Illuminating Myocyte-Fibroblast Homotypic and Heterotypic Gap Junction Dynamics Using Dynamic Clamp.

Fibroblasts play a significant role in the development of electrical and mechanical dysfunction of the heart; however, the underlying mechanisms are only partially understood. One widely studied mechanism suggests that fibroblasts produce excess extracellular matrix, resulting in collagenous septa that slow propagation, cause zig-zag conduction paths, and decouple cardiomyocytes, resulting in a substrate for cardiac arrhythmia. An emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junction (GJ) channels. In the heart, three major connexin (Cx) isoforms, Cx40, Cx43, and Cx45, form GJ channels in cell-type-specific combinations. Because each Cx is characterized by a unique time- and transjunctional voltage-dependent profile, we investigated whether the electrophysiological contributions of fibroblasts would vary with the specific composition of the myocyte-fibroblast (M-F) GJ channel. Due to the challenges of systematically modifying Cxs in vitro, we coupled native cardiomyocytes with in silico fibroblast and GJ channel electrophysiology models using the dynamic-clamp technique. We found that there is a reduction in the early peak of the junctional current during the upstroke of the action potential (AP) due to GJ channel gating. However, effects on the cardiomyocyte AP morphology were similar regardless of the specific type of GJ channel (homotypic Cx43 and Cx45, and heterotypic Cx43/Cx45 and Cx45/Cx43). To illuminate effects at the tissue level, we performed multiscale simulations of M-F coupling. First, we developed a cell-specific model of our dynamic-clamp experiments and investigated changes in the underlying membrane currents during M-F coupling. Second, we performed two-dimensional tissue sheet simulations of cardiac fibrosis and incorporated GJ channels in a cell type-specific manner. We determined that although GJ channel gating reduces junctional current, it does not significantly alter conduction velocity during cardiac fibrosis relative to static GJ coupling. These findings shed more light on the complex electrophysiological interplay between cardiac fibroblasts and myocytes.

AACAP's Strategic Plans to Enhance the Diversity of the Child Psychiatry and Child Mental Health Workforce Across all Mission Areas.

The American Academy of Child and Adolescent Psychiatry (AACAP) promotes the healthy development of children, adolescents, and families through advocacy, education, and research. This requires effectively meeting the mental health needs of historically minoritized communities. A diverse clinician workforce is an essential component of meeting those needs. This article will discuss AACAP's strategic plan for diversifying the workforce, this will be done with 3 main points: promoting diversity, equity, and inclusion (DEI) across all mission area, creating a pipeline of child and adolescent psychiatrists, and monitoring DEI activities and progress on an organizational level.

A Systematic Review and Meta-Analysis: Psychotherapy Interventions for Reducing Suicidal Thoughts and Behaviors Amongst Black Youth.

OBJECTIVE: Suicides continue to increase among youth, with substantial disparities among Black youth. Culturally responsive evidence-based interventions for Black youth are urgently needed to disrupt these inequities. This study aims to identify evidence-based psychotherapy interventions for suicidal thoughts and behaviors (STBs) among Black youth and examine how existing intervention manuals have integrated culturally- relevant content to Black youth. METHOD: Literature searches were conducted to identify relevant articles comparing the effectiveness of interventions for STBs, study population with >30% Black youth, and youth participants up to the age of 25. Published articles and therapy manuals were analyzed on cultural adaptation and on seven content domains for cultural adaptation. Meta-analysis used a random-effects model and explored potential moderators. RESULTS: Of the 755 screened records, 13 studies met eligibility criteria and featured eight manualized interventions. Meta-analysis revealed significant effects in reducing STBs between treatment groups (Hedges' g=1.08 with 95% CI [.07, 2.09])) but low-quality evidence, significant heterogeneity, small sample sizes, and inconsistencies in outcome measures. Only one intervention, Adapted Coping with Stress (A-CWS), specifically focused on Black youth. Culturally relevant content was predominantly absent or contained brief descriptions. The most frequently included content was provider cultural competency training. CONCLUSIONS: The lack of representation of Black youth in treatment studies and sparse literature on culturally responsive treatments for Black youth and their families continues to stall significant advancements to disrupt current suicide trends disproportionately impacting Black youth. We identified several opportunities for implementing cultural adaptations of suicide interventions among Black youth.

Structural Racism and Lessons Not Heard: A Rapid Review of the Telepsychiatry Literature During the COVID-19 Public Health Emergency.

