A suite of enhancer AAVs and transgenic mouse lines for genetic access to cortical cell types.

The mammalian cortex is comprised of cells with different morphological, physiological, and molecular properties that can be classified according to shared properties into cell types. Defining the contribution of each cell type to the computational and cognitive processes that are guided by the cortex is essential for understanding its function in health and disease. We use transcriptomic and epigenomic cortical cell type taxonomies from mice and humans to define marker genes and enhancers, and to build genetic tools for cortical cell types. Here, we present a large toolkit for selective targeting of cortical populations, including mouse transgenic lines and recombinant adeno-associated virus (AAV) vectors containing genomic enhancers. We report evaluation of fifteen new transgenic driver lines and over 680 different enhancer AAVs covering all major subclasses of cortical cells, with many achieving a high degree of specificity, comparable with existing transgenic lines. We find that the transgenic lines based on marker genes can provide exceptional specificity and completeness of cell type labeling, but frequently require generation of a triple-transgenic cross for best usability/specificity. On the other hand, enhancer AAVs are easy to screen and use, and can be easily modified to express diverse cargo, such as recombinases. However, their use depends on many factors, such as viral titer and route of administration. The tools reported here as well as the scaled process of tool creation provide an unprecedented resource that should enable diverse experimental strategies towards understanding mammalian cortex and brain function.

Chagas Disease Diagnostic Practices at Four Major Hospital Systems in California and Texas.

BACKGROUND: Chagas disease (CD) is a parasitic disease that affects ∼300 000 people living in the United States. CD leads to cardiac and/or gastrointestinal disease in up to 30% of untreated people. However, end-organ damage can be prevented with early diagnosis and antiparasitic therapy. METHODS: We reviewed electronic health records of patients who underwent testing for CD at four hospital systems in California and Texas between 2016 and 2020. Descriptive analyses were performed as a needs assessment for improving CD diagnosis. RESULTS: In total, 470 patients were tested for CD. Cardiac indications made up more than half (60%) of all testing, and the most frequently cited cardiac condition was heart failure. Fewer than 1% of tests were ordered by obstetric and gynecologic services. Fewer than half (47%) of patients had confirmatory testing performed at the Centers for Disease Control and Prevention. DISCUSSION: Four major hospitals systems in California and Texas demonstrated low overall rates of CD diagnostic testing, testing primarily among older patients with end-organ damage, and incomplete confirmatory testing. This suggests missed opportunities to diagnose CD in at-risk individuals early in the course of infection when antiparasitic treatment can reduce the risk of disease progression and prevent vertical transmission.

The moderating role of emotion regulation strategies on Asian American parents' discrimination experiences and mental health during the COVID-19 pandemic.

Asian American parents have experienced significant stressors associated with racial discrimination and anticipatory COVID-19-related discrimination fear during the COVID-19 pandemic, which may adversely impact their mental health. Emotion regulation strategies may attenuate the negative effects of discrimination experiences on mental health, but existing findings have been inconsistent regarding the associations between these factors, particularly among the Asian American population. One hundred ninety-three Asian American parents (Mage = 40.58 years, SD = 6.42 years; 82.4% female) were assessed on their discrimination experiences (racial discrimination in the past year, COVID-19 discrimination fear), emotion regulation strategies (cognitive reappraisal, expressive suppression), and mental health (depression, anxiety). Significant interactions emerged between expressive suppression and racial discrimination in the past year on depression (b = .02, p = .006) and anxiety (b = .03, p < .001). Cognitive reappraisal did not significantly moderate the associations between discrimination experiences and mental health. Results indicated that greater use of expressive suppression exacerbated the adverse effects of racial discrimination on the mental health of Asian American parents. These findings inform research and practice regarding the deleterious effects of racial discrimination and the differential impact of using various emotion regulation strategies on the mental health of Asian American parents. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Differential impact of the school context on ethnic and racial identity and depression for monoracial and multiracial early adolescents.

Introduction: This study examined the direct and indirect effects of school context (negative peer relationships, school environment) on ethnic and racial identity (ERI) development in middle school and later depression symptoms in high school. Differences by racial group were examined for non-Hispanic White (NHW) early adolescents, monoracial adolescents, and multiracial adolescents. Methods: This study used existing data from a large, multiwave, longitudinal study that included 593 racial/ethnically diverse adolescents from sixth grade through ninth grade across three public middle schools in the Pacific Northwest. Results: Using multigroup path analysis in structural equation modeling, the findings indicated differences by racial group-school environment was associated with positive ERI development in middle school for NHW and monoracial adolescents but not for multiracial adolescents. For multiracial adolescents, ERI predicted later depression symptoms. Discussion: These findings demonstrated the importance of examining school context and peer relationships in relation to ERI development and psychological wellbeing.

