Biology subjects

Lee, H.-J.

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

At least 19 recordsLinked to original sources

bioRxiv2026

Variant-Specific Rewiring of Lysosomal Positioning by STARD9 Produces Opposite Cholesterol Trafficking Outcomes

Residual cardiovascular risk persists despite lipid-lowering therapy, independent of LDL and Lp(a), reflecting cholesterol dysregulation. We identify STARD9, a lysosomal cholesterol-sensing kinesin, as a causal gene for divergent familial dyslipidemias and premature atherosclerosis. Its START domain binds cholesterol to govern lysosomal positioning. Rare variants segregate with autosomal dominant hypercholesterolemia and premature coronary disease, while common variants associate with reduced HDL and elevated triglycerides. Both converge on lysosomal cholesterol sequestration, ER depletion, mTORC1 SREBP2 activation, impaired autophagy, and NF-kB inflammation, yet diverge through opposite lysosomal positioning: the rare variant disperses lysosomes peripherally, phenocopying START domain loss across cholesterol sequestration, lysosomal positioning, and TFEB activation, triggering LDLR degradation and CASM/TFEB-dependent efflux that preserves HDL, whereas the common variant causes perinuclear retention that suppresses TFEB dependent lipid-handling transcripts, yielding hypertriglyceridemia and low HDL. In Stard9-knockout mice, enterocyte cholesterol sequestration drives SREBP2 dependent NPC1L1 upregulation and apical localization, increasing intestinal cholesterol absorption. These findings position lysosomal cholesterol trafficking as a targetable node in statin-refractory cardiovascular disease.

genetics↗

bioRxiv2026

The anatomical compartment defines distinct immune remodeling within human visceral adipose tissue during aging

Age-associated inflammation varies across tissues, but whether distinct visceral adipose tissue (VAT) depots undergo inflammatory remodeling in a depot-specific manner remains unclear. Here we profiled human peri-organ VAT, comparing kidney-associated fat (KF, from kidney transplantation donors) and gallbladder-associated fat (GBF, from asymptomatic cholecystectomy patients with incidental polyps), using single-cell RNA sequencing, flow cytometry, intracellular protein profiling and in situ analysis. GBF showed broad tissue-residency and granzyme K-associated remodeling across conventional, regulatory and innate-like lymphocyte compartments, whereas KF showed stronger B cell remodeling, greater myeloid representation and more compartmentalized changes within resident effector-like CD8+ T cell states. We further identified age-associated CD20+ T cells with features consistent with local B-T cell interaction and an antigen-experienced, granzyme K-associated inflammatory memory phenotype. In situ analysis revealed age-associated myeloid accumulation and crown-like structure remodeling, accompanied by distinct myeloid inflammatory programs in KF and GBF. Finally, depot-specific immune signatures associated with clinical indices of adjacent kidney and liver function. These findings indicate that age-associated distinct immune programs within peri-organ VAT depots track with local tissue context and the state of the adjacent organ.

immunology↗

bioRxiv2026

Early Visual Cortex Represents Sensory and Mnemonic Orientations in Separate Subspaces with Preserved Geometry

How early visual cortex (EVC) represents working memory (WM) content while continuing to process incoming sensory input remains unclear. Using fMRI with prolonged delays to isolate mnemonic activity, together with analyses of cross-decoding, low-dimensional subspace structure, and representational geometry, we examined the relationship between sensory and mnemonic orientation representations in human EVC. Cross-decoding generalized poorly between sensory and mnemonic epochs, but this did not imply unrelated codes. Rather, the two occupied separable low-dimensional subspaces while preserving representational geometry across epochs. During discrimination and estimation, sensory- and mnemonic-trained decoders yielded dissociable readouts of concurrent sensory and mnemonic information from the same EVC measurements. Mnemonic coding showed little dependence on the retinotopic radial bias that characterized sensory coding, and trial-by-trial variability in mnemonic representation predicted both discrimination choices and estimation reports. Our findings support a population-level account in which mnemonic information in EVC is re-expressed in a separable but geometrically preserved format.

