Integrating developmental neuroscience with community-engaged approaches to address mental health outcomes for housing-insecure youth: Implications for research, practice, and policy.

One in three children in the United States is exposed to insecure housing conditions, including unaffordable, inconsistent, and unsafe housing. These exposures have detrimental impacts on youth mental health. Delineating the neurobehavioral pathways linking exposure to housing insecurity with children's mental health has the potential to inform interventions and policy. However, in approaching this work, carefully considering the lived experiences of youth and families is essential to translating scientific discovery to improve health outcomes in an equitable and representative way. In the current paper, we provide an introduction to the range of stressful experiences that children may face when exposed to insecure housing conditions. Next, we highlight findings from the early-life stress literature regarding the potential neurobehavioral consequences of insecure housing, focusing on how unpredictability is associated with the neural circuitry supporting cognitive and emotional development. We then delineate how community-engaged research (CEnR) approaches have been leveraged to understand the effects of housing insecurity on mental health, and we propose future research directions that integrate developmental neuroscience research and CEnR approaches to maximize the impact of this work. We conclude by outlining practice and policy recommendations that aim to improve the mental health of children exposed to insecure housing.

The IL6/JAK/STAT3 signaling axis is a therapeutic vulnerability in SMARCB1-deficient bladder cancer.

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces tumor growth in SMARCB1 KO orthotopic cell line-derived xenografts and a SMARCB1-deficient patient derived xenograft model. We have identified a gene signature generated from SMARCB1 KO tumors that predicts SMARCB1 deficiency in patients. Overall, these findings support the clinical evaluation of STAT3 inhibitors for the treatment of SMARCB1-deficient bladder cancer.

Ethical applications of digital community-based research with Black immigrant and refugee youth and families.

The capacity to conduct psychology research online has expanded more quickly than have ethics guidelines for digital research. We argue that researchers must proactively plan ways to engage ethically in online psychological research with vulnerable groups, including marginalized and immigrant youth and families. To that end, this article describes the ethical use of internet and cell phone technologies in psychological research with Black immigrant and refugee youth and families, which demands efforts to both deepen and extend the Belmont principles of respect for persons, beneficence, and justice. We describe and apply four research frameworks-community-based participatory research, transdisciplinary team science, representational ethics, and cross-cultural psychology-that can be integrated to offer practical solutions to ethical challenges in digital research with Black immigrant and refugee youth and families. Then, as an illustration, we provide a case example of this approach using the Food, Culture, and Health Study conducted with Black Jamaican American and Somali American youth and families, who experience tridimensional acculturation due to their race and have been disproportionately impacted by the dual pandemics of COVID-19 and racism/Whiteness. We offer this article as a road map for other researchers seeking to conduct ethical digital community-based psychological research with Black immigrant youth and families and other marginalized communities. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Reactivation of the G1 enhancer landscape underlies core circuitry addiction to SWI/SNF.

Several cancer core regulatory circuitries (CRCs) depend on the sustained generation of DNA accessibility by SWI/SNF chromatin remodelers. However, the window when SWI/SNF is acutely essential in these settings has not been identified. Here we used neuroblastoma (NB) cells to model and dissect the relationship between cell-cycle progression and SWI/SNF ATPase activity. We find that SWI/SNF inactivation impairs coordinated occupancy of non-pioneer CRC members at enhancers within 1 hour, rapidly breaking their autoregulation. By precisely timing inhibitor treatment following synchronization, we show that SWI/SNF is dispensable for survival in S and G2/M, but becomes acutely essential only during G1 phase. We furthermore developed a new approach to analyze the oscillating patterns of genome-wide DNA accessibility across the cell cycle, which revealed that SWI/SNF-dependent CRC binding sites are enriched at enhancers with peak accessibility during G1 phase, where they activate genes involved in cell-cycle progression. SWI/SNF inhibition strongly impairs G1-S transition and potentiates the ability of retinoids used clinically to induce cell-cycle exit. Similar cell-cycle effects in diverse SWI/SNF-addicted settings highlight G1-S transition as a common cause of SWI/SNF dependency. Our results illustrate that deeper knowledge of the temporal patterns of enhancer-related dependencies may aid the rational targeting of addicted cancers.

