Biology subjects

Yoo, Y.

Publications and source records attributed to Yoo, Y..

15 recordsLinked to original sources

bioRxiv2026

scVIP: personalized modeling of single-cell transcriptomes for developmental and disease phenotypes

Single-cell transcriptomics resolves cellular heterogeneity within individuals, but connecting molecular states to individual-level phenotypes requires frameworks that explicitly bridge these scales. We present scVIP, a generative model that links gene expression, cell-type composition, and phenotypic measurements within a single probabilistic model, which enables accurate phenotype prediction and interpretable trajectory inference. A cell-type-aware multi-instance learning architecture learns donor embeddings that capture progression while localizing phenotype-associated signals to specific cell populations. Applied across four settings, scVIP accurately predicts cortical developmental age (Pearson r = 0.95), characterizes Huntingtons disease progression (concordance correlation coefficient = 0.90), integrates two Alzheimers disease cohorts recovering disease-relevant microglial and astrocytic programs, and distinguishes healthy from ACPA-positive individuals and non-progressors from early RA individuals, identifying inflammatory T cell programs associated with disease. scVIP enables principled analysis of how cellular states collectively shape organism-level phenotypes across development and disease.

bioinformatics↗

bioRxiv2026

Structural basis of caveolin-driven membrane bending

Caveolins are monotopic membrane proteins essential for caveolae formation and have key roles in signaling and lipid regulation. Caveolins assemble into amphipathic discs with a central {beta}-barrel, an architecture distinct from other membrane-remodeling proteins. These discs embed in the membrane inducing membrane curvature. However, the mechanism of disc-driven bending remains unresolved. Using cryo-electron tomography, structure-guided mutagenesis, and mammalian cell studies, we show that evolutionarily distinct caveolins differ dramatically in their ability to curve membranes despite their conserved architecture. Through computational and theoretical analyses, we demonstrate that patterning of hydrophobic residues along the rim of the disc of human Caveolin-1 induces the deformation of the surrounding leaflet, dictating membrane bending. Finally, we determine a 4.1[A] resolution structure of Caveolin-1 within heterologous caveolae in situ, showing the disc adopts a funnel-like conformation, further shaping membrane architecture. Together, these findings reveal fundamental structural principles that empower caveolins to sculpt and remodel cellular membranes.

cell biology↗

bioRxiv2025

Heterochronic myeloid cell replacement reveals the local brain environment as key driver of microglia aging

Aging, the key risk factor for cognitive decline, impacts the brain in a region-specific manner, with microglia among the most affected cell types. However, it remains unclear whether this is intrinsically mediated or driven by age-related changes in neighboring cells. Here, we describe a scalable, genetically modifiable system for in vivo heterochronic myeloid cell replacement. We find reconstituted myeloid cells adopt region-specific transcriptional, morphological and tiling profiles characteristic of resident microglia. Young donor cells in aged brains rapidly acquired aging phenotypes, particularly in the cerebellum, while old cells in young brains adopted youthful profiles. We identified STAT1-mediated signaling as one axis controlling microglia aging, as STAT1-loss prevented aging trajectories in reconstituted cells. Spatial transcriptomics combined with cell ablation models identified rare natural killer cells as necessary drivers of interferon signaling in aged microglia. These findings establish the local environment, rather than cell-autonomous programming, as a primary driver of microglia aging phenotypes.

neuroscience↗

bioRxiv2025

Defined human tri-lineage brain microtissues

Microglia are the immune cells of the central nervous system and are thought to be key players in both physiological and disease conditions. Several microglial features are poorly conserved between mice and human, such as the function of the neurodegeneration-associated immune receptor Trem2. Induced pluripotent stem cell (iPSC)-derived microglia offer a powerful opportunity to generate and study human microglia. However, human iPSC-derived microglia often exhibit activated phenotypes in vitro, and assessing their impact on other brain cell types remains challenging due to limitations in current co-culture systems. Here, we developed fully defined brain microtissues, composed of human iPSC-derived neurons, astrocytes, and microglia, co-cultured in 2D or 3D formats. Our microtissues are stable and self-sufficient over time, requiring no exogenous cytokines or growth factors. All three cell types exhibit morphologies characteristic of their in vivo environment and show functional properties. Co-cultured microglia develop more homeostatic phenotypes compared to microglia exposed to exogenous cytokines. Hence, these tri-cultures provide a unique approach to investigate cell-cell interactions between brain cell types. We found that astrocytes and not neurons are sufficient for microglial survival and maturation, and that astrocyte-derived M-CSF is essential for microglial survival. Single-cell and single-nucleus RNA sequencing analyses nominated a network of reciprocal communication between cell types. Brain microtissues faithfully recapitulated pathogenic -synuclein seeding and aggregation, suggesting their usefulness as human cell models to study not only normal but also pathological cell biological processes.

