Biology subjects

Park, H. S.

Publications and source records attributed to Park, H. S..

13 recordsLinked to original sources

bioRxiv2026

A self-limiting orexin-habenula circuit for stress resilience

Resilience requires neural systems that mobilise active coping during stress while limiting its persistence to preserve homeostasis under sustained challenge1-4. Here we identify a self-limiting orexin-habenula circuit in which lateral hypothalamic orexin neurons engage aromatic L-amino acid decarboxylase-expressing D-neurons (encoded by Ddc) in the lateral habenula via orexin receptor type 2 (OX2R)5-7. Activation of this pathway increased nucleus accumbens dopamine and promoted active coping and positive valence. Optotagging revealed rapid stress-evoked recruitment followed by post-stress suppression. In lateral habenula neurons, orexin peptides exerted dissociable effects: orexin-A engaged an OX2R-dependent inhibitory programme superimposed on a parallel inward current, whereas orexin-B did not reproduce this inhibitory profile and instead exerted a distinct membrane effect. Chronic stress disrupted this buffering system through coordinated inflammatory activation, promoter methylation and erosion of D-neuron identity and orexin responsiveness. Restoring orexin-A reversed behavioural and molecular deficits through OX2R-dependent suppression of nuclear factor kappa B signalling, preservation of Tet2 expression, and demethylation-linked maintenance of the Ddc programme. Together, these findings define a self-limiting orexin-habenula resilience circuit that enables adaptive coping while constraining stress-induced vulnerability.

neuroscience↗

bioRxiv2025

Primary Cilia Dysfunction in Brown Fat Results in Fatal Thermogenesis Failure in Neonatal Mice

Primary cilium, microtubule-based sensory organelle that has emerged as a central player in coordinating numerous signaling pathways. Although primary cilia are known to regulate cellular signaling and energy metabolism, the relationship between these roles in the context of ciliopathies and brown adipose tissue (BAT) dysfunction remains poorly understood. To elucidate the role of primary cilia in BAT, we generated Ucp1-Cre;Ift88flox/flox mice with BAT-specific ciliary loss. There were no significant differences in body size, weight, or BAT weight relative to body weight between P0 Ucp1-Cre;Ift88flox/flox and P0 Ucp1-Cre;Ift88+/+ pups. Embryos examined at E14.5 and E18.5 also showed no discernible differences in size, morphology, or histology. However, P0 Ucp1-Cre;Ift88flox/flox pups exhibited neonatal lethality caused by defective thermogenesis, despite preserved Ucp1 expression. These mice displayed markedly reduced ketone body levels in both BAT and serum, accompanied by downregulation of Hmgcs2, a key enzyme in ketogenesis. Loss of primary cilia in BAT suppressed ketogenesis and increased ROS production through HMGCS2 downregulation, ultimately impairing non-shivering thermogenesis. Remarkably, neonatal lethality of Ucp1-Cre;Ift88flox/flox pups was completely rescued by thermoneutral housing or {beta}-hydroxybutyrate supplementation. Our findings identified a previously unrecognized mechanism by which primary cilia regulate non-shivering, UCP1-independent thermogenesis via ketogenesis.

cell biology↗

bioRxiv2024

Orange Maker: a CRISPR/Cas9-mediated genome editing and screening project to generate orange-eyed DarkJedi GAL4 lines by undergraduate students

One of the greatest strengths of Drosophila genetics is its easily observable and selectable phenotypic markers. The mini-white marker has been widely used as a transgenic marker for Drosophila transgenesis. Flies carrying a mini-white construct can exhibit various eye colors ranging from pale orange to intense red, depending on the insertion site and gene dosage. Because the two copies of the mini-white marker show a stronger orange color, this is often used for selecting progenies carrying two transgenes together in a single chromosome after chromosomal recombination. However, some GAL4 lines available in the fly community originally have very strong red eyes. Without employing another marker, such as GFP, generating a recombinant chromosome with the strong red-eyed GAL4 and a desired UAS-transgene construct may be difficult. Therefore, we decided to change the red eyes of GAL4 lines to orange color. To change the eye color of the fly, we tested the CRISPR/Cas9 method with a guide RNA targeting the white gene with OK371-GAL4 and elav-GAL4. After a simple screening, we have successfully obtained multiple lines of orange-eyed OK371-GAL4 and elav-GAL4 that still maintain their original expression patterns. All of these simple experiments were performed by undergraduate students, allowing them to learn about a variety of different genetic experiments and genome editing while contributing to the fly research community by creating fruit fly lines that will be used in real-world research.

