Biology subjects

Park, W.-J.

Publications and source records attributed to Park, W.-J..

3 recordsLinked to original sources

bioRxiv2026

Circulating miR-10b-5p drives Kawasaki vasculitis through endothelial reprogramming and nominates CXCL8 as an early diagnostic biomarker

BackgroundKawasaki disease (KD) is an acute systemic vasculitis of unknown etiology and the leading cause of acquired heart disease in children. Coronary artery aneurysm formation represents its most serious complication, yet no specific biomarker exists for early diagnosis at emergency department (ED) presentation. We sought to define the molecular mechanisms driving KD vasculitis and to identify a clinically actionable early diagnostic marker. MethodsWhole microRNA sequencing was performed on buffy coat specimens from KD patients and febrile controls presenting to the ED. Disease-associated miRNA candidates were validated in two independent murine KD-like vasculitis models: Lactobacillus casei cell wall extract (LCWE; n=12-20) and Candida albicans water-soluble fraction (CAWS; n=12). The functional role of miR-10b-5p was assessed by antagomir-mediated inhibition in the LCWE model. Transcriptomic and chromatin-level reprogramming were characterized by single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and assay for transposase-accessible chromatin with sequencing (ATAC-seq) in human coronary artery endothelial cells (HCAECs). Transcription factor binding was validated by in vitro binding assays and chromatin immunoprecipitation. Serum chemokine (C-X-C motif) ligand 8 (CXCL8) was quantified by enzyme-linked immunosorbent assay. ResultsForty miRNAs were upregulated in KD patients and fourteen miRNAs were prioritized for further analysis. miR-10b-5p was consistently elevated across both vasculitis models, and its antagomir-mediated inhibition attenuated aortic root inflammation in vivo. In HCAECs, miR-10b-5p suppressed its direct targets marker of proliferation Ki-67 (MKI67)/Chromobox5 (CBX5), driving a cell-state transition from proliferative/metabolic programs toward a pro-inflammatory phenotype. Consistently, analyses of bulk RNA-seq supported cell-cycle arrest and altered chromatin remodeling. ATAC-seq revealed increased chromatin accessibility at the CXCL8 and Matrix metalloproteinases 10 (MMP10) promoters, and motif analysis identified CCAAT/enhancer-binding protein alpha (CEBPA) as the key transcriptional activator; CEBPA knockdown abrogated miR-10b-5p-induced CXCL8 and MMP10 upregulation. Serum CXCL8 was markedly elevated in KD patients relative to febrile controls at first ED presentation, prior to definitive diagnosis, and declined significantly at 8-week follow-up. ConclusionsWe define a miR-10b-5p-MKI67/CBX5-CEBPA-CXCL8 axis as a mechanistic driver of endothelial reprogramming and neutrophil-recruiting inflammation in KD. Serum CXCL8 emerges as a candidate early diagnostic biomarker that may facilitate timely KD recognition at ED presentation.

molecular biology↗

bioRxiv2024

Multi-stage-mixing to create a core-then-shell structure improves DNA-loaded lipid nanoparticles transfection by orders of magnitude

As they became the dominant gene therapy platform, lipid nanoparticles (LNPs) experienced nearly all their innovation in varying the structure of individual molecules in LNPs. This ignored control of the spatial arrangement of molecules, which is suboptimal because supramolecular structure determines function in biology. To control LNPs supramolecular structure, we introduce multi-stage-mixing (MSM) to successively add different molecules to LNPs. We first utilize MSM to create a core-then-shell (CTS) synthesis. CTS-LNPs display a clear core-shell structure, vastly lower frequency of LNPs containing no detectable mRNA, and improved mRNA-LNP expression. With DNA-loaded LNPs, which for decades lagged behind mRNA-LNPs due to low expression, CTS improved DNA-LNPs protein expression by 2-3 orders of magnitude, bringing it within range of mRNA-LNPs. These results show that supramolecular arrangement is critical to LNP performance and can be controlled by mixing methodology. Further, MSM/CTS have finally made DNA-LNPs into a practical platform for long-term gene expression.

bioengineering↗

bioRxiv2020

Functional reorganization of visual processing following long-term adaptation to optical defects

How we see is fundamentally limited by the eyes optics, which determine retinal image quality and constrain neural processing. Elucidating how long-term exposure to optical defects alters visual processing is vital for understanding the human brains capacity for and limits of sensory plasticity. Using adaptive optics to bypass the eyes optical aberrations, we assessed changes in visual processing in neurotypically-developed adults with keratoconus (KC)--a corneal disease causing severe optical aberrations during adulthood that cannot be fully corrected using conventional methods. As a result, KC patients are chronically exposed to degraded retinal images in their everyday life, making them an ideal model to understand how prolonged exposure to poor optical quality alters visual processing. Here, we show that when tested under similar fully-corrected optical conditions as neurotypical observers, KC patients exhibited altered contrast sensitivity, with impaired sensitivity for fine spatial details and better sensitivity for coarse spatial details. Both gains and losses in contrast sensitivity were more pronounced in patients with poorer habitual optical quality. Moreover, using an equivalent noise paradigm and a computational model of visual processing, we show that these alterations in visual processing are mediated by changes in signal enhancement of spatial frequency selective mechanisms. The present findings uncover fundamental properties of neural compensation mechanisms in response to long-term exposure to optical defects, which alter sensory processing and limit the benefits of improved optics. The outcome is a large-scale functional reorganization favoring the processing of sensory information less affected by the eyes optics. Significance statementThe eyes optics represent an intrinsic limit to human visual perception, determining the quality of retinal images. Neural adaptation optimizes the brains limited sensory processing capacity to the structure of the degraded retinal inputs, providing an exceptional quality of vision given these optical limitations. Here, we show that prolonged exposure to poor optical quality results in a functional reorganization of visual processing that favors sensory information less affected by the eyes optics. The present study helps elucidate how optical factors shape the way the brain processes visual information. Notably, the resulting adaptive neural plasticity limits the immediate perceptual benefits of optical interventions, a factor that must be taken into consideration when treating the increasing human population affected by optical defects.

neuroscience↗