Caseload factors predictive of family abuse and neglect treatment outcomes.

BACKGROUND: In child welfare, caseloads are frequently far higher than optimal. Not all cases are created equal; however, little is known about which combination and interaction of factors make caseloads more challenging and impact child and family outcomes. OBJECTIVE: This study aims to identify which case, provider, and organizational factors most strongly differentiate between families with favorable and less-than-positive treatment outcomes. PARTICIPANTS AND SETTING: Participants were 25 family advocacy program providers and 17 supervisors at 11 Department of the Air Force installations. METHODS: Following informed consent, participants completed demographic and caseload questionnaires, and we collected information about organizational factors. Providers were sent a weekly case update and burnout questionnaire for seven months. We used linear mixed-effects model tree (LMM tree) algorithms to determine the provider, client, and organizational characteristics that best distinguish between favorable vs. unfavorable outcomes. RESULTS: The LMM tree predicting provider-rated treatment success yielded three significant partitioning variables: (a) commander involvement, (b) case complexity, and (c) % of clients in a high-risk field. The LMM predicting client-rated treatment progress yielded seven significant partitioning variables: (a) command involvement; (b) ease of reaching tenant unit command; (c) # of high-risk cases; (d) % of clients receiving Alcohol and Drug Abuse Prevention and Treatment services; (e) ease of reaching command; (f) % of clients with legal involvement; (g) provider age. CONCLUSIONS: This study is a first step toward developing a dynamic caseload management tool. An intelligent, algorithm-informed approach to case assignment could help child welfare agencies operate in their typically resource-scarce contexts in a manner that improves outcomes.

Do Brief Lab-Based Interventions Decrease Coercive Conflict Within Couples and Parent-Child Dyads?

Coercive conflicts between parents and children and between couples are implicated in the pathogenesis of a variety of psychological and physical health problems. Despite its seeming importance to population health, there are no widely available, easy-to-use methods with demonstrated efficacy to engage coercive conflict and reduce it. Identifying and testing potentially efficacious and disseminable micro-interventions (i.e., interventions that can be delivered in under 15 minutes via computer or paraprofessional) for targets with cross-cutting health implications, such as coercive conflict, is the focus of the National Institutes of Health Science of Behavior Change initiative. We experimentally tested four micro-interventions targeting coercive conflict in couple and parent-child dyads in a within-between design. There were mixed but supportive findings for the efficacy of most of the micro-interventions. Attributional reframing, implementation intentions, and evaluative conditioning all reduced coercive conflict as assessed by some but not all measures of observed coercion. No findings indicated any iatrogenic effects. Interpretation bias modification treatment improved at least one measure of coercive conflict for couples, but not for parents and children; additionally, it increased self-reported coercive conflict. Overall, these results are encouraging and suggest that very brief and highly disseminable micro-interventions for coercive conflict are a fruitful direction for inquiry. Optimizing micro-interventions and deploying them across the health care infrastructure could tremendously enhance family functioning and, in turn, health behaviors and health (ClinicalTrials.gov IDs: NCT03163082, NCT03162822).

Predictors of Crosscutting Patterns of Psychological Health and Family Maltreatment.

INTRODUCTION: Psychological problems and family maltreatment are significant public health problems. Although research focuses almost exclusively on either individual psychological problems or family maltreatment, there is substantial co-occurrence of these problems. Similarly, intervention services are often "siloed": individuals with mental health needs are referred for mental health services, individuals with family conflict are referred for family-based treatment, etc. These treatment "silos" may miss the larger picture of the co-occurrence of risk, promotion, and the problems themselves. In a previous paper, we used latent class analysis to identify subgroups of individuals with crosscutting patterns (i.e., classes) of psychological and family maltreatment problems. In this study, we explored the predictors of these latent classes. MATERIALS AND METHODS: Participants consisted of two large population samples of U.S. Air Force active duty members (ns = 27,895 and 30,841) who were married or cohabiting and had one or more children living in their household. Participants completed an anonymous community assessment survey, which included questionnaire items tapping personal, family, and community problems and well-being. Assessments were conducted in 2008 and 2011. All study procedures were approved by the authors' Institutional Review Board. We used exploratory factor analysis and latent class analysis to (1) identify higher-order factors of risk and promotive variables and (2) examine them as predictors of our previously identified latent classes. RESULTS: Findings indicated that individuals who reported better physical well-being as well as personal and family coping, relationship satisfaction, and support were more likely to be in the lowest-risk subgroup. Notably, individuals in the subgroup most at risk for serious violence and suicide, evidencing disinhibitory psychopathology, endorsed lower risk and higher promotive factors than those individuals in other high-risk subgroups who fell along the internalizing/externalizing continuum. CONCLUSIONS: These findings reinforce the need for integrated prevention and treatment of psychological and family maltreatment problems. Not only do these problems often co-occur, but their risk and promotive factors also tend to be intertwined. The unique (i.e., not on the continuum of the other five classes) problem profile of participants evidencing disinhibitory psychopathology is matched by a unique risk/promotive factor profile, and they will thus likely require a unique intervention approach.

