Biology subjects

Park, H.-J.

Publications and source records attributed to Park, H.-J..

13 recordsLinked to original sources

bioRxiv2026

Identification of Lupus Immune Complex-Driven Pathogenic Pro-inflammatory Monocytes and Macrophages in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease characterized by anti-nuclear antibody (ANA) production and inflammation, though the mechanisms by which ANAs induce inflammation and tissue injury are incompletely understood. Here, we identified distinct subsets of mononuclear phagocytes (MPs), including monocytes (Mo) and macrophages (M{Phi}), driven by lupus immune complex (IC), comprised of ANAs and their target antigens. scRNA-seq of human Mo incubated with U1-snRNP (snRNP) lupus IC revealed expansion of distinct pro-inflammatory Mo subsets with upregulation of inflammatory genes including those encoding cytokines, NLRP3, and transcription factors. These transcriptomic changes strongly correlated with protein expression, as determined by proteomic analysis. Mo developed similar pro-inflammatory transcriptomic changes in response to other lupus ICs containing anti-dsDNA and Ro60 antibodies. Interrogation of scRNA-seq datasets from the skin, kidney, and peripheral blood of lupus patients revealed the presence and expansion of pro-inflammatory Mo and M{Phi} populations exhibiting transcriptomic signatures similar to those observed in lupus IC-stimulated Mo. Some of these cells expressing the snRNP IC gene signature exhibited low expression of the type I IFN signature, suggesting that lupus IC and type I IFN signaling may independently affect Mo subsets. In lupus nephritis, infiltration of CD68+ M{Phi} expressing NLRP3 was associated with treatment outcomes. Inhibiting activation of the transcription factor ETS2, a master regulator of Mo/M{Phi}-driven inflammation, attenuated lupus IC-induced activation of pro-inflammatory Mo. Collectively, these findings provide novel insights into the role of lupus IC-driven pro-inflammatory MPs in the pathogenesis of SLE and highlight their relevance as therapeutic targets. Significance StatementSystemic lupus erythematosus (SLE or lupus) is a multi-systemic autoimmune inflammatory disease characterized by anti-nuclear antibody (ANA) production. Lupus immune complex (IC), consisting of ANAs and their target antigens, likely play a critical role in the pathogenesis of lupus through activation of mononuclear phagocytes (MPs), including monocytes (Mo) and macrophages (M{Phi}), which can produce an array of inflammatory molecules. Using transcriptomic and proteomic analyses, our study identified distinct pro-inflammatory Mo populations driven by lupus IC, along with expansion of similar pro-inflammatory Mo and M{Phi} subsets in the skin, kidneys, and peripheral blood of lupus patients. These findings provide novel insights into the pathogenic role of lupus IC-driven pro-inflammatory MPs and support a scientific rationale for therapeutically targeting these cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=155 HEIGHT=200 SRC="FIGDIR/small/700902v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1839430org.highwire.dtl.DTLVardef@175dd1dorg.highwire.dtl.DTLVardef@107b54forg.highwire.dtl.DTLVardef@11096b0_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

A Cross-scale Causal Mapping Framework Pinpoints Macrophage Orchestrators of Balanced Arterial Development

Postnatal pulmonary arteries experience an abrupt surge in flow that demands tightly coordinated remodeling of vascular structure and mechanical compliance. However, the cellular programs orchestrating these multiscale adaptation remain poorly defined, partly due to the absence of analytical tools integrating gene-cell-tissue scales. Here, we present CausaLink, a cross-scale causal mapping framework that predicts how altered gene expression propagates through gene-cell-tissue networks by integrating time-course transcriptomic and tissue morpho-mechanical data. We constructed a single-cell transcriptomic atlas of 11,143 proximal pulmonary artery-derived cells from C57BL/6J mice across five developmental stages (P2, P10, P21, P42, and P84), revealing dynamic lineage transitions and transient mesenchymal population specifying into fibroblasts and smooth muscle cells from P2 to P21. Using this framework, we identified Mgl2 macrophages as central regulators promoting lumen expansion while preventing pathological wall thinning or thickening. To validate these predictions, we established a human induced pluripotent stem cell-derived arterial assembloid enriched in MGLhigh macrophages. In this model, MGLhigh macrophages supported lumen enlargement while maintaining overall wall thickness and induced formation of an adventitia-like fibroblast layer that recapitulated approximately 80% of the native adventitial fraction with balanced collagen-elastin remodeling. By linking predictive modeling to human organoid validation, this study establishes a cross-scale workflow for tracing how gene programs shape vascular architecture, offering mechanistic insights and a foundation for predictive regenerative medicine.

