Molecular mechanism for strengthening E-cadherin adhesion using a monoclonal antibody.

E-cadherin (Ecad) is an essential cell-cell adhesion protein with tumor suppression properties. The adhesive state of Ecad can be modified by the monoclonal antibody 19A11, which has potential applications in reducing cancer metastasis. Using X-ray crystallography, we determine the structure of 19A11 Fab bound to Ecad and show that the antibody binds to the first extracellular domain of Ecad near its primary adhesive motif: the strand-swap dimer interface. Molecular dynamics simulations and single-molecule atomic force microscopy demonstrate that 19A11 interacts with Ecad in two distinct modes: one that strengthens the strand-swap dimer and one that does not alter adhesion. We show that adhesion is strengthened by the formation of a salt bridge between 19A11 and Ecad, which in turn stabilizes the swapped ß-strand and its complementary binding pocket. Our results identify mechanistic principles for engineering antibodies to enhance Ecad adhesion.

The autism spectrum among transgender youth: default mode functional connectivity.

The common intersection of autism and transgender identities has been described in clinical and community contexts. This study investigates autism-related neurophenotypes among transgender youth. Forty-five transgender youth, evenly balanced across non-autistic, slightly subclinically autistic, and full-criteria autistic subgroupings, completed resting-state functional magnetic resonance imaging to examine functional connectivity. Results confirmed hypothesized default mode network (DMN) hub hyperconnectivity with visual and motor networks in autism, partially replicating previous studies comparing cisgender autistic and non-autistic adolescents. The slightly subclinically autistic group differed from both non-autistic and full-criteria autistic groups in DMN hub connectivity to ventral attention and sensorimotor networks, falling between non-autistic and full-criteria autistic groups. Autism traits showed a similar pattern to autism-related group analytics, and also related to hyperconnectivity between DMN hub and dorsal attention network. Internalizing, gender dysphoria, and gender minority-related stigma did not show connectivity differences. Connectivity differences within DMN followed previously reported patterns by designated sex at birth (i.e. female birth designation showing greater within-DMN connectivity). Overall, findings suggest behavioral diagnostics and autism traits in transgender youth correspond to observable differences in DMN hub connectivity. Further, this study reveals novel neurophenotypic characteristics associated with slightly subthreshold autism, highlighting the importance of research attention to this group.

Childhood inhibition predicts adolescent social anxiety: Findings from a longitudinal twin study.

An enduring issue in the study of mental health is identifying developmental processes that explain how childhood characteristics progress to maladaptive forms. We examine the role that behavioral inhibition (BI) has on social anxiety (SA) during adolescence in 868 families of twins assessed at ages 8, 13, and 15 years. Multimodal assessments of BI and SA were completed at each phase, with additional measures (e.g., parenting stress) for parents and twins. Analyses were conducted in several steps: first, we used a cross-lagged panel model to demonstrate bidirectional paths between BI and SA; second a biometric Cholesky decomposition showed that both genetic and environmental influences on childhood BI also affect adolescent SA; next, multilevel phenotypic models tested moderation effects between BI and SA. We tested seven potential moderators of the BI to SA prediction in individual models and included only those that emerged as significant in a final conditional model examining predictors of SA. Though several main effects emerged as significant, only parenting stress had a significant interaction with BI to predict SA, highlighting the importance of environmental moderators in models examining temperamental effects on later psychological symptoms. This comprehensive assessment continues to build the prototype for such developmental psychopathology models.

Observed physical activity among Latinx and White men and women on a new urban trail.

OBJECTIVE: Despite efforts to increase physical activity through new green space infrastructure such as trails, disparities in physical activity may persist. The current study compared observed vigorous physical activity (VPA) engagement among White and Latinx men and women on a new urban trail, and whether engagement varied over time. DESIGN, SAMPLE, AND MEASURES: We used a modified System for Observing Play and Recreation in Communities (SOPARC) methodology to determine observed race/ethnicity, gender, and physical activity level of trail users (n = 15,109). RESULTS: Logistic regression analyses revealed the odds of engaging in VPA were lower for Latina women than all other population subgroups (vs. White men: OR 0.19, CI 0.17-0.22; vs. White women: OR 0.48, CI 0.42-0.54, vs. Latino men: OR 0.23, CI 0.19-0.26). VPA engagement by White and Latina women increased across the study years (OR 1.31, CI 1.17-1.46; OR 1.36, CI 1.08-1.71, respectively) but did not differ significantly by year for White and Latino men. CONCLUSION: Future efforts to address racial/ethnic-gender disparities in VPA should take an intersectional approach to ensure that the needs of the most vulnerable population subgroups are properly accounted for.