Do Fairly-Decided Maltreatment Determinations Significantly Reduce Recidivism? A Quasi-Experimental Evaluation of a System-Level Intervention Implementation.

Two studies examined the impact of the implementation of the Field-tested Assessment, Intervention-planning, and Response (FAIR) system, a system-level intervention for determining whether allegations of family maltreatment meet threshold for abuse or neglect, on alleged recidivism. Data were collected at the 10 U.S. Army installations with the largest family maltreatment caseloads. Participants were family members who had an allegation of family maltreatment (i.e., child maltreatment or partner abuse) during one of the two study periods. Data were collected when Family Advocacy Program staff used the then-in-place system (Case Review Committee) and later the FAIR system. In Study 1, cases were followed for 6 months following the initial maltreatment allegation to measure the occurrence of subsequent allegations of any type. Additionally, at five installations, alleged victims of partner abuse were recruited into a study (Study 2) in which they anonymously reported on intimate partner violence via telephone. In Study 1, the advantage for the FAIR condition was concentrated in cases with unsubstantiated initial determinations; the mean relative risk reduction for recidivism was 0.48. In Study 2, FAIR extended median time to recidivism by approximately 170%. These results replicate and extend earlier findings that employing the FAIR system can result in decreased family maltreatment re-offense.

"Self-report measures of coercive process in couple and parent-child dyads": Correction.

Reports an error in "Self-report measures of coercive process in couple and parent-child dyads" by Danielle M. Mitnick, Michael F. Lorber, Amy M. Smith Slep, Richard E. Heyman, Shu Xu, Lisanne J. Bulling, Sara R. Nichols and J. Mark Eddy (Journal of Family Psychology, 2021[Apr], Vol 35[3], 388-398). In the original article, the full acknowledgment of funding was missing in the author note and should have read "This work was supported by the National Institutes of Health (NIH) Science of Behavior Change Common Fund Program and the National Institute of Dental and Craniofacial Research through an award administered by the National Institute of Dental and Craniofacial Research [1UH2DE025980-01]." The online version of this article has been corrected. (The following abstract of the original article appeared in record 2020-49926-001). One of the most influential behavioral models of family conflict is G. R. Patterson's (1982) coercive family process theory. Self-reports for behaviors related to coercion (e.g., hostility toward a family member) abound; however, there are no self-report measures for coercive process itself, which is, by definition, a dyadic process. Operationalizations of coercive process are measured with behavioral observation, typically including sequential analyzed, microcoded behaviors. Despite its objectivity and rigor, coding of behavior observation is not always feasible in research and applied settings because of the high training, personnel, and time costs the observation requires. Because coercive process has been shown to predict a host of maladaptive outcomes (e.g., parent-child conflict, aggression, negative health outcomes) and given the complete absence of self-report measures of coercive process, we recently designed brief questionnaires to assess coercive process in couple (Couple Coercive Process Scale [CCPS]) and parent-child interactions (Parent-Child Coercive Process Scale [PCCPS]) and tested them via Qualtrics participant panels in samples recruited to mirror socioeconomic generalizability to U.S. Census data. The CCPS and PCCPS exhibited initial evidence of psychometric quality in measuring coercive process in couple and parent-child dyads: Both measures are unifactorial; have evidence of reliability, especially at higher levels of coercive process; and demonstrate concurrent validity with constructs in their nomological networks, with medium to large effect sizes. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Evaluation of Two Approaches for Responding to Allegations of Family Maltreatment in the U.S. Army: Coordinated Community Response Impacts and Costs.

