Biology subjects

Yu, J.

Publications and source records attributed to Yu, J..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Heat-shock pathway activation by TRC051384 protects spiral ganglion neurons from noise-induced hearing loss

Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA sequencing and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and their supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood-labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin-proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. These findings establish proteotoxic stress in SGNs as a key driver of NIHL and identify HSF1 activation as a promising therapeutic strategy.

neuroscience↗

bioRxiv2025

Master clock-thalamic-prefrontal circuit controls circadian social priority

Social behaviors arise from complex brain operations that adapt to changing social contexts and internal states. However, how internal states guide the resolution of competing social goals remains unclear. Here, we show that prioritization between competing instincts follows a circadian pattern via a circuit linking the suprachiasmatic nucleus (SCN) to the medial prefrontal cortex (mPFC). Specifically, SCNVIP neurons project to Vipr2-expressing neurons in the nucleus reuniens (RE), which innervate the mPFC to regulate social prioritization. Vipr2 signaling in the RE is essential for circadian modulation of appetitive and consummatory social behaviors, aligning social behaviors with clock-regulated reproductive system. Overall, this SCN-RE-mPFC circuit provides a neural principle through which the master clock coordinates the prefrontal cortex to resolve a conflict of motivated behaviors by referencing an internal state.

neuroscience↗

bioRxiv2025

Transport of endo-β-mannosidase AtEBM from cytoplasm to the vacuole through autophagy pathway in Arabidopsis

Autophagy is a conserved eukaryotic intracellular degradation pathway that exhibits specialized forms, such as the biosynthetic cytoplasm-to-vacuole targeting (Cvt) pathway in yeast. This pathway selectively delivers several hydrolase precursors to the vacuole. While the core autophagy machinery is highly conserved between yeast and plants, the existence of a similar Cvt-like pathway for vacuolar hydrolase trafficking in plants remains unclear. Here, we found that Arabidopsis thaliana endo-{beta}-mannosidase (AtEBM), a glycosidase involved in degrading vacuolar N-glycans released from glycoproteins, is selectively transported to the vacuole via autophagy. Further analyses revealed that AtEBM directly interacts with the core autophagy protein ATG8 through an ATG8-interacting motif (AIM). This interaction is essential for sequestering AtEBM into autophagosomes. Remarkably, the AIM is conserved among EBM orthologs across the green plant lineage. In addition, several phenotypic studies showed that atebm mutants generated through CRISPR-Cas9 editing did not exhibit autophagy defects, including early senescence and hypersensitivity to nutrient starvation, but rather had reduced fecundity. Thus, these findings reveal a Cvt-like pathway in plants that fulfills a biosynthetic role by selectively delivering the glycosidase AtEBM to the vacuole.

cell biology↗

bioRxiv2025

RNA-Binding Protein NF90 Mediates Polycomb-Independent Transactivation by EZH2 to Promote Cancer Growth

Increasing evidence suggests critical roles of the polycomb-independent transactivation function of EZH2 in promoting some cancers, such as prostate cancer (PCa), yet the underlying mechanism remains poorly understood. Here, we identify the RNA-binding protein NF90 as a key mediator of this activity. NF90 interacts with EZH2, but not with other core components of the polycomb repressive complex 2 (PRC2), through its RNA-binding modules. Conversely, EZH2 engages NF90 via its intrinsically disordered RNA-binding domain in an RNA-dependent manner. NF90 and EZH2 mutually recruit each other to the AR promoter, where they cooperatively activate AR transcription and enhance downstream AR signaling. This NF90-EZH2 complex is essential for PCa cell growth: depletion of either factor abolishes proliferation, an effect rescued by AR re-expression. Similar to EZH2, NF90 promotes cell-cycle gene expression, is upregulated in advanced PCa, and is associated with poor clinical outcomes. Collectively, our findings uncover RNA-mediated protein interactions as a central mechanism underlying PRC2-independent transcriptional activation by EZH2 and establish NF90 as a major EZH2 coactivator, a master regulator of the cell cycle, and a promising therapeutic target in advanced PCa.

cell biology↗

bioRxiv2025

Engineering Apical Integrin-binding Cellular Patches to Directed Cell Reprogramming via Mechanical Remodeling

