Biology subjects

Kim, M. J.

Publications and source records attributed to Kim, M. J..

At least 19 recordsLinked to original sources

bioRxiv2026

Trisomy 21 Perturbs Oligodendrocyte Developmental States and Oligo-Neuron Communication in Human Forebrain Assembloids

Intellectual disability is a hallmark of Down syndrome (DS), caused by the triplication of human chromosome 21. Abnormal neuronal connectivity and impaired myelination are consistently observed in DS, yet the underlying mechanisms remain poorly understood. Here, we used DS-derived isogenic induced pluripotent stem cell-derived forebrain assembloids (FAs) to investigate oligodendrocyte lineage cell (OLLC) development and neuron-glia interactions. Trisomic FAs exhibited an expansion of BCAS1+ pre-myelinating OLLCs, without a corresponding increase in myelin basic protein (MBP) expression. Transcriptomic analyses identified a euploid-enriched, trophic and maturation-supportive state (OLLC_2-TMS) and a trisomy-enriched synaptic interactions and differentiation state (OLLC_3-SID), lacking coordinated enrichment in myelination-promoting programs. Corresponding transcriptional signatures were identified in OLLCs from early postnatal human cortex. Increased excitatory neuronal contacts with pre-myelinating OLLCs accompanied ultrastructural myelin abnormalities in trisomic assembloids. Our findings suggest that trisomy redirects OLLC development toward a pre-myelinating state, uncoupling oligodendrocyte differentiation from productive myelination.

neuroscience↗

bioRxiv2026

TOX enforces the immunosuppressive program of tumor-infiltrating regulatory T cells

Regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) to suppress anti-tumor immunity, but the transcriptional regulators stabilizing their immunosuppressive state remain poorly defined. Here we show that transcriptional factor TOX is selectively upregulated in tumor-infiltrating (TI) Treg cells across human cancers and mouse tumor models, while remaining low in peripheral and naive Treg populations. Treg-specific deletion of TOX reduced tumor burden, impaired TI Treg-mediated immune suppression, and enhanced effector functions of CD8 and CD4 T cells. In mosaic mice, TOX-deficient Tregs were selectively depleted from tumors, accompanied by increased apoptosis. Single-cell RNA sequencing and TCR clonotype analysis linked TOX expression to an effector-like TI Treg state with clonal expansion, whereas TOX loss shifted cells toward a TCF7-associated progenitor-like phenotype. ATAC-seq revealed enrichment of AP-1 motifs in TOX-sufficient TI Tregs. In contrast, TCF7, LEF1, and FOXO1 motifs in TOX-deficient counterparts, uncovering the opposing transcriptional networks downstream of TOX. Furthermore, TOX deficiency augmented CD8 T cell responses to PD-1 blockade. Together, these findings establish TOX as a key regulator of TI Treg fitness and stability, and identify it as a potential therapeutic target to enhance the efficacy of PD-1-based immunotherapy.

immunology↗

bioRxiv2026

Data-driven prioritization of mouse strains for improved preclinical modeling of rare and common disease

Choosing an appropriate mouse genetic background is a persistent challenge for successful translation of preclinical disease modeling. We present Strain Recommender, a genomic framework that prioritizes inbred mouse strains as relatively vulnerable or resilient to a disease state using disease-associated gene signatures and strain-specific transcriptome predictions. The method represents disease states as weighted gene scores, ranks 657 strains based on resemblance to the disease state, and estimates uncertainty via a permutation-derived false positive rate (FPR). In a prospective validation of connective tissue disorder predictions, vulnerable and resilient Collaborative Cross strains showed significantly different cardiovascular abnormalities. In a global retrospective validation predicting previously reported strain background effects, Strain Recommender achieved [≥] 90% sensitivity for 86.6% of diseases with 94.4% mean sensitivity (95% CI: 94.0-94.8%) across 5,890 diseases, including 92.3% (95% CI: 91.6-93.0%) for 2,598 rare diseases, demonstrating its potential to improve the validity of mouse models of human disease.

bioinformatics↗

bioRxiv2026

B7-H3 Modulates Cell Adhesion and Immune Evasion to Promote Tumor Progression and Natural Killer Cell Resistance in Hepatocellular Carcinoma