INTRODUCTION: The U.S. Air Force (USAF) conducted a program of research to develop and disseminate reliable and valid criteria for partner and child maltreatment (comprising abuse [physical, emotional/psychological, and sexual] and neglect). These criteria are now used in all branches of the U.S. military. The U.S. Army was the first service outside the USAF to adopt the criteria sets and computerized decision support tool but maintained the original committee composition (the "Case Review Committee" [CRC]) instead of adopting the entire assessment, allegation determination, and treatment planning process (the "Field-tested Assessment, Intervention-planning, and Response" [FAIR] system). The Army commissioned this study to compare the CRC and FAIR processes by testing (1) intra-committee process (i.e., three facets of committee functioning-fidelity to regulations, cohesion and team process, outsized influence of unit representatives); (2) coordinated community response to maltreatment (i.e., perceptions of fairness to alleged offenders and victims, impact on unit representatives, and (3) collaboration between the Family Advocacy Program (FAP, the military's maltreatment response agency) and outside agencies; and (4) the time expended and cost. MATERIALS AND METHODS: New York University's Institutional Review Board approved the study protocol, and the Army's Human Research Protection Office provided permission to collect data. The ten Army garrisons with the most annual maltreatment cases participated. Committee members, FAP social workers, unit commanders, and independent observers completed assessments of individual meetings and of their overall impression of the processes. A test of whether the means significantly differed between phases was then performed separately for each outcome, and 95% CIs of the unstandardized mean difference between phases were estimated. RESULTS: Independent observers rated FAIR meetings as significantly more faithful to regulations. Unit representatives (i.e., commanders and/or first sergeants) perceived the committee to function better during FAIR (although other committee members and independent observers did not perceive differences). Unit representatives not only rated FAIR as significantly more fair to both alleged offenders and victims (ratings from other committee members did not differ), but also were more likely to attend FAIR meetings and, when they did, rated their ability to serve soldiers and families higher during FAIR. However, FAP social workers rated their relationships with units as being better during CRC, and outside agencies rated their relationship with FAP as significantly better during CRC. Costs to the Army were nearly identical in the two committee structures. CONCLUSION: Results indicated that the CRC and FAIR processes cost almost identical amounts to run and that the FAIR system was superior in ways most likely to impact service members: (1) independent observers judged its meetings to be more faithful to Army and DoD Instructions; (2) unit representatives were more likely to attend and believed the FAIR system to be fairer (to both alleged offenders and victims) and better functioning. Care should be taken, however, in nurturing relationships between FAP and (1) unit representatives and (2) outside agencies, which may have weakened during FAIR.

Self-report measures of coercive process in couple and parent-child dyads.

One of the most influential behavioral models of family conflict is G. R. Patterson's (1982) coercive family process theory. Self-reports for behaviors related to coercion (e.g., hostility toward a family member) abound; however, there are no self-report measures for coercive process itself, which is, by definition, a dyadic process. Operationalizations of coercive process are measured with behavioral observation, typically including sequential analyzed, microcoded behaviors. Despite its objectivity and rigor, coding of behavior observation is not always feasible in research and applied settings because of the high training, personnel, and time costs the observation requires. Because coercive process has been shown to predict a host of maladaptive outcomes (e.g., parent-child conflict, aggression, negative health outcomes) and given the complete absence of self-report measures of coercive process, we recently designed brief questionnaires to assess coercive process in couple (Couple Coercive Process Scale [CCPS]) and parent-child interactions (Parent-Child Coercive Process Scale [PCCPS]) and tested them via Qualtrics participant panels in samples recruited to mirror socioeconomic generalizability to U.S. Census data. The CCPS and PCCPS exhibited initial evidence of psychometric quality in measuring coercive process in couple and parent-child dyads: Both measures are unifactorial; have evidence of reliability, especially at higher levels of coercive process; and demonstrate concurrent validity with constructs in their nomological networks, with medium to large effect sizes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Randomized, Double-Blind, Crossover, Clinical-End-Point Pilot Study to Examine the Use of Exhaled Nitric Oxide as a Bioassay for Dose Separation of Inhaled Fluticasone Propionate.

