Biology subjects

Kim, S. A.

Publications and source records attributed to Kim, S. A..

6 recordsLinked to original sources

bioRxiv2026

Zinc Differentially Modulates Tau Aggregation, Fibril Morphology, and Prion-like Seeding in a Construct-Dependent Manner

The role of tau fibril structure in seeding and propagation of aggregation remains a central unresolved question in tauopathy biology. While non-proteinaceous cofactors are increasingly observed in patient-derived tau filaments, whether they actively determine fibril structure and function is not well understood. Here, we show that zinc, a divalent cation dysregulated in Alzheimers disease (AD), can drive fundamentally different aggregation and seeding outcomes depending on tau sequence context. Using heparin-free conditions, we compared full-length 2N4R tau (residues 1-441) with an AD-tau fragment (residues 304-380) corresponding to the ordered fibril core. Strikingly, Zn2+ exerted opposite effects on these constructs: it accelerated aggregation, increased fibril length, and enhanced cellular seeding for AD-tau, while slowing aggregation, shortening fibrils, and suppressing seeding for full-length tau. These findings demonstrate that cofactor effects are not intrinsic properties of the cofactor itself, but emerge from its interplay with tau sequence and conformational constraints. More broadly, our results support a model in which small-molecule cofactors act as active architects of fibril structure and function, suggesting that chemically distinct environments could generate structurally and biologically distinct tau strains in disease.

biochemistry↗

bioRxiv2026

Single-molecule dissection of CFTR folding defects and pharmacological rescue

Cystic fibrosis is a lethal genetic disorder caused by misfolding of the CFTR protein, most commonly due to the {Delta}F508 mutation. Despite extensive study, CFTRs folding process has remained inaccessible to direct observation. Here, we apply single-molecule magnetic tweezers to resolve the complete folding trajectories of wild-type and {Delta}F508 CFTR with near-amino acid resolution. We find that CFTR follows a hierarchical, template-guided folding pathway in which N-terminal domains scaffold downstream folding. This mechanism tightly couples the free energy states of intermediates, allowing {Delta}F508-induced instability to propagate across the folding pathway. Pharmacological correctors, in synergy with ATP, reshape the entire folding energy landscape by catalyzing transitions rather than simply stabilizing end states. These long-range, allosteric effects reveal a folding-embedded regulatory network. Our work provides a quantitative framework for mapping multidomain protein folding and therapeutic rescue, offering a broadly applicable strategy for interrogating rare mutations and accelerating structure-based drug discovery. Significance StatementMisfolding of CFTR underlies cystic fibrosis, and its complex, multidomain architecture makes it an ideal model for understanding how membrane proteins fold and how small molecules can restore native structure. Using single-molecule magnetic tweezers, we reveal how local instabilities propagate through CFTRs folding pathway and show that pharmacological correctors act by catalyzing specific folding transitions in addition to stabilizing the native fold. These insights establish CFTR as a paradigm for dissecting folding mechanisms in large membrane proteins and for developing general strategies to correct misfolding across diverse human diseases.

biophysics↗

bioRxiv2025

Biomarker Discovery via Integrative Multi-omics for Children exposed to Humidifier Disinfectant

RationaleExposure to humidifier disinfectants has been linked to an array of pulmonary disorders and diminished lung functionality particularly reduced Forced Vital Capacity (FVC). ObjectivesThis investigation sought to identify diagnostic biomarkers for early detection of children at elevated risk of developing chronic respiratory conditions following such exposure. MethodsOur research employed a comprehensive multi-omics strategy analyzing 70 pediatric patients alongside 10 controls, seamlessly integrating clinical assessments with transcriptomics, methylomics, proteomics, and metabolomics data. The analytical framework utilized a sophisticated combination of Non-negative Matrix Factorization (NMF), Multi-Omics Factor Analysis (MOFA), and advanced machine learning algorithms. Measurements and Main ResultsNMF clustering uncovered distinctive protein expression patterns associated with integrin-mediated signaling pathways and immune response mechanisms. Complementarily, MOFA identified latent factors correlating with lung function metrics, highlighting critical molecular pathways involved in integrin cell surface interactions and lipid metabolism regulation. Machine learning-based analysis facilitated the development of a multi-marker panel-comprising IGHV2-70, LysoPC (16:0), and hexadecyl ferulate-which achieved 81.46% accuracy in identifying pulmonary dysfunction cohort. ConclusionsThese findings suggest that alterations in integrin-related signaling networks and dysregulation of lipid metabolism play pivotal roles in mediating the long-term pulmonary consequences of humidifier disinfectant exposure. The proposed multi-marker panel offers significant potential for enhanced risk stratification and timely therapeutic intervention. At a Glance CommentaryO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSExtensive epidemiological evidence has established the causal relationship between humidifier disinfectant exposure and pulmonary dysfunction; however, clinically validated biomarkers for predicting chronic lung disease progression remain limited. Pediatric populations demonstrate unique pathophysiological mechanisms distinct from adults, highlighting the critical necessity for biomarker identification grounded in comprehensive molecular understanding. Despite advances in omics technologies, recent investigations have encountered significant obstacles in achieving deeper mechanistic insights, predominantly attributable to methodological constraints in harmonizing clinical phenotypes with high-dimensional molecular datasets. What This Study Adds to the FieldThis investigation elucidates the fundamental contributions of integrin-mediated signaling cascades and lipid metabolic networks to persistent pulmonary dysfunction following humidifier disinfectant exposure. Our analyses revealed coordinated regulation of integrin signaling pathways and immune response networks through NMF clustering, indicating dynamic temporal evolution of inflammatory responses during chronic disease progression, with temporally distinct molecular signatures identified across discrete observation intervals. Multi-omics factor analysis (MOFA) corroborated integrin pathway dysregulation while additionally uncovering systematic suppression of lipid metabolic processes. Furthermore, machine learning algorithms enabled development of a robust three-component biomarker panel--encompassing IGHV2-70, LysoPC (16:0), and hexadecyl ferulate--demonstrating 81.46% classification accuracy for pulmonary dysfunction phenotypes. Collectively, these findings substantially advance mechanistic understanding of chronic lung injury in vulnerable pediatric cohorts and identify clinically relevant biomarkers with translational potential for risk stratification and therapeutic targeting in clinical practice.

