Biology subjects

Chae, S.

Publications and source records attributed to Chae, S..

12 recordsLinked to original sources

bioRxiv2026

Isocaloric restriction of a high-fat diet under TAK-242 administration: metabolic and gut microbial responses in mice

High-fat feeding promotes obesity in mice largely by increasing energy intake, so diet composition and energy intake are hard to separate without pair-feeding. We previously showed that isocaloric restriction normalizes body weight, glycemia and plasma lipids but not visceral adiposity, adipose inflammation or the fecal microbial community. We hypothesized that, during administration of the TLR4 signaling inhibitor TAK-242, matching energy intake to that of low-fat controls would normalize adiposity, intestinal barrier gene expression and the fecal microbial community. Male C57BL/6 mice (n = 8 per group) received a low-fat diet, a high-fat diet ad libitum, or a high-fat diet pair-fed to controls from week 0 or week 5 for 12 weeks; TAK-242 (3 ug/g, three times weekly) was given to every group from week 0.4, with no vehicle-injected arm. Intake did not differ among groups during a three-week low-fat acclimation (P = .88); over the 12 weeks on the assigned diets the ad libitum high-fat group ate 5.5% more than controls (P = .50). Over the full trajectory the ad libitum high-fat group gained 0.48 g/week more than controls (group x week, P = .012); both pair-fed groups had lower fasting glucose than that group. Adipocyte diameter, visceral fat proportion, ileal barrier genes, CCK-induced satiation and microbial alpha diversity did not differ significantly among groups. Adipose Ccl2 expression differed (P = .043, exploratory), as did fecal community composition (PERMANOVA P = .022), although no pairwise contrast survived correction. Energy restriction did not return the microbial community toward the low-fat profile.

physiology↗

bioRxiv2026

Visual experience-driven switch in endothelial metabolic transporters is essential for cerebrovascular maturation

Angiogenesis and blood-brain barrier (BBB) maturation are tightly regulated by coordinated interactions among neuronal, glial, and endothelial cells. Although neuronal activity is essential for postnatal cerebrovascular development, how it is translated into endothelial programs that coordinate vascular maturation remains unknown. Here, we show that visual experience drives metabolic reprogramming in brain endothelial cells by decreasing the lactate transporter MCT1 while increasing the glucose transporter GLUT1, a switch that is essential for proper vascular development. Sustained endothelial expression of MCT1 impaired vascular development and BBB maturation, resulting in vascular leakage. Mechanistically, the developmental decline in TGF-beta signaling drives the endothelial MCT1-to-GLUT1 transition. Endothelial-derived TGF-beta1 further reinforces the immature angiogenic state through a lactate-dependent autocrine positive feedback loop, whereas sensory experience promotes astrocyte maturation, which attenuates endothelial TGF-beta signaling, potentially by altering the perivascular environment. Together, our findings identify a neuron-astrocyte-endothelial metabolic signaling axis that links sensory experience to endothelial metabolic reprogramming and coordinates the transition from angiogenesis to BBB maturation.

neuroscience↗

bioRxiv2026

Isocaloric restriction normalizes body weight but not relative adiposity, adipose inflammation, or gut microbial diversity in high-fat diet-fed mice