This was a randomized, double-blind, crossover, clinical-end-point pilot study examining the hypothesis that inhaled fluticasone propionate decreases exhaled nitric oxide (eNO) concentrations within a week of beginning treatment and shows evidence of dose separation across the marketed dose range. Subjects had a ≥6-month history of asthma and screening eNO ≥60 parts per billion. At the start of each treatment period, eNO was ≥55 parts per billion, and forced expiratory volume in 1 second was ≥50% predicted. Subjects attended a clinic visit daily on consecutive mornings during each of 3 1-week treatment periods to measure eNO and receive once-daily doses of 100/50, 250/50, or 500/50 fluticasone propionate/salmeterol combination product (Advair® Diskus). Daily eNO value recorded was the highest of 3 measurements; 1 inhalation of treatment was then administered. Procedures were repeated for 3 treatment cycles, separated by 14-day minimum washouts. A total of 105 subjects were screened; 22 were randomized; and 17 completed all treatments. Mean percentage eNO decrease (standard deviation) from day 1 baseline for each treatment period was 36.6 (±18.7), 45.3 (±16.5), and 54.6 (±12.5) with Advair® 100/50, 250/50, and 500/50, respectively. Mean percentage decrease in eNO across each treatment (dose) was modeled using a mixed-model ANOVA. Although the overall treatment was significant (P = .0015), because of the relatively small sample size and within-subject variability, only the 100/50 vs 500/50 (P = .0003) and 250/50 vs 500/50 (P = .047) treatments were significantly different.

Sibling teenage pregnancy and clinic-referred girls' condom use: The protective role of maternal monitoring.

Younger sisters of teenage parents have elevated rates of engaging in unprotected sex. This may result from changes in parenting behavior after a sibling becomes pregnant or impregnates a partner, and be particularly pronounced for girls seeking mental health treatment. The current study examines condom use over time in 211 African-American girls recruited from outpatient psychiatric clinics. Findings indicate that having a sibling with a teenage pregnancy history predicts less consistent condom use two years later. After accounting for earlier condom use and mental health problems, maternal monitoring moderates condom use such that for girls with a sibling with a pregnancy history, more vigilant maternal monitoring is associated with increased condom use, while for girls with no sibling pregnancy history, maternal monitoring is unrelated to adolescents' condom use two years later. Findings suggest that targeted interventions to increase maternal monitoring of high-risk teens may be beneficial for girls with a sibling history of teenage pregnancy.

Economic Hardship, Parent Positive Communication and Mental Health in Urban Adolescents Seeking Outpatient Psychiatric Care.

Economic hardship and poor parenting behaviors are associated with increased risk for mental health problems in community adolescents. However, less is known about the impact of socioeconomic status (SES) and parenting behaviors on youth at elevated risk for mental health problems, such as teens seeking outpatient psychiatric care. This study examined whether family SES and parent positive communication were directly and indirectly associated with mental health symptoms six months later in urban teens seeking outpatient treatment, after accounting for baseline levels of symptoms. At baseline, adolescent participants (N = 346; 42% female; 61% African-American) ages 12 to 19 years old (M = 14.9; SD = 1.8) and their primary caregivers reported on SES and teen internalizing and externalizing symptoms and engaged in a videotaped discussion of a real-life conflict to assess parent positive communication. At 6-month follow-up, 81% (N = 279) of families were retained and teens and caregivers again reported internalizing and externalizing symptoms. Structural Equation Modeling (SEM) was used to test the hypothesized models with a sample of 338, using the full information likelihood method to adjust for missing data. For parent-reported externalizing symptoms, SEM revealed support for the indirect association of SES with follow-up externalizing symptoms via parent positive communication and externalizing symptoms at baseline. For parent reported internalizing symptoms, there was a direct association between SES and follow-up internalizing symptoms, but not an indirect effect via parent positive communication. Youth-reported symptoms were not associated with SES nor with parent positive communication. Current findings extend prior research on adolescent mental health in a diverse sample of urban youth seeking outpatient psychiatric care. These families may benefit from interventions that directly target SES-related difficulties and parent positive communication.

Punishment Insensitivity in Early Childhood: A Developmental, Dimensional Approach.