bioengineering↗

bioRxiv2024

Neural bidomain model for multidimensional ephaptic coupling of neural spike propagation along myelinated fiber bundles with the nodes of Ranvier

A novel mathematical model is proposed to investigate the distributions and functions of ephaptic coupling in generally-shaped neural fiber bundles in a multidimensional space, corresponding to the spatiotemporal interactions between propagating fiber bundles via the extracellular space. The proposed macroscopic model is derived from the classic Frankenhaeuser-Huxley model for neural spike propagation along the general neural fiber bundles in two domains (bidomain) of the nonoverlapping intracellular and extracellular space, except the common nodes of Ranvier. A high-order continuous Galerkin scheme provides an efficient two-dimensional (2D) computational simulation with moving frames (orthonormal basis vectors) representing intracellular and extracellular conductivity and nonoverlapping domains. The governing equation is mathematically and computationally validated against the existing 1D models of propagations along neural fiber bundles with the aligned nodes of Ranvier. The proposed model reveals the critical role of neural fiber bundle configurations by simulating their 2D propagations. For sufficiently large fiber bundles, synchronizing neural spike propagation along two fiber bundles with misaligned nodes of Ranvier is almost impossible. Moreover, the magnitude of interference of propagations passing-by along the fiber bundles depends on the fiber-bundle configuration, significantly depending on the location of the closest distance of two propagations, either in the myelin sheath or nodes of Ranvier. Finally, the curved fiber bundles demonstrate drastically different ephaptic coupling compared to straight fiber bundles due to the unique extracellular potential distribution by the curved fiber bundles. The new simulations highlight the importance of intrinsic fiber-bundle structures in neural spike propagation and brain functions. Author summaryFiber bundles communicate via chemical interactions across synaptic junctions and electrical interactions across gap junctions. Ephaptic coupling is another communication method between fiber bundles, which is of a small magnitude compared with other communication methods. The effect of ephaptic coupling is known on a relatively large scale and is mostly affected by the intrinsic structure of neural fiber bundles. The study of ephaptic coupling has attracted considerable attention since the 1940s, when the term ephaptic coupling was first coined. However, the lack of a multidimensional model of neural spike propagation with various configurations of myelinated fiber bundles has prohibited further investigations of ephaptic coupling in brain subregions. This paper proposes a multidimensional model of neural spike simulation in the context of partial differential equations. The proposed model aims to simulate neural spike propagations in complex configurations of fiber bundles to study the functions of ephaptic coupling in such brain structures. In this paper, the new simulations of the misaligned nodes of Ranvier, interfering opposite-traveling fiber bundles, and curved fiber bundles demonstrate the critical roles of intrinsic fiber-bundle structures, including the location and alignment of the nodes of Ranvier, in neural spike propagation and brain functions.

neuroscience↗

bioRxiv2024

Structure-guided design, synthesis, and characterization of C22- and C32-modified FK520 analogs with enhanced activity against human pathogenic fungi

