Biology subjects

Park, H.

Publications and source records attributed to Park, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Older Adults Show Preserved Neural Signatures of Audiovisual Integration but Altered Links to Speech Comprehension

Older adults often experience difficulty understanding speech in noisy environments despite relatively preserved hearing. Although visual speech cues can improve speech perception, it remains unclear whether the neural mechanisms supporting audiovisual integration are preserved in healthy ageing. We addressed this question using magnetoencephalography (MEG) combined with Rapid Invisible Frequency Tagging (RIFT) during challenging audiovisual speech task. Forty younger and forty older adults attended to one of two competing speech streams while the speaker's lip movements were frequency tagged, with the visual modulation driven by either the attended or unattended speech envelope. Task-Relevant amplitude modulation of frequency tagging in visual speech improved speech comprehension in younger adults as previously reported for this cohort; this accuracy benefit was absent in older adults. Auditory and visual tagging responses were modulated by task relevance similarly across age groups, indicating largely preserved modality-specific sensory processing in older adults. Intermodulation responses, reflecting nonlinear interactions between auditory and visual speech signals, also remained sensitive to task relevance and did not differ in their condition-dependent modulation between age groups. Greater Task-Relevant versus Task-Irrelevant differences in intermodulation coherence were also associated with greater comprehension benefits in younger adults; no significant association was found in older adults, and this relationship differed significantly between age groups. These findings suggest that the absence of a comprehension benefit in older adults is linked to a change in the relationship between audiovisual intermodulation and behaviour, despite largely preserved task-sensitive brain responses.

neuroscience↗

bioRxiv2026

Splanchnic-spinal transmission of gut-initiated α-synucleinopathy

Gut-initiated -synucleinopathy is proposed to spread from the gastrointestinal tract to the CNS, contributing to Parkinson's disease (PD), but whether routes beyond the vagus nerve are involved remains unclear. Using complementary intracolonic rotenone and gastroduodenal -synuclein PFF models, we combined pathway-specific surgical interruption with longitudinal behavioral analysis and anatomical mapping of pathological -synuclein. In the intracolonic rotenone model, interruption of the prevertebral ganglia/splanchnic-spinal axis more strongly attenuated behavioral deficits and -synuclein pathology than vagotomy. In the gastroduodenal PFF model, both vagal and splanchnic-spinal pathways contributed to pathology propagation. Early after PFF inoculation, pathological -synuclein was detected in peripheral neural structures associated with both routes. Consistent with these findings, spinal pathology was evident in human PD. Together, these results identify the splanchnic-spinal pathway as a key component of body-first Parkinson's disease, broadening current models of peripheral-to-central disease progression and informing efforts to target early peripheral disease progression.

neuroscience↗

bioRxiv2026

Nanotherapy-mediated biased antigen-presenting cell reprogramming supports T cell anergy to prevent type 1 diabetes

Engineering immune tolerance using endogenously expressed autoantigens could enable early intervention in autoimmune disease. Present therapies suppress T cells to slow disease progression. Here, we develop rapamycin-loaded poly(ethylene glycol)-b-poly(propylene sulfide) polymersomes (rPS) to modulate antigen-presenting cells (APCs) during disease-associated antigen presentation. The rPS morphology enables lymphatic drainage following subcutaneous administration to access APCs in draining lymph nodes. Treatment reduced APC costimulatory marker coexpression and shifted CD4+ T cells toward an FR4hi CD73hi anergic phenotype. In a type 1 diabetes (T1D) nonobese diabetic (NOD) mouse model, rPS significantly delayed disease onset relative to the standard of care and selectively prevented hyperglycemia. Mediation via APCs, rPS avoids adverse effects including transient lymphopenia. These findings demonstrate how biomaterial-directed drug delivery can reshape APC--T cell interactions, supporting an antigen-agnostic strategy for delaying autoimmune diabetes without systemic lymphocyte depletion.

bioengineering↗

bioRxiv2026

Gut microbially produced phenolic acids have differential and sex-dependent effects on host metabolic health

Gut microbiota-derived metabolites are increasingly recognized as important regulators of host metabolism, but the specific functions of individual metabolites remain poorly understood. We therefore investigated the metabolic effects of two structurally related, phenylalanine-derived microbial metabolites phenylacetic acid (PAA) and phenylpropionic acid (PPA) in a mouse model of diet-induced obesity. Although clinical studies have linked PAA and its downstream product phenylacetylglutamine to metabolic disease, PAA did not alter body mass or adiposity in this model. Instead, it improved glucose tolerance selectively in male mice and markedly remodeled lipid metabolism in both sexes, reducing circulating triglycerides and acylcarnitines and activating hepatic PPAR--associated transcriptional programs associated with fatty acid {omega}-hydroxylation and peroxisomal lipid metabolism. Despite this extensive metabolic remodeling, PAA did not worsen hepatic steatosis, fibrosis, or markers of liver injury. By contrast, PPA had minimal effects on hepatic metabolic pathways but produced pronounced sex-dependent physiological responses, increasing adiposity in female mice and improving glucose tolerance in male mice. These findings show that structurally related microbial metabolites can have distinct, sex-dependent metabolic effects and highlight the need to define the actions of individual microbiome-derived metabolites when developing targeted therapies for metabolic disease.

systems biology↗

bioRxiv2026

The balance of local and distributed excitation shapes brain stability and reflects aging- and Alzheimer's disease-related alterations

Human brain function emerges from the interplay between recurrent local activity and distributed inter-regional interactions. However, a biologically interpretable framework for quantifying this balance between the two factors at the whole-brain level remains lacking. Here, we extended an established biophysical model to quantify inter-regional excitation and newly introduced the recurrent ratio (R-ratio), a measure of the relative balance between intra- and inter-regional excitation. Dynamical analyses showed that an optimal R-ratio supports a trade-off between network stability and flexibility. Applying this framework to healthy aging and Alzheimer's disease revealed progressively increased R-ratios with advancing age and disease severity. In healthy individuals, higher R-ratios were associated with age-related alterations in brain morphology, molecular pathology, and cognitive function, whereas Alzheimer's disease was characterized by increased R-ratios accompanied by reduced dynamical persistence. Together, these findings establish the R-ratio as a biologically interpretable marker of whole-brain excitation balance and demonstrate its utility for linking biophysical mechanisms with large-scale brain dynamics, aging, and neurodegeneration.

neuroscience↗

bioRxiv2026

AnnFlux: object-conditioned neural stochastic differential equations for single-cell perturbation dynamics

Single-cell perturbation profiling measures responses to genetic and chemical interventions, yet most models learn a static map, ignoring how populations move over time and how perturbations combine. AnnFlux, an object-conditioned stochastic differential equation, learns a drift field in latent cell-state space. Conditioning on the perturbing object makes the field queryable one object at a time, yielding per-object drifts comparable across genes and drugs. By learning a drift field tailored to each perturbation context, it interpolates a held-out timepoint in an epithelial-mesenchymal transition time course and predicts unseen perturbations. Beyond point estimates, AnnFlux improves distributional fidelity and predicts responses to held-out perturbation combinations. An IFN-response signature predicted by AnnFlux was associated with TLS proximity in an independent pan-cancer spatial atlas. This framework maps perturbation-driven cell-state evolution as continuous trajectories and represents unseen perturbations using prior-knowledge embeddings.

bioinformatics↗

bioRxiv2026

AI-driven framework modeling perturbation in brain organoids reveals candidate genes for autism

Autism gene discovery is constrained by the rarity and heterogeneity of damaging variants, requiring large cohorts to identify susceptibility genes. Neural organoids and single-cell foundation models enable perturbation modeling in neurodevelopmental contexts. Here, we show that perturbation-informed foundation modeling of neural organoids can provide functional context for prioritizing candidate genes with genomic and clinical support. We constructed a 3.6-million-cell organoid atlas and trained models to predict genome-wide perturbation responses. Benchmarking 17 models identified a telencephalic neuron-specific model best preserving autism-relevant perturbation structure. Genome-wide profiling revealed two clusters associated with mid-fetal synaptic neuronal processes and early radial glia ubiquitin signaling. These clusters were supported by damaging-variant enrichment and clinical phenotypes across 89,916 family-based samples. Logistic-regression prioritization identified 343 candidates, including 167 in the key clusters, with convergence across TADA signals and recurrent evidence for NBEA and KLHDC10. This framework integrates predicted perturbation effects with genomic evidence to support autism candidate prioritization.

bioinformatics↗

bioRxiv2026

Multiple Particle Tracking via Velocity Filtering (MPT-vVF): a velocity filtering framework for robust tracking moving organelles in living cells