Impairment in learning from punishment ("punishment insensitivity") is an established feature of severe antisocial behavior in adults and youth but it has not been well studied as a developmental phenomenon. In early childhood, differentiating a normal: abnormal spectrum of punishment insensitivity is key for distinguishing normative misbehavior from atypical manifestations. This study employed a novel measure, the Multidimensional Assessment Profile of Disruptive Behavior (MAP-DB), to examine the distribution, dimensionality, and external validity of punishment insensitivity in a large, demographically diverse community sample of preschoolers (3-5 years) recruited from pediatric clinics (N = 1,855). Caregivers completed surveys from which a seven-item Punishment Insensitivity scale was derived. Findings indicated that Punishment Insensitivity behaviors are relatively common in young children, with at least 50 % of preschoolers exhibiting them sometimes. Item response theory analyses revealed a Punishment Insensitivity spectrum. Items varied along a severity continuum: most items needed to occur "Often" in order to be severe and behaviors that were qualitatively atypical or intense were more severe. Although there were item-level differences across sociodemographic groups, these were small. Construct, convergent, and divergent validity were demonstrated via association to low concern for others and noncompliance, motivational regulation, and a disruptive family context. Incremental clinical utility was demonstrated in relation to impairment. Early childhood punishment insensitivity varies along a severity continuum and is atypical when it predominates. Implications for understanding the phenomenology of emergent disruptive behavior are discussed.

18F-RB390: innovative ligand for imaging the T877A androgen receptor mutant in prostate cancer via positron emission tomography (PET).

BACKGROUND: Detecting prostate cancer before spreading or predicting a favorable therapy are challenging issues for impacting patient's survival. Presently, 2-[(18) F]-fluoro-2-deoxy-D-glucose ((18) F-FDG) and/or (18) F-fluorocholine ((18) F-FCH) are the generally used PET-tracers in oncology yet do not emphasize the T877A androgen receptor (AR) mutation being exclusively present in cancerous tissue and escaping androgen deprivation treatment. METHODS: We designed and synthesized fluorinated 5α-dihydrotestosterone (DHT) derivatives to target T877A-AR. We performed binding assays to select suitable candidates using COS-7 cells transfected with wild-type or T877A AR (WT-AR, T877A-AR) expressing plasmids and investigated cellular uptake of candidate (18) F-RB390. Stability, biodistribution analyses and PET-Imaging were assessed by injecting (18) F-RB390 (10MBq), with and without co-injection of an excess of unlabeled DHT in C4-2 and PC-3 tumor bearing male SCID mice (n = 12). RESULTS: RB390 presented a higher relative binding affinity (RBA) (28.1%, IC50 = 32 nM) for T877A-AR than for WT-AR (1.7%, IC50 = 357 nM) related to DHT (RBA = 100%). A small fraction of (18) F-RB390 was metabolized when incubated with murine liver homogenate or human blood for 3 hr. The metabolite of RB390, 3-hydroxysteroid RB448, presented similar binding characteristics as RB390. (18) F-RB390 but not (18) F-FDG or (18) F-FCH accumulated 2.5× more in COS-7 cells transfected with pSG5AR-T877A than with control plasmid. Accumulation was reduced with an excess of DHT. PET/CT imaging and biodistribution studies revealed a significantly higher uptake of (18) F-RB390 in T877A mutation positive xenografts compared to PC-3 control tumors. This effect was blunted with DHT. CONCLUSION: Given the differential binding capacity and the favorable radioactivity pattern, (18) F-RB390 represents the portrayal of the first imaging ligand with predictive potential for mutant T877A-AR in prostate cancer for guiding therapy. Prostate 75:348-359, 2015. © 2014 Wiley Periodicals, Inc.

Risking it for love: romantic relationships and early pubertal development confer risk for later disruptive behavior disorders in African-American girls receiving psychiatric care.

Disruptive behavior problems (DBP) represent a growing concern for young women (e.g., Snyder and Sickmund, 2006), but gender-specific investigations have been traditionally underrepresented in this area. The purpose of this study is to examine the associations among gender-relevant risk factors for DBP among 217 African American girls in psychiatric care. African American girls, 12-16 years old (M = 14.6; SD = 1.2), and their primary female caregivers (N = 254) were recruited from outpatient mental health clinics and reported on girls' DBP, heterosexual dating experiences (romantic and sexual), peer relationships, pubertal development, and self-silencing at baseline, 6-, and 12 months. Structural Equation Modeling examined evidence for full versus mediated (via self-silencing) models and the structural relationships (direct and indirect) among key study variables. Results suggest that the full model was a significantly better fit than the mediated model as indicated by a Chi-squared difference test (p < 0.01). In the full model, direct effects of greater romantic dating experiences and lower quality peer relationships at baseline predicted DBP at 12 months. Sexual dating experiences were more strongly linked with DBP at 12 months for early maturing compared to average or later maturing girls. Indirect effects analyses suggested that girls' suppression of relational needs, assessed through a measure of self-silencing, explained the association between peer relationships and DBP. Findings highlight the importance of the relational context for girls' DBP, with treatment implications supporting relationship-based models of care, early intervention, and skill building around negotiating needs with peers and partners.