Invasive fungal infections are a leading cause of death worldwide. Translating molecular insights into clinical benefits is challenging because fungal pathogens and their hosts share similar eukaryotic physiology. Consequently, current antifungal treatments have limited efficacy, may be poorly fungicidal in the host, can exhibit toxicity, and are increasingly compromised by emerging resistance. We have established that the phosphatase calcineurin (CaN) is required for invasive fungal disease and an attractive target for antifungal drug development. CaN is a druggable target, and there is vast clinical experience with the CaN inhibitors FK506 and cyclosporin A (CsA). However, while FK506 and its natural analog FK520 exhibit antifungal activity, they are also immunosuppressive in the host and thus not fungal-selective. We leverage our pathogenic fungal CaN-FK506-FKBP12 complex X-ray structures and biophysical data to support structure-based ligand design as well as structure-activity relationship analyses of broad-spectrum FK506/FK520 derivatives with potent antifungal activity and reduced immunosuppressive activity. Here we apply molecular docking studies to develop antifungal C22- or C32-modified FK520 derivatives with improved therapeutic index scores. Among them, the C32-modified FK520 derivative JH-FK-44 (7) demonstrates a significantly improved therapeutic index compared to JH-FK-08, our lead compound to date. NMR binding studies with C32-derivatives are consistent with our hypothesis that C32 modifications disrupt the hydrogen bonding network in the human complex while introducing favorable electrostatic and cation-{pi} interactions with the fungal FKBP12 R86 residue. These findings further reinforce calcineurin inhibition as a promising strategy for antifungal therapy. SignificanceInvasive fungal infections cause significant mortality worldwide, and current antifungal treatments are often ineffective, toxic, or face growing resistance. This research identifies calcineurin (CaN), a critical protein for fungal survival, as a potential target for developing new antifungal drugs. Although existing CaN inhibitors such as FK506 (tacrolimus) and FK520 (ascomycin) possess antifungal properties, their immunosuppressive effects limit their clinical utility. By studying the structure of human and fungal FKBP12-FK506 or FK520 complexes with CaN, we have designed and synthesized modified FK520 derivatives with strong antifungal activity and reduced immunosuppressive effects. These new derivatives are expected to have significantly improved therapeutic profiles, offering hope for more effective and safer antifungal treatments.

microbiology↗

bioRxiv2024

A Mutation in Tmem135 Causes Progressive Sensorineural Hearing Loss

Transmembrane protein 135 (TMEM135) is a 52 kDa protein with five predicted transmembrane domains that is highly conserved across species. Previous studies have shown that TMEM135 is involved in mitochondrial dynamics, thermogenesis, and lipid metabolism in multiple tissues; however, its role in the inner ear or the auditory system is unknown. We investigated the function of TMEM135 in hearing using wild-type (WT) and Tmem135FUN025/FUN025 (FUN025) mutant mice on a CBA/CaJ background, a normal-hearing mouse strain. Although FUN025 mice displayed normal auditory brainstem response (ABR) at 1 month, we observed significantly elevated ABR thresholds at 8, 16, and 64 kHz by 3 months, which progressed to profound hearing loss by 12 months. Consistent with our auditory testing, 13-month-old FUN025 mice exhibited a severe loss of outer hair cells and spiral ganglion neurons in the cochlea. Our results using BaseScope in situ hybridization indicate that TMEM135 is expressed in the inner hair cells, outer hair cells, and supporting cells. Together, these results demonstrate that the FUN025 mutation in Tmem135 causes progressive sensorineural hearing loss, and suggest that TMEM135 is crucial for maintaining key cochlear cell types and normal sensory function in the aging cochlea.

neuroscience↗

bioRxiv2024

Integrated stress response associated with dark microglia promotes microglial lipogenesis and contributes to neurodegeneration

Microglia, the brains primary resident immune cells, are a heterogeneous population and can assume phenotypes with diverse functional outcomes on brain homeostasis. In Alzheimers disease (AD), where microglia are a leading causal cell type, microglia subsets with protective functions have been well characterized. Yet, the identity of microglia subsets that drive neurodegeneration remains unresolved. Here, we identify a neurodegenerative microglia phenotype that is characterized by a conserved stress signaling pathway, the integrated stress response (ISR). Using mouse models to activate or inhibit ISR in microglia, we show that ISR underlies the ultrastructurally distinct "dark" microglia subset linked to pathological synapse loss. Inducing microglial ISR in murine AD models exacerbates neurodegenerative pathologies, such as Tau pathology and synaptic terminal loss. Conversely, inhibiting microglial ISR in AD models ameliorates these pathologies. Mechanistically, we present evidence that ISR promotes the secretion of toxic long-chain lipids that impair neuron and oligodendrocyte homeostasis in vitro. Accordingly, small molecule-based inhibition of lipid synthesis in AD models ameliorates synaptic terminal loss. Our results demonstrate that activation of ISR within microglia represents a novel pathway contributing to neurodegeneration and suggest that this may be sustained, at least in part, by the secretion of long-chain lipids from ISR-activated microglia.

neuroscience↗

bioRxiv2023

Discrete projections from MCH neurons mediate anti-parkinsonian effects of acupuncture