neuroscience↗

bioRxiv2026

Relating layer fMRI signals to acoustics and intracranial neuronal activity in the human auditory cortex in a naturalistic design

Naturalistic auditory perception engages feedforward and feedback dynamics across cortical depths, yet how these are organized in the human auditory cortex has been difficult to verify noninvasively. Here, we examine depth-dependent coupling between neuronal activity and fMRI during passive music listening. Depth-specific fMRI responses were modeled using neuronal oscillation envelopes elicited by the same naturalistic stimuli from a separate group of patients under intracranial EEG monitoring. From deep toward superficial depths, the relationship between oscillatory power and fMRI responses systematically changed: alpha/beta activity (8-30 Hz) was increasingly associated with negative fMRI responses, mapping top-down feedback, while gamma band (>30 Hz) oscillations showed increasingly positive associations. Relative to a purely acoustical fMRI baseline, broadband high-frequency activity (>70 Hz), a proxy for neuronal firing, showed the strongest coupling to BOLD signals at intermediate cortical depths receiving feedforward inputs from earlier auditory pathways. Our findings reveal a spectrolaminar organization of neurovascular coupling in the human auditory cortex.

neuroscience↗

bioRxiv2026

A full-length GRAS domain protein underpins efficient shoot regeneration in pepper

Pepper (Capsicum annuum L.) is a recalcitrant species regarding shoot regeneration, a trait that serves as a major bottleneck for the application of genetic engineering tools. In this study, comparative genetic analysis between a rare high-regeneration cultivar and a common low-efficiency cultivar identified a single nucleotide polymorphism (SNP) in PHYTOCHROME A SIGNAL TRANSDUCTION 1 (CaPAT1) that determines shoot regeneration efficiency. The T478C SNP in the high-efficiency cultivar converts a stop codon into an Arg codon, leading to translational read-through into the neighboring gene and forming an intact GRAS domain. This SNP-mediated formation of full-length CaPAT1 is essential for its dimerization. Notably, the overexpression of CaPAT1T478C in multiple low-efficiency cultivars, including both hot and bell peppers, significantly improved both shoot regeneration and transformation efficiency in the transformed T0 generation. These findings demonstrate the pivotal role of CaPAT1 in enhancing shoot regeneration and provide a robust strategy to overcome recalcitrance in pepper.

plant biology↗

bioRxiv2025

Structural Basis of Cold and Menthol Sensing by TRPM8

The transient receptor potential melastatin member 8 (TRPM8) is a polymodal ion channel that senses cold and menthol in mammals. Despite prior structural studies, the mechanisms by which cold and menthol activate TRPM8 remain unresolved. Here, we present cryo-EM structures representing the cold and menthol-dependent activation trajectories, combined with extensive functional analyses. We captured snapshots of cooling-dependent pore opening, which involves dramatic pore rearrangement, suggesting a mechanism for cold sensing. Moreover, menthol binds dynamically to induce channel activation, which may underlie menthol specificity for TRPM8. Finally, we show how TRPM8 integrates multiple modalities (cold and menthol) through overlapping but non-identical pathways, revealing the temperature-specific "cold spot". These findings enhance our understanding of the molecular basis of physically and chemically induced cool sensation in mammals.

biophysics↗

bioRxiv2025

FERONIA defines intact tissue boundaries through cuticle development

Plant cuticle is the first hydrophobic barrier between the epidermis and the environment. Upon wounding, damaged tissues undergo healing processes that involve cuticle or callus formation at the wound site. However, signaling pathways that initiate cuticle development and callus formation in the wound-proximal region are still poorly understood. Here, we reveal that the FERONIA receptor-like kinase facilitates cuticle development in the epidermis and FER-mediated cuticle formation limits the propagation of wound-induced reactive oxygen species (ROS), which trigger callus formation. Cuticle defects stimulate NADPH oxidase-dependent ROS production, which leads to unrestricted callus formation. However, the cuticle formed in mesophyll cells in the vicinity of the wound suppresses ROS propagation, thereby preventing unorganized callus formation beyond the wound-proximal site and activating programmed cell death adjacent to the wound. These findings provide valuable insights into cuticle development in aerial tissues and its defensive function for preserving the integrity of undamaged regions.

