Biology subjects

Park, J. Y.

Publications and source records attributed to Park, J. Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Haplotype-resolved genetic mapping using selfed progeny enables simultaneous genome assembly validation and trait dissection in a heterozygous plant

Genetic linkage maps are essential for genome analysis and molecular breeding, but developing suitable mapping populations remains challenging in many plant species. Approaches requiring inbred parental lines are particularly difficult to implement in plants with long generation times or severe inbreeding depression. We developed haplotype-resolved genetic mapping (HRGM) to construct linkage maps from a single heterozygous individual and its selfed progeny without requiring inbred parental lines. HRGM combines haplotype-resolved unitig assemblies from the S0 parent with genotype data from its S1 progeny, using sequence differences between the two haplotypes to define phased SNP markers. Application to Cynanchum wilfordii generated a high-density genetic map comprising 8,147 SNP markers consolidated into 464 bins across 11 linkage groups, spanning 786.4 cM. The map enabled the detection of two loci associated with root development. Recombination patterns derived from the S1 population showed strong concordance with the chromosome-scale genome assembly and exhibited recombination suppression in putative centromeric regions. HRGM integrates recombination-based genome assembly validation and trait mapping within a single framework. By using one generation of selfed progeny and obtaining linkage-phase information directly from phased assemblies, it simplifies mapping population development and extends the utility of genomic resources for genetic analysis and molecular breeding, particularly in species where selfed progeny can be obtained but conventional mapping populations are difficult to establish.

genomics↗

bioRxiv2026

Beyond point estimates: quantifying predictive uncertainty reveals hidden dimensions of biological age acceleration and improves risk interpretation

Biological age estimates are increasingly used to study aging, disease risk, and mortality, yet their predictive uncertainty is rarely quantified. Consequently, conventional age-gap measures can treat deviations as equally informative even when the underlying biological age predictions differ substantially in reliability. We developed a framework for uncertainty-aware biological aging that generates calibrated prediction intervals and individualized probabilities of accelerated or decelerated aging alongside point estimates. We applied this framework to the UK Biobank Pharma Proteomics Project, evaluating three composite and eleven organ-specific biological age clocks. Predictive uncertainty varied substantially both within and across clocks, revealing that apparently extreme age gaps can differ markedly in the strength of evidence supporting accelerated or decelerated aging. In particular, low-accuracy clocks, including many organ-specific clocks, provided little evidence for confidently accelerated or decelerated aging. Beyond biological age gaps, prediction-interval width was independently associated with disease risk and mortality, particularly for composite, brain, and immune clocks, suggesting that predictive uncertainty captures an additional dimension of biological aging that may reflect increased molecular heterogeneity and dysregulation associated with aging and disease. We replicated these findings in Biobank Japan and an independent clinical cohort from Stanford. By incorporating individual-specific predictive uncertainty, our framework provides a more informative characterization of biological aging and enables improved individual-level risk stratification for disease prevention and longitudinal monitoring.

bioinformatics↗

bioRxiv2026

Bovine-derived H5N1 influenza virus efficiently infects lactating swine via the mammary gland

Since 2024, highly pathogenic influenza A(H5N1) viruses have spread extensively among U.S. dairy cattle, where they replicate efficiently in the mammary gland and are shed at high titers in milk. To directly assess susceptibility of commercial swine populations to bovine-derived H5N1 virus, lactating sows with prior influenza virus vaccination histories representative of U.S. commercial swine production systems were inoculated via the intramammary route and co-housed with their 1-week-old piglets to evaluate disease outcomes, viral replication, and potential for vertical transmission. Intramammary inoculation of lactating sows resulted in sustained viral RNA shedding in milk, while piglets exhibited sporadic oral viral RNA positivity that mirrored viral kinetics in milk. Lesions in mammary tissue and viral antigen staining, as well as development of neutralizing antibody responses and changes in milk color and consistency, further confirmed infection in the sows. Despite these molecular findings, none of the animals developed overt clinical disease, and respiratory involvement was not noted during the study period. Collectively, we demonstrate that intramammary exposure results in productive influenza A(H5N1) virus infection in lactating sows despite their vaccination histories, indicating the potential threat of viral spillover into commercial swine populations. The clinically inapparent nature of infection presents a risk of subclinical spread and underscores the importance of expanding viral surveillance to swine.