Differential encoding of temporal context and expectation under representational drift across hierarchically connected areas.

The classic view that neural populations in sensory cortices preferentially encode responses to incoming stimuli has been strongly challenged by recent experimental studies. Despite the fact that a large fraction of variance of visual responses in rodents can be attributed to behavioral state and movements, trial-history, and salience, the effects of contextual modulations and expectations on sensory-evoked responses in visual and association areas remain elusive. Here, we present a comprehensive experimental and theoretical study showing that hierarchically connected visual and association areas differentially encode the temporal context and expectation of naturalistic visual stimuli, consistent with the theory of hierarchical predictive coding. We measured neural responses to expected and unexpected sequences of natural scenes in the primary visual cortex (V1), the posterior medial higher order visual area (PM), and retrosplenial cortex (RSP) using 2-photon imaging in behaving mice collected through the Allen Institute Mindscope's OpenScope program. We found that information about image identity in neural population activity depended on the temporal context of transitions preceding each scene, and decreased along the hierarchy. Furthermore, our analyses revealed that the conjunctive encoding of temporal context and image identity was modulated by expectations of sequential events. In V1 and PM, we found enhanced and specific responses to unexpected oddball images, signaling stimulus-specific expectation violation. In contrast, in RSP the population response to oddball presentation recapitulated the missing expected image rather than the oddball image. These differential responses along the hierarchy are consistent with classic theories of hierarchical predictive coding whereby higher areas encode predictions and lower areas encode deviations from expectation. We further found evidence for drift in visual responses on the timescale of minutes. Although activity drift was present in all areas, population responses in V1 and PM, but not in RSP, maintained stable encoding of visual information and representational geometry. Instead we found that RSP drift was independent of stimulus information, suggesting a role in generating an internal model of the environment in the temporal domain. Overall, our results establish temporal context and expectation as substantial encoding dimensions in the visual cortex subject to fast representational drift and suggest that hierarchically connected areas instantiate a predictive coding mechanism.

Promoting mental and physical health of Vietnamese immigrants through a cultural movement intervention.

OBJECTIVES: Older Vietnamese adults are among the most underserved groups in the United States, despite being at high risk for stress and other negative experiences (e.g., access to same-language practitioners, transportation barriers, lack of health care). Minimal progress has been made in decreasing treatment barriers for this underserved population. One promising approach involves using indigenous, culturally based interventions to enhance psychological and physical well-being. Such interventions may reduce utilization and quality of care disparities because they emphasize a more holistic approach to health, thereby limiting the shame and face loss often experienced due to the stigma associated with mental illness. The present study examined the efficacy of lishi, a traditional East Asian movement form of exercise, in promoting mental and physical health outcomes for older Vietnamese immigrant adults. METHOD: Seventy-one older Vietnamese adults participated in this randomized waitlist control study. Participants were between 60 and 75 years old. Multivariate analysis of covariance was used to determine posttest outcomes differences between the intervention and control groups. RESULTS: Intervention group participants experienced significantly higher levels of self-efficacy and physical energy, less bodily pains, and better body balance at posttest compared to the control group. CONCLUSIONS: Lishi may be an effective culturally valid intervention for older Vietnamese adults and demonstrated promise at engaging this hard-to-reach population in treatment and services. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

MAdCAM-1 costimulation in the presence of retinoic acid and TGF-ß promotes HIV infection and differentiation of CD4+ T cells into CCR5+ TRM-like cells.

CD4+ tissue resident memory T cells (TRMs) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-ß, promote the differentiation of CD4+ T cells into a distinct subset α4ß7+CD69+CD103+ TRM-like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of TRM-like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4+ TRMs to persistent viral reservoirs and HIV pathogenesis.

