Biology subjects

Chen, H.-Y.

Publications and source records attributed to Chen, H.-Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Dopamine synthesis capacity and tau pathology differentially modulate rest-to-task functional network dynamics

Optimal cognition relies on large-scale functional brain networks which balance segregation at rest with selective integration during task performance. In aging, these network dynamics are altered. We examined two prominent features of brain aging: dysregulated dopamine function and Alzheimer's disease (AD)-related pathology to examine impacts on brain network dynamics. Young adults and cognitively unimpaired older adults completed resting-state and task-based fMRI and PET imaging of dopamine synthesis capacity ([18F]fluoro-m-L-tyrosine). Older adults were classified as {beta}-amyloid negative/positive using [11C]Pittsburgh Compound-B PET(PiB- or PiB+) and underwent tau-PET scanning ([18F]flortaucipir). Greater rest-to-task network stability and task-related network segregation were associated with better subsequent memory. Compared to young adults, PiB+ older adults showed reduced network stability and both PiB+ and PiB- older adults showed reduced segregation during rest. Higher ventral striatal dopamine synthesis capacity was associated with greater stability within associative networks in young adults, but this relationship was attenuated in older adults and absent in PiB+ participants. In PiB+ older adults, higher tau burden was associated with a task-induced collapse of network segregation across large-scale networks. These findings reveal dissociable influences of dopamine and tau on rest-to-task network organization, highlighting the value of integrating neuromodulatory and pathological markers in aging research.

neuroscience↗

bioRxiv2026

Lipid diffusion enhanced by molecular motors

An experimental study of myosin I motors on a supported lipid membrane with a nematic actin filament layer is presented. The activities of myosin I motors re-organize the actin layer, in particular the morphology of +1/2 nematic defects. Data from single-particle tracking (SPT) of lipid molecules reveal two interesting features. First, the distribution of average lipid speed over a track shows two groups of lipids (high-speed and low-speed), and the proportion of lipids to be high-speed is higher in regions rich in actin. Second, by classifying short-time movement of the lipids into normal diffusion, directed motion, confined motion, and subdiffusion states, we found that lipids in regions rich in actin have a lower probability to stay in the confined and subdiffusion states and more likely to perform normal diffusion. Furthermore, fluorescence recovery after photobleaching (FRAP) measurements show that the diffusion of lipids in the actin-rich regions is enhanced. The SPT and FRAP results suggest that myosin I motor activities turn low-speed lipids to high-speed ones, and affect the lipid moving state by reducing confined and subdiffusive motion. As a result, lipid diffusion is enhanced by motor activities.

biophysics↗

bioRxiv2026

Phenolic Chemical Defense Contributes to Resistance against Multiple Soybean Cyst Nematode Populations in Wild Soybean

Soybean cyst nematode (Heterodera glycines, SCN) is one of the most damaging pathogens of soybean worldwide. Virulence diversity among SCN populations and reliance on a limited number of resistance sources present major challenges for durable SCN management. Here, we investigated a wild soybean (Glycine soja) genotype (WsR), that is resistant to two SCN populations, race 2 (HG type 1.2.5.7) and race 5 (HG type 2.5.7), and compared its transcriptional and metabolic responses with those of the susceptible genotype (WsS). WsR exhibited a substantially stronger defense-associated transcriptional response to both SCN populations, including preferential induction of genes associated with Ca2+/calmodulin and salicylic acid signaling. Integration of transcriptomic and time-resolved metabolomic analyses revealed convergence on phenolic metabolism, with enhanced accumulation of phenolic acids, flavonoids, and isoflavonoids in resistant WsR. Genes involved in phenolic biosynthesis and modification were also preferentially induced in WsR, linking transcriptional reprogramming with the observed metabolic response. Importantly, two resistance-associated phenolic compounds, 4-hydroxybenzaldehyde and 2,3-dihydroxybenzoic acid, directly increased mortality of SCN second-stage juveniles from both populations in a concentration-dependent manner. By connecting resistance-associated transcriptional responses and metabolic reprogramming with direct activity of specific phenolic compounds against SCN, our study provides functional evidence linking phenolic metabolism to chemical defense against SCN. Together, these findings identify enhanced phenolic chemical defense as a major component of resistance to multiple SCN populations in wild soybean and highlight wild soybean as a valuable source of molecular and biochemical diversity for SCN resistance.