Living cells are highly dynamic and densely crowded environments in which organelles such as vesicles undergo continuous motion that is essential for cellular processes. Therefore, accurate tracking of individual organelles is crucial for understanding intercellular dynamics and functions. However, precise tracking of individual organelles in living cells remains challenging due to high organelle densities, frequent particle overlap, and the coexistence of stationary and motile organelles. In particular, stationary organelles can obscure the trajectories of moving organelles, leading to tracking errors and fragmented tracks. To overcome these challenges, we developed Multiple Particle Tracking via Velocity Filtering (MPT-vVF), an unbiased, semi-automated tracking framework that incorporates a mathematically derived velocity-filtering algorithm to selectively identify and track moving organelles with high accuracy in crowded intracellular environments. MPT-vVF integrates denoising, background subtraction, and a velocity-matching detection step that discriminates true particle motion from noise based on spatiotemporal continuity, followed by robust trajectory linking. We demonstrate that MPT-vVF can accurately resolve nanometer-scale displacements of immobilized beads, highlighting its high tracking precision. We also validate the robustness of MPT-vVF by quantifying the transport of brain-derived neurotrophic factor (BDNF)-mRFP-containing vesicles in living hippocampal neurons. Furthermore, MPT-vVF reveals that exposure to 50-nm nanoplastics impairs vesicular transport, reducing both travel length and speed of BDNF-containing vesicles in living neurons. These findings establish MPT-vVF as a powerful method for quantitative analysis of intracellular organelles in crowded living cells and suggest its broad application to biophysics, cell biology, and soft matter research.

biophysics↗

bioRxiv2026

Synaptic engram underlies memory

Memory encoding cells, or engram cells, are sparsely distributed across the brain. Recent findings have shown that memory formation coincides with the strengthening of interregional synaptic connectivity between engram ensembles. However, whether this learning-induced synaptic reorganization causally supports memory, independently or in concert with heterosynaptic and intrinsic plasticity, remains elusive. Here we developed optically implemented spike-timing-dependent plasticity (oSTDP), which induces synaptic depression selectively at target synapses by controlling the relative timing of pre- and postsynaptic activity. In vivo application of oSTDP to the synapses between entorhinal cortex (EC) and dentate gyrus (DG) engram cells caused a significant synaptic depression and the resultant memory impairment. Our results demonstrate that plasticity of functional connectivity between memory-encoding ensembles causally underlies memory.

neuroscience↗

bioRxiv2026

Proteomic Profiling Identifies CLDN3 as a Tumor-Selective Therapeutic Target in Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains a highly lethal disease with limited targetable surface antigens beyond delta-like ligand 3 (DLL3). We sought to systematically identify and validate tumor-selective cell-surface targets in relapsed SCLC. To this end, we developed an integrated proteogenomic pipeline combining single-cell RNA sequencing, combinatorial optimization, mass spectrometry-based proteomics, and immunohistochemistry to systematically map the SCLC surfaceome of 49 tumors across 25 patients with relapsed SCLC. Using this approach we found claudin-3 (CLDN3) to be a consistently expressed and tumor-selective antigen, with broader coverage than DLL3, which is the current clinical benchmark. CLDN3 was highly expressed across various treatment states, while maintaining low expression in most nonmalignant tissues. Functional validation using a novel CLDN3-specific monoclonal antibody (ABN501) demonstrated NK cell-mediated cytotoxicity in vitro and tumor regression in vivo, as well as a favorable safety profile. These findings support clinical development of CLDN3-directed therapies and demonstrate the utility of integrated proteogenomic approaches for antigen discovery in solid tumors.

cancer biology↗

bioRxiv2026

ProteinSketch translates spatial intuition into protein design with bimanual interaction in VR

Generative AI-based protein design can create diverse structures for desired functions but offers human designers limited control over three-dimensional architectures. We developed ProteinSketch, a bimanual virtual reality platform in which immersive backbone sketches and volumetric envelopes are directly created and translated into constraints for diffusion-based protein generation. RFdiffusion-based real-time refinement enabled interactive exploration and construction of user-specified protein topologies. Volumetric conditioning of sketched envelopes enabled high-fidelity control of anisometric geometries, confirmed by cryo-electron microscopy. These user-defined volumetric constraints enabled functional-binder design and extension of pre-existing minibinders to surfaces otherwise difficult to access within complex molecular environments using conventional design approaches. This collaborative human-AI framework integrates human spatial reasoning with generative AI for spatially directed, shape-controlled design of protein structure and function. One-sentence summaryImmersive ProteinSketch embeds human spatial reasoning in AI-guided design of protein topology, shape, and function.