Background/Objectives: The separate contributions of excess energy intake and diet composition to high-fat diet (HFD)-induced adiposity, adipose inflammation, and gut microbial changes are unclear. We tested whether restricting HFD intake to the energy intake of low-fat (LF)-fed mice (isocaloric restriction) prevents or reverses these outcomes. Subjects/Methods: Male C57BL/6 mice (n = 8/group) received for 12 weeks an LF diet (LF/LF) or HFD (HF/HF) ad libitum, HFD ad libitum then isocaloric HFD from week 7 (HF/IHF), or isocaloric HFD throughout (IHF/IHF). Adiposity, plasma markers, adipose and ileal gene expression, and fecal microbiota (16S rRNA sequencing, n = 4/group) were assessed. Results: Final body weight in IHF/IHF did not differ from LF/LF (difference 0.1 g, 95% CI -6.5 to 6.7; P > 0.99) and was lower than in HF/HF (-8.2 g, -14.7 to -1.6; P = 0.011). Switching to isocaloric feeding reduced weight gain during weeks 6-12 (HF/IHF vs HF/HF, -6.4 g, -9.8 to -3.1; P < 0.001). IHF/IHF mice had lower glucose (P = 0.031) and cholesterol (P = 0.005) than HF/HF mice. However, visceral fat relative to body weight remained higher than in LF/LF in IHF/IHF (+1.5 percentage points, 0.04 to 2.9; P = 0.042) and HF/IHF (+1.8, 0.4 to 3.3; P = 0.008). Adipose Tnf expression remained elevated in HF/IHF (log2 difference 2.2, 0.2 to 4.2; P = 0.025), and fecal phylogenetic diversity was lower in IHF/IHF than in LF/LF (Faith's PD -3.1, -5.9 to -0.4; P = 0.024). Ileal barrier genes and plasma lipopolysaccharide-binding protein were unchanged. Conclusions: Limiting HFD energy intake normalized body weight, glycemia, and plasma lipids but not relative adiposity, adipose Tnf expression, or the loss of gut microbial diversity. Diet composition affects these outcomes independently of energy intake, so normal body weight does not indicate their reversal.

physiology↗

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↗

bioRxiv2026

Deep Plasma Proteomics Coupled with Functional Genomics Reveals Drivers of Parkinson's Disease Progression and Levodopa Response

Parkinsons disease (PD) is a progressive neurodegenerative disorder lacking disease-modifying therapies, and its clinical management is limited by the absence of accessible biomarkers for tracking disease progression and treatment response. To map these complex disease trajectories, we implemented an ultra-deep plasma proteomics workflow integrating Mag-Net extracellular vesicle enrichment with Orbitrap Astral mass spectrometry to profile longitudinal samples from PD patients. This approach quantified 6,481 plasma proteins at unprecedented depth in PD studies, revealing distinct signatures directly associated with disease duration and dopaminergic therapy exposure. Candidate biomarkers were subsequently validated in an independent cohort using ELISA, demonstrating robust predictive utility in AI-driven prediction models. To uncover the mechanistic drivers underlying these systemic changes, we intersected our proteomic data with novel proteome-wide gene overexpression perturbation screens designed to identify regulators of alpha-synuclein pre-formed fibril (PFF) uptake and PFF-induced neuronal toxicity. Finally, an integrative network analysis combining three independent proteome-wide assays revealed that key pathological hubs, such as CD14, IFNG, and PLAT, are targets of currently approved pharmacological agents. Collectively, these findings provide a comprehensive, systems-level map for PD biomarker discovery and highlight druggable pathways to advance precision medicine strategies.

neuroscience↗

bioRxiv2025

Biophysical Modeling Elucidates Mechanistic Principles for Rational Molecular Glue Design

Molecular glues are small molecules that offer a powerful strategy to target previously "undruggable" proteins of interest (POI) by enhancing their interactions with other proteins (effector). Depending on the nature of the effectors, molecular glues can induce stabilizing sequestration or degradation of POI. However, their rational design has been hindered by a poor understanding of how kinetic parameters impact their performance. To address this, we developed a unified mathematical framework that accurately analyzes the dynamics of both glue degraders and stabilizers. Our model reveals that the strong binding affinity of the ternary complex is the key determinant of performance across both modalities, provided that the initial component concentrations and degradation rate constants are fixed. Furthermore, we demonstrate that degrader performance is ultimately limited by its catalytic efficiency and the target proteins natural half-life. We also identify distinct roles for effector abundance, showing that the relative concentrations of the effector and POI are critical for stabilizers but less so for degraders. This quantitative framework provides mechanistic principles for the rationale design and optimization of molecular glues.