plant biology↗

bioRxiv2026

Manipulating Excitation-Inhibition Balance by Temporal Interference Brain Stimulation at Different Frequencies

Temporal interference brain stimulation (TIBS) is a non-invasive neuromodulation approach that can reach deep brain targets by delivering two kilohertz-frequency currents through scalp electrodes, producing a low-frequency amplitude envelope where the fields intersect. Conventional deep brain stimulation suppresses its targets at 130 Hz, and TIBS studies of epilepsy have adopted the same range. However, which neurons TIBS recruits at different frequencies has never been measured. Here, we recorded from genetically defined populations in the mouse hippocampus across envelope frequencies from 10 to 130 Hz, using cell-type-specific fiber photometry, retrograde viral labelling, and immunohistochemistry. A 10 Hz envelope drives both glutamatergic pyramidal neurons and GABAergic interneurons. From 20 Hz onward pyramidal activity falls below baseline while interneuron activity keeps rising, and the two separate maximally at 100 Hz. Retrogradely labelled cortical neurons projecting to CA2 respond weakly and show no frequency dependence, placing the switch inside the local circuit, and c-fos co-staining identifies parvalbumin interneurons as the population recruited at 100 Hz. Overall, this study provides the first in vivo cell-type-resolved evidence for envelope-frequency-dependent neuromodulation and shows that TIBS envelope frequency is a tunable parameter for excitation-inhibition balance. These findings can guide the choice of envelope frequency in the clinical research of TIBS.

neuroscience↗

bioRxiv2026

Morphogenesis of a stratified cell mound at a vortex defect

Although topological defects in cell monolayers have been recognized as mechanical organizing centers in morphogenetic processes, the mechanism by which cells coordinate their motion at such defects and self-organize into higher-order structures remains elusive. Here, we report the formation of three-dimensional (3D) multicellular mounds in unconfined myoblast monolayers, at well-controlled vortex topological defects. Prior to the onset of bilayering, the vortex structure induces millimeter-scale cell flows converging toward the defect center. As a result, 3D cell mounds form at the defect core, layer-by-layer. These mounds grow by interlayer permeation sustained by the converging cell flows. At late stages, the bell shape of the structured mounds can be modeled with a dynamics driven by these converging flows. Our results therefore highlight the crucial role of integer topological defects in driving large-scale cell flows yielding the formation of highly ordered 3D tissues from a monolayer. We propose that similar mechanisms may be at play in certain morphogenetic and tumorigenic events.

biophysics↗

bioRxiv2026

Dopamine Compensates for Amyloid-Induced Default Mode Network Dysfunction to Support Learning

Throughout the preclinical phase of Alzheimers disease (AD) {beta}-amyloid (A{beta}) accumulates preferentially within the default mode network (DMN), yet the functional and behavioural consequences of this pathological burden remain poorly understood. Using task-based fMRI combined with A{beta}, tau, and dopamine PET in cognitively normal older adults, we show that A{beta} burden impairs learning independent of tau, but this learning performance is recovered with higher dorsolateral striatal dopamine synthesis capacity. Investigating the neural mechanisms that support this learning, we observe that A{beta} positive individuals show attenuated DMN activity to error related feedback, a metric that relates to poorer learning. When estimating the effective connectivity during feedback, computational modelling reveals that A{beta} induces dis-inhibition of the DMN during error processing. Critically, dopamine synthesis capacity in the dorsolateral striatum rebalances effective connectivity between the DMN and frontostriatal network, thereby opposing A{beta} related disruption. These findings establish a systems-level framework in which A{beta} impairs learning by disrupting dynamic DMN modulation during feedback, a disruption for which dopaminergic function can partially compensate. This suggests that learning in the presence of A{beta} may be subserved by dopamine-dependent network rebalancing, a candidate mechanism of cognitive resilience to support learning in preclinical AD.