systems biology↗

bioRxiv2024

Extracellular Vesicle-Mediated Delivery of HIF1a Reprograms Macrophages for resolutive response in Sepsis

In sepsis, the liver functions as a central filter organ, where hepatic macrophages form a primary antimicrobial defense layer by eliminating bacteria and regulating immune responses. Therefore, precise regulation of the immune response in hepatic macrophages is crucial for triggering effective defense mechanisms. We aim to modulate the defense immune response by delivering transcription factor HIF1, a key regulator of monocyte/macrophage reprogramming in sepsis. Transcription factors are promising candidates because they dynamically modulate gene expression across diverse conditions, though delivering them remains challenging. In this study, we suggest a novel method for loading HIF1 into extracellular vesicles (EVs) to enhance immune defense and resolve sepsis. By delivering HIF1 to macrophages during sepsis, we promoted the differentiation of Nr1h3-dependent pro-efferocytic MoMFs and C/ebp{beta}-dependent pro-survival MoMFs. Pro-efferocytic MoMFs eliminate damaged hepatocytes and immune cells and pro-survival MoMFs withstand inflammatory conditions and trigger innate memory responses. Particularly, the zonation of these macrophages in the periportal region ensures effective pathogen clearance and minimizes tissue damage. These findings suggest that EV-mediated HIF1 delivery could be a promising therapeutic option for managing sepsis.

bioengineering↗

bioRxiv2023

Static and dynamic analysis of in-vivo imaging for early-detection of lymphedema via near-infrared fluorescence indocyanine green lymphangiography

BackgroundNear-infrared fluorescence indocyanine green (NIRF-ICG) lymphangiography, a primary modality for detecting lymphedema, which is a disease due to lymphatic obstruction, enables real-time observations of lymphatic flow and reveals not only the spatial distribution of drainage (static analysis), but also information on the lymphatic contraction (dynamic analysis). MethodsWe have produced lymphatic obstruction models in upper limbs through the dissection of proximal lymph nodes (LNs) and radiation (dissection limbs). After the model formation during 1 week, the static and dynamic analysis using NIRF-ICG lymphangiography were performed for six weeks. The drainage pattern and leakage of lymph fluid were observed and time-domain signals of lymphatic contraction were measured in the distal lymph vessels. The obtained signals were converted to the frequency-domain spectrums using the signal processing. ResultsThe results of both static and dynamic analyses proved to be effective in accurately identify the extent of lymphatic disruption in the dissection limbs. The static analysis showed abnormal drainage patterns and an increased leakage of lymph fluid to the periphery of the vessels compared to the control limbs. Meanwhile, the waveforms were changed and the frequency of the contractile signals was increased by 58% in the dynamic analysis. Specifically, our findings revealed that regular lymphatic contractions, observed at a frequency range of 0.08 [~] 0.13 Hz in the control limbs, were absent in the dissection limbs. The contractile regularity was not fully restored until the end of the follow-up, indicating a persistent lymphatic disruption in the dissected limbs. ConclusionThe dynamic analysis was consistent with the static analysis, and it could detect the abnormalities of lymphatic circulation by observing the characteristics of signals without the need for a control group. As NIRF-ICG lymphangiography is currently used in clinical practice, our findings may be useful for the early detection of the lymphatic circulation problem.

bioengineering↗

bioRxiv2019

Noncoding de novo mutations contribute to autism spectrum disorder via chromatin interactions

Three-dimensional chromatin structures regulate gene expression across genome. The significance of de novo mutations (DNMs) affecting chromatin interactions in autism spectrum disorder (ASD) remains poorly understood. We generated 931 whole-genome sequences for Korean simplex families to detect DNMs and identified target genes dysregulated by noncoding DNMs via long-range chromatin interactions between regulatory elements. Notably, noncoding DNMs that affect chromatin interactions exhibited transcriptional dysregulation implicated in ASD risks. Correspondingly, target genes were significantly involved in histone modification, prenatal brain development, and pregnancy. Both noncoding and coding DNMs collectively contributed to low IQ in ASD. Indeed, noncoding DNMs resulted in alterations, via chromatin interactions, in target gene expression in primitive neural stem cells derived from human induced pluripotent stem cells from an ASD subject. The emerging neurodevelopmental genes, not previously implicated in ASD, include CTNNA2, GRB10, IKZF1, PDE3B, and BACE1. Our results were reproducible in 517 probands from MSSNG cohort. This work demonstrates that noncoding DNMs contribute to ASD via chromatin interactions.

neuroscience↗