Longitudinal effects of family psychopathology and stress on pubertal maturation and hormone coupling in adolescent twins.

Adolescents experience profound neuroendocrine changes, including hormone "coupling" between cortisol, testosterone, and dehydroepiandrosterone. Emerging research has only begun to elucidate the role of hormone coupling, its genetic and environmental etiology, and the extent to which coupling is impacted by gender, puberty, and family context. We included measures on parent and child mental health, parenting stress, and family conflict of 444 twin pairs and their parents across two timepoints, when youth were on average 8 and 13 years old, respectively. Structural equation models examined the impact of family context effects on coupling during adolescence. Biometric twin models were then used to probe additive genetic, shared, and non-shared environmental effects on hormone coupling. Hormones were more tightly coupled for females than males, and coupling was sensitive to parental depression and co-twin psychopathology symptoms and stress exposure in females. The association between family context and coupling varied across specific neuroendocrine measures and was largely distinct from pubertal maturation. Biometric models revealed robust shared and non-shared environmental influences on coupling. We found that family antecedents modify the strength of coupling. Environmental influences account for much of the variation on coupling during puberty. Gender differences were found in genetic influences on coupling.

Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment.

Skeletal muscle morphogenesis depends upon interactions between developing muscle fibers and the extracellular matrix (ECM) that anchors fibers to the myotendinous junction (MTJ). The pathways that organize the ECM and regulate its engagement by cell-matrix adhesion complexes (CMACs) are therefore essential for muscle integrity. Here, we demonstrate the impact of transmembrane protein 2 (tmem2) on cell-matrix interactions during muscle morphogenesis in zebrafish. Maternal-zygotic tmem2 mutants (MZtmem2) exhibit muscle fiber detachment, in association with impaired laminin organization and ineffective fibronectin degradation at the MTJ. Similarly, disorganized laminin and fibronectin surround MZtmem2 cardiomyocytes, which could account for their hindered movement during cardiac morphogenesis. In addition to ECM defects, MZtmem2 mutants display hypoglycosylation of α-dystroglycan within the CMAC, which could contribute to the observed fiber detachment. Expression of the Tmem2 ectodomain can rescue aspects of the MZtmem2 phenotype, consistent with a possible extracellular function of Tmem2. Together, our results suggest that Tmem2 regulates cell-matrix interactions by affecting both ECM organization and CMAC activity. These findings evoke possible connections between the functions of Tmem2 and the etiologies of congenital muscular dystrophies, particularly dystroglycanopathies.

Adrenocortical and autonomic attunement between romantic partners in emerging adulthood.

Parent-child physiological attunement, particularly during stressful situations, appears adaptive as shared stress reactivity may promote dyadic engagement. Romantic partners eventually replace parents as the primary support figure, yet it remains unclear whether romantic partners buffer physiological stress or display physiological attunement as most studies on adults examine attunement during conflict paradigms. The present study examined physiological attunement in 63 emerging adult romantic partner dyads (one partner was the active participant, the other the observer) during the Trier Social Stress Task (TSST). Heart rate (HR) and respiratory sinus arrhythmia (RSA) were continuously monitored across the visit. Repeated saliva samples were assayed for cortisol. Physiological attunement was operationalized as a correlation in biomarkers between the TSST participant and their partner; sex, social support, and physical proximity were examined as moderators. We then compared the biomarker profiles of partnered-TSST participants to individuals who participated in the TSST solo (n = 63) to determine if partner presence buffered stress biomarker reactivity during the TSST. RSA attunement between partners was found but was not further moderated by social support or sex. Adrenocortical attunement was moderated, such that lower social support and increased proximity resulted in higher attunement. HR attunement was higher when the participant was male and when partners were in close physical proximity. Compared to TSST solo, romantic partner presence increased participant cortisol levels and altered HR reactivity, suggesting that emerging adult romantic partners do not buffer physiological stress reactivity. Future research should examine whether physiological attunement and partner presence is protective in more established relationships.

Brain PET Imaging of α7-nAChR with [18F]ASEM: Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia.

Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) estimates in healthy volunteers. Repeated sessions of PET in 5 healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions: The current results confirm the reproducibility of [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.

