Biology subjects

Han, D. D.

Publications and source records attributed to Han, D. D..

3 recordsLinked to original sources

bioRxiv2025

Epicardial contributions to fibro-inflammatory signaling in a Pkp2-deficient arrhythmogenic cardiomyopathy model

BackgroundArrhythmogenic Cardiomyopathy (ACM) is an inherited disease that is characterized by lethal ventricular arrhythmias stemming from myocyte dysfunction. ACM is associated with considerable subepicardial fibrosis and inflammation with right ventricle predominance. Most cases of gene positive ACM are caused by a desmosome protein mutation, with plakophilin-2 (Pkp2) mutations being most common. We hypothesized Pkp2-deficiency in epicardium-derived cells (EPDCs) contributes to fibro-inflammatory signaling and ACM pathogenesis. MethodsWe developed transgenic mice that lack Pkp2 in cardiomyocytes (Pkp2-cKO) or in both cardiomyocyte and EPDC (Pkp2-ceKO) via the tissue-specific expression of tamoxifen-inducible Cre recombinase. Non-myocyte populations were isolated 21 days post-tamoxifen injection for single cell RNA-sequencing (scRNA-seq). Immunohistochemistry, flow cytometry, qRT-PCR, and echocardiography were used to interrogate cardiac physiology and cellular composition. ResultsWe identified a population of epicardium-derived fibroblasts characterized by the expression of Ccl2, Ccl7, Thbs1, and Ptx3 that accumulated upon Pkp2 deletion. While pro-inflammatory EPDCs are found in Pkp2-cKO mice, they become significantly enriched in Pkp2-ceKO mice. Pro-inflammatory fibroblasts acquired the senescence-associated secretory phenotype (SASP), correlating with elevated Senescence Associated (SA)-{beta}gal staining in the right ventricle. Gene expression, flow cytometry, and histological data also revealed an exaggerated inflammatory response in Pkp2-ceKO mice, that progresses from right to bi-ventricular predominance. Importantly, macrophages and B cells accumulate in both Pkp2-cKO and Pkp2-ceKO mice compared to controls. Antibody-mediated B cell depletion delays the early inflammatory and fibrosis response but did not significantly alter end-stage cardiac physiology. ConclusionPkp2 deletion in EPDC facilitates the emergence of a fibro-inflammatory phenotype that may contribute to ACM pathogenesis.

cell biology↗

bioRxiv2024

Awe is characterized as an ambivalent experience in the human behavior and cortex: integrated virtual reality-electroencephalogram study

Ambivalent feelings are a defining feature of awe, which has been understood as a possible source of its psychosocial benefits. However, due to the conventional unidimensional model of affective valence, behavior and neural representation of ambivalent feelings during awe remain elusive. To address this gap, we combined awe-inducing virtual reality clips, electroencephalogram, and a deep learning-based dimensionality reduction technique (N = 43). Behaviorally, awe ratings were precisely predicted by the duration and intensity of ambivalent feelings, not by single valence-related metrics. In the electrophysiological analysis, we identified latent neural space for each participant sharing valence representation structures across individuals and stimuli. In these spaces, ambivalent feelings during awe were distinctly represented from positive and negative ones, and the variability in their distinctiveness specifically predicted awe ratings. Additionally, frontal delta oscillations mainly engaged in differentiating valence representations. Our findings demonstrate that awe is fundamentally an ambivalent experience reflected in both behavior and electrophysiological activities. This work provides a new framework for understanding complex emotions and their neural underpinnings, with potential implications for affective neuroscience and relevant fields.

neuroscience↗

bioRxiv2019

Impaired Therapeutic Efficacy of Bone Marrow Cells from Post-Myocardial Infarction Patients in the TIME and LateTIME Clinical Trials

Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.

physiology↗