plant biology↗

bioRxiv2025

The patient-specific mouse model with Foxg1 frameshift mutation provides insights into the pathophysiology of FOXG1 syndrome

AbstractsSingle allelic mutations in the forebrain-specific transcription factor gene FOXG1 lead to FOXG1 syndrome (FS). To decipher the disease mechanisms of FS, which vary depending on FOXG1 mutation types, patient-specific animal models are critical. Here, we report the first patient-specific FS mouse model, Q84Pfs heterozygous (Q84Pfs-Het) mice, which emulates one of the most predominant FS variants. Remarkably, Q84Pfs-Het mice recapitulate various human FS phenotypes across cellular, brain structural, and behavioral levels, such as microcephaly, corpus callosum agenesis, movement disorders, repetitive behaviors, and anxiety. Q84Pfs-Het cortex showed dysregulations of genes controlling cell proliferation, neuronal projection and migration, synaptic assembly, and synaptic vesicle transport. Interestingly, the FS-causing Q84Pfs allele produced the N-terminal fragment of FOXG1, denoted as Q84Pfs protein, in Q84Pfs-Het mouse brains. Q84Pfs fragment forms intracellular speckles, interacts with FOXG1 full-length protein, and triggers the sequestration of FOXG1 to distinct subcellular domains. Q84Pfs protein also promotes the radial glial cell identity and suppresses neuronal migration in the cortex. Together, our study uncovered the role of the FOXG1 fragment derived from FS-causing FOXG1 variants and identified the genes involved in FS-like cellular and behavioral phenotypes, providing essential insights into the pathophysiology of FS.

neuroscience↗

bioRxiv2024

The ventral CA2 region of the hippocampus and its differential contributions to social memory and social aggression

Although it is well-known that the hippocampus mediates declarative memory (the repository of information of people, places, things and events) and influences behavior, the differential contributions of the dorsal and ventral hippocampus to specific forms of memory and behavior remain largely unknown. Studies to date show that the dorsal hippocampal CA1 region is important for cognitive and spatial tasks whereas the ventral CA1 region is associated with affective or emotional processing. Whether other regions and forms of hippocampal-dependent memory and behavior show a similar distinction remains unclear. Here we examine how social memory and related social behaviors are encoded across the dorso-ventral axis of the hippocampus. Although recent studies show that the dorsal hippocampal CA2 region is required for social memory and acts to promote social aggression, the behavioral role of ventral CA2 remains unknown. Indeed, whether a defined CA2 region extends throughout ventral hippocampus is controversial. Here, we report that a molecularly, anatomically and electrophysiologically defined CA2 region extends to the extreme ventral pole of hippocampus, with both similarities and important differences in its projection patterns and synaptic impact compared to dorsal CA2. Of particular importance, we find that ventral CA2 is not required for social memory but is critical for promoting social aggression. These results support the view that the ventral region of hippocampus is more generally tuned for emotionally-related behaviors compared to the cognitively-tuned dorsal hippocampus.

neuroscience↗

bioRxiv2024

Identification of cortical targets for modulating function supported by the human hippocampal network