Prenatal Life Events, Maternal Employment, and Postpartum Depression across a Diverse Population in New York City.

This study examined racial/ethnic disparities in three core postpartum depression (PPD) symptoms, and identified specific predictors of PPD including sociodemographic variables, life stressors and maternal employment. White, African American, Hispanic, and Asian/Pacific Islander women from the New York City area (n = 3010) completed the 2009-2011 Pregnancy Risk Assessment Monitoring System. African American women were less likely to have PPD than White women. Maternal employment during the postpartum was associated with an increased likelihood of PPD for White women relative to women who were not employed. Life stressors and maternal employment should be considered as culturally contextualized factors related to postpartum depression.

Visible-Light-Accelerated Copper(II)-Catalyzed Regio- and Chemoselective Oxo-Azidation of Vinyl Arenes.

The visible-light-accelerated oxo-azidation of vinyl arenes with trimethylsilylazide and molecular oxygen as stoichiometric oxidant was achieved. In contrast to photocatalysts based on iridium, ruthenium, or organic dyes, [Cu(dap)2 ]Cl or [Cu(dap)Cl2 ] were found to be unique for this transformation, which is attributed to their ability to interact with the substrates through ligand exchange and rebound mechanisms. CuII is proposed as the catalytically active species, which upon coordinating azide will undergo light-accelerated homolysis to form CuI and azide radicals. This activation principle (CuII -X→CuI +X. ) opens up new avenues for copper-based photocatalysis.

Social evaluative threat with verbal performance feedback alters neuroendocrine response to stress.

Laboratory stress tasks such as the Trier Social Stress Test (TSST) have provided a key piece to the puzzle for how psychosocial stress impacts the hypothalamic-pituitary-adrenal axis, other stress-responsive biomarkers, and ultimately wellbeing. These tasks are thought to work through biopsychosocial processes, specifically social evaluative threat and the uncontrollability heighten situational demands. The present study integrated an experimental modification to the design of the TSST to probe whether additional social evaluative threat, via negative verbal feedback about speech performance, can further alter stress reactivity in 63 men and women. This TSST study confirmed previous findings related to stress reactivity and stress recovery but extended this literature in several ways. First, we showed that additional social evaluative threat components, mid-task following the speech portion of the TSST, were still capable of enhancing the psychosocial stressor. Second, we considered stress-reactive hormones beyond cortisol to include dehydroepiandrosterone (DHEA) and testosterone, and found these hormones were also stress-responsive, and their release was coupled with one another. Third, we explored whether gain- and loss-framing incentive instructions, meant to influence performance motivation by enhancing the personal relevance of task performance, impacted hormonal reactivity. Results showed that each hormone was stress reactive and further had different responses to the modified TSST compared to the original TSST. Beyond the utility of showing how the TSST can be modified with heightened social evaluative threat and incentive-framing instructions, this study informs about how these three stress-responsive hormones have differential responses to the demands of a challenge and a stressor.

Compliance with parents' rules: between-person and within-person predictions.

The current study focused on the childhood to adolescence transition and sought to determine why some children are more compliant than others as well as why children comply more often with some of their parents' rules than with others. Indices of parents' agency and children's agency were tested as predictors of compliance. Parent-based decision-making and parents' responses to expressed disagreement served as indices of parents' agency while children's beliefs regarding the legitimacy of parents' rules and felt obligation to obey rules served as indices of children's agency. Parent-child dyads (n = 218; 51% female, 49% European American, 47% African American) were interviewed during the summers following the children's 5th (M adolescent age = 11.9 years) and 6th grade school years. Children who felt that their parents' rules were more legitimate were more compliant overall than were children who felt that the rules were less legitimate. Children compiled more with rules governing topics perceived to be legitimately regulated by parents, when parents made more decisions regarding the topic and when parents responded to disagreement by standing strong. Results were generally consistent across parents' and children's reports of compliance and across cross-sectional and longitudinal analyses. At the transition from childhood to adolescence, only children's agency explained why some children are more compliant than others, but parents' and children's agency helped to explain why children complied with some rules more than others.

Transgenerational effect of Mothers' experiences of discrimination on Black youths' hormone coupling in response to laboratory stress.