microbiology↗

bioRxiv2025

Inhibition of AXL dependent non-professional efferocytosis sensitizes pancreatic cancer to immune checkpoint blockade

AXL, a receptor tyrosine kinase, is upregulated in the majority of pancreatic adenocarcinoma (PDAC) and is associated with aggressive tumor behavior. Canonically, AXL is essential for efferocytosis, or the immunologically silent phagocytic clearance of apoptotic cells. While crucial to ensure self-tolerance, efferocytosis in cancer removes tumor antigens and dampens the antitumor response to create a pro-tumorigenic environment. Here, we show that PDAC cells co-opt the AXL pathway to act as non-professional efferocytes and clear chemotherapy induced apoptotic cells from their environment in vitro and in vivo. Inhibition of AXL with the selective inhibitor BGB324 inhibits efferocytosis and increases apoptotic cell burden, immunogenic cell death, and CD8 T cell infiltration in gemcitabine treated tumors in vivo. Single cell RNA expression analysis reveal that AXL inhibited gemcitabine treated tumors are enriched in the immunecheckpoint responsive TCF1+ CD8 T cells and respond to anti-PD1 therapy in vivo. We establish a novel ability of pancreatic cancer cells to engage in non-professional efferocytosis in response to chemotherapy. Inhibiting this response can be leveraged to sensitize this classically immune quiescent cancer to immunotherapy.

cancer biology↗

bioRxiv2025

Laminar Shear Stress Increases the Cytosolic Pool of PINK1 in Endothelial Cells and Enhances Mitophagic Sensitivity Toward Dysfunctional Mitochondria

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) is an essential molecule in mitophagy process in mammalian cells. Mutation or deficiency of PINK1 has been closely related to several disease conditions. The purpose of this study was to determine PINK1 expression levels and subcellular localization under exercise-mimic laminar shear stress (LSS) condition in human aortic endothelial cells (HAECs) or in exercising mice, and its implication on endothelial homeostasis and cardiovascular disease (CVD) prevention. First, LSS significantly elevated both full-length PINK1 (FL-PINK1) mRNA and protein expressions in ECs. Mitochondrial fractionation assays and confocal microscopic analysis showed reduced FL-PINK1 accumulation on mitochondria with an increase in a cytosolic pool of FL-PINK1 under LSS. Mitophagy flux, determined by a mtKeima probe, decreased with intact mitochondrial morphology and membrane potential under LSS, suggesting that elevated cytosolic PINK1 is not utilized for immediate mitophagy inductions. However, increased cytosolic PINK1 seems to elevate mitophagic sensitivity toward dysfunctional mitochondria in pathological conditions. LSS-preconditioned ECs showed lower angiotensin II (AngII)-induced mtDNA lesions and displayed rapid Parkin recruitment and mitophagy induction in response to mitochondrial uncoupler (CCCP) treatment. Exercise-preconditioned mice, a physiological LSS-enhanced model, showed elevated PINK1 expression in ECs of the thoracic aorta compared to sedentary control. In addition, exercise enhanced AngII-induced mitophagy induction in ECs and reduced AngII-induced mtDNA lesion formation in the mouse aorta. Taken together, LSS increases a cytosolic pool of FL-PINK1, which may elevate the mitophagic sensitivity toward dysfunctional mitochondria in ECs.

physiology↗

bioRxiv2025

Microengineered transplantation of human solid tumors for in vitro studies of CAR T immunotherapy

