INTRODUCTION: Racial discrimination is a distinct health threat that increases disease risk among Black Americans. Psychosocial stress may compromise health through inflammatory mechanisms. This study examines incident experiences of racial discrimination and changes in the inflammatory biomarker C-reactive protein (CRP) over a two-year period among Black women with systemic lupus erythematosus (SLE)-an inflammatory autoimmune disease sensitive to psychosocial stress and characterized by stark racial inequities in outcomes. METHODS: Data are from the Black Womens Experiences Living with Lupus (BeWELL) Study. Participants (n = 380) from metropolitan Atlanta, Georgia were enrolled from April 2015 to May 2017. Incident racial discrimination was assessed bi-annually via self-report using the Experiences of Discrimination measure. CRP was assessed annually over a two-year period. Latent change score analyses modeled longitudinal within-person associations between incident racial discrimination and change in log-transformed CRP from baseline to Year 2. RESULTS: Incident experiences of racial discrimination were associated with elevated log-CRP across the two-year study period (b = 0.039, SE = 0.017, 95% CI: 0.006, 0.071). For each domain of incident racial discrimination experienced, CRP increased 3.98%. CONCLUSION: This study contributes to growing evidence on the biological consequences of racism and is the first to document an association between incident racial discrimination and changes in inflammation among Black women with SLE. Racial inequities in SLE outcomes and other diseases driven by inflammatory pathways may be explained in part through experiences of racial discrimination.

Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents; however, their use is hampered by subsequent cardiotoxicity risk. Our understanding of cardiomyocyte protective pathways activated following anthracycline-induced cardiotoxicity (AIC) remains incomplete. Insulin-like growth factor binding protein (IGFBP) 3 (Igfbp-3), the most abundant IGFBP family member in the circulation, is associated with effects on the metabolism, proliferation, and survival of various cells. Whereas Igfbp-3 is induced by Dox in the heart, its role in AIC is ill-defined. We investigated molecular mechanisms as well as systems-level transcriptomic consequences of manipulating Igfbp-3 in AIC using neonatal rat ventricular myocytes and human-induced pluripotent stem cell-derived cardiomyocytes. Our findings reveal that Dox induces the nuclear enrichment of Igfbp-3 in cardiomyocytes. Furthermore, Igfbp-3 reduces DNA damage, impedes topoisomerase IIβ expression (Top2β) which forms Top2β-Dox-DNA cleavage complex leading to DNA double-strand breaks (DSB), alleviates detyrosinated microtubule accumulation-a hallmark of increased cardiomyocyte stiffness and heart failure-and favorably affects contractility following Dox treatment. These results indicate that Igfbp-3 is induced by cardiomyocytes in an effort to mitigate AIC.

Racial discrimination has been linked to allostatic load (i.e., cumulative biological stress) among African American women. However, limited attention has been given to psychosocial processes involved in the stress response-critical for understanding biological pathways to health-in studies examining racial discrimination as a social determinant of health. We examined whether the superwoman schema (SWS), a multidimensional culture-specific framework characterizing psychosocial responses to stress among African American women, modifies the association between racial discrimination and allostatic load. We used purposive sampling to recruit a community sample of African American women ages 30-50 from five San Francisco Bay Area counties (n = 208). Path analysis was used to test for interactions while accounting for the covariance among SWS subscales using both linear and quadratic models. Significant interactions were observed between racial discrimination and four of the five SWS subscales. Feeling obligated to present an image of strength and an obligation to suppress emotions were each protective whereas feeling an intense motivation to succeed and feeling an obligation to help others exacerbated the independent health risk associated with experiencing racial discrimination. Our findings affirm the need to consider individual variability in coping and potentially other psychosocial processes involved in the stress response process, and offer several insights that may help elucidate the mechanisms by which racial discrimination gets under the skin.

Aptamers, short RNA or DNA molecules that bind distinct targets with high affinity and specificity, can be identified using high-throughput systematic evolution of ligands by exponential enrichment (HT-SELEX), but scalable analytic tools for understanding sequence-function relationships from diverse HT-SELEX data are not available. Here we present AptaTRACE, a computational approach that leverages the experimental design of the HT-SELEX protocol, RNA secondary structure, and the potential presence of many secondary motifs to identify sequence-structure motifs that show a signature of selection. We apply AptaTRACE to identify nine motifs in C-C chemokine receptor type 7 targeted by aptamers in an in vitro cell-SELEX experiment. We experimentally validate two aptamers whose binding required both sequence and structural features. AptaTRACE can identify low-abundance motifs, and we show through simulations that, because of this, it could lower HT-SELEX cost and time by reducing the number of selection cycles required.

Cancer immunotherapy shows promising potential for treating breast cancer. While patients may have heterogeneous treatment responses for adjuvant therapy, it is challenging to predict an individual patients response to cancer immunotherapy. Here, we report primary tumor-derived organotypic cell clusters (POCCs) for rapid and reliable evaluation of cancer immunotherapy. By using a label-free, contactless, and highly biocompatible acoustofluidic method, hundreds of cell clusters could be assembled from patient primary breast tumor dissociation within 2 min. Through the incorporation of time-lapse living cell imaging, the POCCs could faithfully recapitulate the cancer-immune interaction dynamics as well as their response to checkpoint inhibitors. Superior to current tumor organoids that usually take more than two weeks to develop, the POCCs can be established and used for evaluation of cancer immunotherapy within 12 h. The POCCs can preserve the cell components from the primary tumor due to the short culture time. Moreover, the POCCs can be assembled with uniform fabricate size and cell composition and served as an open platform for manipulating cell composition and ratio under controlled treatment conditions with a short turnaround time. Thus, we provide a new method to identify potentially immunogenic breast tumors and test immunotherapy, promoting personalized cancer therapy.