genetics↗

bioRxiv2023

A Spatial Transcriptomics based Label-Free Method for Assessment of Human Stem Cell Distribution and Effects in a Mouse Model of Lung Fibrosis

Recently, cell therapy has emerged as a promising treatment option for various disorders. Given the intricate mechanisms of action (MOA) and heterogenous distribution in target tissues inherent to cell therapy, it is necessary to develop more sophisticated, unbiased approaches to evaluate the distribution of administered cells and the molecular changes at a microscopic level. In this study, we present a label-free approach for assessing the tissue distribution of administered human mesenchymal stem cells (hMSCs) and their MOA, leveraging spatially resolved transcriptomics (ST) analysis. We administered hMSCs to mouse model of lung fibrosis and utilized ST to visualize the spatial distribution of hMSCs within the tissue. This was achieved by capitalizing on interspecies transcript differences between human and mouse. Furthermore, we could examine molecular changes associated with the spatial distribution of hMSCs. We suggest that our method has the potential to serve as an effective tool for various cell-based therapeutic agents.

bioinformatics↗

bioRxiv2023

Vutiglabridin Alleviates Cellular Senescence Process of Dysfunctional Replication, Metabolic Regulation, and Circadian Clock in Primary Human Dermal Fibroblasts

The process of cellular senescence, which is characterized by stable cell cycle arrest, is strongly associated with dysfunctional cellular metabolism and circadian rhythmicity, both of which are reported to result from and also be causal to cellular senescence. As a result, modifying any of them - senescence, metabolism, or the circadian clock - may affect all three simultaneously. Obesity accelerates aging by disrupting the homeostasis of reactive oxygen species (ROS) via an increased mitochondrial burden of fatty acid oxidation. As a result, if senescence, metabolism, and circadian rhythm are all linked, anti-obesity treatments may improve metabolic regulation while also alleviating senescence and circadian rhythm. Vutiglabridin is a small molecule in clinical trials that improves obesity by enhancing mitochondrial function. We found that chronic treatment of senescent primary human dermal fibroblasts (HDFs) with vutiglabridin alleviates all investigated markers of cellular senescence (SA-{beta}-gal, CDKN1A, CDKN2A) and dysfunctional cellular circadian rhythm (BMAL1), while remarkably preventing the alterations of mitochondrial function and structure that occur during the process of cellular senescence. Our results demonstrate the significant senescence-alleviating effects of vutiglabridin, specifically with the restoration of cellular circadian rhythmicity and metabolic regulation. These data support the potential development of vutiglabridin against aging-associated diseases and corroborate the intricate link between cellular senescence, metabolism, and the circadian clock.

physiology↗

bioRxiv2022

Vutiglabridin improves neurodegeneration in MPTP-induced Parkinson's disease mice by targeting mitochondrial paraoxonase-2

Parkinsons disease (PD), characterized by degeneration of dopaminergic neurons, share pathogenic features with obesity, including mitochondrial dysfunction and oxidative stress. Paraoxonase 2 (PON2) is an inner mitochondrial membrane protein that is highly expressed in dopaminergic neurons and is involved in the regulation of mitochondrial oxidative stress. However, no drug targeting PON2 has ever been developed for the treatment of PD. Here, we show that vutiglabridin, a clinical phase 2-stage drug for the treatment of obesity, has therapeutic effects in PD models, targeting mitochondrial PON2. Vutiglabridin penetrates into the brain, binds to PON2, and restores 1-methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction in SH-SY5Y neuroblastoma cells. Knockdown of PON2 by lentiviral shRNA infection abolished the effects of vutiglabridin on mitochondria. In mice, vutiglabridin significantly alleviated motor impairments and damage to dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model, and these effects were also abolished in PON2-knockdown mice, suggesting that vutiglabridin is neuroprotective via PON2. Extensive in vitro and in vivo assessment of potential neurotoxicity showed vutiglabridin to be safe. Overall, these findings provide support for the clinical development of vutiglabridin as a novel PON2 modulator for the treatment of PD. One Sentence SummaryTargeting paraoxonase-2 by a clinical-stage compound vutiglabridin provides neuroprotective effects in preclinical models of Parkinsons disease.