Treatment of solid malignancies using chimeric antigen receptor (CAR) T cells remains a significant challenge, but current efforts to advance this therapy are challenged by our limited capacity to probe and understand cancer-immune interactions in human solid tumors. Here, we present a microengineered platform for in vitro modeling of malignant solid tumors during CAR T therapy. This system makes it possible to vascularize human tumor explants and perfuse them with blood-borne immune cells in a controlled manner. We first present a microphysiological model of human lung adenocarcinomas infused with CAR-T cells and show how this system can be used to simulate, visualize, and interrogate tumor-directed trafficking and effector function of CAR T cells. We then demonstrate the proof-of-principle of testing a chemokine-directed CAR T cell engineering strategy in a model of malignant pleural mesothelioma and validating our in vitro assessment using a matching in vivo mouse model. Finally, we describe a potential therapeutic target discovered by single-cell RNA sequencing that can be pharmacologically modulated to increase the efficacy of CAR T cells for lung adenocarcinoma, for which we also present specific biomarkers identified by global metabolomics analysis. We believe that the bioengineering principle demonstrated here will make important contributions to developing new capabilities for preclinical studies of adoptive cell therapies for cancer and other complex diseases.

bioengineering↗

bioRxiv2025

An arginine switch drives the stepwise activation of β-arrestin

{beta}-arrestins ({beta}arrs) play a crucial role in regulating G protein-coupled receptor (GPCR) signaling and trafficking. Canonically, interactions of {beta}arr with the phosphorylated intracellular GPCR-tail induce a multi-step conformational transition that results in the activation of {beta}arr. Depending on the specific interaction pattern with the receptor, {beta}arrs adopt multiple conformational states, each tightly linked to a specific functional outcome of {beta}arr recruitment. Despite its physiological relevance, the structural determinants of {beta}arr activation remain poorly understood. Using a combination of molecular dynamics simulations, biochemical and cell-based experiments, we reveal how specific interactions with a prototypical GPCR promote the unbinding of the {beta}arr2 C-tail--a crucial step in arrestin activation. Importantly, we observe that the expulsion of the C-tail is promoted by the displacement of a conserved arginine residue (Arg394) within the {beta}arr polar core, which we dub "the arginine switch." Our study uncovers a previously unknown molecular switch that, upon engagement, destabilizes the polar core as a crucial step in the GPCR-induced {beta}arr activation.

biochemistry↗

bioRxiv2024

Mapping individual differences in intermodal coupling in neurodevelopment

Within-individual coupling between measures of brain structure and function evolves in development and may underlie differential risk for neuropsychiatric disorders. Despite increasing interest in the development of structure-function relationships, rigorous methods to quantify and test individual differences in coupling remain nascent. In this article, we explore and address gaps in approaches for testing and spatially localizing individual differences in intermodal coupling, including a new method, called CEIDR. CEIDR controls false positives in individual differences in intermodal correlations that arise from mean and variance heterogeneity and improves statistical power by adopting adaptive cluster enhancement. Through a comparison across different approaches to testing individual differences in intermodal coupling, we delineate subtle differences in the hypotheses they test, which may ultimately lead researchers to arrive at different results. Finally, we illustrate these differences in two applications to brain development using data from the Philadelphia Neurodevelopmental Cohort.

neuroscience↗

bioRxiv2024

Elucidating DNA-binding protein dynamics in Salmonella Typhimurium within macrophages using a breakthrough low-input ChIP-exo approach

Genome-wide identification of binding profiles for DNA-binding proteins in Salmonella Typhimurium within macrophages is crucial for understanding virulence gene expression and cellular processes. However, this task remains challenging due to the limited amount of intracellular bacterial cells. Here, we present ChIP-mini, a low-input ChIP-exo utilizing 5,000-fold reduced number of initial bacterial cells and analysis pipeline (DiffExo), to identify genome-wide binding dynamics of DNA-binding proteins in host-infected pathogens. Applying ChIP-mini to intracellular S. Typhimurium, we identified 642 and 1,837 binding sites of H-NS and RpoD, respectively, with near-base pair resolution, elucidating their roles in transcriptional initiation. Post-infection, we observed 21 significant reductions in H-NS binding at intergenic regions, exposing the promoter region of virulence genes, such that those in Salmonella pathogenicity islands-2, 3 and effectors, facilitating RpoD binding for transcription initiation. Furthermore, we identified 24 novel RpoD binding sites and 19 significantly increased RpoD bindings at the transcription start sites of virulence genes. These findings substantially enhance our understanding of how H-NS and RpoD simultaneously coordinate the transcription initiation of virulence genes within macrophages. Collectively, this optimized method demonstrates a tool that can be broadly adapted to elucidate transcriptional regulatory networks of host-infected pathogens, revealing critical interactions between host and microbe.