Exposure to pervasive racial discrimination of Black Americans is transgenerational in that mothers' experiences of discriminatory violence impacts their children. This study explored whether stress-related biomarkers reflect transgenerational racial stress by implementing a "dual activation" framework to probe how adrenal and gonadal hormones underlying adolescent development are co-regulated during a laboratory stressor. Data were collected from 120 Black families in the United States. Children completed the Trier Social Stress Task (TSST-C) and provided 4 saliva samples across 2 days that were assayed for cortisol (C), dehydroepiandrosterone (DHEA), and testosterone (T). Mothers reported their experiences of total discrimination and racial discrimination related to skin color/race. Thirty four percent reported experiences of discrimination and on average 46.7% reported experiences of discrimination due to their race or skin tone. Mothers' experiences of racial discrimination were associated with their child's hormonal reactivity to and recovery from the TSST-C. Youth showed stronger positive hormone coupling between C-T if their mother experienced greater discrimination. Mothers' experiences of racial discrimination influenced both C-T coupling and youths' cortisol recovery from the TSST-C. For youths with high testosterone, cortisol recovery was blunted. Results suggest that associations between racism and hormonal stress response may be transgenerational. Mothers' experiences of discrimination had a profound impact on their children's hormonal co-regulation.

Aging and Pubertal Development Differentially Predict Symptoms of ADHD, Depression, and Impairment in Children and Adolescents: An Eight-Year Longitudinal Study.

Activational effects of the reproductive neuroendocrine system may explain why some youths with ADHD are at greater risk for exacerbated ADHD symptoms (hyperactivity, inattention, impulsivity) during adolescence. For youths diagnosed with ADHD, first signs of ADHD symptoms become noticeable by multiple reporters (e.g., teachers, parents) when children enter schools, typically around kindergarten. The current study examined possible sex differences in ADHD, impairment, and comorbidity due to pubertal effects, as the role of pubertal development in ADHD is understudied. ADHD symptoms, depressive symptoms, impairment, and pubertal stage were assessed annually by multiple reporters in a well-characterized community sample of 849 children over-recruited for ADHD over eight years. Ages ranged from 7 to 13 years (38.16% female) at wave 1. Multilevel models indicated that males had higher levels of hyperactivity, impulsivity, and inattention than females, but that females had higher levels of impairment than males. Inattention symptoms did not show marked maturation changes. Hyperactivity and impulsivity declined as youth aged and impairment increased as youth aged. Lastly, depressive symptoms largely increased as youth aged and were higher amongst youth at later pubertal stages. Put together, aging and pubertal development are associated with improved ADHD symptoms but not for youth with high impairment. Findings from this study contributes to understanding the role that aging, pubertal status, and pubertal development plays in ADHD, impairment, and comorbidity in children and adolescents.

Examining the Pathologic Adaptation Model of Community Violence Exposure in Justice Involved Adolescents: the Moderating and Mediating Effects of Moral Disengagement.

According to the pathologic adaptation model (Ng-Mak et al. in The American Journal of Orthopsychiatry, 72, 92-101, 2002), youth who experience community violence exposure may become desensitized to these experiences. Moral disengagement, which refers to changing one's moral or ethical standards to justify engaging in destructive or harmful behavior, has been proposed as a construct to explain the relation between community violence exposure and desensitization (Bandura et al., 1996). The purpose of the current study was to test the pathologic adaptation model of community violence exposure and examine the role of moral disengagement in these pathways. The current study included a sample of justice-involved adolescents (n = 1,170; M age = 16.05, SD = 1.16) from the Pathways to Desistance study. The PROCESS bootstrapping procedure for SPSS was used to examine whether moral disengagement mediates the associations from community violence to aggressive behaviors and depressive. Exploratory analyses examined moral disengagement as a moderator these associations. Moral disengagement significantly moderated the association between witnessing violence and self-reported offending such that witnessing violence at baseline significantly positively predicted offending for individuals who were moderate to high (but not low) in moral disengagement. In contrast, moral disengagement did not moderate the linear association between community violence exposure and depressive symptoms. Further, moral disengagement did not mediate the association between community violence exposure and offending. Results from this study highlight the need to increase access to mental health services and re-entry programs to reduce offending behaviors for justice-involved youth.

Coping socialization in Black families: A latent profile analysis.