bioengineering↗

bioRxiv2026

Augmenting Speech Comprehension using Rapid Frequency Tagging

Speech comprehension under adverse listening conditions benefits from visual speech, but whether visual input can be modulated to improve listening remains unclear. Here we used rapid frequency tagging, a non-invasive sensory stimulation technique, in which the visual tag at 55 Hz over the mouth region of a talking face was amplitude-modulated by the envelope of either the task-relevant or task-irrelevant speech stream. When the visual modulation followed the task-relevant speech envelope, comprehension improved relative to task-irrelevant modulation and to an unmodulated tagging control. MEG responses showed enhanced 55 Hz visual tagging, altered 40 Hz auditory tagging and a non-linear 15 Hz intermodulation. Individual comprehension gains were associated with intermodulation responses in left inferior frontal cortex, linking behavioural benefit to audiovisual interaction. These findings show that task-relevant visual stimulation can improve comprehension by strengthening audiovisual interaction, establishing amplitude-modulated frequency tagging as a tool for probing and supporting comprehension in challenging environments.

neuroscience↗

bioRxiv2026

Identification of srh-30 as a 2-nonanone receptor in C. elegans

C. elegans detects food, mates, and danger through a large repertoire of chemosensory receptors. The volatile odorant 2-nonanone is a well-established aversive stimulus that reliably elicits avoidance chemotaxis. However, the receptor(s) responsible for its detection have not been identified. Here, we leveraged CeNGEN single-cell expression profiles to identify candidate receptors required for sensing 2-nonanone. We narrowed the list of candidate chemoreceptor genes by selecting genes expressed in the aversive amphid neurons AWB and ASH while excluding genes expressed in other amphid sensory neurons. We tested available mutants from the C. elegans Genetics Center (CGC) and identified srh-30 as a candidate required for normal 2-nonanone avoidance. Two independent srh-30 null alleles generated using CRISPR-Cas9 confirmed that loss of srh-30 causes a partial defect in 2-nonanone sensing. srh-30 promoter-driven fluorescent reporter, mKate, localized to the distal tips of AWB sensory cilia, consistent with a direct sensory role. Finally, ectopic expression of srh-30 in the attractive AWA neuron shifted the behavioral response to 2-nonanone toward neutrality, supporting srh-30 as a sensory receptor. Together, these results identify srh-30 as a sensory receptor mediating 2-nonanone-evoked avoidance and demonstrate a transcriptome-guided strategy for mapping odor receptors.

neuroscience↗

bioRxiv2026

ProMiSE: Protein Multi-State Evaluation Benchmark in Biological Contexts

Proteins are inherently dynamic, with biological functions often emerging from transitions between multiple conformational states. While recent breakthroughs have largely addressed the static structure prediction problem, no systematic benchmark exists to demonstrate how well current models capture functionally relevant dynamics. We introduce ProMiSE, the first benchmark that provides both a dataset and an evaluation scheme, based on native biological assemblies and integrating major conformational change mechanisms--intrinsic, ligand-induced, and protein-induced--within a single curated dataset. We conducted a comprehensive evaluation of state-of-the-art structure prediction models, including Al-phaFold3 and recent generative approaches. Our findings reveal that current models exhibit a limited ability to sample intrinsic multi-states and are often insensitive to biological context in induced scenarios. Internal representation analysis suggests that training-data exposure can shift predictions toward dominant conformational states over alternative biologically relevant states, primarily at the structure module. In contrast, results from BioEmu indicate that reducing decoding-stage bias can substantially improve multi-state sampling without major changes to upstream pair representations.

bioinformatics↗

bioRxiv2026

SPOTTER: Automated Tissue-Barcoding Platform for Spatial Proteomics and Phosphoproteomics

Spatial proteomics aims to characterize proteome in situ with regional resolution, linking molecular states to tissue architecture and microenvironments. While recent advances have expanded our access to spatially resolved proteomics, major barriers in scalability and throughput remain. Building on our prior SPOT (Spatial Proteomics through On-site Tissue-protein-labeling) framework1, we introduce SPOTTER, a customizable robotic platform that enables automated, micron-scale spatial barcoding directly on intact tissue sections. SPOTTER barcodes proteins by labeling tissue proteins in situ to encode spatial origin across the whole tissue section. This strategy enables unbiased whole-tissue proteome mapping and, for the first time, spatial phosphoproteome profiling from intact sections. Coupled with high-resolution LC-MS/MS, SPOTTER achieves deep proteome and phosphoproteome coverage while preserving histological integrity. By replacing labor-intensive laser capture microdissection workflows and low-plex antibody arrays, SPOTTER provides a scalable route to high-plex spatial proteomics, resolving spatially distinct regions within a single experiment.