Cancer cells driven by runaway transcription factor networks frequently depend on the cellular machinery that promotes DNA accessibility. For this reason, recently developed small molecules that impair SWI/SNF (or BAF) chromatin remodeling activity have been under active evaluation as anti-cancer agents. However, exactly when SWI/SNF activity is essential in dependent cancers has remained unknown. By combining live-cell imaging and genome-wide profiling in neuroblastoma cells, Cermakova et al. discover that SWI/SNF activity is needed for survival only during G1 phase of the cell cycle. The authors reveal that in several cancer settings, dependency on SWI/SNF arises from the need to reactivate factors involved in G1-S transition. Because of this role, authors find that SWI/SNF inhibition potentiates cell-cycle exit by retinoic acid.

Validation of an electronic self-administered version of the Dimensional Inventory of Stress and Trauma Across the Lifespan in a large sample of young adults.

Recent advances in the dimensional assessment of traumatic stress have initiated research examining correlates of exposure to specific features of stress. However, existing tools require intensive, in-person, clinician administration to generate the rich phenotypic data required for such analyses. These approaches are time consuming, costly, and substantially restrict the degree to which assessment tools can be disseminated in large-scale studies, constraining the refinement of existing dimensional models of early adversity. Here, we present an electronic adaptation of the Dimensional Inventory of Stress and Trauma Across the Lifespan (DISTAL), called the DISTAL-Electronic (DISTAL-E), present descriptive statistics drawn from a large sample of N = 500 young adult participants who completed the novel measure, and provide information about its psychometric properties. Results suggest that the DISTAL-E adequately assesses the following dimensional indices of traumatic stress exposure: type, chronicity, age of onset, severity, proximity, caregiver involvement, controllability, predictability, betrayal, threat, and deprivation and that it has excellent content and convergent validity and good test-retest reliability over a 7-11 day period. Although the development of the DISTAL-E facilitates the broad assessment of dimensions of stress exposure in large-scale datasets and has the potential to increase access to stress-related research to a wider group of participants who may not be able to access clinical research in traditional, in-person, clinic-based settings, the generalizability of results of the present study may be constrained by the fact that study participants were primarily White, educated, and with middle-to-high income. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Multivariate links between the developmental timing of adversity exposure and white matter tract integrity in adulthood.

Early-life adversity is pervasive worldwide and represents a potent risk factor for increased mental health burden across the lifespan. However, there is substantial individual heterogeneity in associations between adversity exposure, neurobiological changes, and mental health problems. Accounting for key features of adversity such as the developmental timing of exposure may clarify associations between adversity, neurodevelopment, and mental health. The present study leverages sparse canonical correlation analysis to characterize modes of covariation between age of adversity exposure and the integrity of white matter tracts throughout the brain in a sample of 107 adults. We find that adversity exposure during middle childhood (ages 5-6 and 8-9 in particular) is consistently linked with alterations in white matter tract integrity, such that tracts supporting sensorimotor functions display higher integrity in relation to adversity exposure while tracts supporting cortico-cortical communication display lower integrity. Further, latent patterns of tract integrity linked with adversity experienced across preschool age and middle childhood (ages 4-9) were associated with trauma-related symptoms in adulthood. Our findings underscore that adversity exposure may differentially affect white matter in a function- and developmental-timing specific manner and suggest that adversity experienced between ages 4-9 may shape the development of global white matter tracts in ways that are relevant for adult mental health.

Development and validation of the Dimensional Inventory of Stress and Trauma Across the Lifespan (DISTAL): A novel assessment tool to facilitate the dimensional study of psychobiological sequelae of exposure to adversity.

Decades of research underscore the profound impact of adversity on brain and behavioral development. Recent theoretical models have highlighted the importance of considering specific features of adversity that may have dissociable effects at distinct developmental timepoints. However, existing measures do not query these dimensions in sufficient detail to support the proliferation of this approach. The Dimensional Inventory of Stress and Trauma Across the Lifespan (DISTAL) was developed with the aim to thoroughly and retrospectively assess the timing, severity (of exposure and reaction), type, persons involved, controllability, predictability, threat, deprivation, proximity, betrayal, and discrimination inherent in an individual's exposure to adversity. Here, we introduce this instrument, present descriptive statistics drawn from a sample of N = 187 adults who completed the DISTAL, and provide initial information about its psychometric properties. This novel measure facilitates the expansion of research focused on assessing the relative impact of exposure to key dimensions of adversity on the brain and behavior across development.