neuroscience↗

bioRxiv2025

High-resolution cryo-EM structures of small protein-ligand complexes near the theoretical size limit

Cryo-electron microscopy (cryo-EM) is widely used to determine macromolecular structures at atomic resolution. The theoretical size lower limit of particles for cryo-EM analysis is 38 kDa, limited by factors such as contrast and particle alignment accuracy. To date, no cryo-EM structures have been reported for proteins near this size limit. This study presents cryo-EM structures of two protein-ligand complexes around 40 kDa. The structure of maltose-binding protein (43 kDa) was determined at 2.32 [A] resolution, clearly revealing the bound maltose and water molecules. Additionally, the kinase domain of human PLK1 (37 kDa), slightly below the theoretical limit, was determined at 3.04 [A] resolution, allowing the identification of the bound ligand, onvansertib. These findings demonstrate that cryo-EM can be effectively employed for structure determination and structure-based drug screening of small proteins or domains.

biophysics↗

bioRxiv2025

Cell-surface proteomic profiling identifies CD72 as a regulator of microglial tiling

Microglial tiling--the phenomenon of consistent cell-to-cell distances and non-overlapping processes--is regarded as a qualitative indicator of homeostasis, but mechanisms of microglial tiling are unknown. We used cell-surface proximity labeling and mass spectrometry to profile the microglial cell-surface proteome in an in vitro model of homeostatic glial physiology and used single-cell RNA sequencing and public databases to identify candidate cell-surface proteins that might modulate tiling. We designed an image-based functional assay which measures six morphological/spatial readouts to screen these proteins for modulation of tiling. CD72, a coreceptor to the B cell receptor that is expressed by microglia, disrupted tiling; we validated its effects in vitro and in situ in organotypic hippocampal brain slices. Phosphoproteomic studies revealed that CD72 modulates pathways associated with cell adhesion, repulsive receptors, microglial activation, and cytoskeletal organization. These results lay the groundwork for further investigation of the functional roles of tiling in homeostasis and disease.

neuroscience↗

bioRxiv2025

Oncogenic mutations disrupt lineage differentiation via epigenetic perturbations

Understanding lineage differentiation is an ongoing challenge in the field of stem cell research. We acquired eight gain-of-function (GOF) oncogenic mutations associated with DNA methylation alteration from the TCGA datasets. After introducing each oncogene into wild-type stem cells separately, we found that the mutant stem cells are difficult to reprogram to iPSCs and terminally differentiate to induced neuronal cells, and retain proliferation capacity in the process of differentiation. This findings suggests that oncogenic mutations impair the lineage differentiation. After analyzing the resulting DNA methylation profiles, we identified many novel lineage differentiation genes in mutant cells showing DNA methylation alteration compared with wild-type cells, which is consistent with their methylation states in low-grade gliomas (LGGs) compared with control brain. Collectively, our results indicate that oncogenic mutations in stem cells are associated with DNA methylation changes for genes related to multipotency maintenance, differentiation resistance, and tumorigenesis, therefore, displaying impairment in lineage commitment.

cell biology↗

bioRxiv2025

Soil and water microbial communities: A source of novel antibiotics for sustainable plant disease control

Pathogenic microorganisms pose a significant threat to plant health and agricultural productivity worldwide. Herein, this study explores the potential of natural microbial communities as sources of biopesticides. We analyzed 20 soil and water samples from remote areas, isolating 121 colonies using nutrient agar. Antibacterial activity was assessed through agar diffusion, revealing that 12 colonies exhibited significant inhibitory effects against various pathogenic bacteria. Measurement of inhibition zones indicated that these colonies could produce antibiotics. Subsequently, molecular characterization with 16S rRNA and BLAST searches of 12 unidentified sequences highlighted substantial microbial diversity within the samples. This research underscores the promise of these natural microbial communities in developing biocontrol agents for managing plant diseases in greenhouse and field environments. Extraction and purification techniques could further refine these antibiotics, advancing sustainable agricultural practices.

