Biology subjects

Kim, S.-W.

Publications and source records attributed to Kim, S.-W..

6 recordsLinked to original sources

bioRxiv2026

AI-driven framework modeling perturbation in brain organoids reveals candidate genes for autism

Autism gene discovery is constrained by the rarity and heterogeneity of damaging variants, requiring large cohorts to identify susceptibility genes. Neural organoids and single-cell foundation models enable perturbation modeling in neurodevelopmental contexts. Here, we show that perturbation-informed foundation modeling of neural organoids can provide functional context for prioritizing candidate genes with genomic and clinical support. We constructed a 3.6-million-cell organoid atlas and trained models to predict genome-wide perturbation responses. Benchmarking 17 models identified a telencephalic neuron-specific model best preserving autism-relevant perturbation structure. Genome-wide profiling revealed two clusters associated with mid-fetal synaptic neuronal processes and early radial glia ubiquitin signaling. These clusters were supported by damaging-variant enrichment and clinical phenotypes across 89,916 family-based samples. Logistic-regression prioritization identified 343 candidates, including 167 in the key clusters, with convergence across TADA signals and recurrent evidence for NBEA and KLHDC10. This framework integrates predicted perturbation effects with genomic evidence to support autism candidate prioritization.

bioinformatics↗

bioRxiv2023

Mediodorsal thalamic nucleus mediates resistance to ethanol through Cav3.1 T-type Ca2+ regulation of neural activity

Thalamocortical activity is known to orchestrate sensory gating and consciousness switching. The precise thalamic regions involved, or the firing patterns related to the unconsciousness remain unclear. Interestingly, the highly-expressed thalamic T-type calcium currents have been considered as a candidate for the ionic mechanism for the generation of thalamo-cortically-driven change in conscious state. Here, we tested the hypothesis that Cav3.1 T-type channels in the mediodorsal thalamic nucleus (MD) might control neuronal firing during unconsciousness using Cav3.1 T-type channel knock-out (KO) and knock-down (KD) mice under natural sleep and ethanol-induced unconsciousness. During natural sleep, the MD neurons in KO mice showed general characteristics of sustained firing across sleep stages. We found that KO and MD-specific KD mice showed enhanced resistance to ethanol. During ethanol-induced unconscious state, wild-type (WT) MD neurons showed a significant reduction in neuronal firing from baseline with increased burst firing, whereas Cav3.1 KO neurons showed well sustained neural firing, within the level of wakefulness, and no burst firing. Further, 20 Hz optogenetic and electrical activation of MD neurons mimicked the ethanol resistance behavior in WT mice. These results suggest that maintaining MD neural firing at a wakeful level is sufficient to induce resistance to ethanol-induced hypnosis in WT mice. This work has important implications for the design of treatments for consciousness disorders using thalamic stimulation of deeper nuclei including the targeting of the mediodorsal thalamic nucleus. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=161 HEIGHT=200 SRC="FIGDIR/small/558585v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1ad68ccorg.highwire.dtl.DTLVardef@1bb698aorg.highwire.dtl.DTLVardef@10de4f0org.highwire.dtl.DTLVardef@1314b27_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Noncovalent antibody catenation on a target surface drastically increases the antigen-binding avidity

Immunoglobulin G (IgG) antibodies are widely used for diagnosis and therapy. Given the unique dimeric structure of IgG, we hypothesized that, by genetically fusing a homodimeric protein (catenator) to the C-terminus of IgG, reversible catenation of antibody molecules could be induced on a surface where target antigen molecules are abundant, and that it could be an effective way to greatly enhance the antigen-binding avidity. A thermodynamic simulation shows that quite low homodimerization affinity of a catenator, e.g. dissociation constant of 100 M, can enhance nanomolar antigen-binding avidity to a picomolar level, and that the fold enhancement sharply depends on the density of the antigen. In a proof-of-concept experiment where antigen molecules are immobilized on a biosensor tip, C-terminal fusion of a weakly homodimerizing protein to two different antibodies enhanced the antigen-binding avidity by at least 210 to 5,120 folds from the intrinsic binding avidity. Thus, the homodimerization-induced antibody catenation would be a simple, powerful and general approach to improve many antibody applications, including the detection of scarce biomarkers and targeted anticancer therapies.