systems biology↗

bioRxiv2024

Differences in systemic immune parameters in individuals with lung cancer according to race

IntroductionRacial and ethnic disparities in the presentation and outcomes of lung cancer are widely known. To evaluate potential factors contributing to these observations, we measured systemic immune parameters in Black and White patients with lung cancer. MethodsPatients scheduled to receive cancer immunotherapy were enrolled in a multi-institutional prospective biospecimen collection registry. Clinical and demographic information were obtained from electronic medical records. Pre-treatment peripheral blood samples were collected and analyzed for cytokines using a multiplex panel and for immune cell populations using mass cytometry. Differences between Black and White patients were determined and corrected for multiple comparisons. ResultsA total of 187 patients with non-small cell lung cancer (Black, 19; White, 168) were included in the analysis. There were no significant differences in baseline characteristics between Black and White patients. Compared to White patients, Black patients had significantly lower levels of CCL23 and CCL27, and significantly higher levels of CCL8, CXCL1, CCL26, CCL25, CCL1, IL-1 b, CXCL16, and IFN-{gamma} (all P<0.05, FDR<0.1). Black patients also exhibited greater populations of non-classical CD16+ monocytes, NKT-like cells, CD4+ cells, CD38+ monocytes, and CD57+ gamma delta T cells (all P<0.05). ConclusionsBlack and White patients with lung cancer exhibit several differences in immune parameters, with Black patients exhibiting greater levels of numerous pro-inflammatory cytokines and cell populations. The etiology and clinical significance of these differences warrant further evaluation.

cancer biology↗

bioRxiv2024

Type I interferon alters invasive extravillous trophoblast function.

Inappropriate type I interferon (IFN) signaling during embryo implantation and placentation is linked to poor pregnancy outcomes. Here, we evaluated the consequence of elevated type I IFN exposure on implantation using a biomimetic model of human implantation in an organ-on-a-chip device. We found that type I IFN reduced extravillous trophoblast (EVT) invasion capacity. Analyzing single-cell transcriptomes, we uncovered that IFN truncated endovascular EVT emergence in the implantation-on-a-chip device by stunting EVT epithelial-to-mesenchymal transition. Disruptions to the epithelial-to-mesenchymal transition is associated with the pathogenesis of preeclampsia, a life-threatening hypertensive disorder of pregnancy. Strikingly, unwarranted IFN stimulation induced genes associated with increased preeclampsia risk and a preeclamptic gene-like signature in EVTs. These dysregulated EVT phenotypes ultimately reduced EVT-mediated endothelial cell vascular remodeling in the implantation-on-a-chip device. Overall, our work indicates IFN signaling can alter EVT epithelial-to-mesenchymal transition progression which results in diminished EVT-mediated spiral artery remodeling and a preeclampsia gene signature upon sustained stimulation. Our work implicates unwarranted type I IFN as a maternal disturbance that can result in abnormal EVT function that could trigger preeclampsia.

immunology↗

bioRxiv2023

SAN: mitigating spatial covariance heterogeneity in cortical thickness data collected from multiple scanners or sites

In neuroimaging studies, combining data collected from multiple study sites or scanners is becoming common to increase the reproducibility of scientific discoveries. At the same time, unwanted variations arise by using different scanners (inter-scanner biases), which need to be corrected before downstream analyses to facilitate replicable research and prevent spurious findings. While statistical harmonization methods such as ComBat have become popular in mitigating inter-scanner biases in neuroimaging, recent methodological advances have shown that harmonizing heterogeneous covariances results in higher data quality. In vertex-level cortical thickness data, heterogeneity in spatial autocorrelation is a critical factor that affects covariance heterogeneity. Our work proposes a new statistical harmonization method called SAN (Spatial Autocorrelation Normalization) that preserves homogeneous covariance vertex-level cortical thickness data across different scanners. We use an explicit Gaussian process to characterize scanner-invariant and scanner-specific variations to reconstruct spatially homogeneous data across scanners. SAN is computationally feasible, and it easily allows the integration of existing harmonization methods. We demonstrate the utility of the proposed method using cortical thickness data from the Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) study. SAN is publicly available as an R package.

