Ada Zhu

Abstract Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction of lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1 -positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1 -positive cells identified a large enhancer proximal to Interleukin-1 beta (Il1b) , and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1 , resulting in a profibrotic response in human cardiac fibroblasts. In vivo , antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1 , inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling.

Supplementary tables for article which includes: Supplementary Table 1: Univariate and multivariate logistic regression for likelihood of receiving TB verbal risk assessment Supplementary Table 2: Univariate and multivariate logistic regression for likelihood of receiving order for serum TB test

Epidermolysis bullosa (EB) is a group of rare genetic blistering skin diseases, with EB simplex (EBS) being the most common subtype, accounting for around 70% of cases. Although there is no cure for EB, recent advancements led to the historic FDA-approvals of two treatments for dystrophic and junctional EB in 2023 and a third for dystrophic EB in 2025. However, no approved treatments exist for EBS despite its relative prevalence. Here, we outline established and emerging therapies for EBS. Supportive EBS management focuses on five key areas: skin-directed wound care, sweating reduction, keratoderma management, EBS-severe specific considerations, and blister reduction/prevention. Environmental measures target friction and moisture control to prevent blistering with the proper socks, footwear, and ambulation assistive device use. Wound care strategies include draining blisters without unroofing, nonstick dressing protection, and dilute vinegar or bleach baths to prevent infection and mitigate itch. Absorptive powders, glycopyrrolate, oxybutynin, and botulinum toxin target hyperhidrosis reduction. Painful keratoderma management, while challenging, includes mechanical debridement and topical keratolytic agents; targeted treatments including topical sirolimus have been explored in early phase study. A number of emerging treatments targeting EBS inflammatory pathways under investigation include apremilast, dapsone, diacerein ointment, deucravacitinib, and topical broccoli sprout extract. Tetracycline antibiotics are commonly used off-label for blister prevention. Ongoing bench research and gene-editing techniques like siRNA, TALEN, and CRISPR-Cas9 offer hope for translational advancements.

Supplementary Tables for Article.