neuroscience↗

bioRxiv2026

Artificial Intelligence Models for Classifying Wrist Ligament Injuries Using Synthetically-Generated Joint Proximity Maps from Finite Element Models

Background/PurposeDiagnosing wrist ligament injuries is challenging; early detection and treatment are important to prevent osteoarthritis progression. Interosseous proximity maps, a proxy measure for joint space, can be generated from volumetric imaging data and may provide important information about wrist health. Artificial intelligence (AI) could enhance accuracy of noninvasive diagnosis based on imaging-derived metrics. This work demonstrates feasibility of AI training using synthetic proximity map data generated from finite element models (FEMs). MethodsPersonalized wrist FEMs for two asymptomatic participants were created from four-dimensional computed tomography-derived anatomic and kinematic data. Monte Carlo sampling varied 22 ligament material properties and simulated 7,500 unique injury scenarios generating 9,000,000 labeled red, green, and blue (RGB) images of interosseous proximity vector fields from FEM-derived motions. Images were associated with 17 descriptive metrics, including gross wrist angles and bone surface pairs, and used to develop mixed-input convolutional neural networks (CNNs). Model performance was evaluated for identifying specific ligament injuries. ResultsAverage area under receiver operating characteristic curve (AUROC) for CNNs was 0.757 across all injury types and kinematics. In a subset with clinically-relevant functional angles, the average AUROC was 0.824. Best-performing individual ligament AUROCs ranged from 0.807 to 0.999. Sensitivities and specificities exceeded 0.99 for some ligament injury simulations under specific wrist angles and bone surface pairs. ConclusionThis study demonstrates the feasibility of using synthetic data from FEMs to train AI models for classifying wrist ligament injuries. Proximity-based RGB images may be a relevant biomarker of ligamentous injury.

biophysics↗

bioRxiv2026

Coordinated immune-epithelial dynamics in the nasal epithelium protect against respiratory virus infection

Epithelial remodeling is a hallmark of host antiviral responses that strengthen barrier defenses against infection. Our current understanding of viral pathophysiology within the nasal epithelium, the initial site of most respiratory viral infections, remains incomplete due to limited understanding of the native tissue architecture and protective epithelial remodeling during immune events. Leveraging coronavirus disease 2019 (COVID-19) as a model, we applied spatial multi-omics on nasal cross-sectional tissues to characterize the immune-epithelial landscape during infection, identifying a coordinated increase in goblet cells and suppressive macrophages associated with elevated IL13 in the immune compartment. Our results further reveal that goblet cell and suppressive macrophage enrichment are spatially linked in proximity to IL13-expressing CD4 T cells, consistent with IL13-driven remodeling in situ. Using a primary human nasal air-liquid interface model, we demonstrate that IL13 alone is sufficient to remodel epithelial composition and morphology, subsequently restricting viral infection by reshaping the apical mucus barrier of the nasal epithelium. Our findings uncover a spatially organized, IL13-driven circuit for immune-epithelial remodeling as a protective barrier against respiratory viral infections.

immunology↗

bioRxiv2026

Development and Validation of the Transcranial Magnetic Stimulation Reporting Assessment Tool(TMS-RAT)

HighlightsO_LIWe introduce the TMS-RAT, a reporting (assessment) tool for TMS studies C_LIO_LIDeveloped within a community-informed, iterative process rating 333 TMS studies C_LIO_LIEmpirically evaluated for usability, inter-rater, and test-retest reliability C_LIO_LIA validated subset enables reliable retrospective assessment of reporting C_LIO_LIThe modular structure enables use across a wide range of TMS study designs C_LI BackgroundA standardised tool for comprehensive reporting can improve transparency, support consistent documentation, and enable comparison across transcranial magnetic stimulation (TMS) studies. The most used reporting checklist lacks clear definitions of full reporting and was not initially evaluated for usability or inter-rater reliability. A scoping review of studies using this checklist shows that its items are reported only 50% of the time, suggesting that method descriptions are often incomplete. MethodsWe developed the TMS Reporting Assessment Tool (TMS-RAT), a comprehensive reporting framework that provides clear definitions and examples for its items, covering a wide range of TMS protocols. We tested the usability and reliability of the TMS-RAT by rating all studies published between 1991 and 2025 using afferent conditioning (n = 333), a protocol encompassing many reporting categories identified during tool development. Seventeen independent raters contributed across three development phases, a validation phase, and a retest phase, with naive raters introduced in each phase. Iterative refinements of the tool were informed by inter-rater reliability, qualitative rater feedback, and consultation with external TMS experts. ResultsWe present two versions of the tool: the 72-item TMS-RAT v1.0, designed to guide comprehensive reporting, and the TMS-RAT v1.1, a subset of 50 items with the highest inter-rater (overall AC1 = 0.78, range = [0.60-0.99]) and test-retest reliability (overall AC1 = 0.82, range = [0.65-1.0]), intended for retrospective evaluation of reporting in systematic reviews, meta-analyses. ConclusionThe TMS-RAT is a comprehensive, reliable tool that seeks to improve transparency and reproducibility in TMS research.

neuroscience↗

bioRxiv2025

Multi-Omics analyses reveal dynamic interactions between DNA methylation and transcriptional regulation during black raspberry ripening

We profiled developmental-series transcriptome, methylome, and metabolome profiling to reveal extensive epigenetic reprogramming during black raspberry (Rubus occidentalis) fruit ripening. Fruit tissues exhibit globally higher DNA methylation than leaves, particularly in CHG and CHH contexts. Local methylation in all cytosine contexts progressively decreases in promoter regions during ripening, whereas CHG and CHH methylation increase in transposon-rich regions. Two primary methylation transitions--promoter hypomethylation and CHH hypermethylation--govern transcriptional shifts in genes involved in ripening processes. Methyl-binding transcription factors with activation potential likely promote CHH hypermethylation-linked transcriptional activation. Multi-omics integration revealed coordinated anthocyanin accumulation parallels expression of biosynthetic and regulatory genes within coherent networks. Elevated non-CG methylation in heterochromatin coincides with increased transcription of histone variants mediating chromatin compaction, suggesting chromatin remodelers fine-tune accessibility for methyltransferases. Our study highlights both genome-wide and locus-specific epigenetic reprogramming and demonstrates a coordinated interplay between DNA methylation and transcriptional regulation during black raspberry fruit ripening.

genomics↗

bioRxiv2025

Dephosphorylation of YES kinase-mediated co-chaperone DNAJB6b phosphorylation attenuates tau protein aggregation

Alzheimers disease (AD) is a neurodegenerative disorder characterized by a gradual deterioration of memory. Here, we examine the biological consequences of phosphorylation-mediated chaperone activity in AD-associated tau aggregates. Increased phosphorylation of DNAJB6b at Y53 is observed in the brain lysates of AD patients. Our research found that an activated Src family kinase, YES, phosphorylates Y53 within the J-domain of DNAJB6b and enhances the binding between DNAJB6b and Hsp70. The strengthened association between DNAJB6b and Hsp70 may lead to the accumulation of tau aggregates. These findings suggest that the up-regulation of YES kinase modifies DNAJB6b, and that the resulting alteration of DNAJB6b-dependent tau disaggregation may contribute to an increased risk of developing AD. Additionally, phosphor-DNAJB6b at Y53 may serve as a biomarker for the prognosis and diagnosis of AD.

neuroscience↗

bioRxiv2025

Age-Related Changes in Curiosity: The Influence of Locus Coeruleus on Information-Seeking Behavior

Curiosity enhances learning and memory and has been linked to the locus coeruleus (LC), which undergoes age-related decline. To examine how aging affects curiosity and information-seeking, we developed the Photographic Art Storytelling Task. Participants (sixty-eight young and sixty-five older adults) viewed photographs, rated their curiosity, and later read stories associated with selected images. The stories were deliberately constructed to be either interesting or boring, functioning as rewards that elicited prediction errors. Participants reappraised their curiosity, allowing us to separate intrinsic motivation from story-driven reward influences. Associations between performance and both pupil diameter and MRI measures of LC integrity supported a role of LC in curiosity regulation. Aging was associated with greater reliance on novelty-driven (initial) curiosity and a shift away from prediction error-related information-seeking. Both age groups showed curiosity-driven memory enhancement, with older adults exhibiting youth-like effects, suggesting a role for intrinsic motivation in preserving cognitive function in aging.

neuroscience↗

bioRxiv2025

MNase stratification reveals heterogeneous 5hmC in naive B cells

DNA demethylation is essential for gene activation and is primarily mediated by the Ten-Eleven-Translocation (TET) dioxygenase family. TET initiates the demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), a chemically stable derivative that is not only an intermediate in demethylation but also an epigenetic mark. 5hmC is enriched at active gene bodies, promoters, and enhancers that exist at accessible chromatin. Yet, 75-90% of genomic DNA is physically packaged in nucleosomes, raising the question about where 5hmC resides relative to nucleosomes. To address this question, we used micrococcal nuclease (MNase) to biochemically stratify 5hmC according to nucleosome protection in naive mouse B cells. Using multiple approaches, we showed that [~]95% of 5hmC peaks are retained after MNase digest, suggesting that 5hmC is nucleosome-associated. Despite the majority of 5hmC being similar in nucleosomal DNA compared to total DNA, we identified minor subsets that were MNase-sensitive (accessible 5hmC, [~]3%) or further MNase-resistant (protected 5hmC, [~]1-2%). Integrative analyses revealed that the accessible 5hmC is preferentially located at promoters and enhancers, and the presence of promoter-proximal accessible 5hmC showed a stronger correlation with gene expression than total 5hmC. In contrast, protected 5hmC is enriched in chromatin states with mixed active and repressive features. These results shed new light on the relationship between 5hmC and accessible chromatin, suggesting 5hmC is predominantly associated with nucleosomes and revealing heterogeneous 5hmC subsets with potential distinct regulatory roles.

molecular biology↗

bioRxiv2025

Engineering B cells to Express Fully Customizable Antibodies with Enhanced Fc Functions

Genome editing within the constant region of the immunoglobulin Heavy chain locus (IGH) can reprogram B cells to express Heavy chain only antibodies (HCAbs) containing custom antigen-recognition domains. HCAb-engineered cells express both surface B cell receptor (BCR) and secreted antibody isoforms and respond to antigen. By selecting alternate editing sites within IGH, we extended this approach to also allow customization of the constant (Fc) domain of the Heavy chain, producing HCAbs with enhanced effector functions or containing mutations to extend antibody half-life. We also introduced mutations to force obligate HCAb homodimers and prevent unwanted pairing with endogenous antibody chains. Finally, we showed that additional domains could be accommodated at the HCAb C-terminus and preferentially expressed in the secreted isoform. Together these data demonstrate the flexibility of the HCAb editing platform to express fully customized molecules that take advantage of the properties of B cells.