BackgroundIndividualized transcranial magnetic stimulation (TMS) targeting using functional connectivity analysis of functional magnetic resonance imaging (fMRI) has been demonstrated to be advantageous in inducing neuroplasticity. However, how this approach can benefit modulating the episodic memory function supported by the hippocampal network remains elusive. ObjectiveWe use the resting-state fMRI data from a large cohort to reveal tentative TMS targets at cortical regions within the hippocampal network. MethodsFunctional MRI from 1,133 individuals in the Human Connectome Project was used to analyze the hippocampal network using seed-based functional connectivity. ResultsUsing a weighted sum of time series at the cortex, we identified the average centroids of individualized targets at the medial prefrontal cortex (mPFC) and posterior parietal cortices (PPC) at (-10, 49, 7) and (-40, -67, 30) in the left hemisphere, respectively. The mPFC and PPC coordinate at the right hemispheres are (11, 51, 6) and (48, -59, 24) in the right hemisphere, respectively. These coordinates can be reliably identified (>90% of individuals). ConclusionOur results suggest candidate TMS target coordinates to modulate the hippocampal function.

neuroscience↗

bioRxiv2024

Synthesis and Biological Assessment of Chalcone and Pyrazoline Derivatives as novel inhibitor for ELF3-MED23 Interaction

HER2 overexpression significantly contributes to the aggressive nature and recurrent patterns observed in various solid tumors, notably gastric cancers. Trastuzumab, HER2-targeting monoclonal antibody drug, has shown considerable clinical success, however, readily emerging drug resistance emphasizes the pressing need for improved interventions in HER2-overexpressing cancers. To address this, we proposed targeting the protein-protein interaction (PPI) between ELF3 and MED23 as an alternative therapeutic approach to trastuzumab. In this study, we synthesized a total of 26 compounds consisting of 10 chalcones, 7 pyrazoline acetyl, and 9 pyrazoline propionyl derivatives, and evaluated their biological activity as potential ELF3-MED23 PPI inhibitors. Upon systematic analysis, candidate compound 10 was selected due to its potency in downregulating reporter gene activity of ERBB2 promoter confirmed by SEAP activity and its effect on HER2 protein and mRNA levels. Compound 10 effectively disrupted the binding interface between the ELF3 TAD domain and the 391-582 amino acid region of MED23, resulting in successful inhibition of the ELF3-MED23 PPI. This intervention led to a substantial reduction in HER2 levels and its downstream signals in the HER2-positive gastric cancer cell line. Subsequently, compound 10 induced significant apoptosis and anti-proliferative effects, demonstrating superior in vitro and in vivo anticancer activity overall. We found that the anticancer activity of compound 10 was not only restricted to trastuzumab-sensitive cases, but was also valid for trastuzumab-refractory clones. This suggests its potential as a viable therapeutic option for trastuzumab-resistant gastric cancers. In summary, compound 10 could be a novel alternative therapeutic strategy for HER2-overexpressing cancers, overcoming the limitations of trastuzumab.

pharmacology and toxicology↗

bioRxiv2023

Targeting the Hippo pathway in cancers via ubiquitination dependent TEAD degradation

The Hippo pathway is among the most frequently altered key signaling pathways in cancer. TEAD1-4 are essential transcription factors and key downstream effectors in the Hippo pathway in human cells. Here, we identified RNF146 as a ubiquitin ligase (E3) of TEADs, which negatively regulates their stability in cells through proteasome-mediated degradation. We show that RNF146-mediated TEAD ubiquitination is dependent on the TEAD PARylation state. We further validated the genetic interaction between RNF146 and the Hippo pathway in cancer cell lines and the model organism Drosophila melanogaster. Despite the RNF146 and proteasome-mediated degradation mechanisms, TEADs are stable proteins with a long half-life in cells. We demonstrate that degradation of TEADs can be greatly enhanced pharmacologically with heterobifunctional chemical inducers of protein degradation (CIDEs). These TEAD-CIDEs can effectively suppress activation of YAP/TAZ target genes in a dose-dependent manner and exhibit significant anti-proliferative effects in YAP/TAZ-dependent tumor cells, thus phenocopying the effect of genetic ablation of TEAD protein. Collectively, this study demonstrates that the ubiquitin-proteasome system plays an important role in regulating TEAD functions and provides a proof-of-concept demonstration that pharmacologically induced TEAD ubiquitination could be leveraged to target YAP/TAZ-driven cancers.

cancer biology↗

bioRxiv2023

Periodontitis promotes bacterial extracellular vesicle-induced neuroinflammation in the brain and trigeminal ganglion

Gram-negative bacteria derived extracellular vesicles (EVs), also known as outer membrane vesicles, have attracted significant attention due to their pathogenic roles in various inflammatory diseases. We recently demonstrated that EVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) can cross the blood-brain barrier (BBB) and that their extracellular RNA cargo can promote the secretion of proinflammatory cytokines, such as IL-6 and TNF-, in the brain. To gain more insight into the relationship between periodontal disease (PD) and neuroinflammatory diseases, we investigated the effect of Aa EVs in a mouse model of ligature-induced PD. When EVs were administered through intragingival injection or EV-soaked gel, proinflammatory cytokines were strongly induced in the brains of PD mice. The use of TLR (Toll-like receptor)-reporter cell lines and MyD88 knockout mice confirmed that the increased release of cytokines was triggered by Aa EVs via TLR4 and TLR8 signaling pathways and their downstream MyD88 pathway. Furthermore, the injection of EVs through the epidermis and gingiva resulted in the direct retrograde transfer of Aa EVs from axon terminals to the cell bodies of trigeminal ganglion (TG) neurons and the subsequent activation of TG neurons. We also found that the Aa EVs changed the action potential of TG neurons. These findings suggest that EVs derived from periodontopathogens such as Aa might be involved in pathogenic pathways for neuroinflammatory diseases, neuropathic pain, and other systemic inflammatory symptoms as a comorbidity of periodontitis. Author summaryExtracellular vesicles (EVs) secreted from bacterial cells play a key role in microbe-host cell communication. Bacterial EVs (bEVs) may be closely linked to the pathogenesis underlying neuroinflammatory diseases. In the current experiments, bEVs caused the brain to release proinflammatory cytokines by activating the host TLR signaling pathway. This induction of neuroinflammation was significantly more prominent in the periodontitis disease model, implying a substantial link between periodontal and neuroinflammatory diseases through bEVs. We also show that bEVs are translocated to the neuronal cell body via retrograde axonal transport, where they directly activate neuronal proinflammatory signals (Fig 8). Our findings reveal that bEVs are a pathogenic pathway for neurological conditions potentially linked to periodontitis, such as Alzheimers disease and trigeminal neuropathic pain. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/548287v1_fig8.gif" ALT="Figure 8"> View larger version (32K): org.highwire.dtl.DTLVardef@ff2928org.highwire.dtl.DTLVardef@1e72688org.highwire.dtl.DTLVardef@92e002org.highwire.dtl.DTLVardef@b0e125_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFig 8.C_FLOATNO Graphic summary. Model of bacterial EV (bEVs) function in the brain and trigeminal neuron. bEVs have the ability to enter host brain cells through the bloodstream and to enter the trigeminal ganglion neuronal cell body through retrograde axonal transport, where they directly trigger proinflammatory neuronal signals. Through the TLR4/TLR8-MyD88 and NF-{kappa}B signaling pathways, bEVs and their RNA cargo can stimulate the production of TNF- and IL-6 in the host cells. The production of neuroinflammation is noticeably more pronounced in the periodontitis disease model, suggesting a strong association between periodontal and neuroinflammatory diseases via bEVs. C_FIG

pathology↗

bioRxiv2023

Decision-consistent bias mediated by drift dynamics of human visual working memory

Sensory evidence tends to be fleeting, often unavailable when we categorize or estimate world features. To overcome this, our brains sustain sensory information in working memory. Although keeping that information accurate while acting on it is vital, humans display two canonical biases: estimates are biased toward a few stimuli ("stimulus-specific bias") and prior decisions ("decision-consistent bias"). Integrative--especially neural mechanistic--accounts of these biases remain scarce. Here, we identify drift dynamics toward discrete attractors as a common source of both biases in orientation estimation, with decisions further steering memory states. Behavior and neuroimaging data reveal how these biases co-evolve through the decision-steered attractor dynamics. Task-optimized recurrent neural networks suggest neural mechanisms that enable categorical decisions to emerge from working memory for continuous stimuli while updating its trajectory, warping decision-consistent biases under stimulus-specific drift.