Engineering extracellular microenvironments to control stem cell fate remains a central challenge in regenerative medicine. Here, we develop ECM-mimetic cellular patches formed by the supramolecular assembly of laminin-derived, integrin-binding ligands. The resulting fibrillar networks exhibit well-defined molecular packing and nanoscale ligand distribution, enabling specific engagement of apical integrin {beta}1 on mesenchymal stem cells. This controlled interface converts molecular assembly into hierarchical mechanotransduction, coordinating cytoskeletal remodeling, nuclear deformation, and chromatin reorganization to drive neuronal reprogramming without genetic or chemical induction. Mechanistic studies reveal that the interplay between ligand assembly, spatial orientation, and network stability governs integrin activation and downstream transcriptional regulation These findings demonstrate how molecularly programmed assemblies can transform passive matrices into active, cell-instructive materials. This work establishes a framework for designing supramolecular systems that couple structural hierarchy with mechanotransductive control to direct stem cell fate and advance regenerative material strategies.

bioengineering↗

bioRxiv2025

Hidden-driver inference reveals synergistic brain-penetrant therapies for medulloblastoma

Effective therapies for high-risk medulloblastoma (MB), particularly MYC-driven Group 3 (G3) MB, remain elusive due to limited druggable mutations, poor blood-brain barrier (BBB) penetration, and rapid resistance. We developed SINBA (Synergy Inference by Data-driven Network-Based Bayesian Analysis), a systems biology framework that computationally prioritizes synergistic, BBB-permeable drug combinations by identifying hidden drivers sustaining oncogenic programs. Integrating MB-specific networks, transcriptomic data, and drug-gene interactions, SINBA nominated 32 candidates, of which 19 were experimentally validated as synergistic. Through iterative prioritization and experimental refinement, the MEK inhibitor mirdametinib and p38 inhibitor regorafenib emerged as the top brain-penetrant pair, suppressing G3 MB progression and extending survival in xenograft and immunocompetent models, with efficacy enhanced by low-dose radiation. Single-cell analysis revealed selective targeting of developmental origins and immune reprogramming. These findings establish SINBA as a computationally assisted discovery framework for clinically actionable combinations in high-risk MB.

cancer biology↗

bioRxiv2025

Brain-wide Genome Editing via STEP-RNPs for Treatment of Angelman Syndrome

Brain-wide genome-editing remains a major hurdle for the treatment of neurogenetic disorders. Here, we report a non-viral, non-nanoparticle, chemical modification-based method, called Stimuli-Responsive Traceless Engineering Platform (STEP) that achieves highly efficient and brain-wide genome-editing of neurons in mice. Using cholesterol-based STEP as a lead, we show that a single administration of STEP-ribonucleoproteins (RNPs) results in functional genetic rescue with significant improvements across a battery of neurobehavioral domains in the Angelman syndrome (AS) mouse model. No significant off-target events or general toxicity effects are observed. STEP-RNPs are also highly efficient at editing human neurons and cortical brain organoids differentiated from AS patient-derived iPSCs. scRNA-seq analysis confirms functional genetic rescue via reactivation of Ube3a/UBE3A expression in human and mouse STEP-RNP-treated neuronal cells. Genome editing via STEP-RNPs has broad applications and the potential to treat many other neurogenetic disorders.

genetics↗

bioRxiv2025

Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC

Glutathione peroxidase 4 (GPX4) is a master regulator of ferroptosis, a process that has been proposed as a potential therapeutic strategy for cancer. Here we have unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous KrasLSL-G12D/+Lkb1fl/fl (KL) and KrasLSL-G12D/+Tp53fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells exerts the opposite effect. GPX4-deficient tumor cells evade ferroptosis by upregulating the expression of DGAT1/2 to promote the synthesis of triacylglycerol (TAG) and oxidized TAG (oxTAG) and the formation of lipid droplets in cells. In addition, GPX4-deficient tumor cells secrete TAG and oxTAG into the extracellular space to induce dysfunction of antitumor CD8+ T cells, thereby coordinating an immunoinhibitory tumor microenvironment (TME). Consistently, treatment with DGAT1/2 inhibitors or inducible overexpression of GPX4 in tumor cells significantly resensitizes tumor cells to ferroptosis and ignites the activation of T cells in the TME to inhibit NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression and provide potential therapeutic strategies for NSCLC.

cell biology↗

bioRxiv2025

EMT activates ER-to-Golgi trafficking through upregulation of REEP2 to promote lung cancer progression

Membrane trafficking governs the transport of molecules to both intracellular and extracellular locations, thereby maintaining cell homeostasis. During cancer progression, alterations in membrane trafficking are frequently observed. However, the mechanisms underlying the dysregulation of membrane trafficking in cancer progression remain largely unresolved. Recent evidence has demonstrated that epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma (LUAD) employs a membrane trafficking program to coordinate cancer cell invasion and immunosuppression in the tumor microenvironment (TME). To further dissect the pro-tumorigenic membrane trafficking program, here we conducted a CRISPR interference (CRISPRi) in vivo screen for membrane trafficking regulators in a syngeneic mouse model with a complete immune system. This screen identified REEP2, an endoplasmic reticulum (ER) shaping protein, as a novel regulator of the EMT-dependent membrane trafficking program, which is associated with a poor prognosis in LUAD patients and is required for LUAD metastasis in a syngeneic orthotopic LUAD mouse model. Mechanistically, the EMT activator ZEB1 upregulates REEP2 expression through miR-183- and miR-193a-mediated regulation that promotes the transportation of secretory cargoes from the ER exit site (ERES) to the Golgi, thereby augmenting the secretion of pro-tumorigenic factors. The REEP2-driven secretion promotes cancer cell proliferation, migration, and the infiltration of myeloid-derived suppressor cells (MDSCs) in the TME. These findings identify REEP2 as a critical mediator of the EMT-driven pro-metastatic membrane trafficking program, revealing a specific vulnerability in mesenchymal LUAD.

cancer biology↗

bioRxiv2025

Differential controls of forelimb versus whole-body movements by striatum

Spikes in the dorsolateral striatum (DLS) of the basal ganglia correlate with forelimb and whole-body movements, but the extent to which they contribute to movement remains unclear. Using behavior-timed optogenetic inhibition in rats performing a lever-release task, we found that DLS inhibition delayed the initiation of forelimb reaching and conditioned lever release and, when delivered during reaching, interrupted execution. Inhibition during reward retrieval impaired locomotion, especially turning, reducing movement speed and resulting in less efficient trajectories. By contrast, inhibition before the nose poke that triggered reward delivery had little effect, despite substantial DLS activity at the nose poke. These effects were accompanied by bidirectional changes in firing rates in the substantia nigra pars reticulata, a basal ganglia output nucleus, and were much weaker when the dorsomedial striatum was perturbed. Together, these findings suggest that expression of many, but not all, learned movement patterns depends continuously on DLS activity. TeaserBriefly silencing striatal neurons during behavior reveals that the dorsolateral striatum helps initiate and control the execution of forelimb and whole-body movements in rats.

neuroscience↗

bioRxiv2025

Thalamofrontal synaptic weakening underlies short-term memory deficits from adolescent NMDAR hypofunction

N-methyl-D-aspartate receptor (NMDAR) hypofunction is linked to schizophrenia, but prevailing models centered on reduced number and activity of inhibitory interneurons, and the resulting excitation-inhibition (E-I) imbalance, do not explain selective cognitive impairments. Here, we show that repeated adolescent NMDAR antagonism produces short-term memory (STM) deficits by weakening thalamofrontal (TF) synaptic transmission. In mice repeatedly exposed to ketamine, STM impairment coincided with reduced release probability and vesicle refilling at mediodorsal thalamus (MD) [->] dorsomedial prefrontal cortex (dmPFC) synapses, without detectable changes in layer 2/3 [->] layer 2/3 synaptic release probability, intrinsic excitability, or synaptic ultrastructure. These presynaptic deficits were accompanied by diminished direction-selective population coding in the dmPFC, as revealed by decoding analysis, and impaired delayed alternation performance in the Y-maze. Chemogenetic strengthening of MD [->] dmPFC projections restored both neural selectivity and behavior. Our findings identify a circuit-specific presynaptic mechanism linking adolescent NMDAR hypofunction to cognitive dysfunction, challenging interneuron-centric models and establishing TF synapses as a potential therapeutic target in NMDAR-related disorders.