neuroscience↗

bioRxiv2023

Behavioral and neuropathological features of Alzheimer's disease are attenuated in 5xFAD mice treated with intranasal GHK peptide

Efforts to find disease modifying treatments for Alzheimers disease (AD) have met with limited success in part because the focus has been on testing drugs that target a specific pathogenic mechanism. Multiple pathways have been implicated in the pathogenesis of AD. Hence, the probability of more effective treatment for AD is likely increased by using an intervention that targets more than one pathway. The naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), as a GHK-Cu complex, supports angiogenesis, remodeling, and tissue repair, has anti-inflammatory and antioxidant properties, and has been shown to improve cognitive performance in aging mice. In order to test GHK-Cu as a neurotherapeutic for AD, male and female 5xFAD transgenic mice on the C57BL/6 background at 4 months of age were given 15 mg/kg GHK-Cu intranasally 3 times per week for 3 months until 7 months of age. Results showed that intranasal GHK-Cu treatment delayed cognitive impairment, reduced amyloid plaques, and lowered inflammation levels in the frontal cortex and hippocampus. These observations suggest additional studies are warranted to investigate the potential of GHK-Cu peptide as a promising treatment for AD.

neuroscience↗

bioRxiv2023

Intranasal GHK peptide enhances resilience to cognitive decline in aging mice

Brain aging and cognitive decline are aspects of growing old. Age-related cognitive impairment entails the early stages of cognitive decline, and is extremely common, affecting millions of older people. Investigation into early cognitive decline as a treatable condition is relevant to a wide range of cognitive impairment conditions, since mild age-related neuropathology increases risk for more severe neuropathology and dementia associated with Alzheimers Disease. Recent studies suggest that the naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine) in its Cu-bound form, has the potential to treat cognitive decline associated with aging. In order to test this concept, male and female C57BL/6 mice, 20 months of age, were given intranasal GHK-Cu, 15 mg/kg daily, for two months. Results showed that mice treated with intranasal GHK-Cu had an enhanced level of cognitive performance in spatial memory and learning navigation tasks, and expressed decreased neuroinflammatory and axonal damage markers compared to mice treated with intranasal saline. These observations suggest that GHK-Cu can enhance resilience to brain aging, and has translational implications for further testing in both preclinical and clinical studies using an atomizer device for intranasal delivery.

neuroscience↗

bioRxiv2023

Spatial-extent inference for testing variance components in reliability and heritability studies

Clusterwise inference is a popular approach in neuroimaging to increase sensitivity, but most existing methods are currently restricted to the General Linear Model (GLM) for testing mean parameters. Statistical methods for testing variance components, which are critical in neuroimaging studies that involve estimation of narrow-sense heritability or test-retest reliability, are underdeveloped due to methodological and computational challenges, which would potentially lead to low power. We propose a fast and powerful test for variance components called CLEAN-V (CLEAN for testing Variance components). CLEAN-V models the global spatial dependence structure of imaging data and computes a locally powerful variance component test statistic by data-adaptively pooling neighborhood information. Correction for multiple comparisons is achieved by permutations to control family-wise error rate (FWER). Through analysis of task-fMRI data from the Human Connectome Project across five tasks and comprehensive data-driven simulations, we show that CLEAN-V outperforms existing methods in detecting test-retest reliability and narrow-sense heritability with significantly improved power, with the detected areas aligning with activation maps. The computational efficiency of CLEAN-V also speaks of its practical utility, and it is available as an R package.

neuroscience↗

bioRxiv2023

Intrathecal Cu-albumin PET reveals age-related decline of cerebrospinal fluid (CSF)-lymphatic efflux