C. elegans vab-6 encodes a KIF3A kinesin and functions cell non-autonomously to regulate epidermal morphogenesis.

Cells undergo strict regulation to develop their shape in a process called morphogenesis. Caenorhabditis elegans with mutations in the variable abnormal (vab) class of genes have been shown to display epidermal and neuronal morphological defects. While several vab genes have been well-characterized, the function of the vab-6 gene remains unknown. Here, we show that vab-6 is synonymous with a subunit of the kinesin-II heterotrimeric motor complex called klp-20/Kif3a, a motor well-understood to be involved in developing sensory cilia in the nervous system. We show that certain klp-20 alleles cause animals to develop a bumpy body phenotype that is variable but most severe in mutants containing single amino-acid substitutions in the catalytic head-domain sites of the protein. Surprisingly, animals carrying a klp-20 null allele do not show the bumpy epidermal phenotype suggesting genetic redundancy and only when mutant versions of the KLP-20 protein are present, the epidermal phenotype is observed. The bumpy epidermal phenotype was not observed in other kinesin-2 mutants, suggesting that KLP-20 is functioning independently from its role in intraflagellar transport (IFT) during ciliogenesis. Interestingly, despite having such a prominent epidermal phenotype, KLP-20 is not expressed in the epidermis, strongly suggesting a cell non-autonomous role in which it regulates epidermal morphogenesis.

Asian American parents' experiences of stress, discrimination, and mental health during COVID-19.

INTRODUCTION: COVID-19 has placed Asian Americans (AA) at higher risk for discrimination within the U.S. This exacerbates the mental health distress of AA parents, who are also experiencing COVID-19-related stress (e.g., health, financial, work, childcare). The risk factors associated with mental health outcomes for AA parents are not well understood. This brief report examined the relationships among COVID-19 stress, discrimination, and psychological distress of AA parents during the initial months of the pandemic. METHOD: Baseline data of an ongoing longitudinal examination into the COVID-19 experiences of AA parents and their families were utilized. Participants were 166 AA parents of children ages 2-19 years. They completed an online survey about their experiences of COVID-19-related stress (i.e., childcare, school, work), discrimination, and psychological distress. RESULTS: The majority of AA parents were highly stressed due to school closures and childcare changes; school-age parents reported significantly more stress resulting from school closures than parents of young children or adolescents. Over 21% of AA parents experienced some discrimination resulting from COVID-19; the majority reported discrimination fears for themselves and their family/friends. Experiencing discrimination was positively associated with psychological distress, as was COVID-19 stress related to work performance and relationship quality. Conversely, the majority of parents reported increased quality time with their family (i.e., children, partners). DISCUSSION: AA parents are experiencing high levels of COVID-19-related stress, and have the added psychological burden of experiencing and fearing racial/ethnic discrimination. However, the pandemic has led to families spending more quality time together. Implications for future studies are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A 44-y perspective on the influence of cash on Ju/'hoansi Bushman networks of sharing and gifting.

Money has been portrayed by major theorists as an agent of individualism, an instrument of freedom, a currency that removes personal values attached to things, and a generator of avarice. Regardless, the impact of money varies greatly with the cultural turf of the recipient societies. For traditional subsistence economies based on gifting and sharing, surplus perishable resources foraged from the environment carry low costs to the giver compared with the benefits to the receiver. With cash, costs to the giver are usually the same as benefits to the receiver, making sharing expensive and introducing new choices. Using quantitative data on possessions and expenditures collected over a 44-y period from 1974 to 2018 among the Ju/'hoansi (!Kung) in southern Africa, former hunter-gatherers, we look at how individuals spend monetary income, how a partial monetary economy alters traditional norms and institutions (egalitarianism, gifting, and sharing), and how institutions from the past steer change. Results show that gifting declines as cash is spent to increase the well-being of individual families and that gifting and sharing decrease and networks narrow. The sharing of meals and casual gifting hold fast. Substantial material inequalities develop, even between neighbors, but social, gender, and political equalities persist. A strong tradition for individual autonomy combined with monetary income allows individuals to spend their money as they choose, adapt to modern conditions, and pursue new options. However, new challenges are emerging to develop greater community cooperation and build substantial and sustainable economies in the face of such centrifugal forces.

A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states.

Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. Here, we present a screening platform to systematically elucidate functional consequences of genetic perturbations in human induced pluripotent stem cell-derived microglia. We developed an efficient 8-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the 'druggable genome'. These screens uncovered genes controlling microglia survival, activation and phagocytosis, including neurodegeneration-associated genes. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. A disease-associated state characterized by osteopontin (SPP1) expression was selectively depleted by colony-stimulating factor-1 (CSF1R) inhibition. Thus, our platform can systematically uncover regulators of microglial states, enabling their functional characterization and therapeutic targeting.

