The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening.

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.

Assessing the Survival of Human Plasma Cells Ex Vivo.

One way memory B cells provide protection is by rapidly differentiating into plasma cells. Plasma cells are vital in providing long-term protection against pathogens; however, they can also be detrimental to health in the case of antibody-mediated autoimmunity. Therefore, compounds which modulate the survival of plasma cells have been of interest for therapeutic intervention. Investigation of ex vivo plasma cell survival has previously been limited by the low frequency of plasma cells in the blood. Here we describe a novel ex vivo culture system that only requires 3000-5000 cells per condition. This method permits the assessment of human plasma cell survival derived from blood and can assess the impact of small molecule inhibitors on plasma cell viability.

Autonomy-supportive parenting as a moderator of associations between ethnic and racial identity processes and psychological adjustment during college.

OBJECTIVES: The purpose of this study was to test the roles of ethnic and racial identity (ERI) processes and autonomy-supportive parenting on college students' psychological adjustment. METHOD: American college students of color (N = 505) completed questionnaires assessing ERI exploration and commitment, autonomy-supportive parenting, and psychological adjustment (self-esteem, depressive symptoms). Key variables were operationalized as latent constructs, and main and interaction effects were tested using the latent moderated structural equation modeling approach. RESULTS: Higher levels of ERI commitment (but not exploration) and parental autonomy support each uniquely predicted higher levels of self-esteem and lower levels of depressive symptoms. Parental autonomy support moderated associations between ERI processes and psychological adjustment, and the nature of moderation did not differ across Black and Latino/a/x students. CONCLUSIONS: Supporting the psychological adjustment of college students of color necessitates acknowledging the importance of both parental and institutional efforts to encourage students' autonomy strivings and ERI processes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Differential induction of T-cell tolerance by tumour fibroblast subsets.

T-cell immunotherapy is now a first-line cancer treatment for metastatic melanoma and some lung cancer subtypes, which is a welcome clinical success. However, the response rates observed in these diseases are not yet replicated across other prominent solid tumour types, particularly stromal-rich subtypes with a complex microenvironment that suppresses infiltrating T cells. Cancer-associated fibroblasts (CAFs) are one of the most abundant and pro-pathogenic players in the tumour microenvironment, promoting tumour neogenesis, persistence and metastasis. Accumulating evidence is clear that CAFs subdue anti-tumour T-cell immunity and interfere with immunotherapy. CAFs can be grouped into different subtypes that operate synergistically to suppress T-cell function, including myofibroblastic CAFs, inflammatory CAFs and antigen-presenting CAFs, among other nomenclatures. Here, we review the mechanisms used by CAFs to induce T- cell tolerance and how these functions are likely to affect immunotherapy outcomes.

Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity.

Objectives: B cells drive the production of autoreactive antibody-secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long-term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI-1 could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods: Use of a BMI-1 inhibitor in both mouse and human autoimmune settings was investigated. Lyn -/- mice, a model of SLE, were treated with the BMI-1 small molecule inhibitor PTC-028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast-based assay was established, and the impact of PTC-028 on ASCs derived from Sjögren's syndrome patients was evaluated. Results: BMI-1 inhibition significantly decreased splenic and bone marrow ASCs in Lyn -/- mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti-DNA IgG. PTC-028 was also efficacious in reducing ex vivo plasma cell survival from both Sjögren's syndrome patients and age-matched healthy donors. Conclusion: These data provide evidence that inhibiting BMI-1 can deplete ASC in a variety of contexts and thus BMI-1 is a viable therapeutic target for antibody-mediated autoimmune diseases.

Financial, resource, and psychological impacts of COVID-19 on U.S. College students: Who is impacted and what are the implications for adjustment and well-being?

The COVID-19 pandemic has been highly disruptive for college students and has altered their living, learning, and working environments. COVID-19-related financial impact, access to needed resources, and psychological impacts are reported amongst college students, though research has yet to examine how severity and type of impact varies by student. This study investigated how undergraduate college students were impacted during the COVID-19 pandemic regarding finances, access to needed resources, and psychological well-being, and explored outcomes associated with patterns of perceived impact. Participants were 894 college students at a southeastern university who completed an online survey during the Spring 2021 semester. Students reported on how the COVID-19 pandemic affected their finances, resources, and psychological health; students also reported their current self-esteem, and adjustment to college (academic and relational). Latent profile analysis was utilized to develop profiles of COVID-19-related impact. Results indicated that most participants experienced moderate levels of financial and psychological impact but low resource impact (34.6%) or experienced low impact across the range of financial, resource, and psychological domains (32.5%). Seventeen percent were highly impacted across all domains and 15.8% experienced moderate financial and resource impact but low psychological impact. Student gender identity, generational status, and first-year status were significant predictors of profile membership - student race was not associated with profile membership. Highly impacted students had significantly lower self-esteem and college adjustment compared to students in relatively less-impacted profiles.

