. Results suggest that increasing structured parenting is an effective strategy for children at higher genetic risk for psychopathology, but may be detrimental for those at lower genetic risk.

Examining Research Domain Criteria (RDoC) constructs for anger expression and regulation in toddlers.

The present study is focused on anger expression and regulation within the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) construct of Frustrative Nonreward. Although previous studies have examined associations between child anger regulation and expression, these studies do not directly address the dynamic processes involved in Frustrative Nonreward using microlongitudinal methods. The current study used data from 561 adopted children, their adoptive parents, and birth parents and aimed to address gaps in the literature by examining: (a) temporal associations between anger expression during a frustrating situation, and behaviors thought to regulate emotions (e.g., attempt-to-escape, support-seeking, distraction, and focus-on-restraint) on a microlongitudinal scale during an arm restraint task assessed at 27 months; (b) birth parent externalizing problems and overreactive parenting by adoptive parents as predictors of child anger expression and moderators of the moment-to-moment associations estimated in Step 1; and (c) longitudinal associations (linear vs. quadratic) between anger expressions and externalizing behaviors at 4.5 years. Findings indicated that children's attempt-to-escape and support-seeking predicted an increase in anger expression in the following 3-s interval, whereas distraction and focus-on-restraint were not associated with changes in anger expression. Furthermore, we found that birth parents' externalizing problems were significantly associated with child anger expression, suggesting heritable influences. Anger expression showed a U-shaped longitudinal association with paternal report of externalizing behaviors at 4.5 years. Taken together, the findings emphasize the significance of integrating microlongitudinal analysis approaches into the RDoC framework, helping to advance our understanding of dynamic processes underlying reactions to Frustrative Nonreward. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Reexamining the association between the interparental relationship and parent-child interactions: Incorporating heritable influences.

Family systems research has identified two key processes (spillover and compensatory), linking interparental relationship quality to the parent-child relationship. However, previous research has focused on the parent as the sole initiator and had not often considered the role of the child in these processes. The present study adds to the literature by leveraging a genetically informed design to examine possible child evocative effects on spillover and compensatory processes. Participants were from a longitudinal parent-offspring adoption sample of 361 linked sets of adoptive parents of an adopted child (57% male), and the child's birth parents. Adoptive parents reported on child pleasure and anger at 18 months and the interparental relationship at 27 months. Parent-child interactions were observed at child age 6 years, and heritable influences were assessed via birth mother self-report at 5 months. Our results indicated a dampening effect where higher interparental warmth at child age 27 months was associated with less adoptive mother-child coercion at child age 6 years, and a compensatory effect where higher interparental conflict was associated with more adoptive father-child positive engagement. Moreover, our results indicated child-driven effects via both genetic and environmental pathways. Specifically, higher levels of birth mother negative affect (heritable characteristic) were associated with lower levels of adoptive father-child coercion. Also, child anger was positively associated with interparental conflict, and child pleasure was positively associated with interparental warmth. These findings support findings from the family literature with evidence of compensatory mechanisms, while also highlighting the active role children play in shaping family interactions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Mice with muscle-specific deletion of Bin1 recapitulate centronuclear myopathy and acute downregulation of dynamin 2 improves their phenotypes.

Mutations in the BIN1 (Bridging Interactor 1) gene, encoding the membrane remodeling protein amphiphysin 2, cause centronuclear myopathy (CNM) associated with severe muscle weakness and myofiber disorganization and hypotrophy. There is no available therapy, and the validation of therapeutic proof of concept is impaired by the lack of a faithful and easy-to-handle mammalian model. Here, we generated and characterized the Bin1mck-/- mouse through Bin1 knockout in skeletal muscle. Bin1mck-/- mice were viable, unlike the constitutive Bin1 knockout, and displayed decreased muscle force and most histological hallmarks of CNM, including myofiber hypotrophy and intracellular disorganization. Notably, Bin1mck-/- myofibers presented strong defects in mitochondria and T-tubule networks associated with deficient calcium homeostasis and excitation-contraction coupling at the triads, potentially representing the main pathomechanisms. Systemic injection of antisense oligonucleotides (ASOs) targeting Dnm2 (Dynamin 2), which codes for dynamin 2, a BIN1 binding partner regulating membrane fission and mutated in other forms of CNM, improved muscle force and normalized the histological Bin1mck-/- phenotypes within 5 weeks. Overall, we generated a faithful mammalian model for CNM linked to BIN1 defects and validated Dnm2 ASOs as a first translatable approach to efficiently treat BIN1-CNM.