microbiology↗

bioRxiv2023

RAPIDASH: A tag-free enrichment of ribosome-associated proteins reveals compositional dynamics in embryonic tissues and stimulated macrophages

Ribosomes are emerging as direct regulators of gene expression, with ribosome-associated proteins (RAPs) allowing ribosomes to modulate translational control. However, a lack of technologies to enrich RAPs across many sample types has prevented systematic analysis of RAP number, dynamics, and functions. Here, we have developed a label-free methodology called RAPIDASH to enrich ribosomes and RAPs from any sample. We applied RAPIDASH to mouse embryonic tissues and identified hundreds of potential RAPs, including DHX30 and LLPH, two forebrain RAPs important for neurodevelopment. We identified a critical role of LLPH in neural development that is linked to the translation of genes with long coding sequences. Finally, we characterized ribosome composition remodeling during immune activation and observed extensive changes post-stimulation. RAPIDASH has therefore enabled the discovery of RAPs ranging from those with neuroregulatory functions to those activated by immune stimuli, thereby providing critical insights into how ribosomes are remodeled.

molecular biology↗

bioRxiv2023

Differential encoding of odor and place in mouse piriform and entorhinal cortex

The integration of olfactory and spatial information is critical for guiding animal behavior. The lateral entorhinal cortex (LEC) is reciprocally interconnected with cortical areas for olfaction and the hippocampus and thus ideally positioned to encode odor-place associations. Here, we used mini-endoscopes to record neural activity in the mouse piriform cortex (PCx) and LEC. We show that in head-fixed mice, odor identity could be decoded from LEC ensembles, but less accurately than from PCx. In mice freely navigating a linear track, LEC ensemble activity at the odor ports was dominated by spatial information. Spatial position along the linear track could be decoded from LEC and PCx activity, however, PCx but not LEC exhibited strong behavior-driven modulation of positional information. Together, our data reveal that information about odor cues and spatial context is differentially encoded along the PCx-LEC axis. Significance statementFor most animals, the sense of smell is essential for successfully navigating the environment to find food, shelter, and mates. However, how olfactory and spatial information is integrated in the brain to support olfactory-guided behaviors remains poorly understood. In mammals, candidate brain regions thought to support odor-place associations include the olfactory (piriform, PCx) cortex, entorhinal cortex, and hippocampus. We here characterize the activity of cells in the PCx and lateral entorhinal cortex (LEC) of freely moving mice in response to odor cues presented in a linear track. Using mini-endoscope microscopy and population coding analyses, we find that information about odors, spatial location, and behavior is differentially encoded along the PCx-LEC axis.

neuroscience↗

bioRxiv2023

Augmentation of a neuroprotective myeloid state by hematopoietic cell transplantation

Multiple sclerosis (MS) is an autoimmune disease associated with inflammatory demyelination in the central nervous system (CNS). Autologous hematopoietic cell transplantation (HCT) is under investigation as a promising therapy for treatment-refractory MS. Here we identify a reactive myeloid state in chronic experimental autoimmune encephalitis (EAE) mice and MS patients that is surprisingly associated with neuroprotection and immune suppression. HCT in EAE mice leads to an enhancement of this myeloid state, as well as clinical improvement, reduction of demyelinated lesions, suppression of cytotoxic T cells, and amelioration of reactive astrogliosis reflected in reduced expression of EAE- associated gene signatures in oligodendrocytes and astrocytes. Further enhancement of myeloid cell incorporation into the CNS following a modified HCT protocol results in an even more consistent therapeutic effect corroborated by additional amplification of HCT-induced transcriptional changes, underlining myeloid-derived beneficial effects in the chronic phase of EAE. Replacement or manipulation of CNS myeloid cells thus represents an intriguing therapeutic direction for inflammatory demyelinating disease.

neuroscience↗

bioRxiv2019

Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population

BackgroundA substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking.\n\nMethodsGenetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Pathogenic variants were selected and evaluated based on a comparison to patient symptoms and genetic properties of the variants were analyzed.\n\nResultsDisease-causing variants, including newly discovered variants, were identified in in 57.5% of the probands of the KND cohort. Of the 553 patients, 47.4% harbored variants that were previously reported as being pathogenic, and 35.1% of the previous reported pathogenic variants were inherited in a recessive manner. Genes that cause recessive disorders tend to be less constrained by loss-of-function variants and enriched in metabolic and mitochondrial pathways. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated.\n\nConclusionsWe suggest that the odds are high for healthy individuals carrying a potentially pathogenic variant, and its genetic properties. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

genetics↗

bioRxiv2019

False-positive neuroimaging: Undisclosed flexibility in testing spatial hypotheses allows presenting anything as a replicated finding