Examining risk and protective predictors of substance use among low-income Native Hawaiian and Pacific Islander adolescents.

Substance use (SU) among adolescents is a critical public health concern that increases the risk for negative outcomes. Although Asian American (AA) adolescents tend to report low rates of SU, Native Hawaiian and Pacific Islander (NH/PI) adolescents often report significantly higher rates of use. Yet, NH/PI youth are seldom studied as a separate group. Consequently, little is known about the factors involved in SU among NH/PI adolescents and how to prevent it. This prospective study investigated the effect of ecological risk and protective factors at the individual, family, and school levels on SU for NH/PI adolescents. This prospective study utilized longitudinal data from 120 NH/PI adolescents who were7 part of an SU prevention program. Information was collected at two time points-Time 1 and Time 2 (32 weeks later)-and included adolescents' SU behaviors and individual, family, and school factors. The parents of these adolescents also provided data; all information was self-report. Positive academic attitudes at Time 1 were negatively associated with alcohol and other drug (e.g., marijuana) use at Time 2. Specifically, NH/PI adolescents who had more positive attitudes toward their school, peers, and teachers reported less alcohol and other SU. Prevention efforts may be most effective for NH/PI adolescents if addressed within the school context. This may include programs implemented in schools, utilizing teachers as role models, and/or promoting prosocial peer relationships to support positive behaviors. Additional implications are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A Three-Tiered Model for Addressing the Mental Health Needs of Immigrant-Origin Youth in Schools.

To date, little research has systematically considered the ways in which schools can better address the needs of immigrant-origin youth (IOY). Further, considering the increased negative attitudes toward and policies targeting IOY and families within the U.S., there is a need to go beyond targeting just IOY at risk for mental health concerns and promote a culture of inclusion throughout the school. The goal of this paper is to address ways in which schools can best attend to the mental health needs of IOY by systematically integrating prevention and intervention efforts across three tiers of support within the school setting. Specifically, we propose a three-tiered model of school based mental health services for IOY. Based on a thorough review of current literature, we propose universal, selective, and targeted programming to support the MH needs of IOY and families. We discuss implications for implementation as well as future directions for research.

Determinants of Depression Risk among Three Asian American Subgroups in New York City.

Objective: Although the fastest growing minority group, Asian Americans receive little attention in mental health research. Moreover, aggregated data mask further diversity within Asian Americans. This study aimed to examine depression risk by detailed Asian American subgroup, and further assess determinants within and between three Asian ethnic subgroups. Methods: Needs assessment surveys were collected in 16 Asian American subgroups (six Southeast Asian, six South Asian, and four East Asian) in New York City from 2013-2016 using community-based sampling strategies. A final sample of N=1,532 completed the PHQ-2. Bivariate comparisons and multivariable logistic models explored differences in depression risk by subgroup. Results: Southeast Asians had the greatest depression risk (19%), followed by South Asians (11%) and East Asians (9%). Among Southeast Asians, depression risk was associated with lacking health insurance (OR=.2, 95% CI: 0-.6), not having a provider who speaks the same language (OR=3.2, 95% CI: 1.3-8.0), and lower neighborhood social cohesion (OR= .94, 95% CI: .71-.99). Among South Asians, depression risk was associated with greater English proficiency (OR=3.9, 95% CI: 1.6-9.2); and among East Asians, depression risk was associated with ≤ high school education (OR=4.2, 95% CI: 1.2-14.3). Additionally, among Southeast Asians and South Asians, the highest depression risk was associated with high levels of discrimination (Southeast Asian: OR=9.9, 95% CI: 1.8-56.2; South Asian: OR=7.3, 95% CI: 3.3-16.2). Conclusions: Depression risk and determinants differed by Asian American ethnic subgroup. Identifying factors associated with depression risk among these groups is key to targeting limited public health resources for these underserved communities.

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.

Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis.

Dysregulation of neuronal excitability underlies the pathogenesis of tauopathies, including frontotemporal dementia (FTD) with tau inclusions. A majority of FTD-causing tau mutations are located in the microtubule-binding domain, but how these mutations alter neuronal excitability is largely unknown. Here, using CRISPR/Cas9-based gene editing in human pluripotent stem cell (iPSC)-derived neurons and isogenic controls, we show that the FTD-causing V337M tau mutation impairs activity-dependent plasticity of the cytoskeleton in the axon initial segment (AIS). Extracellular recordings by multi-electrode arrays (MEAs) revealed that the V337M tau mutation in human neurons leads to an abnormal increase in neuronal activity in response to chronic depolarization. Stochastic optical reconstruction microscopy of human neurons with this mutation showed that AIS plasticity is impaired by the abnormal accumulation of end-binding protein 3 (EB3) in the AIS submembrane region. These findings expand our understanding of how FTD-causing tau mutations dysregulate components of the neuronal cytoskeleton, leading to network dysfunction.