Objective: To assess the extent to which articles examining telepsychiatry after the start of the COVID-19 pandemic provided racial and sociodemographic characteristics for people receiving audiovisual (video) versus audio-only telepsychiatry.Data Sources, Study Selection, and Data Extraction: We employed the keyword telepsychiatry and screened all peer-reviewed articles in PubMed published from March 1, 2020, until November 23, 2022, prior to the federal government's announcement of the impending end to the COVID-19 public health emergency. We retrieved and reviewed the full-text articles of 553 results for potential inclusion, of which 266 were original research articles.Results: We found that 106 of 553 articles had any mention of differences between audio-only and audiovisual telepsychiatry. Twenty-nine of 553 articles described potential socioeconomic differences in the distribution of people receiving audio-only versus audiovisual telepsychiatry, and 20 of 553 described potential racial/ethnic differences. Among research articles, most (213/266) did not differentiate between videoconferencing and audio-only/telephone-based telehealth services. A total of 4 research articles provided racial and sociodemographic characteristics of individuals who received audio-only versus audiovisual telepsychiatry services during the COVID-19 pandemic, all of which were conducted in relatively small regional samples that could not be generalized to the US as a whole.Conclusions: Overall, this analysis underscores that empirical data are lacking on racial and sociodemographic distribution of audio-only versus audiovisual telepsychiatry services since the COVID-19 pandemic.Prim Care Companion CNS Disord 2023;25(6):23r03563. Author affiliations are listed at the end of this article.

Using Digital Technology to Overcome Racial Disparities in Child and Adolescent Psychiatry.

Racial inequity in mental health care quality is influenced by many systems-level factors, as elucidated by critical race theory, structural competency, and other keystone frameworks.1 A growing body of literature also suggests provider-level bias to be a key driver.1-3 There is specific evidence that racism is an important driver of health inequities among youth4 and that it is mediated, in part, by provider-level processes related to diagnosis and treatment.2 For example, in child and adolescent psychiatry, youth who are Black, Indigenous, and People of Color (BIPOC) experience disproportionate rates of delayed diagnosis and treatment of autism spectrum disorder, overdiagnosis of conduct disorder, and underdiagnosis of attention-deficit/hyperactivity disorder.4 Black and multiracial adolescents are at highest risk of suicide,5 yet are least likely to receive preventive psychotherapy.4.

Selective fluorescent labeling of S-nitrosothiols (S-FLOS): a novel method for studying S-nitrosation.

Protein S-nitrosation is a reversible post-translation modification critical for redox-sensitive cell signaling that is typically studied using the Biotin Switch method. This method and subsequent modifications usually require avidin binding or Western blot analysis to detect biotin labeled proteins. We describe here a modification of the Biotin Switch assay that eliminates the need for Western blot or avidin enrichment protocols and allows direct comparison of the S-nitrosation state proteins from two different samples in the same gel lane or on the same 2D gel. This S-FLOS method offers detection, identification and quantification of S-nitrosated proteins, with the potential for site-specific identification of nitrosation events.

Computational Approaches to Understanding the Role of Fibroblast-Myocyte Interactions in Cardiac Arrhythmogenesis.

The adult heart is composed of a dense network of cardiomyocytes surrounded by nonmyocytes, the most abundant of which are cardiac fibroblasts. Several cardiac diseases, such as myocardial infarction or dilated cardiomyopathy, are associated with an increased density of fibroblasts, that is, fibrosis. Fibroblasts play a significant role in the development of electrical and mechanical dysfunction of the heart; however the underlying mechanisms are only partially understood. One widely studied mechanism suggests that fibroblasts produce excess extracellular matrix, resulting in collagenous septa. These collagenous septa slow propagation, cause zig-zag conduction paths, and decouple cardiomyocytes resulting in a substrate for arrhythmia. Another emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junctions. Due to the challenges of investigating fibroblast-myocyte coupling in native cardiac tissue, computational modeling and in vitro experiments have facilitated the investigation into the mechanisms underlying fibroblast-mediated changes in cardiomyocyte action potential morphology, conduction velocity, spontaneous excitability, and vulnerability to reentry. In this paper, we summarize the major findings of the existing computational studies investigating the implications of fibroblast-myocyte interactions in the normal and diseased heart. We then present investigations from our group into the potential role of voltage-dependent gap junctions in fibroblast-myocyte interactions.

Aberrant heart rate and brainstem brain-derived neurotrophic factor (BDNF) signaling in a mouse model of Huntington's disease.

Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD.