Biology subjects

Kim, J.-W.

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

16 recordsLinked to original sources

bioRxiv2026

Immune signatures of protection and progression in the airways of recent human tuberculosis household contacts

Whilst the majority of individuals infected with M. tuberculosis control the infection and remain asymptomatic, only 5-10% progress to active tuberculosis (TB)1. Previous or current infection with M. tuberculosis is detected using antigen-specific interferon (IFN)-{gamma} release assays (IGRA), which cannot identify those who will remain healthy or progress to active TB1. However, 18F-Fluorodeoxyglucose positron emission-computed tomography (PET-CT) can detect increased immune cell metabolic activity in lung parenchyma and intrathoracic lymph nodes associated with infection2. The local early immune factors dictating protection or disease progression have not been defined. To address this, we interrogated the airway immune response at single cell resolution in bronchoalveolar lavage (BAL) from extensively clinically characterised recent household contacts of TB patients, who either controlled the infection or progressed to TB disease. Using unbiased analysis of bulk and scRNA-seq of BAL samples, we define type I IFN-dependent and -independent neutrophil signatures in active TB patients and contacts that progressed to TB. We additionally report an inverse relationship between airway neutrophils and T cells, with T cells showing signatures of exhaustion, cytotoxicity and cell death in progressors and TB patients with a neutrophil dominated airway profile. Conversely, T cell signatures of protection in contacts who remained healthy were dominated by genes related to regulation, quiescence and a stem-like profile. We show that both the inflammatory neutrophil signature of TB progression and the stem-like T cell signature of non-progressors from human airways were recapitulated in scRNA-seq data from non-human primate (NHP) granulomas, associated with disease or immune protection, respectively. Our findings from early human airway responses in TB contacts reveal genes, pathways and cell states that may dictate infection outcome and inform strategies for host-directed therapy and vaccine studies.

immunology↗

bioRxiv2026

Fructose utilization by GM-CSF-differentiated macrophages aggravates autoimmune inflammation via MG-derived AGE-RAGE signaling

Excessive fructose intake is increasingly associated with metabolic and inflammatory pathologies; however, the direct impact of fructose metabolism on immune cell function remains insufficiently understood. Here, we demonstrate that GM-CSF-differentiated macrophages markedly upregulate the fructose-specific transporter GLUT5, enabling efficient fructose utilization through two complementary metabolic pathways. Using 13C-fructose tracing, we identified distinct carbon fluxes via a hexokinase (HK)-dependent glycolytic route and a ketohexokinase (KHK)-ALDOB-mediated fructolytic route. The HK-dependent pathway sustains glycolytic activity under glucose-limiting conditions, stabilizing HIF-1 and preserving pro-inflammatory gene expression. Conversely, the KHK-ALDOB axis increases dihydroxyacetone phosphate (DHAP) production, leading to methylglyoxal-derived advanced glycation end-products (MG-AGEs) that engage receptor for AGE (RAGE) signaling. This activation enhances MMP9 expression in macrophages and drives Th17 differentiation in CD4 T cells, amplifying inflammatory and tissue-remodeling processes. In vivo, fructose intake exacerbates autoimmune arthritis in SKG mice, and elevated fructose-driven glycolysis and MG-AGE accumulation are observed in monocytes from patients with rheumatoid arthritis. These results link fructose-driven carbonyl stress to macrophage effector programs and downstream T cell polarization. Collectively, these findings uncover a dual fructose metabolic program that integrates nutrient stress with persistent inflammation via the MG-AGE-RAGE axis and underscore the immunometabolic risks of excessive fructose exposure.

immunology↗

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

Clonal Hematopoiesis Mutations Increase Risk of Alzheimer's Disease with APOE ϵ3/ϵ3 Genotype

Clonal hematopoiesis of indeterminate potential (CHIP) represents clonal expansion of blood cells, and increases the risk of hematological malignancies and cardiovascular disorders. Recent studies have studied CHIP mutations in individuals with Alzheimers disease (AD), but it is unclear whether their role in AD pathogenesis is protective, detrimental, or neutral. In this study, we used molecular-barcoded deep gene panel sequencing ([~]400X) to examine CHIP mutations in 298 blood samples from AD and neurotypical individuals 60 years and older. The AD patients exhibited a significantly higher burden of CHIP mutations compared to the age-matched controls (p < 2e-7, odds ratio (OR) = 2.89), particularly in low-frequency variants often not captured by standard whole exome or whole genome sequencing (WGS). This increase was driven by individuals with the APOE {varepsilon}3/{varepsilon}3 genotype and absent in {varepsilon}4 carriers. Analysis of an independent dataset from the Alzheimers Disease Sequencing Project (ADSP), comprised of WGS data from [~]30,000 individuals, confirmed increased CHIP mutations in AD versus control (p < 0.02, OR = 1.32), again driven by individuals with APOE {varepsilon}3/{varepsilon}3 genotype. CHIP mutations in AD patients also showed stronger positive selection than in controls. Our results indicate that AD patients show significantly more CHIP mutations in their blood than controls, involving more than one third of AD patients, and contributing to AD risk through a mechanism independent of APOE {varepsilon}4.

genetics↗

bioRxiv2024

Elucidating Interactome Dynamics of the A2A Adenosine Receptor

Polydeoxyribonucleotide (PDRN) is a tissue regeneration substance that resembles human DNA and is present in human cells, mullets, salmons, and flatfish. It stimulates physiological regeneration and metabolic activity. The regenerative and metabolic effects of PDRN are attributed to the activation of Adenosine A2A receptors (ADORA2A), which increases the production of angiogenesis factors and growth factors. Activation of ADORA2A leads to the activation of ADORA2A-interacting proteins with similar functions. To investigate the changes and dynamics of proteins in the presence of PDRN, we conducted selected reaction monitoring-mass spectrometry (SRM-MS) to quantify 491 proteins, 3,852 peptides. Through peptide-level analysis, we founded 374 proteins and 1,193 peptides demonstrating both up-regulation and down-regulation in expression. We conducted gene ontology (GO) analysis and physical network analysis and discovered a novel network of proteins related to neuronal differentiation among the ADORA2A-interacting protein. Based on network analysis, we found indirect interactions with MAPK1 and MP2K1, which are known to influence neuronal cell differentiation and suggest the formation of a network involving MAPK signaling transduction. Finally, using AlphaFold multimer, we were able to predict interaction sites among ADORA2A-interacting proteins in the network associated with neuronal cell differentiation. Specifically, we predicted five interaction sites between ADORA2A and NTRK1 (which interacts with ADORA2A), forming the edge. Thus, we provided indicators for further research using ADORA2A present in robust network and highlighted the potential of PDRN to impact neuronal differentiation.

systems biology↗

bioRxiv2024

Loss of p21-activated kinase 4 (PAK4) suppresses pancreatic tumor progression and metastasis through regulating E-cadherin

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor prognosis with early and frequent metastasis. While p21-activated kinase 4 (PAK4) has been implicated in cell migration, and invasion, the molecular mechanisms in PDAC remain unknown. In this study, we found that PAK4 overexpression was correlated with poor survival in PDAC patients through analysis of TCGA data. PAK4-amplified PDAC cells showed enhanced mobility in contrast with wild-type. PAK4 knockdown in PAK4 amplified cells inhibited cell migration, invasion, and displacement by increased and stabilized E-cadherin, which was attributed to decreased activity of Cdc42. PAK4 knock-in in PAK4 wild-type models enhanced cell migration, invasion, and displacement by reduced E-cadherin through elevated Cdc42 activity. PAK4 bounded to E-cadherin, Cdc42, and p120ctn in immunoprecipitation. In confocal imaging, the colocalization of PAK4, E-cadherin, p120ctn, and Cdc42 was also identified. In an orthotopic PDAC mouse model, PAK4 knockdown decreased primary tumor size and occurrence of malignant ascites by activation of E-cadherin. Notably, in patients tissue specimens, inverse correlation on expression of PAK4 and E-cadherin were also shown. In conclusion, our study highlights that PAK4 promotes invasive and metastatic behavior by regulating E-cadherin in PDAC. PAK4 could be a potential therapeutic target for PDAC patients. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/594599v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1755a23org.highwire.dtl.DTLVardef@170b2a1org.highwire.dtl.DTLVardef@1df96edorg.highwire.dtl.DTLVardef@2dc46b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Neuro-Regenerative Behavior of Adipose-Derived Stem Cells in Aligned Collagen I Hydrogels

Peripheral nerve injuries persist as a major clinical issue facing the US population and can be caused by stretch, laceration, or crush injuries. Small nerve gaps are simple to treat, and the nerve stumps can be reattached with sutures. In longer nerve gaps, traditional treatment options consist of autografts, hollow nerve guidance conduits, and, more recently, manufactured fibrous scaffolds. These manufactured scaffolds often incorporate stem cells, growth factors, and/or extracellular matrix (ECM) proteins to better mimic the native environment but can have issues with homogenous cell distribution or uniformly oriented neurite outgrowth in scaffolds without fibrous alignment. Here, we utilize a custom device to fabricate collagen I hydrogels with aligned fibers and encapsulated adipose-derived mesenchymal stem cells (ASCs) for potential use as a peripheral nerve repair graft. Analysis of these scaffolds in vitro revealed heightened therapeutic secretome from ASCs, ECM deposition, and dorsal root ganglia (DRG) neurite outgrowth along the axis of fiber alignment. Our platform serves as an in vitro testbed platform to assess neuro-regenerative potential of ASCs in aligned collagen fiber scaffolds and may provide guidance on next-generation nerve repair scaffold design.

bioengineering↗

bioRxiv2023

Comparing rapid rule-learning strategies in humans and monkeys

Inter-species comparisons are key to deriving an understanding of the behavioral and neural correlates of human cognition from animal models. We perform a detailed comparison of macaque monkey and human strategies on an analogue of the Wisconsin Card Sort Test, a widely studied and applied multi-attribute measure of cognitive function, wherein performance requires the inference of a changing rule given ambiguous feedback. We found that well-trained monkeys rapidly infer rules but are three times slower than humans. Model fits to their choices revealed hidden states akin to feature-based attention in both species, and decision processes that resembled a Win-stay lose-shift strategy with key differences. Monkeys and humans test multiple rule hypotheses over a series of rule-search trials and perform inference-like computations to exclude candidates. An attention-set based learning stage categorization revealed that perseveration, random exploration and poor sensitivity to negative feedback explain the under-performance in monkeys.

animal behavior and cognition↗

bioRxiv2022

Predicting Lung Cancer in Korean Never-Smokers with Polygenic Risk Scores

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer. Hence, recently, genetic data have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs). PRSs were calculated using a thresholding-pruning-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23), and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLongs test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.

bioinformatics↗

bioRxiv2022

Repulsive Sema3E-Plexin-D1 signaling coordinates both axonal extension and steering via activating an autoregulatory factor, Mtss1

Axon guidance molecules are critical for neuronal pathfinding because they regulate directionality and growth pace during nervous system development. However, the molecular mechanisms coordinating proper axonal extension and turning are poorly understood. Here, Metastasis Suppressor 1 (Mtss1), a membrane protrusion protein, ensured axonal extension while sensitizing axons to the Semaphorin 3E (Sema3E)-Plexin-D1 repulsive cue. Sema3E-Plexin-D1 signaling enhanced Mtss1 expression in projecting striatonigral neurons. Mtss1 localized to the neurite axonal side and regulated neurite outgrowth in cultured neurons. Mtss1 also aided Plexin-D1 trafficking to the growth cone, where it signaled a repulsive cue to Sema3E. Mtss1 ablation reduced neurite extension and growth cone collapse in cultured neurons. Mtss1-knockout mice exhibited fewer striatonigral projections and irregular axonal routes and these defects were recapitulated in Plxnd1- or Sema3e-knockout mice. These findings demonstrate that repulsive axon guidance activates an exquisite autoregulatory program coordinating both axonal extension and steering during neuronal pathfinding.

developmental biology↗

bioRxiv2022

Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors

We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient, and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 (54.5%), followed by TP53 (45.5%), and FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia, BilIN), but some of them were subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. In combined analysis with metastatic tumors (n=11), branching evolution was identified in 9 (81.8%) patients. Of these, 8 patients (88.9%) had a total of 11 subclones expanded at least 7-fold during metastasis. These subclones harbored putative metastasis-driving mutations in tumor suppressor genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, 6 mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and the clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.

genetics↗

bioRxiv2021

Early mitochondrial stress and metabolic imbalance lead to photoreceptor cell death in retinal degeneration

Neurodegenerative diseases exhibit extensive genetic heterogeneity and complex etiology with varying onset and severity. To deduce the mechanism leading to retinal degeneration, we adopted a temporal multi-omics approach and examined molecular and cellular events before the onset of photoreceptor cell death in the widely-used Pde6brd1/rd1 (rd1) mouse model. Transcriptome profiling of neonatal and developing rods revealed early downregulation of genes associated with anabolic pathways and energy metabolism. Quantitative proteomics of rd1 retina showed early changes in calcium signaling and oxidative phosphorylation, with specific partial bypass of complex I electron transfer, which precede the onset of cell death. Concurrently, we detected alterations in central carbon metabolism, including dysregulation of components associated with glycolysis, pentose phosphate and purine biosynthesis. Ex vivo assays of oxygen consumption and transmission electron microscopy validated early and progressive mitochondrial stress and abnormalities in mitochondrial structure and function of rd1 rods. These data uncover mitochondrial over-activation and related metabolic alterations as early determinants of pathology and implicate dysregulation of calcium signaling as the initiator of higher mitochondrial stress, which then transitions to mitochondrial damage and photoreceptor cell death in retinal degeneration. Our studies support the "one hit model" arguing against the cumulative damage hypothesis but suggest that cell death in neurodegenerative disease is initiated by specific rather than a random event.

neuroscience↗

bioRxiv2021

The in vitro and in vivo potency of CT-P59 against Delta and its associated variants of SARS-CoV-2

The Delta variant originally from India is rapidly spreading across the world and causes to resurge infections of SARS-CoV-2. We previously reported that CT-P59 presented its in vivo potency against Beta and Gamma variants, despite its reduced activity in cell experiments. Yet, it remains uncertain to exert the antiviral effect of CT-P59 on the Delta and its associated variants (L452R). To tackle this question, we carried out cell tests and animal study. CT-P59 showed reduced antiviral activity but enabled neutralization against Delta, Epsilon, and Kappa variants in cells. In line with in vitro results, the mouse challenge experiment with the Delta variant substantiated in vivo potency of CT-P59 showing symptom remission and virus abrogation in the respiratory tract. Collectively, cell and animal studies showed that CT-P59 is effective against the Delta variant infection, hinting that CT-P59 has therapeutic potency for patients infected with Delta and its associated variants. HighlightsO_LICT-P59 exerts the antiviral effect on authentic Delta, Epsilon and Kappa variants in cell-based experiments. C_LIO_LICT-P59 showed neutralizing potency against variants including Delta, Epsilon, Kappa, L452R, T478K and P681H pseudovirus variants. C_LIO_LIThe administration of clinically relevant dose of CT-P59 showed in vivo C_LIO_LIprotection against Delta variants in animal challenge experiment. C_LI

microbiology↗

bioRxiv2020

Proneural genes define ground state rules to regulate neurogenic patterning and cortical folding

Transition from smooth, lissencephalic brains to highly-folded, gyrencephalic structures is associated with neuronal expansion and breaks in neurogenic symmetry. Here we show that Neurog2 and Ascl1 proneural genes regulate cortical progenitor cell differentiation through cross-repressive interactions to sustain neurogenic continuity in a lissencephalic rodent brain. Using in vivo lineage tracing, we found that Neurog2 and Ascl1 expression defines a lineage continuum of four progenitor pools, with double+ progenitors displaying several unique features (least lineage-restricted, complex gene regulatory network, G2 pausing). Strikingly, selective killing of double+ progenitors using split-Cre;Rosa-DTA transgenics breaks neurogenic symmetry by locally disrupting Notch signaling, leading to cortical folding. Finally, consistent with NEUROG2 and ASCL1 driving discontinuous neurogenesis and folding in gyrencephalic species, their transcripts are modular in folded macaque cortices and pseudo-folded human cerebral organoids. Neurog2/Ascl1 double+ progenitors are thus Notch-ligand expressing niche cells that control neurogenic periodicity to determine cortical gyrification. HIGHLIGHTSO_LINeurog2 and Ascl1 expression defines four distinct transitional progenitor states C_LIO_LIDouble+ NPCs are transcriptionally complex and mark a lineage branch point C_LIO_LIDouble+ NPCs control neurogenic patterning and cortical folding via Notch signaling C_LIO_LINeurog2 and Ascl1 expression is modular in folded and not lissencephalic cortices C_LI eTOC BLURBEmergence of a gyrencephalic cortex is associated with a break in neurogenic continuity across the cortical germinal zone. Han et al. identify a pool of unbiased neural progenitors at a lineage bifurcation point that co-express Neurog2 and Ascl1 and produce Notch ligands to control neurogenic periodicity and cortical folding.

developmental biology↗

bioRxiv2019

Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species

Activation of the Hedgehog (Hh) signaling pathway by mutations within its components drives the growth of several cancers. However, the role of Hh pathway activation in lung cancers has been controversial. We demonstrate that the Hh signaling pathway is activated in lung stroma in a paracrine manner. Genetic deletion of Shh in autochthonous murine lung adenocarcinoma had no effect on survival. Early abrogation of the pathway by an anti-SHH/IHH antibody 5E1 led to significantly worse survival with increased tumor and metastatic burden. Loss of IHH by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, not SHH, activates the pathway in stroma to drive its tumor suppressive effects - a novel role for IHH in the lung. Tumors from mice treated with 5E1 had decreased blood vessel density and increased reactive oxygen species (ROS). Treatment of KP mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor ROS levels, inhibited tumor growth and prolonged mouse survival suggesting that increased ROS levels from stromal Hh pathway inhibition spurred lung tumor growth. Thus, IHH induces stromal Hh pathway activation to suppress tumor growth and metastases, in part, by limiting ROS production.

cancer biology↗

bioRxiv2019

YAP nuclear translocation through dynein and acetylated microtubule controls fibroblast activation.

Myofibroblasts are the major cell type that are responsible for increase the mechanical stiffness in fibrotic tissues. It has well documented that the TGF-{beta}/Smad axis is required for myofibroblast differentiation under the rigid substrate condition. However, the mechanism driving myofibroblast differentiation in soft substrates remains unknown. In this research, we demonstrated that interaction of yes-associated protein (YAP) and acetylated microtubule via dynein, a microtubule motor protein drives nuclear localization of YAP in soft matrix, which in turn increased TGF-{beta}1 induced transcriptional activity of Smad for myofibroblast differentiation. Pharmacological and genetical disruption of dynein impaired the nuclear translocation of YAP and decreased the TGF-{beta}1 induced Smad activity even though phosphorylation and nuclear localization of Smad occurred normally in -tubulin acetyltransferase (-TAT1) knockout cell. Moreover, microtubule acetylation prominently appeared in the fibroblast-like cells nearby the blood vessel in the fibrotic liver induced by CCl4 administration which were conversely decreased by TGF-{beta} receptor inhibitor. As a result, quantitative inhibition of microtubule acetylation may be suggested as a new target for overcome the fibrotic diseases.

cell biology↗