The purpose of the present study was to employ latent profile analysis (LPA) to identify distinct profiles of Black caregivers based on how they socialize their children to cope with stress. Participants included 126 Black female caregivers (Mage = 40.67, SD = 9.73) who provided data on 149 4th-8th-grade children (61% female; Mage = 11.21, SD = 1.52). Caregivers self-reported on socialization of child coping, caregiver support, and caregiver coping behaviors; children reported on caregiver socialization of coping, caregiver support, and child coping. The LPA revealed three distinct socialization profiles: A low diversified socialization profile, an engagement socialization profile, and a high diversified socialization profile. Caregivers in the low diversified socialization profile reported lower levels of primary and secondary engagement and disengagement coping, as well as increased parental support, compared to both the engagement socialization profile and high diversified socialization profile. Furthermore, results revealed that the three socialization profiles did not differ on children's self-report of coping. Results from the present study suggest variability among Black caregivers' coping socialization strategies and additional research is needed to maximize best outcomes for Black youth and their families. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Transient equilibrium determination of dopamine D2/D3 receptor densities and affinities in brain.

Long-term alteration of dopaminergic neurotransmission is known to modulate the D2/D3 receptor expression in the brain. The modulation can occur as a response to pathological processes or pharmacological intervention. The receptor density can be monitored by in vivo positron emission tomography (PET) of [11C] raclopride. To obtain accurate measurements of receptor-ligand interaction, it is essential to estimate binding parameters at true (if transient) equilibrium of bound and unbound ligand quantities. We designed this study as a comparison of two quantitative approaches to transient equilibrium, the TRansient EquilibriuM BoLus Estimation (TREMBLE) method and the Transient Equilibrium Model (TEM) method, to determine binding parameters at transient equilibrium with bolus injection of the radioligand. The data demonstrates that TREMBLE unlike TEM identified the time at which equilibrium existed. TREMBLE revealed that equilibrium prevailed at one or more times after bolus injection and identified differences of receptor density among regions such as putamen and caudate nucleus. We demonstrated that TREMBLE is a quantitative approach suitable for the study of pathophysiological conditions of certain types of neurotransmission the brain.

Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a promising drug target in Gram-negative bacteria. Previously, we described a correlation between the residence time of inhibitors on Pseudomonas aeruginosa LpxC (paLpxC) and the post-antibiotic effect (PAE) caused by the inhibitors on the growth of P. aeruginosa. Given that drugs with prolonged activity following compound removal may have advantages in dosing regimens, we have explored the structure-kinetic relationship for paLpxC inhibition by analogues of the pyridone methylsulfone PF5081090 (1) originally developed by Pfizer. Several analogues have longer residence times on paLpxC than 1 (41 min) including PT913, which has a residence time of 124 min. PT913 also has a PAE of 4 h, extending the original correlation observed between residence time and PAE. Collectively, the studies provide a platform for the rational modulation of paLpxC inhibitor residence time and the potential development of antibacterial agents that cause prolonged suppression of bacterial growth.

Hyper- and hypo-cortisol functioning in post-institutionalized adolescents: The role of severity of neglect and context.

Understanding the developmental timing of stress exposure may help inform mechanisms underlying how stress "gets under the skin" and influences the stress response system, including the HPA axis and its end-product cortisol. Early adversity may be particularly detrimental; however, it is difficult to disentangle the timing of adversity from its cumulative burden because there is typically high continuity between early and later adversity. Moreover, context and the different stressors inherent in various contexts may interact with stress exposure to influence psychophysiological functioning. To address this issue, we examined adolescents who had been reared in institutions and suffered neglect or social deprivation ranging from approximately six months to several years of life prior to adoption into U.S. homes. We focused on the stress hormone cortisol because it can reflect continued regulatory problems in youth, even years after youth transition to typical homes. We examined cortisol morning levels and diurnal rhythms across multiple contexts (home, school, lab) on 5 separate days in 41 post-institutionalized youth and 78 comparison youth. Employing hierarchical linear modeling, we found that when assessed in the lab, post-institutionalized (PI) youth displayed lower morning cortisol levels and flatter diurnal slopes than the control youth. Yet at home, PI youth displayed higher morning cortisol levels than the control youth. In addition to group effects, we also examined severity of early adversity and found that PI kids who had endured the most severe early adversity displayed lower home cortisol levels than controls. No significant predictors of diurnal cortisol on school days were identified. These data fit with the notion that the HPA axis is impacted by early adversity, even years after adoption, and with emerging theories that postulate that stress physiology calibrates within youth to help them adapt to their context. In the case of severe early adversity, the cost of such adaptation may not be desirable. It also highlights the important role of context when assessing HPA axis activity, particularly in post-institutionalized youth.