neuroscience↗

bioRxiv2025

Infusible Extracellular Matrix Biomaterial Enhances Cell-Specific Pro-Repair Responses Following Acute Myocardial Infarction

To mitigate the pathological effects of myocardial infarction, we developed and investigated pro-reparative decellularized extracellular matrix (ECM) biomaterials: an intravascularly infusible ECM (iECM). However, the cellular and molecular mechanisms by which iECM mediates repair are unknown because investigations have relied on bulk techniques. Here, we leverage single nucleus RNA sequencing (snRNAseq) to measure pro-repair in various cell types across acute timepoints (1, 3 and 7 days post infusion). In iECM, we found pro-reparative macrophage activation, fibroblast remodeling, increased vasculaure development, lymphangiogenesis, cardioprotection, and neurogenesis. These findings were validated through spatial transcriptomics. Thus, we define the pro-reparative nature of decellularized ECM biomaterials on cardiac cell types and elucidate previously undiscovered therapeutic pathways, further demonstrating the potential of iECM as an MI therapy as well as display the wealth of data generated from next-generation sequencing.

bioengineering↗

bioRxiv2025

Benchmarking Real-World Applicability of Molecular Generative Models from De novo Design to Lead Optimization with MolGenBench

Structure-based drug design (SBDD) has been profoundly reshaped by the advent of deep generative models, yet their practical impact on drug discovery remains limited. A central issue is the absence of a rigorous, application-oriented benchmark that mirrors the multi-stage, target-aware workflows of real-world pharmaceutical development. Inspired by recent advances in benchmarking for computer vision and large language models, where systematic evaluation has catalysed rapid progress, we introduce MolGenBench, a comprehensive benchmark designed to close the gap between molecular generation algorithms and tangible drug discovery outcomes. MolGenBench integrates a structurally diverse, large-scale dataset spanning 120 protein targets, 5,433 chemical series comprising 220,005 experimentally confirmed active molecules. Beyond conventional de novo generation, it incorporates a dedicated hit-to-lead (H2L) optimization scenario, which represents a critical phase in hit optimization that is seldom evaluated in existing benchmarks. We further introduce novel, pharmaceutically grounded metrics that assess a models ability to both rediscover target-specific actives or progressively optimize compounds for potency. Through extensive evaluation, MolGenBench uncovers significant gaps between current generative models and the demands of real-world drug development, establishing a foundational resource for building generative models with enhanced practical impact and accelerated translational potential.

bioinformatics↗

bioRxiv2025

Using the simple telegraph model to decipher transcriptional burst regulation across genome-wide data

Gene transcription is a stochastic bursting process, with burst frequency and burst size as core parameters. Deciphering its genome-wide regulation is challenging, as complex models (capturing detailed biology) are impractical for large-scale use due to unstable inference and high computation. We proposed a simple telegraph model-based framework to analyze genome-wide scRNA-seq and smFISH datasets, addressing these limitations. When sample size [≥] 500 and burst parameter change [≥] 3-fold, its inferred burst frequency- and size-dominated variations reliably proxy true regulation. Analyses across mouse cells (CAST/C57 alleles, fibroblasts vs. embryonic stem cells) and healthy/hypertrophic cardiomyopathy (HCM) human heart tissues revealed key rules: 1) Burst frequency- or size-dominated regulation was primary (over 70% of variable genes), with more bursty-regulated genes in HCM; 2) TATA-initiator synergy (enhancing burst size-dominated regulation) was lost in HCM; 3) Burst frequency-dominated genes enriched in genome stability/cell cycle/apoptosis (via TFs like Foxo4/Mcm2), while burst size-dominated ones in signaling/metabolism/proteostasis (via TFs like Zfp322a/Smchd1/Ppargc1a), and their interdependent dysregulation accelerated HCM. This study establishes the simple telegraph model as a scalable framework linking transcriptional burst dynamics to cell fate and pathology.

molecular biology↗

bioRxiv2025

For colonization success, should hosts and microbes travel alone, together, or swap partners along the way?