Interaction modules that impart specificity to disordered protein.

Intrinsically disordered regions (IDRs) are especially enriched among proteins that regulate chromatin and transcription. As a result, mechanisms that influence specificity of IDR-driven interactions have emerged as exciting unresolved issues for understanding gene regulation. We review the molecular elements frequently found within IDRs that confer regulatory specificity. In particular, we summarize the differing roles of disordered low-complexity regions (LCRs) and short linear motifs (SLiMs) towards selective nuclear regulation. Examination of IDR-driven interactions highlights SLiMs as organizers of selectivity, with widespread roles in gene regulation and integration of cellular signals. Analysis of recurrent interactions between SLiMs and folded domains suggests diverse avenues for SLiMs to influence phase-separated condensates and highlights opportunities to manipulate these interactions for control of biological activity.

SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia.

In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition in AML cells reduced DNA accessibility and binding of these factors at PU.1 sites and redistributed PU.1 to promoters. Analysis of nontumor hematopoietic cells revealed that similar effects also impair PU.1-dependent B-cell and monocyte populations. Nevertheless, SWI/SNF inhibition induced profound therapeutic response in an immunocompetent AML mouse model as well as in primary human AML samples. In vivo, SWI/SNF inhibition promoted leukemic differentiation and reduced the leukemic stem cell burden in bone marrow but also induced leukopenia. These results reveal a variable therapeutic window for SWI/SNF blockade in AML and highlight important off-tumor effects of such therapies in immunocompetent settings. SIGNIFICANCE: Disruption of PU.1-directed enhancer programs upon SWI/SNF inhibition causes differentiation of AML cells and induces leukopenia of PU.1-dependent B cells and monocytes, revealing the on- and off-tumor effects of SWI/SNF blockade.

The TFIIS N-terminal domain (TND): a transcription assembly module at the interface of order and disorder.

Interaction scaffolds that selectively recognize disordered protein strongly shape protein interactomes. An important scaffold of this type that contributes to transcription is the TFIIS N-terminal domain (TND). The TND is a five-helical bundle that has no known enzymatic activity, but instead selectively reads intrinsically disordered sequences of other proteins. Here, we review the structural and functional properties of TNDs and their cognate disordered ligands known as TND-interacting motifs (TIMs). TNDs or TIMs are found in prominent members of the transcription machinery, including TFIIS, super elongation complex, SWI/SNF, Mediator, IWS1, SPT6, PP1-PNUTS phosphatase, elongin, H3K36me3 readers, the transcription factor MYC, and others. We also review how the TND interactome contributes to the regulation of transcription. Because the TND is the most significantly enriched fold among transcription elongation regulators, TND- and TIM-driven interactions have widespread roles in the regulation of many transcriptional processes.

Neural effects of controllability as a key dimension of stress exposure.

Cross-species evidence suggests that the ability to exert control over a stressor is a key dimension of stress exposure that may sensitize frontostriatal-amygdala circuitry to promote more adaptive responses to subsequent stressors. The present study examined neural correlates of stressor controllability in young adults. Participants (N = 56; Mage = 23.74, range = 18-30 years) completed either the controllable or uncontrollable stress condition of the first of two novel stressor controllability tasks during functional magnetic resonance imaging (fMRI) acquisition. Participants in the uncontrollable stress condition were yoked to age- and sex-matched participants in the controllable stress condition. All participants were subsequently exposed to uncontrollable stress in the second task, which is the focus of fMRI analyses reported here. A whole-brain searchlight classification analysis revealed that patterns of activity in the right dorsal anterior insula (dAI) during subsequent exposure to uncontrollable stress could be used to classify participants' initial exposure to either controllable or uncontrollable stress with a peak of 73% accuracy. Previous experience of exerting control over a stressor may change the computations performed within the right dAI during subsequent stress exposure, shedding further light on the neural underpinnings of stressor controllability.