B7-H3 (CD276) is an immune checkpoint molecule frequently overexpressed in hepatocellular carcinoma (HCC) and represents a promising therapeutic target. However, its roles in tumor cell adhesion, metastatic behavior and immune evasion--particularly in interactions with natural killer (NK) cells--remain incompletely understood. In the present study, B7-H3 was depleted using small interfering RNA and CRISPR/Cas9 in epithelial (Huh7 and HepG2) and mesenchymal (SNU449) HCC cell lines. Tumor cell survival, apoptosis, adhesion, migration and invasion were evaluated using functional assays. Expression of adhesion molecules and immune checkpoint proteins was assessed by flow cytometry and western blotting. Oncogenic signaling pathways were analyzed by examining phosphorylation of Akt, ERK, FAK and STAT3. NK cell-mediated cytotoxicity was assessed using primary human NK cells. B7-H3 depletion reduced clonogenic survival and increased apoptosis in mesenchymal HCC cells under anchorage-independent conditions. Loss of B7-H3 impaired cell adhesion, migration and invasion, accompanied by downregulation of PTGFRN, E-cadherin, integrin 3 and integrin V, and reduced cell-to-cell aggregation under anchorage-independent conditions. B7-H3 depletion also decreased surface expression of PD-L1, PD-L2 and CD47. Notably, B7-H3-deficient cells exhibited enhanced susceptibility to primary NK cell-mediated cytotoxicity. Mechanistically, B7-H3 promoted tumorigenic signaling through Akt/S6, MVP/ERK and FAK/Src pathways in epithelial cells, and through FAK/Src and JAK2/STAT3 pathways in mesenchymal cells. Together, these findings reveal previously unrecognized roles for B7-H3 in coordinating adhesion and NK immune evasion in HCC, and support its therapeutic targeting for next-generation immunotherapies.

cancer biology↗

bioRxiv2026

Coordinated yet asymmetric striatal neuromodulatory dynamics encode associative learning

The striatum integrates dopamine and acetylcholine to support learning and behavioral flexibility, yet how these neuromodulators coordinate during associative learning remains unclear. Using longitudinal dual-color fiber photometry in mice, we simultaneously tracked both signals in the anterior dorsolateral striatum throughout Pavlovian conditioning. We find that learning recruits distinct forms of neuromodulatory plasticity: dopamine maintains rapid, contingency-dependent cue responses, whereas acetylcholine undergoes broader reorganization across training. Despite these differences, trial-by-trial covariance between the two signals converges onto a compact low-dimensional structure that reliably captures learned behavioral state and distinguishes associative learning from sensory exposure alone. Granger causality analyses further reveal a directional asymmetry, present in both paired and unpaired mice, whereby dopamine reliably predicts subsequent acetylcholine fluctuations, with only weak reciprocal prediction. Together, our results identify a low-dimensional organizational principle for dopamine-acetylcholine interactions, and suggest that dopamine acts as a leading temporal signal that shapes cholinergic dynamics during striatal learning.

neuroscience↗

bioRxiv2026

Organic Components Modulate the Morphology of Respirable Aerovirology Relevant Aerosols

Airborne transmission of pathogens occurs via aerosol particles, whose morphology provides insights into the microenvironments that pathogens experience. Aerosol morphology includes particle size, shape, phase state, and chemical homogeneity, yet systematic studies remain limited. Here, we characterized model bioaerosol morphologies generated from (1) NaCl-organic two-component mixtures, (2) common cell culture media, and (3) artificial respiratory fluids. Particles were collected using a virtual impactor and Andersen cascade impactor and analyzed by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Results show that organic components modulate the morphology: dipalmitoylphosphatidylcholine (DPPC) promotes organic-inorganic phase separation while proteins prohibit formation of large crystals and leads to better mixing among components. At 30% RH with a drying period of 10 seconds, most aerosols appeared desiccated, though NaCl-glucose, DMEM-complete-media and artificial saliva with mucin remained semi-solid or gel-like. Among all formulations examined EMEM-complete-media and artificial saliva (non mucin) show a size-dependent morphology. Our study demonstrates how chemical composition and size alters surrogate bioaerosol phase (semi-solid or solid) and morphology and provides new insights into the microenvironment of aerosol particles for aerovirology investigations.

biochemistry↗

bioRxiv2025

Neuronal APOE4 reduction with an APOE-I3-targeting ASO protects against neurodegeneration and neuroinflammation in an Alzheimer's disease mouse model

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimers disease (AD). Within the central nervous system (CNS), APOE is produced by a variety of cell types, with differential roles in AD pathogenesis. Studies have shown that APOE4 produced by neurons plays a central role in promoting the development of major AD pathologies, including p-tau accumulation, neuroinflammation, and neurodegeneration, highlighting its role as an upstream initiating factor that affects other cell types and downstream AD-related pathologies. Here, we demonstrate that antisense oligonucleotides (ASOs) targeting APOE-I3, a neuron-specific splicing variant of APOE mRNA, effectively reduce APOE expression in neurons in vitro and in vivo. Treating PS19 tauopathy mice expressing APOE4 with this APOE-I3-targeting ASO reduces neuronal APOE4, rescues neurodegeneration, and diminishes neuroinflammation. Strikingly, the extent of neuronal APOE4 reduction predicts the efficacy of rescuing neurodegeneration. Single nucleus RNA-sequencing demonstrated that APOE-I3-targeting ASO treatment decreases disease associated neuronal and glial subtypes and increases a disease-protective microglial subtype. These findings suggest that preferential knockdown of neuronal APOE4 with an APOE-I3-targeting ASO protects against key hallmarks of AD pathology, elucidating a potential therapeutic approach for treating APOE4-driven AD.

neuroscience↗

bioRxiv2025

Neuronal APOE4 drives damaging lipid accumulation via contact-dependent neuron-oligodendrocyte-microglia interaction in Alzheimer's disease

Apolipoprotein E4 (APOE4) confers the greatest genetic risk for developing Alzheimers disease (AD). With APOE4 broadly expressed in the brain, its cell-type-specific roles in AD pathogenesis are only beginning to be defined. Here, we show that neuronal APOE4 expression drives damaging lipid accumulation in hippocampal neurons, oligodendrocytes, and microglia, with preferential buildup of peroxidized lipids in microglia in a tauopathy mouse model. Neuron-specific removal of APOE4 abolished this lipid phenotype, whereas neuron-specific expression of APOE4 was sufficient to recapitulate it, demonstrating that neuronal APOE4 is both necessary and sufficient for lipid accumulation. Strikingly, the association between lipid burden, microgliosis, and neurodegeneration was strongest in mice with neuron-specific APOE4 expression. Single-nucleus RNA sequencing revealed neuronal APOE4-vulnerable neuron populations, as well as enrichment of disease-associated microglia and oligodendrocytes, all promoting lipid pathology. Primary mouse co-culture experiments showed that neuronal APOE4 drives microglial lipid accumulation via contact-dependent mechanisms involving uptake of lipids from neurons and oligodendrocytes. These findings establish neuronal APOE4 as a key driver of lipid accumulation via neuron-oligodendrocyte-microglia interactions, providing mechanistic insight into APOE4-driven lipid pathology in AD.

neuroscience↗

bioRxiv2025

Senescence-Linked Fibrosis in the Aging Human Ovary Revealed by p16-Based Histological Profiling and Spatial Transcriptomics

Cellular senescence is implicated as a driver of ovarian aging, but senescent cells in the human postmenopausal ovary remain poorly defined. Using spatially resolved p16INK4a protein expression, a canonical senescence marker, we identified and mapped senescent cells in postmenopausal ovaries. We integrated p16 immunohistochemistry, multiplexed immunofluorescence, spatial transcriptomics, and AI-guided digital pathology to map senescent microenvironments. p16-positive cells formed discrete stromal, vascular, and cyst-associated clusters that increased with age and were enriched for macrophages and myofibroblast-like cells. Wholetranscriptome profiling of 92 spatial regions uncovered a 32-gene p16-associated signature, BuckSenOvary, that distinguished p16-positive regions across cortex and medulla. BuckSenOvary is characterized by suppression of cell-cycle regulators and activation of inflammatory and extracellular-matrix remodelling genes. AI-based collagen matrix analysis confirmed that p16-positive regions exhibit more architecturally complex collagen, demonstrating that focal senescent microenvironments are fibro-inflammatory. These findings position senescent ovarian niches as therapeutic targets to preserve ovarian function.

cell biology↗

bioRxiv2025

Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model

Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimers disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation--the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target.

neuroscience↗

bioRxiv2025

VEGFR2 blockade overcomes acquired KRAS G12D inhibitor resistance driven by PI3Kγ activation

KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent studies have characterized features associated with primary and acquired resistance to KRAS inhibitors, strategies to overcome such resistance, particularly in the context of gastrointestinal cancers, remain underexplored. Here, we have generated nine human gastrointestinal cancer models, including three patient-derived organoids (PDOs), with acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. Using single-cell RNA sequencing analysis, we identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) signatures in the resistant model compared to the parental PDO. Across all resistant models, VEGFA expression and VEGFR2 phosphorylation were uniformly elevated, which were driven by AKT activation and SP1 nuclear translocation. Mechanistic investigations uncovered increased PI3K{gamma} activity in MRTX1133-resistant models via complex formation of KRAS with p110{gamma} and p101. This leads to an autocrine VEGFA-VEGFR2 signaling loop formation and EMT induction. Therapeutically, the disruption of VEGFA-VEGFR2 signaling restored MRTX1133 sensitivity and inhibited EMT. Furthermore, cancer-endothelial paracrine signaling amplified angiogenesis, hypoxia, and EMT signatures in cancer cells and simultaneously promoted endothelial cell proliferation, reinforcing an adaptive feedback mechanism. In a mouse model of MRTX1133-resistant tumor xenograft, a combination of anti-VEGFR2 therapy and MRTX1133 more effectively reduced tumor growth, angiogenesis, and proliferation markers than monotherapy without significant body weight change. These findings establish VEGFA-VEGFR2 signaling by PI3K{gamma} activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers. HighlightO_LIVEGFA-VEGFR2 signaling activation is a common feature of MRTX1133 resistance in KRASG12D cancer cells C_LIO_LINuclear translocation of SP1 by AKT activation promotes VEGFA transcription in MRTX1133-resistant models C_LIO_LIInteraction of p110{gamma}-p101 with KRAS activates PI3K{gamma} in the resistant models C_LIO_LIVEGFA-VEGFR2 inhibition reverses MRTX1133 resistance in vitro and in vivo C_LI

cancer biology↗

bioRxiv2025

RNA 2'-OH modification with stable reagents enabled bynucleophilic catalysis

RNA modification at 2-OH has typically required highly reactive acylating species that exhibit short half-lives in water, challenging purification, and limited shelf lives. Here, we investigate the use of more stable species as electrophilic reagents, employing nucleophilic catalysis to promote reactions. Results show that multiple previously unreported electrophiles can react in high stoichiometric yields with RNA under appropriate catalysis. Most notably, aryl esters can transfer acyl groups to RNA in one hour, but are stable for months even in pure water. The results expand the functional chemotypes of RNA-reactive species, and identify reagent classes with improved stability and selectivity.

biochemistry↗

bioRxiv2025

Fluorogenic Covalent Probes for RNA

Sequence-generalized fluorescent labels and stains for RNA can enable imaging, tracking and analysis of the biopolymer. However, current non-covalent RNA dyes are poorly selective for RNA over DNA, interact weakly with their target, and can show limited utility in cellular RNA staining due to poor selectivity and high background signals. Here we report a fluorogenic covalent labeling approach based on acylimidazole-mediated reaction of donor-acceptor fluorophores with 2'-hydroxyl (2'-OH) groups of RNA, providing a wavelength-tunable, sequence-independent strategy for selective labeling of the biopolymer. This reactive probe design enables labeling and imaging under mild aqueous conditions, providing up to 390-fold fluorescence enhancement and 970-fold selectivity for RNA over DNA, with four emission colors documented. The covalent fluorophore platform enables improved new tools for RNA-specific analysis and imaging in gels, in solution, and in living cells.

biochemistry↗

bioRxiv2024

Personalized cue-reactive delta-theta oscillations guide deep brain stimulation for opioid use disorder

Abstract / SummarySubstance use disorder (SUD) is a significant public health concern, with over 30% of the affected population not responding to available treatments. Severe SUD is characterized by drug-cue reactivity that has been reported to predict treatment-failure. We leveraged this pathophysiological feature to optimize deep brain stimulation (DBS) of the nucleus accumbens region (NAc) in an adult with SUD. A personalized drug cue-reactivity task was administered while recording NAc region electrophysiology from a lead externalized for clinical purposes. We identified a drug cue-evoked signal in the ventral NAc associated with intensification of opioid-related cravings, which attenuated subsequent to stimulation delivered to the same area. DBS was then programmed to engage this focal region, which resulted in sustained suppression of drug-related cravings. This finding heralds the potential for personalized strategies to optimize DBS for SUD.