Hypothesis testing in neuroimaging studies relies heavily on treating named anatomical regions (e.g., \"the amygdala\") as unitary entities. Though data collection and analyses are conducted at the voxel level, inferences are often based on anatomical regions. The discrepancy between the unit of analysis and the unit of inference leads to ambiguity and flexibility in analyses that can create a false sense of reproducibility. For example, hypothesizing effects on \"amygdala activity\" does not provide a falsifiable and reproducible definition of precisely which voxels or which patterns of activation should be observed. Rather, it comprises a large number of unspecified sub-hypotheses, leaving room for flexible interpretation of findings, which we refer to as \"model degrees of freedom.\" From a survey of 135 functional Magnetic Resonance Imaging studies in which researchers claimed replications of previous findings, we found that 42.2% of the studies did not report any quantitative evidence for replication such as activation peaks. Only 14.1% of the papers used exact coordinate-based or a priori pattern-based models. Of the studies that reported peak information, 42.9% of the replicated findings had peak coordinates more than 15 mm away from the original findings, suggesting that different brain locations were activated, even when studies claimed to replicate prior results. To reduce the flexible and qualitative region-level tests in neuroimaging studies, we recommend adopting quantitative spatial models and tests to assess the spatial reproducibility of findings. Techniques reviewed here include permutation tests on peak distance, Bayesian MANOVA, and a priori multivariate pattern-based models. These practices will help researchers to establish precise and falsifiable spatial hypotheses, promoting a cumulative science of neuroimaging.

neuroscience↗

bioRxiv2018

Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

ImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).\n\nObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.\n\nDesign, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Childrens Hospital.\n\nExposuresWES of patients and parents and subsequent evaluation of genetic variants.\n\nMain outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.\n\nResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.\n\nConclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.\n\nKey pointsO_ST_ABSQuestionC_ST_ABSWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?\n\nFindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.\n\nMeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

genetics↗

bioRxiv2018

Inhibitory Effect of Bacillus velezensis on Biofilm Formation by Streptococcus mutans

Streptococcus mutans plays a key role in the development of dental caries and promotes the formation of oral biofilm produced by glucosyltransferases (GTFs). Bacillus velezensis K68 was isolated from traditional fermented foods and inhibits biofilm formation mediated by S. mutans. Gene amplification results demonstrated that B. velezensis K68 contained genes for the biosynthesis of 1-deoxynojirimycin (1-DNJ), a known GTF expression inhibitor. The presence of the GabT1, Yktc1, and GutB1 genes required for 1-DNJ synthesis in B. velezensis K68 was confirmed. Supernatant from B. velezensis K68 culture medium inhibited biofilm formation by 84% when S. mutans was cultured for 48 h, and inhibited it maximally when 1% glucose was added to the S. mutans culture medium as a GTF substrate. In addition, supernatant from B. velezensis K68 medium containing 3 ppb 1- DNJ decreased S. mutans cell surface hydrophobicity by 79.0 {+/-} 0.8% compared with that of untreated control. The supernatant containing 1-DNJ decreased S. mutans adherence by 99.97% and 98.83% under sugar-dependent and sugar-independent conditions, respectively. S. mutans treated with the supernatant exhibited significantly reduced expression of the essential GTF genes gtfB, gtfC, and gtfD compared to that in the untreated group. Thus, B. velezensis inhibits the biofilm formation, adhesion, and GTF gene expression of S. mutans through 1- DNJ production.\n\nIMPORTANCEDental caries is among the most common infectious diseases worldwide, and its development is closely associated with physiological factors of bacteria, such as the biofilm formation and glucosyltransferase production of Streptococcus mutans. Biofilms are difficult to remove once they have formed due to the exopolysaccharide matrix produced by the microorganisms residing in them; thus, inhibiting biofilm formation is a current focal point of research into prevention of dental caries. This study describes the inhibitory properties of Bacillus velezensis K68, an organism isolated from traditional Korean fermented foods, against biofilm formation by S. mutans. Herein, we show that B. velezensis inhibits the biofilm formation, adherence to surfaces, and glucosyltransferase production of S. mutans.

microbiology↗