A Novel Blueprint Storyboarding Method Using Digitization for Efficient Cultural Adaptation of Prevention Programs to Serve Diverse Youth and Communities.

There is a pressing need for prevention programs that address increasing rates of epidemics and pandemics, including noncommunicable diseases. However, many populations face substantial systemic barriers to accessing traditional prevention programs. To minimize persistent service utilization gaps for underserved populations, the field requires effective, efficient, and sustainable methods to increase accessibility and cultural relevance of prevention programming to multiple audiences. Cultural adaptation is one such strategy, but it can be daunting for many preventionists. Therefore, this paper presents a step-by-step guide to streamline the cultural adaptation of prevention programs through digitization and use of a novel application of storyboarding methodology, called "blueprint storyboarding." This innovative approach to cultural adaptation is designed to increase systematicity through manualization, efficiency, cost-effectiveness, and adaptability for multiple cultures and developmental stages. We illustrate this novel method by describing how we applied the blueprint storyboarding approach after digitization to culturally adapt the JUS Media? Programme, a food-focused media literacy program designed to buffer media-related obesity risks for diverse youth.

Immune profiling of adeno-associated virus response identifies B cell-specific targets that enable vector re-administration in mice.

Adeno-associated virus (AAV) vector-based gene therapies can be applied to a wide range of diseases. AAV expression can last for months to years, but vector re-administration may be necessary to achieve life-long treatment. Unfortunately, immune responses against these vectors are potentiated after the first administration, preventing the clinical use of repeated administration of AAVs. Reducing the immune response against AAVs while minimizing broad immunosuppression would improve gene delivery efficiency and long-term safety. In this study, we quantified the contributions of multiple immune system components of the anti-AAV response in mice. We identified B-cell-mediated immunity as a critical component preventing vector re-administration. Additionally, we found that IgG depletion alone was insufficient to enable re-administration, suggesting IgM antibodies play an important role in the immune response against AAV. Further, we found that AAV-mediated transduction is improved in µMT mice that lack functional IgM heavy chains and cannot form mature B-cells relative to wild-type mice. Combined, our results suggest that B-cells, including non-class switched B-cells, are a potential target for therapeutics enabling AAV re-administration. Our results also suggest that the µMT mice are a potentially useful experimental model for gene delivery studies since they allow repeated dosing for more efficient gene delivery from AAVs.

Neural circuitry involved in conditioned inhibition via safety signal learning is sensitive to trauma exposure.

Exposure to trauma throughout the lifespan is prevalent and increases the likelihood for the development of mental health conditions such as anxiety and post-traumatic stress disorder (PTSD). Safety signal learning (SSL)--a form of conditioned inhibition that involves reducing fear via conditioned safety--has been shown to effectively attenuate fear responses among individuals with trauma exposure, but the association between trauma exposure and the neural mechanisms of SSL remains unknown. Adults with varied prior exposure to trauma completed a conditioned inhibition task during functional MRI scanning and collection of skin conductance response (SCR). Conditioned safety signals reduced psychophysiological reactivity (i.e., SCR) in the overall sample. Although exposure to a higher number of traumatic events was associated with elevated SCR across all task conditions, SCR did not differ between threat in the presence of conditioned safety (i.e., SSL) relative to threat alone in a trauma-related manner. At the neural level, however, higher levels of trauma exposure were associated with lower hippocampal, amygdala, and dorsolateral prefrontal cortical activation during SSL. These findings suggest that while conditioned safety signals can reduce fear in the presence of threat even among individuals exposed to higher degrees of trauma, the neural circuitry involved in SSL is in fact sensitive to trauma exposure. Future research investigating neural processes during SSL among individuals with PTSD or anxiety can further elucidate the ways in which SSL and its neural correlates may reduce fear and link trauma exposure with later mental health conditions.

Lack of robust associations between prepandemic coping strategies and frontolimbic circuitry with depression and anxiety symptoms during the COVID-19 pandemic: A preregistered longitudinal study.