immunology↗

bioRxiv2025

Identification of PKN2 and MOB4 as Coordinators of Collective Cell Migration

In animals, collective cell migration is critical during development and adult life for repairing organs. It remains, however, poorly understood compared with single cell migration. The polymerization of branched actin by the RAC1-WAVE-Arp2/3 pathway is established to power membrane protrusions at the front of migrating cells, but also to maintain cell junctions in epithelial monolayers. Here we have identified novel regulators of collective cell migration using a two-pronged approach: candidates were extracted from publicly available RAC1-WAVE-Arp2/3 dependency maps and screened in a second step using CRISPR/Cas9 genetic inactivation. In a wound healing assay, PKN2 knockout (KO) MCF10A cells display decreased collective migration due to destabilization of adherens junctions, whereas MOB4 KO cells display increased collective migration with a loss of migration orientation. Upon wound healing, PKN2 relocalizes to lateral junctions and maintains coordinated migration in the monolayer, whereas MOB4 relocalizes to the front edge of leader and follower cells collectively migrating towards the wound. The role of MOB4 in controlling collective migration requires YAP1, since MOB4 KO cells fail to activate YAP1 and their phenotype is rescued by constitutively active YAP1. Together, these findings reveal two complementary activities required for coordinating cells in collective migration.

cell biology↗

bioRxiv2024

Structural insights into terminal arabinosylation biosynthesis of the mycobacterial cell wall arabinan

The emergence of drug-resistant strains exacerbates the global challenge of tuberculosis caused by Mycobacterium tuberculosis (Mtb). Central to the pathogenicity of Mtb is its complex cell envelope, which serves as a barrier against both immune system and pharmacological attacks. Two key components of this envelope, arabinogalactan (AG) and lipoarabinomannan (LAM) are complex polysaccharides that contain integral arabinan domains important for cell wall structural and functional integrity. The arabinofuranosyltransferase AftB terminates the synthesis of these arabinan domains by catalyzing the addition of {beta}-(1[->]2)-linked terminal arabinofuranose residues. Here, we present the cryo-EM structures of Mycobacterium chubuense AftB in its apo and donor substrate analog-bound form, determined to 2.9 [A] and 3.4 [A] resolution, respectively. Our structures reveal that AftB has a GT-C fold transmembrane (TM) domain comprised of eleven TM helices and a periplasmic cap domain. AftB has an irregular tube-shaped cavity that bridges the two proposed substrate binding sites. By integrating structural analysis, biochemical assays, and molecular dynamics simulations, we elucidate the molecular basis of the reaction mechanism of AftB and propose a model for catalysis.

biochemistry↗

bioRxiv2023

Reprogramming human B cells with custom heavy chain antibodies

We describe a genome editing strategy to reprogram the immunoglobulin heavy chain (IgH) locus of human B cells to express custom molecules that respond to immunization. These heavy chain antibodies (HCAbs) comprise a custom antigen-recognition domain linked to an Fc domain derived from the IgH locus and can be differentially spliced to express either B cell receptor (BCR) or secreted antibody isoforms. The HCAb editing platform is highly flexible, supporting antigen-binding domains based on both antibody and non-antibody components, and also allowing alterations in the Fc domain. Using HIV Env protein as a model antigen, we show that B cells edited to express anti-Env HCAbs support the regulated expression of both BCRs and antibodies, and respond to Env antigen in a tonsil organoid model of immunization. In this way, human B cells can be reprogrammed to produce customized therapeutic molecules with the potential for in vivo amplification.

immunology↗

bioRxiv2023

TCF4 mutations disrupt synaptic function through dysregulation of RIMBP2 in patient-derived cortical neurons

Genetic variation in the transcription factor 4 (TCF4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of ASD called Pitt Hopkins Syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models is shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. Here we show that cortical neurons derived from patients with TCF4 mutations have deficits in spontaneous synaptic transmission, network excitability and homeostatic plasticity. Transcriptomic analysis indicates these phenotypes result from altered expression of genes involved in presynaptic neurotransmission and identifies the presynaptic binding protein, RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. Together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.

neuroscience↗