Fibroblastic reticular cells provide a supportive niche for lymph node-resident macrophages.

The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis, but key factors controlling this niche are undefined. Here, we show that fibroblastic reticular cells (FRCs) are an essential component of the LN macrophage niche. Genetic ablation of FRCs caused rapid loss of macrophages and monocytes from LNs across two in vivo models. Macrophages co-localized with FRCs in human LNs, and murine single-cell RNA-sequencing revealed that FRC subsets broadly expressed master macrophage regulator CSF1. Functional assays containing purified FRCs and monocytes showed that CSF1R signaling was sufficient to support macrophage development. These effects were conserved between mouse and human systems. These data indicate an important role for FRCs in maintaining the LN parenchymal macrophage niche.

Impact of the COVID-19 pandemic on first-year college students: Racial/ethnic differences.

Prior research has shown that the COVID-19 pandemic has negatively impacted American college students; however, few studies have focused on first-year students and their experiences with attending college during unprecedented circumstances. To address this gap, first-year college students (N = 268) completed online questionnaires assessing their perceptions of the extent to which the COVID-19 pandemic had impacted them in terms of access to resources and psychological well-being. Students also completed a measure of college-specific adjustment in the relational, psychological, and educational domains. Greater perceived COVID-19-specific resources impact was associated with lower educational adjustment. Greater perceived COVID-19-specific psychological impact was associated with lower levels of relational college adjustment and lower levels of psychological college adjustment. A multi-group analysis indicated that although the association between perceived psychological impact and college-specific psychological adjustment was significant for both White students and Black students, it was stronger among White students.

Parental Self-Efficacy and Physiological Responses to Stress among Mothers of Early Adolescents.

Little research addresses how parental self-efficacy is related to stress responses, and no research does so among parents of early adolescents. To fill this research gap, the current study examined the association between maternal self-efficacy and physiological stress responses during early adolescence. Participants were 68 mother-early adolescent dyads with youth in the 6th grade (M = 11 years; 56% female). Physiological responses (i.e., skin conductance, respiratory sinus arrythmia, cortisol) were measured before and after mothers observed their children engage in a modified Trier Social Stress Test for Children. Mothers reported on parental self-efficacy. Mothers with higher parental self-efficacy exhibited a more moderate skin conductance response to the speech portion of the task, and a smaller increase in cortisol, compared to mothers with lower parental self-efficacy. Respiratory sinus arrhythmia change was not related to parental self-efficacy. The findings are consistent with a "caring but confident" physiological profile among mothers with high parental self-efficacy, suggesting that greater confidence about parental influence might reduce parents' experience of stress/anxiety as they observe children face certain challenges.

3D Collagen-Nanocellulose Matrices Model the Tumour Microenvironment of Pancreatic Cancer.

Three-dimensional (3D) cancer models are invaluable tools designed to study tumour biology and new treatments. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of cancer, has been progressively explored with bioengineered 3D approaches by deconstructing elements of its tumour microenvironment. Here, we investigated the suitability of collagen-nanocellulose hydrogels to mimic the extracellular matrix of PDAC and to promote the formation of tumour spheroids and multicellular 3D cultures with stromal cells. Blending of type I collagen fibrils and cellulose nanofibres formed a matrix of controllable stiffness, which resembled the lower profile of pancreatic tumour tissues. Collagen-nanocellulose hydrogels supported the growth of tumour spheroids and multicellular 3D cultures, with increased metabolic activity and matrix stiffness. To validate our 3D cancer model, we tested the individual and combined effects of the anti-cancer compound triptolide and the chemotherapeutics gemcitabine and paclitaxel, resulting in differential cell responses. Our blended 3D matrices with tuneable mechanical properties consistently maintain the growth of PDAC cells and its cellular microenvironment and allow the screening of anti-cancer treatments.

Fibroblasts: The B's knees of follicular lymphoma.

Fibroblasts are the immunological architects of lymph nodes. In this issue of Immunity, Mourcin et al. describe the human tonsil fibroblast landscape and predicted T and B cell interactions. Transcriptomic changes in follicular lymphoma could provide untapped clinical targets.

A bird's eye view of fibroblast heterogeneity: A pan-disease, pan-cancer perspective.

Fibroblasts, custodians of tissue architecture and function, are no longer considered a monolithic entity across tissues and disease indications. Recent advances in single-cell technologies provide an unrestricted, high-resolution view of fibroblast heterogeneity that exists within and across tissues. In this review, we summarize a compendium of single-cell transcriptomic studies and provide a comprehensive accounting of fibroblast subsets, many of which have been described to occupy specific niches in tissues at homeostatic and pathologic states. Understanding this heterogeneity is particularly important in the context of cancer, as the diverse cancer-associated fibroblast (CAF) phenotypes in the tumor microenvironment (TME) are directly impacted by the expression phenotypes of their predecessors. Relationships between these heterogeneous populations often accompany and influence response to therapy in cancer and fibrosis. We further highlight the importance of integrating single-cell studies to deduce common fibroblast phenotypes across disease states, which will facilitate the identification of common signaling pathways, gene regulatory programs, and cell surface markers that are going to advance drug discovery and targeting.