Longitudinal Trajectories of Parenting Stress Among Ethnic Minority Adolescent Mothers.

OBJECTIVES: Parenting stress has been linked with negative outcomes for parents and their infants (e.g., parental depression, negative parenting behaviors, poor attachment). Racial/ethnic minority adolescent mothers have increased risk for experiencing parenting stress compared to their White counterparts. Little is known about the changes in parenting stress over time for this population. METHODS: Growth mixture modeling (GMM) was conducted to determine the growth trajectory classes of 185 African American and Latina/Hispanic adolescent mothers over 2 years. Risk and protective factors (e.g., maternal depression, social support, self-esteem) were examined to determine their influence on parenting stress trajectories. RESULTS: Three distinct trajectories of parenting stress were found: low stable stress (40.90%), decreasing stress (35.78%), and high stable stress (23.28%). Lower maternal depression (OR = 2.35), higher self-esteem (OR = 1.29), lower perceived social support from family (OR = 0.53) and higher perceived support from friends (OR = 1.65) predicted placement into the low stable parenting stress group over the high stable parenting stress group. Adolescents living with family (OR = 2.74) and Latina race/ethnicity (OR = 2.78) also served as predictors of placement into the low stable parenting stress group. Higher self-esteem (OR = 1.66) predicted placement into the decreasing parenting stress group over the high stable parenting stress group. CONCLUSIONS: These findings highlight the importance of perceived peer support by adolescent mothers, regardless of their support family support (e.g., living at home and receiving child care). Considering developmental factors such as peer relationships may be important when working with adolescent mothers.

Racial/ethnic differences in alcohol use trajectories among adolescents involved in child welfare.

This study examined racial/ethnic differences in growth trajectories of alcohol use for a nationally representative sample of U.S. adolescents in the child welfare system (CWS), and how individual, family, and child welfare (i.e., proximal) factors predicted alcohol use trajectories for these adolescents. The study included 1,080 Hispanic, African American, and White adolescents aged 11 to 14 years old (at baseline) from the National Survey of Child and Adolescent Well-Being dataset, which is a nationally representative sample of U.S. children in the CWS. Latent growth modeling was used to determine alcohol use growth over 36 months, and multigroup analyses were conducted to examine racial/ethnic differences on alcohol use trajectories and the proximal factors predicting these trajectories. Findings indicated that CWS adolescents demonstrated similar trends in alcohol use growth and initiation compared to adolescents in the general population, especially the Hispanic CWS adolescents. This may reflect an overall shift in nativity status of Hispanic youth in the overall U.S. population. African American adolescents had the fewest significant predictors; this may suggest that factors more relevant for these adolescents and their alcohol use are missing from CWS research. Family-level factors were found to differentially affect use for CWS adolescents compared to adolescents in the general population. Overall, these findings point to a need for improvements in the assessment of CWS adolescents of color in research and practice settings to fully capture the complexity of experiences for these youth and their families. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Caseworker assessment of child risk and functioning and their relation to service use in the child welfare system.

Children within the child welfare system are more likely to experience emotional and behavioral problems than children not involved with the system. Many states have adopted standardized risk and assessment measures to inform decision-making on appropriate levels of care related to placement or service intensity for children within the system. This study examined the relationship of caseworker ratings of risk across multiple domains to youth functioning and service use for a sample of children open to the child welfare system. The study identified a stratified random sample of youth who were between the ages of five and 21 and open to the child welfare system (n = 184). Stratification was based on current placement (i.e., in-home, foster home, congregate care, and juvenile justice placements). Administrative data was used to access caseworker ratings of risk across child, parent, and family domains using a standardized risk assessment tool. Children's caseworkers (n = 103) completed a standardized measure of child functioning and reported on youth utilization of services across multiple sectors including specialty mental health, school-based, juvenile justice, and medical settings. Regression analyses using variance-corrected estimation for clustered data (by caseworker) revealed higher levels of child risk were associated with poorer child functioning, which, in turn, were associated with higher rates of multi-sector service use. Recommendations and future directions are discussed.