Objective

Telomeres are protective sequences of DNA capping the ends of chromosomes that shorten over time. Leukocyte telomere length (LTL) is posited to reflect the replicative history of cells and general systemic aging of the organism. Chronic stress exposure leads to accelerated LTL shortening, which has been linked to increased susceptibility to and faster progression of aging-related diseases. This study examined longitudinal associations between LTL and experiences of racial discrimination, a qualitatively unique source of minority psychosocial stress, among African Americans.

Method

Data are from 391 African Americans in the Coronary Artery Risk Development in Young Adults (CARDIA) Telomere Ancillary Study. We examined the number of domains in which racial discrimination was experienced in relation to LTL collected in Years 15 and 25 (Y15: 2000/2001; Y25: 2010/2011). Multivariable linear regression examined if racial discrimination was associated with LTL. Latent change score analysis (LCS) examined changes in racial discrimination and LTL in relation to one another.

Results

Controlling for racial discrimination at Y15, multivariable linear regression analyses indicated that racial discrimination at Y25 was significantly associated with LTL at Y25. This relationship remained robust after adjusting for LTL at Y15 (b = -.019, p = .015). Consistent with this finding, LCS revealed that increases in experiences of racial discrimination were associated with faster 10-year LTL shortening (b = -.019, p = .015).

Conclusions

This study adds to evidence that racial discrimination contributes to accelerated physiologic weathering and health declines among African Americans through its impact on biological systems, including via its effects on telomere attrition. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Background and objectives

African American women experience faster telomere shortening (i.e., cellular aging) compared with other racial-gender groups. Prior research demonstrates that race and gender interact to influence culturally specific norms for responding to socially-relevant stress and other stress-coping processes, which may affect healthy aging.

Research design and methods

Data are from African American Women's Heart & Health Study participants who consented to DNA extraction (n = 140). Superwoman Schema (SWS) was measured using 5 validated subscales: presenting strength, emotion suppression, resisting vulnerability, motivation to succeed, and obligation to help others. Racial identity was measured using 3 subscales from the Multidimensional Inventory of Black Identity: racial centrality, private regard, and public regard. Relative telomere length (rTL) was measured using DNA extracted from blood samples. Path analysis tested associations and interactions between SWS and racial identity dimensions with rTL.

Results

For SWS, higher resistance to being vulnerable predicted longer telomeres. For racial identity, high private regard predicted longer telomeres while high public regard predicted shorter telomeres. Interactions were found between public regard and 2 SWS dimensions: among women with high public regard, emotion suppression (β = 0.20, p < .05) and motivation to succeed (β = 0.18, p < .05) were associated with longer rTL. The interaction between high centrality and emotion suppression predicted shorter rTL (β = -0.17, p < .05).

Discussion and implications

Culturally specific responses to gendered racism and racial identity, developed early in life and shaped over the life course, are important psychosocial determinants of cellular aging among African American women.

Rationale

Cardiac fibroblasts do not form a syncytium but reside in the interstitium between myocytes. This topological relationship between fibroblasts and myocytes is maintained throughout postnatal life until an acute myocardial injury occurs, when fibroblasts are recruited to, proliferate and aggregate in the region of myocyte necrosis. The accumulation or aggregation of fibroblasts in the area of injury thus represents a unique event in the life cycle of the fibroblast, but little is known about how changes in the topological arrangement of fibroblasts after cardiac injury affect fibroblast function.

Objective

The objective of the study was to investigate how changes in topological states of cardiac fibroblasts (such as after cardiac injury) affect cellular phenotype.

Methods and results

Using 2 and 3-dimensional (2D versus 3D) culture conditions, we show that simple aggregation of cardiac fibroblasts is sufficient by itself to induce genome-wide changes in gene expression and chromatin remodeling. Remarkably, gene expression changes are reversible after the transition from a 3D back to 2D state demonstrating a topological regulation of cellular plasticity. Genes induced by fibroblast aggregation are strongly associated and predictive of adverse cardiac outcomes and remodeling in mouse models of cardiac hypertrophy and failure. Using solvent-based tissue clearing techniques to create optically transparent cardiac scar tissue, we show that fibroblasts in the region of dense scar tissue express markers that are induced by fibroblasts in the 3D conformation. Finally, using live cell interferometry, a quantitative phase microscopy technique to detect absolute changes in single cell biomass, we demonstrate that conditioned medium collected from fibroblasts in 3D conformation compared with that from a 2D state significantly increases cardiomyocyte cell hypertrophy.

Conclusions

Taken together, these findings demonstrate that simple topological changes in cardiac fibroblast organization are sufficient to induce chromatin remodeling and global changes in gene expression with potential functional consequences for the healing heart.

After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis. Given the complexity of COVID-19-associated cell injury and immunopathogenesis processes, we investigated Hippo pathway dynamics in SARS-CoV-2 infection by utilizing COVID-19 lung samples and human cell models based on pluripotent stem cell-derived cardiomyocytes (PSC-CMs) and human primary lung air-liquid interface (ALI) cultures. SARS-CoV-2 infection caused activation of the Hippo signaling pathway in COVID-19 lung and in vitro cultures. Both parental and Delta variant of concern (VOC) strains induced Hippo pathway. The chemical inhibition and gene knockdown of upstream kinases MST1/2 and LATS1 resulted in significantly enhanced SARS-CoV-2 replication, indicating antiviral roles. Verteporfin, a pharmacological inhibitor of the Hippo pathway downstream transactivator, YAP, significantly reduced virus replication. These results delineate a direct antiviral role for Hippo signaling in SARS-CoV-2 infection and the potential for this pathway to be pharmacologically targeted to treat COVID-19.