Parkinsons disease (PD) presents with typical motor dysfunction and non-motor symptoms, including memory loss. Although acupuncture is suggested as an alternative therapy for PD, its neuroanatomical mechanisms remain unclear. We demonstrate that acupuncture ameliorates both motor and memory deficits in PD mice through activation of melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus and zona incerta (LH/ZI)--MCHLH/ZI-- via nerve conduction. We identify two distinct subpopulations of MCHLH/ZI projecting to the substantia nigra and hippocampus, each of which is responsible for controlling motor and memory function. This effect can be attributed to MCH-mediated recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, MCHLH/ZI constitutes not only the neuroanatomical basis of acupuncture but also a potential cellular target for treating both motor and non-motor PD symptoms. One-Sentence SummaryAcupuncture alleviates both motor and non-motor symptoms in Parkinsons disease by activating two distinct MCH projections.

neuroscience↗

bioRxiv2023

Characterization and Applications of Evoked Responses During Epidural Electrical Stimulation

Epidural electrical stimulation (EES) of the spinal cord has been FDA approved and used therapeutically for decades. However, there is still not a clear understanding of the local neural substrates and consequently the mechanism of action responsible for the therapeutic effects. Epidural spinal recordings (ESR) are collected from the electrodes placed in the epidural space. ESR contains multi-modality signal components such as the evoked neural response (due to tonic or BurstDR waveforms), evoked muscle response, stimulation artifact, and cardiac response. The tonic stimulation evoked compound action potential (ECAP) is one of the components in ESR and has been proposed recently to measure local neural activation during EES. Here, we first review and investigate the referencing strategies, as they apply to ECAP component in ESR in the domestic swine animal model. We then examine how ECAP component can be used to sense lead migration, an adverse outcome following lead placement that can reduce therapeutic efficacy. Lastly, we show and isolate concurrent activation of local back and leg muscles during EES, demonstrating that the ESR obtained from the recording contacts contain both ECAP and EMG components. These findings may further guide the implementation of recording and reference contacts in an implantable EES system and provide preliminary evidence for the utility of ECAP component in ESR to detect lead migration. We expect these results to facilitate future development of EES methodology and implementation of use of different components in ESR to improve EES therapy.

physiology↗

bioRxiv2022

Altered CD8+ T cell associated aging gene signature in the peripheral blood of patients with Alzheimer's disease.

INTRODUCTIONEffector memory (EM) CD8+ T cells have been associated with poor cognition in Alzheimers disease (AD). Our lab recently discovered an age-associated gene expression signature of IL-7 receptor alpha (IL-7R)low EM CD8+ T cells. We hypothesized that individuals with AD have altered levels of this IL-7Rlow aging gene expression. METHODSForty genes associated with IL-7Rlow EM CD8+ T cells, AD, or memory, were analyzed in peripheral blood of participants with normal cognition, mild cognitive impairment, and dementia by qPCR. RESULTSOf the eight genes that were found to be differentially expressed based on clinical diagnosis, 5 genes (62.5%) were IL-7Rlow aging genes. Principal component analysis revealed 3 clusters of participants with dementia which had distinct expression levels of IL-7Rlow aging genes and cognitive function. DISCUSSIONOur findings support the possible relationship of the IL-7Rlow EM CD8+ T cell aging signature with cognition in individuals with dementia due to AD.

immunology↗

bioRxiv2022

Single nuclei RNAseq analysis of HD mouse models and human brain reveals impaired oligodendrocyte maturation and potential role for thiamine metabolism

The complexity of affected brain regions and cell types is a challenge for Huntingtons disease (HD) treatment. Here we used single nucleus RNA sequencing (snRNAseq) to investigate mechanism of pathology in the cortex and striatum from R6/2 mice at 8 and 12w and in three regions of human HD post-mortem tissue. We identified cell type-specific and cell agnostic signatures and found changes suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) were arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 were negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells showed decreased accessibility of sites regulated by OL maturation genes. Glucose and lipid metabolism were implicated in abnormal cell maturation and PRKCE and Thiamine Pyrophosphokinase 1 were identified as central genes. High dose thiamine/biotin treatment of R6/1 HD mice to target thiamine metabolism not only restored OL maturation, but also rescued pathology in neurons. These findings reveal insights into HD OL pathology that spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.