biophysics↗

bioRxiv2022

Inhibiting 5-lipoxygenase prevents skeletal muscle atrophy by targeting organogenesis signaling and insulin-like growth factor-1

BackgroundSkeletal muscle atrophy can occur in response to numerous factors, such as aging and certain medications, and produces a major socioeconomic burden. At present, there are no approved drugs for treating skeletal muscle atrophy. Arachidonate 5-lipoxygenase (Aox5) is a drug target for a number of diseases. However, pharmacological targeting of Alox5, and its role in skeletal muscle atrophy, is unclear. MethodsThe potential effects of gene knockdown and pharmacological targeting of Alox5 on skeletal muscle atrophy was investigated using cell-based models, animal models, and human skeletal muscle tissue cultures. Malotilate, a clinically safe drug developed for enhancing liver regeneration and Alox5 inhibitor, was investigated as a repurposing candidate. Mechanism(s) of action in skeletal muscle atrophy were assessed by measuring the expression level or activation status of key regulatory pathways, and validated using gene knockdown and RNA sequencing. ResultsMyotubes treated with the atrophy-inducing glucocorticoid, dexamethasone, were protected from catabolic responses by treatment with malotilate (+41.29%, P < 0.01). Similar anti-atrophy effects were achieved by gene knockdown of Alox5 (+30.4%, P < 0.05). Malotilate produced anti-atrophy effects without affecting the myogenic differentiation program. In an in vivo model of skeletal muscle atrophy, malotilate treatment enhanced muscle performance (Grip strength: +35.72%, Latency to fall: +553.1%, P < 0.05), increased mass and fiber cross sectional area (Quadriceps: +23.72%, Soleus: +33.3%, P < 0.01), and down-regulated atrogene expression (Atrogin-1: -61.58%, Murf-1: -66.06%, P < 0.01). Similar, beneficial effects of malotilate treatment were observed in an aging muscle, which also showed the preservation of fast twitch fibers (Type 2a: +56.48%, Type 2b: +37.32%, P < 0.01). Leukotrine B4, a product of Alox5 activity with inflammatory and catabolic functions, was found to be elevated in skeletal muscle undergoing atrophy (Quadriceps: +224.4%, P < 0.001). Cellular transcriptome analysis showed that targeting Alox5 upregulated biological processes regulating organogenesis and increased the expression of insulin-like growth factor-1, a key anti-atrophy hormone (+226.5%, P < 0.05). Interestingly, these effects were restricted to the atrophy condition and not observed in normal skeletal muscle cultures with Alox5 inhibition. Human skeletal muscle tissue was also protected from atrophy by pharmacological targeting of Alox5 (+23.68%, P < 0.05). ConclusionThese results shed new light on novel drug targets and mechanisms underpinning skeletal muscle atrophy. Alox5 is a regulator and drug target for muscle atrophy, and malotilate is an attractive compound for repurposing studies to treat this disease.

cell biology↗

bioRxiv2018

Comparative genetic architectures of schizophrenia in East Asian and European populations

Author summarySchizophrenia is a severe psychiatric disorder with a lifetime risk of about 1% world-wide. Most large schizophrenia genetic studies have studied people of primarily European ancestry, potentially missing important biological insights. Here we present a study of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant schizophrenia associations in 19 genetic loci. Over the genome, the common genetic variants that confer risk for schizophrenia have highly similar effects in those of East Asian and European ancestry (rg=0.98), indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries revealed 208 genome-wide significant schizophrenia associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping more precisely isolated schizophrenia causal alleles in 70% of these loci. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.

genetics↗

bioRxiv2017

LARGE, an AMPA receptor interactor, plays a large role in long-term memory formation by driving homeostatic scaling-down

Dynamic trafficking of AMPA-type glutamate receptor (AMPA-R) in neuronal cells is a key cellular mechanism for learning and memory in the brain, which is regulated by AMPA-R interacting proteins. LARGE, a protein associated with intellectual disability, was found to be a novel component of the AMPA-R protein complex in our proteomic study. Here, our functional study of LARGE showed that during homeostatic scaling-down, increased LARGE expression at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to downregulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired long-term memory formation. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for memory stability in the brain. Our study thus provides novel insights into the pathophysiology of brain disorders associated with intellectual disability.

neuroscience↗