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Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis. To model DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with heterozygous DSP truncating variants (DSPtvs) and a gene-edited homozygous deletion cell line ([DSP.sup.-/-]). At baseline, [DSP.sup.-/-] EHTs displayed a transcriptomic signature of innate immune activation, which was mirrored by cytokine release. Importantly, [DSP.sup.- /-] EHTs were hypersensitive to Toll-like receptor (TLR) stimulation, demonstrating more contractile dysfunction compared with isogenic controls. Relative to [DSP.sup.-/-] EHTs, heterozygous DSPtv EHTs had less functional impairment. DSPtv EHTs displayed heightened sensitivity to TLR stimulation, and when subjected to strain, DSPtv EHTs developed functional deficits, indicating reduced contractile reserve compared with healthy controls. Colchicine or NF-[kappa]B inhibitors improved straininduced force deficits in DSPtv EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs. Thus, EHTs replicate electrical and contractile phenotypes seen in human myocarditis, implicating cytokine release as a key part of the myogenic susceptibility to inflammation. The heightened innate immune activation and sensitivity are targets for clinical intervention., Introduction Myocarditis is a life-threatening heart condition characterized by inflammation, cellular infiltrate, chest pain, reduced heart function, and arrhythmias (1). Myocarditis affects as many as 10-20 per 100,000 people, with [...]

In this current study, hydrogels based on acacia gum (AG), polyacrylamide (PAM), and carboxymethyl tamarind kernel gum (CMTKG) were successfully developed and ciprofloxacin (drug) incorporated into it. To optimize the hydrogel, the concentrations of crosslinker and initiator were varied, and their effects on the swelling were examined. The hydrogel was subjected to characterization techniques such as Powder X‐ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), Attenuated Total Reflection‐Fourier Transform Infrared spectroscopy (ATR‐FTIR), and Thermogravimetric analysis (TGA). The hydrogel swelling and in vitro drug release were assessed in pH 1.2 and 7.4 buffer solutions. The findings revealed that an alkaline pH yielded superior results for the swelling and in vitro drug release experiments compared to an acidic pH. The drug release kinetic of the ciprofloxacin‐loaded AG/PAM/CMTKG hydrogel followed the Korsmeyer–Peppas model, demonstrating non‐fickian diffusion at pH 7.4 and fickian mechanism at pH 1.2. The pH‐dependent behavior of ciprofloxacin‐loaded AG/PAM/CMTKG hydrogel displayed its potential implications for site‐specific ciprofloxacin release. [ABSTRACT FROM AUTHOR]

Glucocorticoid steroids are commonly prescribed for many inflammatory conditions, but chronic daily use produces adverse effects, including muscle wasting and weakness. In contrast, shorter glucocorticoid pulses may improve athletic performance, although the mechanisms remain unclear. Muscle is sexually dimorphic and comparatively little is known about how male and female muscles respond to glucocorticoids. We investigated the impact of once-weekly glucocorticoid exposure on skeletal muscle performance comparing male and female mice. One month of once-weekly glucocorticoid dosing improved muscle specific force in both males and females. Transcriptomic profiling of isolated myofibers identified a striking sexually dimorphic response to weekly glucocorticoids. Male myofibers had increased expression of genes in the IGF1/PI3K pathway and calcium handling, while female myofibers had profound upregulation of lipid metabolism genes. Muscles from weekly prednisone-treated males had improved calcium handling, while comparably treated female muscles had reduced intramuscular triglycerides. Consistent with altered lipid metabolism, weekly prednisone-treated female mice had greater endurance relative to controls. Using chromatin immunoprecipitation, we defined a sexually dimorphic chromatin landscape after weekly prednisone. These results demonstrate that weekly glucocorticoid exposure elicits distinct pathways in males versus females, resulting in enhanced performance., Introduction Glucocorticoids are powerful stress hormones that modulate the body's carbohydrate, lipid, and protein metabolism in response to external or circadian stimuli. Synthetic glucocorticoids such as prednisone are used as [...]