neuroscience↗

bioRxiv2022

Neural mechanism of acute stress management by trace aminergic signalling in the lateral habenula

Stress management is a prerequisite for the survival of vertebrates because chronic stress may cause depression and is known to negatively modulate the dopaminergic reward system1. Enhanced excitability of neurons in the lateral habenula (LHb) induced by chronic stress is essential for silencing dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neurons in the rostromedial tegmental nucleus (RMTg)2-10. However, the effect of acute stress on the LHb-RMTg-VTA pathway is unknown11-14. Here, we show that both aromatic L-amino acid decarboxylase (AADC)-expressing neurons (D-neurons)15 in the LHb and dopaminergic neurons in the VTA are activated by acute stress, whereas GABAergic neurons in the RMTg are not. Selective stimulation of LHb D-neurons and AADC knockdown of these neurons reverse-regulate the RMTg-VTA pathway. Circuit tracing and electrophysiology data demonstrate that trace aminergic signalling by LHb D-neurons directly suppresses RMTg GABAergic neurons. Furthermore, local activation of trace amine-associated receptor 1 (TAAR1; a trace amine receptor) in the RMTg is sufficient to rescue the despair-like behaviour produced by the loss of AADC expression. Our results identify a novel efferent pathway from the LHb to the RMTg whereby trace aminergic signalling allows the brain to manage acute stress by preventing VTA dopaminergic neuron hypoactivity. The TAAR1-mediated trace aminergic signalling in the LHb-RMTg pathway may hold promise as a therapeutic target for stress-mediated psychological diseases.

neuroscience↗

bioRxiv2021

Hierarchical organization of rhesus macaque behavior

Primatologists, psychologists and neuroscientists have long hypothesized that primate behavior is highly structured. However, fully delineating that structure has been impossible due to the difficulties of precision behavioral tracking. Here we analyzed a dataset consisting of continuous measures of the 3D position of fifteen body landmarks from two male rhesus macaques (Macaca mulatta) performing three different tasks in a large unrestrained environment over many hours. Using an unsupervised embedding approach on the tracked joints, we identified commonly repeated pose patterns, which we call postures. We found that macaques behavior is characterized by 49 distinct identifiable postures, lasting an average of 0.6 seconds each. We found evidence that behavior is hierarchically organized, in that transitions between poses tend to occur within larger modules, which correspond to intuitively identifiably actions; these actions are in turn organized hierarchically. Our behavioral decomposition allows us to identify universal (cross-individual and cross-task) and unique (specific to each individual and task) principles of behavior. These results demonstrate the hierarchical nature of primate behavior and provide a method for the automated "ethogramming" of primate behavior.

animal behavior and cognition↗

bioRxiv2021

Synthetic glabridin derivatives mitigate steatohepatitis in a diet-induced biopsy-confirmed non-alcoholic steatosis hepatitis mouse model through paraoxonase-2

Limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH), a common immunometabolic disease that can progress to hepatic cirrhosis and cancer. Glabridin and its derivatives are potential therapeutics for some metabolic diseases. However, the therapeutic effects of glabridin and its derivatives on NASH and their biological functions are unclear. This study demonstrated the role of synthetic glabridin derivatives (SGDs) in alleviating hepatic steatosis and inflammation in a biopsy-confirmed rodent NASH model. SGDs exerted therapeutic effects by activating autophagy and the antioxidant defense system, which mitigate NASH pathogenesis. The cellular target of HSG4112, an SGD, was paraoxonase 2. These findings will enable the development of novel therapeutics for NASH in the future.

pharmacology and toxicology↗

bioRxiv2021

OpenMonkeyChallenge: Dataset and Benchmark Challenges for Pose Tracking of Non-human Primates