Understanding what determines colonization success is a key challenge of global change ecology. Microbiomes that enhance host performance are likely to be co-introduced with hosts during colonization due to their intimate association. Yet, it is unclear how co-introduced microbes will impact host colonization, as both the microbiome and its effects could vary upon introduction into a new habitat. Here, we used duckweeds --a cosmopolitan, freshwater angiosperm-- and their microbiome to track colonization dynamics during an experimental co-introduction in the wild. Notably, we found that host performance was substantially reduced when plants were co-introduced with microbes non-local to the introduced habitat, relative to hosts with a local microbiome. Moreover, negative impacts from the non-local microbiome persisted for multiple host generations despite a rapid turnover in microbiome composition during colonization. Overall, we suggest that considering the co-introduced microbiome can help predict host colonization success under global change.

ecology↗

bioRxiv2025

Tahoe-x1: Scaling Perturbation-Trained Single-CellFoundation Models to 3 Billion Parameters

Foundation models have transformed natural language processing and computer vision, yet their potential in single-cell biology--particularly for complex diseases such as cancer-- remains underexplored. We present Tahoe-x1 (Tx1), a family of perturbation-trained single-cell foundation models with up to 3 billion parameters. Tx1 is pretrained on large-scale single-cell transcriptomic datasets, including the Tahoe-100M perturbation compendium, and fine-tuned for cancer-relevant tasks. Through architectural optimizations, data loader refinements, and efficient training strategies, Tx1 achieves 3-30x higher compute efficiency than prior implementations of cell-state models. Tx1 jointly learns representations of genes, cells, and compounds using a masked-expression generative objective that incorporates a drug token, enabling flexible adaptation to diverse downstream applications. We evaluate Tx1 across four key disease-relevant benchmarks: (1) prediction of overall and context-specific gene essentiality, (2) identification of genes contributing to the hallmarks of cancer, (3) cell-type classification, and (4) prediction of perturbation responses in held-out cellular contexts. Tx1 achieves state-of-the-art performance across all tasks. We release pretrained checkpoints, training code, and evaluation workflows to accelerate the development of perturbation-trained single-cell foundation models for applications in precision oncology and beyond. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=52 SRC="FIGDIR/small/683759v1_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@aa33d5org.highwire.dtl.DTLVardef@310a38org.highwire.dtl.DTLVardef@195f204org.highwire.dtl.DTLVardef@143f7e3_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2025

Adjacent Rare-Earth Separation via a Protein Atomic Ruler

The separation of rare-earth elements (REEs) poses a formidable challenge due to their nearly identical ionic radii and chemical properties. Here, we present a transformative strategy for REE separation using a multimetal ion-stacking metalloprotein framework (MIF) that functions as an atomic ruler, effectively amplifying subtle differences in REE ionic radii. This approach achieves exceptional selectivity, enabling the separation of all 13 adjacent REE pairs with ultrahigh purity (up to 99.999%). Remarkably, the MIF retains its lanthanide-binding capacity over 410 consecutive absorption-desorption cycles, demonstrating outstanding stability. Structural insights reveal that the MIFs densely packed REE coordination environment magnifies minute radius variations--a key mechanism underlying its unparalleled separation efficiency. Our MIF-based strategy offers a sustainable, scalable solution to rare-earth separation in industrial applications.

biophysics↗

bioRxiv2025

Lamin B1 physically regulates neuronal migration by modulating nuclear deformability in the developing cortex

Neuronal migration is a vital process that positions billions of neurons to create a functional brain. To navigate the constrained microenvironments within the cortex, precise control over the nuclear mechanics in migrating neurons is indispensable. Here, we show that Lamin B1 (LB1) regulates neuronal migration by modulating nuclear deformability. Excess LB1 in neurons halted migration without altering laminar identity or overall gene expressions in vivo, while in vitro, it elevated nuclear stiffness and impaired neuronal motility in confined spaces. Moreover, mispositioned neurons resulted in electrophysiological defects in the brain. Computational modeling predicted a temporal relationship between nuclear deformation and enhanced migration velocity, which was validated experimentally through live imaging. Notably, cerebral organoid assays using iPS cells established from patients with LMNB1 duplication exhibited impaired neuronal migration in a human model. Collectively, these findings demonstrate that LB1 is a critical regulator of nuclear mechanics, ensuring the accurate spatiotemporal positioning of neurons.

neuroscience↗