Age-related cognitive decline is associated with dysfunctional lymphatic efflux of cerebrospinal fluid (CSF) through meningeal lymphatic vessels. Intrathecal [64Cu]Cu-albumin positron emission tomography (PET) was applied in mice for the evaluation of lymphatic efflux of CSF and its age-related variation. [64Cu]Cu-albumin PET was done at multiple time points after intrathecal injection of [64Cu]Cu-albumin with the infusion speed of 700 nl/min in the adult and aged mice of 15-25 months old age. CSF clearance and paravertebral lymph nodes were quantified after injection and at later stationary phase. Representing perturbed state by 6 l (1/7 of CSF volume with twice the production rate for 9 minutes of intrathecal injection) and at the next day of stationary return of CSF dynamics in mice, CSF clearance half-time from the subarachnoid space was 93.4 {+/-} 19.7 in adult and 123.3 {+/-} 15.6 minutes in aged mice (p = 0.01). The % injected dose at 4, 6 and 24 hours were higher in aged mice than in the adult mice (p < 0.05) and the visualized paravertebral lymph node activity tended to be lower in the aged, which was different from [64Cu]Cu-NOTA or [64Cu]Cu-ESION PET. [64Cu]Cu-albumin PET enabled quantification of CSF-lymphatic efflux over all the levels of brain spinal cords and visualization with quantifiability of lymph node activity. [64Cu]Cu-albumin PET revealed an age-related decrease in CSF-lymphatic efflux due to less efflux from the subarachnoid space, especially at stationary phase in the aged mice.

neuroscience↗

bioRxiv2022

Disrupting peroxisomes alters lipid metabolism in melanoma and uncovers a novel therapeutic vulnerability in combination with MAPK-targeted therapies

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKi) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiates the pro-apoptotic effects of MAPKi via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Co-targeting PEX3 and UGCG selectively eliminates a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKi and delaying resistance. Increased levels of peroxisomal genes and UGCG are found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restores MAPKi sensitivity in multiple models of therapy resistance. Finally, triple therapy comprised of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor and a MAPKi demonstrates potent anti-tumor activity in pre-clinical melanoma models, thus representing a promising approach for melanoma treatment. HighlightsO_LIInhibiting peroxisome biogenesis uncovers a metabolic vulnerability in melanoma C_LIO_LICD36+ persister melanoma cells tolerate MAPK-targeted therapy through peroxisome/UGCG mediated metabolic rewiring C_LIO_LIDual blockade of PEX3 and UGCG potentiates melanoma response to MAPK-targeted therapies and restores therapeutic sensitivity in MAPKi-resistant tumors C_LIO_LINNC 55-0396 is a PEX3-PEX19 binding inhibitor with potent anti-tumor activity in melanoma C_LI

cancer biology↗

bioRxiv2022

A structured multivariate approach for removal of latent batch effects

Combining data collected from multiple study sites is becoming common and is advantageous to researchers to increase the generalizability and replicability of scientific discoveries. However, at the same time, unwanted inter-scanner biases are commonly observed across neuroimaging data collected from multiple study sites or scanners, rendering difficulties in integrating such data to obtain reliable findings. While several methods for handling such unwanted variations have been proposed, most of them use univariate approaches that could be too simple to capture all sources of scanner-specific variations. To address these challenges, we propose a novel multivariate harmonization method, called RELIEF (REmoval of Latent Inter-scanner Effects through Factorization) for estimating and removing both explicit and latent scanner effects. Our method is the first approach to introduce the simultaneous dimension reduction and factorization of interlinked matrices to a data harmonization context, which provides a new direction in methodological research for correcting inter-scanner biases. Analyzing diffusion tensor imaging (DTI) data from the Social Processes Initiative in Neurobiology of the Schizophrenia (SPINS) study and conducting extensive simulation studies, we show that RELIEF outperforms existing harmonization methods in mitigating inter-scanner biases and retaining biological associations of interest to increase statistical power. RELIEF is publicly available as an R package.

neuroscience↗