The COVID-19 pandemic is an ongoing stressor that has resulted in the exacerbation of mental health problems worldwide. However, longitudinal studies that identify preexisting behavioral and neurobiological factors associated with mental health outcomes during the pandemic are lacking. Here, we examined associations between prepandemic coping strategy engagement and frontolimbic circuitry with internalizing symptoms during the pandemic. In 85 adults (71.8% female; age 18-30 years), we assessed prototypically adaptive coping strategies (Connor-Davidson Resilience Scale), resting-state functional magnetic resonance imaging functional connectivity (FC) of frontolimbic circuitry, and depression and anxiety symptoms (Beck Depression Inventory, Screen for Child Anxiety-Related Emotional Disorders-Adult, respectively). We conducted general linear models to test preregistered hypotheses that (1) lower coping engagement prepandemic and (2) weaker frontolimbic FC prepandemic would predict elevated symptoms during the pandemic; and (3) coping would interact with FC to predict symptoms during the pandemic. Depression and anxiety symptoms worsened during the pandemic (ps < .001). Prepandemic adaptive coping engagement and frontolimbic FC were not associated with depression or anxiety symptoms during the pandemic (uncorrected ps > .05). Coping interacted with insula-rostral anterior cingulate cortex (ACC) FC (p = .003, pFDR = .014) and with insula-ventral ACC FC (p < .001, pFDR < .001) to predict depression symptoms, but these findings did not survive FDR correction after removal of outliers. Findings from our preregistered study suggest that specific prepandemic factors, particularly adaptive coping and frontolimbic circuitry, are not robustly associated with emotional responses to the pandemic. Additional studies that identify preexisting neurobehavioral factors implicated in mental health outcomes during global health crises are needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Associations between early-life stress exposure and internalizing symptomatology during the COVID-19 pandemic: Assessing the role of neurobehavioral mediators.

Background: The ongoing COVID-19 pandemic is a major stressor that has been associated with increased risk for psychiatric illness in the general population. Recent work has highlighted that experiences of early-life stress (ELS) may impact individuals' psychological functioning and vulnerability for developing internalizing psychopathology in response to pandemic-related stress. However, little is known about the neurobehavioral factors that may mediate the association between ELS exposure and COVID-related internalizing symptomatology. The current study sought to examine the mediating roles of pre-pandemic resting-state frontoamygdala connectivity and concurrent emotion regulation (ER) in the association between ELS and pandemic-related internalizing symptomatology. Methods: Retrospective life-stress histories, concurrent self-reported ER strategies (i.e., reappraisal and suppression), concurrent self-reported internalizing symptomatology (i.e., depression- and anxiety-related symptomatology), and resting-state functional connectivity data from a sample of adults (N = 64, M age = 22.12, female = 68.75%) were utilized. Results: There were no significant direct associations between ELS and COVID-related internalizing symptomatology. Neither frontoamygdala functional connectivity nor ER strategy use mediated an association between ELS and COVID-related internalizing symptomatology (ps > 0.05). Exploratory analyses identified a significant moderating effect of reappraisal use on the association between ELS and internalizing symptomatology (ß = -0.818, p = 0.047), such that increased reappraisal use buffered the impact of ELS on psychopathology. Conclusions: While frontoamygdala connectivity and ER do not appear to mediate the association between ELS and COVID-related internalizing symptomatology, our findings suggest that the use of reappraisal may buffer against the effect of ELS on mental health during the pandemic.

A ubiquitous disordered protein interaction module orchestrates transcription elongation.

During eukaryotic transcription elongation, RNA polymerase II (RNAP2) is regulated by a chorus of factors. Here, we identified a common binary interaction module consisting of TFIIS N-terminal domains (TNDs) and natively unstructured TND-interacting motifs (TIMs). This module was conserved among the elongation machinery and linked complexes including transcription factor TFIIS, Mediator, super elongation complex, elongin, IWS1, SPT6, PP1-PNUTS phosphatase, H3K36me3 readers, and other factors. Using nuclear magnetic resonance, live-cell microscopy, and mass spectrometry, we revealed the structural basis for these interactions and found that TND-TIM sequences were necessary and sufficient to induce strong and specific colocalization in the crowded nuclear environment. Disruption of a single TIM in IWS1 induced robust changes in gene expression and RNAP2 elongation dynamics, which underscores the functional importance of TND-TIM surfaces for transcription elongation.