neuroscience↗

bioRxiv2020

Constitutive overexpression of RAM1 increases arbuscule density during arbuscular mycorrhizal symbiosis in Brachypodium distachyon

Arbuscular mycorrhizal (AM) symbiosis is a mutually beneficial association of plants and fungi of the sub-phylum Glomeromycotina. The endosymbiotic AM fungi colonize the inner cortical cells of the roots, where they form branched hyphae called arbuscules that function in nutrient exchange with the plant. To support arbuscule development and subsequently bidirectional nutrient exchange, the root cortical cells undergo substantial transcriptional re-programming. REDUCED ARBUSCULAR MYCORRHIZA 1 (RAM1), studied in several dicot plant species, is a major regulator of this cortical cell transcriptional program. Here, we generated ram1 mutants and RAM1 overexpressors in a monocot, Brachypodium distachyon. The AM phenotypes of two ram1 lines revealed that RAM1 is only partly required to enable arbuscule development in B. distachyon. Transgenic lines constitutively overexpressing BdRAM1 showed constitutive expression of AM-inducible genes even in the shoots. Following inoculation with AM fungi, BdRAM1-overexpressing roots showed higher arbuscule densities relative to controls, indicating the potential to manipulate the relative proportion of symbiotic interfaces via modulation of RAM1. However, the overexpressors also show altered expression of hormone biosynthesis genes and aberrant growth patterns including stunted bushy shoots and poor seed set. While these phenotypes possibly provide additional clues about BdRAM1s scope of influence, they also indicate that directed approaches to increase the density of symbiotic interfaces will require a more focused, potentially cell-type specific manipulation of transcription factor gene expression.

plant biology↗

bioRxiv2019

Dynamic causal modeling for calcium imaging data reveals differential effective connectivity for sensory processing in a barrel cortical column

Multi-photon calcium imaging (CaI) is an important tool to assess activity among neural populations within a column in the sensory cortex. However, the complex asymmetrical interactions among neural populations, termed effective connectivity, cannot be directly assessed by measuring the activity of each neuron using CaI but calls for computational modeling. To estimate effective connectivity among neural populations, we proposed a dynamic causal model (DCM) for CaI by combining a convolution-based dynamic neural state model and a dynamic calcium ion concentration model for CaI signals. After conducting a simulation study to evaluate DCM for CaI, we applied it to an experimental CaI data measured at the layer 2/3 of a barrel cortical column that differentially responds to hit and error whisking trails in mice. We first identified neural populations and constructed computational models with intrinsic connectivity of neural populations within the layer 2/3 of the barrel cortex and extrinsic connectivity with latent external modes. Bayesian model inversion and comparison shows that a top-down model with latent inhibitory and excitatory external modes explains the observed CaI signals during hit and error trials better than any other model, with a single external mode or without any latent modes. The best model also showed differential intrinsic and extrinsic effective connectivity between hit and error trials (corresponding to the bottom-up and top-down processes) in the functional hierarchical architecture. Both simulation and experimental results suggest the usefulness of DCM for CaI in terms of exploration of the hierarchical interactions among neural populations observed in CaI.

neuroscience↗

bioRxiv2018

Organization of state transitions in the resting-state human cerebral cortex

The resting-state brain is often considered a nonlinear dynamic system transitioning among multiple coexisting stable states. Despite the increasing number of studies on the multistability of the brain system, the processes of state transitions have rarely been systematically explored. Thus, we investigated the state transition processes of the human cerebral cortex system at rest by introducing a graph-theoretic analysis of the state transition network. The energy landscape analysis of brain state occurrences, estimated using the pairwise maximum entropy model for resting-state fMRI data, identified multiple local minima, some of which mediate multi-step transitions toward the global minimum. The state transition among local minima is clustered into two groups according to state transition rates and most inter-group state transitions were mediated by a hub transition state. The distance to the hub transition state determined the path length of the inter-group transition. The cortical system appeared to have redundancy in inter-group transitions when the hub transition state was removed. Such a hub-like organization of transition processes disappeared when the connectivity of the cortical system was altered from the resting-state configuration. In summary, the resting-state cerebral cortex has a well-organized architecture of state transitions among stable states, when evaluated by nonlinear systematic approach.

neuroscience↗