bioengineering↗

bioRxiv2026

Posture and support geometry, rather than body size, dictate lateral dynamic stability in walking mammalian quadrupeds

Body size and limb posture vary widely across mammals and are expected to shape locomotor stability, yet direct comparative evidence remains limited. Here, we tested whether smaller, crouched mammals exhibit greater lateral dynamic stability than larger, more upright species by comparing treadmill walking in mice and cats at dynamically similar speeds. Using kinematic analyses and size normalized measures of stability, we show that mice are substantially more laterally stable than cats. This increased stability is associated with relatively wider step widths and more crouched limb posture, indicating that support geometry and posture play dominant roles in stabilizing locomotion. Despite these differences, both species regulate lateral balance on a step-by-step basis, as revealed by relationships between center of mass motion and subsequent adjustments of the border of support. Our findings demonstrate that locomotor stability does not scale simply with body size but depends critically on posture dependent strategies that differ across species. These results identify lateral stability as a key factor of locomotor adaptation and suggest that crouched postures in small mammals may reduce reliance on active neural control while enhancing robustness in complex environments. SUMMARY STATEMENTLateral dynamic stability during quadrupedal locomotion depends primarily on limb posture and support geometry rather than body size. Smaller mammals achieve greater stability through crouched postures and wider step widths, whereas larger mammals operate closer to stability limits and rely more heavily on active control.

neuroscience↗

bioRxiv2026

The combination of EWSR1-FLI1 and loss of one EWSR1 allele leads to the induction of trisomy 8

Ewing sarcoma is a pediatric cancer that develops in skeletal elements. The majority of Ewing sarcoma patients carry the aberrant EWSR1-FLI1 fusion gene. Despite trisomy 8 being an additional common aberration associated with a poor prognosis for patients, its induction mechanism remains unknown. When the EWSR1-FLI1 gene is formed, the cell loses one wildtype EWSR1 allele. To elucidate the induction mechanism of trisomy 8, we generated a cell line that allows for the conditional induction of EWSR1-FLI1 expression and EWSR1 knockdown (derived from a single EWSR1 allele. Specifically, the conditional cell line was generated by integrating the Tet-on EWSR1-FLI1 construct into the AAVS locus and adding a miniAID tag at the 5 end of the EWSR1 locus using auxin-degron system. A combination of the EWSR1-FLI1 expression and degradation of one allele-derived EWSR1 induced a high incidence of trisomy 8 within eight days, enhancing colony formation. Mechanistically, trisomy 8 is induced by the haploinsufficiency of EWSR1, and the remaining EWSR1 proteins are likely inhibited by interaction with EWSR1-FLI1. Our data showed that the knockout of EWSR1 alone was sufficient to increase the incidence of trisomy 8. Expression of wild-type EWSR1 in EWSR1 knockout cells rescued the high incidence of trisomy 8. In contrast, the EWSR1:R565A mutant, which lacks the ability to interact with Aurora B kinase, failed to rescue this phenotype. We propose that the combination of EWSR1-FLI1 expression and loss of EWSR1 contributes to the induction of trisomy 8 through the compromised EWSR1-Aurora B pathway. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/726567v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@999891org.highwire.dtl.DTLVardef@1ef6748org.highwire.dtl.DTLVardef@65e475org.highwire.dtl.DTLVardef@179da40_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Volumetric Cyclic Immunofluorescence for 3D Spatial Profiling of Immune Structures in Human FFPE Tissue

Mapping how parenchymal, immune, and stromal cells interact with extended structures such as blood vessels and nerves is challenging using conventional thin-section tissue imaging. Volumetric methods such as light-sheet fluorescence microscopy (LSFM) are ideal in these cases and LSFM is widely used in animal models such as fish and mice. This is enabled by well-established clearing methods, genetically encoded reporters, and vascular dyes. However, LSFM is rarely utilized for human tissue, which is primarily available as formaldehyde-fixed paraffin embedded (FFPE) specimens. Here, we present an approach to volumetric cyclic immunofluorescence (v-CyCIF) that enables 40-plex or greater imaging of immune and other cell types in human specimens up to 1 mm thick. We demonstrate the use of v-CyCIF to study neuroimmune interactions and lymphoid structures in normal and cancer tissues. Following LSFM imaging, specimens can be re-embedded and sectioned to ~50 {micro}m thick for high-resolution confocal imaging of punctate structures and cell-cell junctions. v-CyCIF therefore provides a flexible framework for multi-scale 3D profiling of clinical specimens across imaging formats and resolutions.

cancer biology↗