molecular biology↗

bioRxiv2025

Targeted stimulation of motor cortex neural ensembles drives learned movements

During the execution of learned motor skills, the neural population in the layer 2/3 (L2/3) of the primary motor cortex (M1) expresses a reproducible spatiotemporal activity pattern. It is debated whether M1 actively participates in generating this activity pattern and whether this learned pattern causally drives the learned movement. To address these questions, we utilized in vivo two-photon calcium imaging combined with holographic optogenetic stimulation of functionally defined M1 L2/3 neuronal ensembles in mice performing a skilled lever-pressing task. A brief and synchronous stimulation of [~]20 neurons whose activity onset in voluntary trials precedes movement onsets induced movements that resembled the learned movement, while producing spatiotemporal activity patterns in other M1 neurons that resembled those during the voluntary learned movement. Moreover, trial-by-trial variability of optogenetically triggered population activity correlated with the variability in the induced movements. These trial-by-trial variabilities were predicted by the initial state of M1 population activity immediately preceding the stimulation. In some trials, the stimulation induced the learned activity without inducing overt movements, indicating that the learned activity is not simply a reflection of movements and instead can be induced internally. The stimulation failed to generate movements or learned activity when mice were disengaged from the task. Stimulation of the neurons whose activity followed voluntary movement onsets failed to induce the learned movement in task-engaged mice. Taken together, the learned activity pattern in M1 L2/3 can be generated when the M1 network is prepared at the optimal initial state and receives precise triggering inputs, supporting the active role of M1 in the generation of learned activity and learned movements.

neuroscience↗

bioRxiv2024

Back-to-the-future motion analysis using machine intelligence predicts the potential risk of mood disorders

Motion encodes emotional value. Decoding the hidden information within the complexity and randomness of motion may aid in the early diagnosis and prevention of mood disorders. In this study, we utilized machine intelligence to predict the risk of mood disorders by analyzing random motion patterns in mice. The support vector machine, trained on motion data collected before chronic social defeat stress (CSDS), predicted a significant correlation between these data and the degree of CSDS-induced social avoidance. Unsupervised clustering revealed key motion biomarkers of stress susceptibility, accounting for approximately 70% of the onset of social avoidance in a new group of mice before exposure to CSDS. These findings suggest that motion analysis using machine intelligence could provide a non-invasive approach for predicting the risk of mood disorders.

animal behavior and cognition↗

bioRxiv2023

Differential formation of motor cortical dynamics during movement preparation according to the predictability of go timing

Motor cortex not only executes but also prepares movement, as motor cortical neurons exhibit preparatory activity that predicts upcoming movements. In movement preparation, animals adopt different strategies in response to uncertainties existing in nature such as the unknown timing of when a predator will attack--an environmental cue informing go. However, how motor cortical neurons cope with such uncertainties is less understood. In this study, we aim to investigate whether and how preparatory activity is altered depending on the predictability of go timing. We analyze firing activities of anterior lateral motor cortex (ALM) in mice during two auditory delayed-response tasks each with predictable or unpredictable go timing. When go timing is unpredictable, preparatory activities immediately reach and stay in a neural state capable of producing movement anytime to a sudden go cue. When go timing is predictable, preparation activity reaches the movement-producible state more gradually, to secure more accurate decisions. Surprisingly, this preparation process entails a longer reaction time (RT). We find that as preparatory activity increase in accuracy, it takes longer for a neural state to transition from the end of preparation to the start of movement. Our results suggest that motor cortex fine-tunes preparatory activity for more accurate movement using the predictability of go timing. Significant statementsAnticipating when to move is important in movement preparation. However, it is unclear how motor cortex prepares movement depending on how easy that anticipation is. To answer this, we examine motor cortical activity of mice during a delayed-response task. While motor cortical activity rapidly reaches a "movement-ready" state with unpredictable timing of a go signal (go timing), it does so more gradually when go timing is predictable. Moreover, when go timing is more predictable, motor cortex produces more accurate movement with, unexpectedly, a longer response time. This suggests that rodent motor cortical neurons can resource time information.

neuroscience↗

bioRxiv2023

A single-cell, time-resolved profiling of Xenopus mucociliary epithelium reveals non-hierarchical model of development