The ability to automatically track non-human primates as they move through the world is important for several subfields in biology and biomedicine. Inspired by the recent success of computer vision models enabled by benchmark challenges (e.g., object detection), we propose a new benchmark challenge called OpenMonkeyChallenge that facilitates collective community efforts through an annual competition to build generalizable non- human primate pose tracking models. To host the benchmark challenge, we provide a new public dataset consisting of 111,529 annotated (17 body landmarks) photographs of non-human primates in naturalistic contexts obtained from various sources including the internet, three National Primate Research Centers, and the Minnesota Zoo. Such annotated datasets will be used for the training and testing datasets to develop generalizable models with standardized evaluation metrics. We demonstrate the effectiveness of our dataset quantitatively by comparing it with existing datasets based on seven state-of-the-art pose tracking models.

animal behavior and cognition↗

bioRxiv2021

Microbial byproducts determine reproductive fitness of free-living and parasitic nematodes

A distinguishing feature of Trichuris nematodes is that these parasitic worms reproduce within the digestive tracts of humans and other mammalian hosts shedding thousands of eggs daily, facilitating their sustained presence in the environment and hampering eradication efforts. Although this aspect of the lifecycle places Trichuris in a microbiota-rich environment, metabolic byproducts of bacteria that facilitate the reproductive development of parasites are unknown. Here, we employ a pipeline using the well-characterized free-living nematode C. elegans to identify microbial factors with conserved roles in the reproduction of nematodes. A screen for E. coli mutants that impair C. elegans fertility identified genes in fatty acid biosynthesis and ethanolamine utilization pathways, including fabH and eutN. Trichuris muris eggs displayed defective hatching in the presence of E. coli deficient in fabH or eutN due to reduction in arginine or elevated levels of aldehydes, respectively. Remarkably, T. muris reared in gnotobiotic mice colonized with these E. coli mutants displayed profound abnormalities including morphological defects and a failure to lay viable eggs. These findings indicate that microbial byproducts mediate evolutionarily conserved transkingdom interactions that impact the reproductive fitness of distantly-related nematodes.

microbiology↗

bioRxiv2021

Characterizing stored red blood cells using ultra-high throughput holographic cytometry

Holographic cytometry is introduced as an ultra-high throughput implementation of quantitative phase image based on off-axis interferometry of cells flowing through parallel microfluidic channels. Here, it is applied for characterizing morphological changes of red blood cells during storage under regular blood bank condition. The approach allows high quality phase imaging of a large number of cells greatly extending our ability to study cellular phenotypes using individual cell images. Holographic cytology measurements show multiple physical traits of the cells, including optical volume and area, which are observed to consistently change over the storage time. In addition, the large volume of cell imaging data can serve as training data for machine learning algorithms. For the study here, logistic regression is used to classify the cells according to the storage time points. The results of the classifiers demonstrate the potential of holographic cytometry as a diagnostic tool.

bioengineering↗

bioRxiv2020

OpenMonkeyStudio: Automated Markerless Pose Estimation in Freely Moving Macaques

The rhesus macaque is an important model species in several branches of science, including neuroscience, psychology, ethology, and several fields of medicine. The utility of the macaque model would be greatly enhanced by the ability to precisely measure its behavior, specifically, its pose (position of multiple major body landmarks) in freely moving conditions. Existing approaches do not provide sufficient tracking. Here, we describe OpenMonkeyStudio, a novel deep learning-based markerless motion capture system for estimating 3D pose in freely moving macaques in large unconstrained environments. Our system makes use of 62 precisely calibrated and synchronized machine vision cameras that encircle an open 2.45mx2.45mx2.75m enclosure. The resulting multiview image streams allow for novel data augmentation via 3D reconstruction of hand-annotated images that in turn train a robust view-invariant deep neural network model. This view invariance represents an important advance over previous markerless 2D tracking approaches, and allows fully automatic pose inference on unconstrained natural motion. We show that OpenMonkeyStudio can be used to accurately recognize actions and track two monkey social interactions without human intervention. We also make the training data (195,228 images) and trained detection model publicly available.

neuroscience↗