neuroscience↗

bioRxiv2024

Longitudinal analysis of glioblastoma response to oncolytic HSV1 guides PLX3397 combination for enhanced viral permissiveness

Clinical trial data underscores the need to improve oncolytic virus (OV) distribution within tumors, a challenge compounded by the lack of predictive biomarkers and limited opportunities for post-treatment analysis. To decipher the factors influencing treatment outcomes, we employed multimodal bioluminescence imaging (MM-BLI) in conjunction with magnetic resonance imaging (MRI) to monitor OV infection, replication, and tumor viability in orthotopic brain glioma mouse models. This approach revealed two distinct therapeutic responses: "Responders" with tumor regression and "Non-Responders" with tumor progression. In-depth analysis of individual brains from both groups uncovered dynamic interactions between the OV and the tumor microenvironment, highlighting the involvement of Iba-1+ microglia and tumor necrosis in hindering OV distribution within the tumor. To address this, we incorporated a CSF-1 receptor inhibitor (PLX3397), which improved tumor control by enhancing OVs direct cytopathic effects and reducing microglial interference. Our findings highlight microglia as a significant barrier to effective OV therapy, suggesting that targeting brain-resident immune cells could enhance the therapeutic efficacy of OVs in resistant brain tumors.

bioengineering↗

bioRxiv2024

plantMASST - Community-driven chemotaxonomic digitization of plants

Understanding the distribution of hundreds of thousands of plant metabolites across the plant kingdom presents a challenge. To address this, we curated publicly available LC-MS/MS data from 19,075 plant extracts and developed the plantMASST reference database encompassing 246 botanical families, 1,469 genera, and 2,793 species. This taxonomically focused database facilitates the exploration of plant-derived molecules using tandem mass spectrometry (MS/MS) spectra. This tool will aid in drug discovery, biosynthesis, (chemo)taxonomy, and the evolutionary ecology of herbivore interactions.

plant biology↗

bioRxiv2023

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimers Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice. We found that both neuronal APOE and microglial presence were important for the formation of A{beta} and tau pathologies in an APOE isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory microglial subtypes with high MHC-II gene expression that are enriched in chimeric mice with human APOE4 neuron transplants. These findings highlight the concerted roles of neuronal APOE, especially APOE4, and microglia in AD pathogenesis. HIGHLIGHTSO_LITransplanted human APOE4 neurons generate A{beta} and p-tau aggregates in APOE4-KI mouse hippocampus. C_LIO_LIHuman neuronal APOE4 promotes the formation of dense-core A{beta} plaques and p-tau aggregates. C_LIO_LIMicroglia is required for human neuronal APOE4-driven formation of p-tau aggregates. C_LIO_LIscRNA-seq reveals enrichment of MHC-II microglia in mice with human APOE4 neuron transplants. C_LI

neuroscience↗

bioRxiv2023

Heroes and villains: opposing narrative roles engage neural synchronization in the lateral inferior frontal gyrus

Neuroscientific studies have highlighted the role of the default mode network (DMN) in processing narrative information. Here, we examined whether the neural synchronization of the DMN tracked the appearances of characters with different narrative roles (i.e., protagonists versus antagonists) when viewing highly engaging, socially rich audiovisual narratives. Using inter-subject correlation analysis on two independent, publicly available movie-watching functional magnetic resonance imaging datasets (Sherlock and The Grand Budapest Hotel), we computed whole-brain neural synchronization during the appearance of the protagonists and antagonists. Results showed that the inferior frontal gyrus (IFG) and orbitofrontal cortex (OFC), which are components of the DMN, had higher ISC values during the appearance of the protagonists compared to the antagonists. Importantly, these findings were commonly observed in both datasets. We discuss the present results in the context of information integration and emotional empathy, which are relevant functions known to be supported by the DMN. Our study presents generalizable evidence that regions within the DMN - particularly the IFG and OFC - show distinctive synchronization patterns due to differences in narrative roles.

neuroscience↗