The specialized cell-types of the mucociliary epithelium (MCE) lining the respiratory tract enable continuous airway clearing, with its defects leading to chronic respiratory diseases. The molecular mechanisms driving cell-fate acquisition and temporal specialization during mucociliary epithelial development remain largely unknown. Here, we profile the developing Xenopus MCE from pluripotent to mature stages by single-cell transcriptomics, identifying novel, multipotent early epithelial progenitors that execute multi-lineage cues before specialising into late-stage ionocytes, goblet and basal cells. Combining in silico lineage inference, in situ hybridization and single-cell multiplexed RNA imaging, we capture the initial bifurcation into early epithelial and multiciliated progenitors, chart cell- type emergence and fate progression into specialized cell-types. Comparative analysis of nine airway atlases reveals an evolutionary conserved transcriptional module in ciliated cells, whereas secretory and basal types execute distinct function-specific programmes across vertebrates. We uncover a continuous non-hierarchical model of MCE development alongside a significant data resource for understanding respiratory biology.

developmental biology↗

bioRxiv2022

CD244 regulates both innate and adaptive immune axes in melanoma by inhibiting autophagy-mediated M1 macrophage maturation

Accumulating data have highlighted the role of monocytes/macrophages in immune escape by generating immunologically "cold" tumors that do not respond to immunotherapy. CD244 (SLAMF4, 2B4), a member of the signaling lymphocyte activation molecule family, is expressed on myeloid cells, but its precise role has not been elucidated. Using monocyte lineage-specific CD244-deficient (LysM-cre+/-CD244fl/fl;cKO) mice challenged with B16F10 melanoma, we report for the first time that CD244 negatively regulates tumor immunity by inhibiting the differentiation and functional maturation of CD11b+Ly6ChiF4/80lo monocytes into CD11b+Ly6CloF4/80hi macrophages within the tumor microenvironment. CD244-deficient macrophages more effectively activated antigen-specific T cell responses compared to WT macrophages, thus delaying tumor growth in the B16F10 melanoma model. Moreover, combinatorial intervention of anti-PD-L1 antibodies with CD244-KO BMDM markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with WT BMDM. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset (SCP398 from single-cell portal), revealed 221 differentially expressed genes of CD244- monocytes/macrophages were associated with phagocytosis, antigen presentation, and autophagy. Additionally, cell type deconvolution analysis within melanoma patients bulk RNA-seq datasets from TCGA database, revealed presence of CD244- monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. Hence, we proposed that CD244 serve as a critical immune checkpoint receptor on macrophages, and CD244-deficient macrophages may represent a novel therapeutic modality to convert immunologically "cold" tumors to "hot" tumors, which can function synergistically with checkpoint blockade therapies.

immunology↗

bioRxiv2020

SUMO-specific protease 2 (SENP2) suppresses browning of white adipose tissue through C/EBPβ modulation

SUMO-specific protease 2 (SENP2) is highly expressed in white adipose tissue (WAT) and plays an important role in the early stages of adipogenesis. To investigate the function of SENP2 in adipocytes, we generated adipocyte-specific Senp2 knock-out (Senp2-aKO) mice. Compared to wild-type mice, Senp2-aKO mice had reduced adipose tissue mass and smaller multi-locular adipocytes in inguinal WAT (iWAT). Body temperatures of Senp2-aKO mice were effectively regulated during cold exposure. Additionally, Senp2-aKO mice were resistant to high-fat-diet-induced obesity and insulin resistance and exhibited an increase in energy expenditure rates. Expression of thermogenic genes, including Ucp1, was significantly increased in iWAT (and less efficiently in epidydimal WAT [eWAT]) of Senp2-aKO mice, suggesting that SENP2 depletion accelerates browning of WAT. Further, suppression of HOXC10 was essential for beige adipocyte formation in SENP2-deficient cells of iWAT, and Hoxc10 transcriptional suppression was mediated by C/EBP{beta}, a direct target of SENP2. Sumoylated C/EBP{beta} efficiently inhibited Hoxc10 transcription through recruitment of the transcriptional co-repressor DAXX. Similarly, Senp2 knockdown using siRNAs during adipogenesis promoted thermogenic adipocyte differentiation of precursor cells in both iWAT and eWAT, and C/EBP{beta} was a common mediator. Together these results suggest that SENP2 plays critical role in white adipocyte differentiation by suppressing differentiation toward thermogenic adipocytes through modulation of C/EBP{beta} in both iWAT and eWAT.

cell biology↗