Parenting in the Context of the Child: Genetic and Social Processes.

The focus on the role of parenting in child development has a long-standing history. When measures of parenting precede changes in child development, researchers typically infer a causal role of parenting practices and attitudes on child development. However, this research is usually conducted with parents raising their own biological offspring. Such research designs cannot account for the effects of genes that are common to parents and children, nor for genetically influenced traits in children that influence how they are parented and how parenting affects them. The aim of this monograph is to provide a clearer view of parenting by synthesizing findings from the Early Growth and Development Study (EGDS). EGDS is a longitudinal study of adopted children, their birth parents, and their rearing parents studied across infancy and childhood. Families (N = 561) were recruited in the United States through adoption agencies between 2000 and 2010. Data collection began when adoptees were 9 months old (males = 57.2%; White 54.5%, Black 13.2%, Hispanic/Latinx 13.4%, Multiracial 17.8%, other 1.1%). The median child age at adoption placement was 2 days (M = 5.58, SD = 11.32). Adoptive parents were predominantly in their 30s, White, and coming from upper-middle- or upper-class backgrounds with high educational attainment (a mode at 4-year college or graduate degree). Most adoptive parents were heterosexual couples, and were married at the beginning of the project. The birth parent sample was more racially and ethnically diverse, but the majority (70%) were White. At the beginning of the study, most birth mothers and fathers were in their 20s, with a mode of educational attainment at high school degree, and few of them were married. We have been following these family members over time, assessing their genetic influences, prenatal environment, rearing environment, and child development. Controlling for effects of genes common to parents and children, we confirmed some previously reported associations between parenting, parent psychopathology, and marital adjustment in relation to child problematic and prosocial behavior. We also observed effects of children's heritable characteristics, characteristics thought to be transmitted from parent to child by genetic means, on their parents and how those effects contributed to subsequent child development. For example, we found that genetically influenced child impulsivity and social withdrawal both elicited harsh parenting, whereas a genetically influenced sunny disposition elicited parental warmth. We found numerous instances of children's genetically influenced characteristics that enhanced positive parental influences on child development or that protected them from harsh parenting. Integrating our findings, we propose a new, genetically informed process model of parenting. We posit that parents implicitly or explicitly detect genetically influenced liabilities and assets in their children. We also suggest future research into factors such as marital adjustment, that favor parents responding with appropriate protection or enhancement. Our findings illustrate a productive use of genetic information in prevention research: helping parents respond effectively to a profile of child strengths and challenges rather than using genetic information simply to identify some children unresponsive to current preventive interventions.

Mu opioid receptor in microglia contributes to morphine analgesic tolerance, hyperalgesia, and withdrawal in mice.

A major challenge in medicine is developing potent pain therapies without the adverse effects of opiates. Neuroinflammation and in particular microglial activation have been shown to contribute to these effects. However, the implication of the microglial mu opioid receptor (MOR) is not known. We developed a novel conditional knockout (cKO) mouse line, wherein MOR is deleted in microglia. Morphine analgesic tolerance was delayed in both sexes in cKO mice in the hot plate assay. Opioid-induced hyperalgesia (OIH) as measured in the tail immersion assay was abolished in male cKO mice, and physical dependence to morphine as assessed by naloxone-induced withdrawal was attenuated in female cKO mice. Our results show a sex-dependent contribution of microglial MOR in morphine analgesic tolerance, OIH, and physical dependence. In conclusion, our data suggest that blockade of microglial MOR could represent a therapeutic target for opiate analgesia without the opiate adverse effects.