In Vitro Suppression of T Cell Proliferation Is a Conserved Function of Primary and Immortalized Human Cancer-Associated Fibroblasts.

T cell immunotherapy is now a mainstay therapy for several blood-borne cancers as well as metastatic melanoma. Unfortunately, many epithelial tumors respond poorly to immunotherapy, and the reasons for this are not well understood. Cancer-associated fibroblasts (CAFs) are the most frequent non-neoplastic cell type in most solid tumors, and they are emerging as a key player in immunotherapy resistance. A range of immortalized CAF lines will be essential tools that will allow us to understand immune responses against cancer and develop novel strategies for cancer immunotherapy. To study the effect of CAFs on T cell proliferation, we created and characterized a number of novel immortalized human CAFs lines (Im-CAFs) from human breast, colon, and pancreatic carcinomas. Im-CAFs shared similar phenotypes, matrix remodeling and contraction capabilities, and growth and migration rates compared to the primary CAFs. Using primary isolates from breast carcinoma, colorectal carcinoma, and pancreatic ductal adenocarcinoma, we report that CAFs across major tumor types are able to potently suppress T cell proliferation in vitro. Im-CAFs retained this property. Im-CAFs are a key tool that will provide important insights into the mechanisms of CAF-mediated T cell suppression through techniques such as CRISPR-Cas9 modification, molecular screens, and pipeline drug testing.

Cancer-Associated Fibroblasts and T Cells: From Mechanisms to Outcomes.

Over the past decade, T cell immunotherapy has changed the face of cancer treatment, providing robust treatment options for several previously intractable cancers. Unfortunately, many epithelial tumors with high mortality rates respond poorly to immunotherapy, and an understanding of the key impediments is urgently required. Cancer-associated fibroblasts (CAFs) comprise the most frequent nonneoplastic cellular component in most solid tumors. Far from an inert scaffold, CAFs significantly influence tumor neogenesis, persistence, and metastasis and are emerging as a key player in immunotherapy resistance. In this review, we discuss the physical and chemical barriers that CAFs place between effector T cells and their tumor cell targets, and the therapies poised to target them.

The fibroblastic T cell niche in lymphoid tissues.

Fibroblastic reticular cells (FRCs) are a necessary immunological component for T cell health. These myofibroblasts are specialized for immune cell support and develop in locations where T and B lymphocyte priming occurs, usually secondary lymphoid organs, but also tertiary lymphoid structures and sites of chronic inflammation. This review describes their dual supportive and suppressive functions and emerging evidence on the co-ordination required to balance these competing roles.

Youth Parasympathetic Functioning Moderates Relations between Cumulative Family Risk and Internalizing Behaviors.

Problematic family functioning places young adolescents at risk for internalizing behaviors. However, not all adolescents who experience family risk develop internalizing behaviors during early adolescence. Informed by a cumulative risk perspective, the current study examined whether associations between cumulative family risk, as well as particular family risk domains, and youth internalizing behaviors are moderated by youth parasympathetic reactivity. Participants include 68 young adolescents in 6th grade. Youth were 56% female, 41% African American, and 54% European American. For young adolescents who experienced higher change in respiratory sinus arrhythmia during a challenge/stressor task, greater cumulative family risk, exposure to more family risk domains, and several particular risk factors (maternal psychological well-being, marital/family system risk), were associated with higher levels of internalizing behaviors. The findings from this study demonstrate that the extent to which both particular family risk factors and cumulative family risk place youth at increased risk for internalizing behaviors depends on youth's parasympathetic functioning.

Sympathetic and Parasympathetic Nervous System Functioning and Experiences of Peer Exclusion: Links to Internalizing Problems in Early Adolescence.

This study examines the moderating effect of both branches of the autonomic nervous system (sympathetic and parasympathetic) on associations between peer exclusion and internalizing behaviors. Young adolescents (N = 68) self-reported their perceptions of peer exclusion and internalizing problems and participated in stress-inducing public speaking tasks. Skin conductance and respiratory sinus arrhythmia were assessed at baseline (skin conductance baseline, SCLB; respiratory sinus arrhythmia baseline, RSAB) and during the challenge task to provide measures of physiological reactivity (skin conductance reactivity, SCLR; respiratory sinus arrhythmia reactivity, delta RSA). Youth with high delta RSA (low vagal suppression) had higher levels of internalizing problems when they perceived more peer exclusion in their social environments. The combination of low SCLR and high delta RSA (reciprocal parasympathetic) predicted higher levels of internalizing problems, whereas the combination of high SCLR and high delta RSA (coactivation) predicted lower levels of internalizing problems. The association between peer exclusion and youth internalizing problems was not moderated by ANS reactivity profiles which reflected combinations of SCLR and delta RSA.