neuroscience↗

bioRxiv2023

Early cellular and molecular signatures correlate with severity of West Nile Virus infection

Infection with West Nile Virus (WNV) can drive a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence at 3 months and 1 year employing multiplexed single cell protein and transcriptional profiling (CyTOF and Seq-Well) complemented with matched serum proteomics and metabolomics. At the acute time point, we detected both an elevated proportion of pro-inflammatory markers in innate immune cell types and reduced frequency of regulatory T cell activity in participants with severe infection compared to those with asymptomatic infection. Single-cell transcriptomics of paired samples revealed that asymptomatic donors had higher expression of genes associated with innate immune pathways, in particular anti-inflammatory CD16+ monocytes at the acute time point. A multi-omics analysis identified factors--beyond those from individual analyses--that distinguished immune state trajectory between severity groups. Here we highlighted the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.

immunology↗

bioRxiv2023

Design of a holder for the improved maneuvering of the concurrent TMS-MRI setup

BackgroundConcurrent transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) is time-consuming because of the limited space in the MRI bore and the sophisticated placement and orientation of the TMS coil to elicit the desired brain activities and behaviors. ObjectiveWe developed a TMS coil holder capable of quick adjustment of the TMS coil position and orientation. The holder can also hold an MRI receiver coil array. MethodsA holder with one controlling knob, two omni-direction rotation joints, and two in-plane rotation joints was developed. ResultsDifferent TMS coil positions and orientations can be arranged and fixed in seconds. The holder can also accommodate two TMS coils to allow for multi-coil TMS-MRI. ConclusionOur development significantly improves the workflow of the concurrent TMS-MRI in new neuroscience studies and clinical applications.

bioengineering↗

bioRxiv2023

What humans learn from corrective feedback for perceptual decision-making

Corrective feedback received on perceptual decisions is crucial for adjusting decision-making strategies to improve future choices. However, its complex interaction with other decision components, such as previous stimuli and choices, challenges a principled account of how it shapes subsequent decisions. One popular approach, based on animal behavior and extended to human perceptual decision-making, employs reinforcement learning, a principle proven successful in reward-based decision-making. The core idea behind this approach is that decision-makers, although engaged in a perceptual task, treat corrective feedback as rewards from which they learn choice values. Here, we explore an alternative idea, which is that humans consider corrective feedback on perceptual decisions as evidence of the actual state of the world rather than as rewards for their choices. By implementing these feedback-as-reward and feedback-as-evidence hypotheses on a shared learning platform, we show that the latter outperforms the former in explaining how corrective feedback adjusts the decision-making strategy along with past stimuli and choices. Our work suggests that humans learn about what has happened in their environment rather than the values of their own choices through corrective feedback during perceptual decision-making.

neuroscience↗

bioRxiv2023

Neural evidence for boundary updating as the source of the repulsive bias in classification

Binary classification, an act of sorting items into two classes by setting a boundary, is biased by recent history. One common form of such biases is repulsive bias, a tendency to sort an item into the class opposite to its preceding items. Sensory-adaptation and boundary-updating are considered as two contending sources of the repulsive bias, yet no neural support has been provided for either source. Here we explored human brains, using fMRI, to find such supports by relating the brain signals of sensory-adaptation and boundary-updating to human classification behavior. We found that the stimulus-encoding signal in the early visual cortex adapted to previous stimuli, yet its adaptation-related changes were dissociated from current choices. Contrastingly, the boundary-representing signals in the inferior-parietal and superior-temporal cortices shifted to previous stimuli and covaried with current choices. Our exploration points to boundary-updating, rather than sensory-adaptation, as the origin of the repulsive bias in binary classification.

neuroscience↗