Gender differences in the effects of community violence on mental health outcomes in a sample of low-income youth receiving psychiatric care.

Previous research suggests that community violence impacts mental health outcomes, but much of this research has not (a) distinguished between different types of community violence, (b) examined gender differences, and (c) focused on youth living in urban poverty. The current study addresses these questions. Participants were 306 youth (23 % girls) and one parent/guardian receiving outpatient psychiatric services for disruptive behavior disorders in a large urban city. Youth and parents reported on youth's experience of different types of community violence (being a direct victim, hearing reports, and witnessing violence), and whether violence was directed toward a stranger or familiar. Outcomes included youth externalizing, internalizing, and posttraumatic stress symptoms assessed via parent and youth reports. Being a direct victim of violence accords risk for all mental health outcomes similarly for both boys and girls. However, gender differences emerged with respect to indirect violence, such that girls who hear reports of violence against people they know are at increased risk for all assessed mental health outcomes, and girls who witness violence against familiars are at increased risk for externalizing mental health symptoms in particular. There are gender differences in violence-related mental health etiology, with implications for intervention assessment and design.

Free energy landscape of G-protein coupled receptors, explored by accelerated molecular dynamics.

G-protein coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. They are known to adopt multiple conformational states (e.g., inactive, intermediate and active) during their modulation of various cell signaling pathways. Here, the free energy landscape of GPCRs is explored using accelerated molecular dynamics (aMD) simulations as demonstrated on the M2 muscarinic receptor, a key GPCR that regulates human heart rate and contractile forces of cardiomyocytes. Free energy profiles of important structural motifs that undergo conformational transitions upon GPCR activation and allosteric signaling are analyzed in detail, including the Arg(3.50)-Glu(6.30) ionic lock, the Trp(6.48) toggle switch and the hydrogen interactions between Tyr(5.58)-Tyr(7.53).

Advancing a multidimensional, developmental spectrum approach to preschool disruptive behavior.

OBJECTIVE: Dimensional approaches are gaining scientific traction. However, their potential for elucidating developmental aspects of psychopathology has not been fully realized. The goal of this article is to apply a multidimensional, developmental framework to model the normal-abnormal spectrum of preschool disruptive behavior. The Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB), a novel measure, was used to model dimensional severity across developmental parameters theorized to distinguish the normative misbehavior of early childhood from clinically salient disruptive behavior. The 4 MAP-DB dimensions are Temper Loss, Noncompliance, Aggression, and Low Concern for Others. METHOD: Parents of a diverse sample of 1,488 preschoolers completed the MAP-DB. Multidimensional item response theory (IRT) was used for dimensional modeling. RESULTS: The 4-dimensional, developmentally informed model demonstrated excellent fit. Its factor loadings did not differ across demographic subgroups. All dimensions provided good coverage of the abnormal end of the severity continuum, but only Temper Loss and Noncompliance provided good coverage of milder, normatively occurring behaviors. The developmental expectability and quality of behaviors distinguished normative from atypical behaviors. The point at which frequency of behaviors was atypical varied based on dimensional location for Temper Loss, Noncompliance, and Aggression. CONCLUSION: The MAP-DB provides an innovative method for operationalizing developmentally specified, dimensional phenotypes in early childhood. Establishing the validity of these dimensional phenotypes in relation to clinical outcomes, neurocognitive substrates, and etiologic pathways will be a crucial test of their clinical utility.

Punishment insensitivity and impaired reinforcement learning in preschoolers.

BACKGROUND: Youth and adults with psychopathic traits display disrupted reinforcement learning. Advances in measurement now enable examination of this association in preschoolers. The current study examines relations between reinforcement learning in preschoolers and parent ratings of reduced responsiveness to socialization, conceptualized as a developmental vulnerability to psychopathic traits. METHODS: One hundred and fifty-seven preschoolers (mean age 4.7 ± 0.8 years) participated in a substudy that was embedded within a larger project. Children completed the 'Stars-in-Jars' task, which involved learning to select rewarded jars and avoid punished jars. Maternal report of responsiveness to socialization was assessed with the Punishment Insensitivity and Low Concern for Others scales of the Multidimensional Assessment of Preschool Disruptive Behavior (MAP-DB). RESULTS: Punishment Insensitivity, but not Low Concern for Others, was significantly associated with reinforcement learning in multivariate models that accounted for age and sex. Specifically, higher Punishment Insensitivity was associated with significantly lower overall performance and more errors on punished trials ('passive avoidance'). CONCLUSIONS: Impairments in reinforcement learning manifest in preschoolers who are high in maternal ratings of Punishment Insensitivity. If replicated, these findings may help to pinpoint the neurodevelopmental antecedents of psychopathic tendencies and suggest novel intervention targets beginning in early childhood.

Mapping of allosteric druggable sites in activation-associated conformers of the M2 muscarinic receptor.

G-protein-coupled receptors (GPCRs) are key cellular signaling proteins and have been targeted by approximately 30-40% of marketed drugs for treating many human diseases including cancer and heart failure. Recently, we directly observed activation of the M2 muscarinic receptor through long-timescale accelerated molecular dynamics (aMD) simulation, which revealed distinct inactive, intermediate and active conformers of the receptor. Here, FTMAP is applied to search for 'hot spots' in these activation-associated conformers using a library of 16 organic probe molecules that represent fragments of potential drugs. Seven allosteric (non-orthosteric) binding sites are identified in the M2 receptor through the FTMAP analysis. These sites are distributed in the solvent-exposed extracellular and intracellular mouth regions, as well as the lipid-exposed pockets formed by the transmembrane α helices TM3-TM4, TM5-TM6 and TM7-TM1/TM2. They serve as promising target sites for designing novel allosteric modulators as receptor-selective drugs.

Activation and dynamic network of the M2 muscarinic receptor.

G-protein-coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. Although significant advances have been made in structural studies of GPCRs, details of their activation mechanism remain unclear. The X-ray crystal structure of the M2 muscarinic receptor, a key GPCR that regulates human heart rate and contractile forces of cardiomyocytes, was determined recently in an inactive antagonist-bound state. Here, activation of the M2 receptor is directly observed via accelerated molecular dynamics simulation, in contrast to previous microsecond-timescale conventional molecular dynamics simulations in which the receptor remained inactive. Receptor activation is characterized by formation of a Tyr206(5.58)-Tyr440(7.53) hydrogen bond and ∼6-Å outward tilting of the cytoplasmic end of transmembrane α-helix 6, preceded by relocation of Trp400(6.48) toward Phe195(5.47) and Val199(5.51) and flipping of Tyr430(7.43) away from the ligand-binding cavity. Network analysis reveals that communication in the intracellular domains is greatly weakened during activation of the receptor. Together with the finding that residue motions in the ligand-binding and G-protein-coupling sites of the apo receptor are correlated, this result highlights a dynamic network for allosteric regulation of the M2 receptor activation.

Structure-based network analysis of an evolved G protein-coupled receptor homodimer interface.

Crystallographic structures and experimental assays of human CXC chemokine receptor type 4 (CXCR4) provide strong evidence for the capacity to homodimerize, potentially as a means of allosteric regulation. Even so, how this homodimer forms and its biological significance has yet to be fully characterized. By applying principles from network analysis, sequence-based approaches such as statistical coupling analysis to determine coevolutionary residues, can be used in conjunction with molecular dynamics simulations to identify residues relevant to dimerization. Here, the predominant coevolution sector lies along the observed dimer interface, suggesting functional relevance. Furthermore, coevolution scoring provides a basis for determining significant nodes, termed hubs, in the network formed by residues found along the interface of the homodimer. These node residues coincide with hotspots indicating potential druggability. Drug design efforts targeting such key residues could potentially result in modulation of binding and therapeutic benefits for disease states, such as lung cancers, lymphomas and latent HIV-1 infection. Furthermore, this method may be applied to any protein-protein interaction.