Biology subjects

Wang, J.

Publications and source records attributed to Wang, J..

At least 361 records · Page 20Linked to original sources

bioRxiv2026

A Deep Quantitative Proteome Turnover Platform for Human iPSC-derived Neurons

Quantitative evaluation of protein turnover in human neurons is crucial for understanding neuron homeostasis and guiding drug development for neurological diseases. However, measuring protein turnover in postmitotic neurons remains challenging due to the high dynamic range of protein half-lives and limited proteome coverage in SILAC (Stable Isotope Labeling by Amino acids in Cell culture) experiments. Despite broad applications of dynamic SILAC proteomics to measure protein turnover in rodent tissues and primary neurons, few studies have measured protein half-lives in human neurons with limited proteome coverage. Here, we established a comprehensive platform to quantify protein half-lives in human induced pluripotent stem cell (iPSC)-derived neurons. By integrating optimized dynamic SILAC labeling in human neuron cultures, extensive peptide fractionation, optimized data-dependent and data-independent LC-MS/MS acquisition methods, and a streamlined computational pipeline, we achieved deep and accurate measurement of 10,792 protein half-lives from 162,854 unique peptides. We then compared the protein turnover and abundances in iPSC-derived glutamatergic cortical neurons and spinal motor neurons, revealing globally conserved proteome dynamics alongside subtype-specific differences consistent with specialized neuronal functions. To enable broad community access, we created NeuronProfile (www.neuronprofile.com), an interactive web platform for exploring protein turnover, abundance, and subcellular location in human neurons. Together, this work provides a comprehensive analytical platform to assess human neuronal proteostasis and a foundational resource for neurological disease research and therapeutic development.

neuroscience↗

bioRxiv2026

ACENet: a graph neural network for predicting enzyme pHmin using structure and sequence insights

The acid activity of enzymes, characterized by the minimum pH at which enzymes remain active (pHmin), is crucial for industrial applications in acidic environments. However, the rational design of acid-active enzymes remains challenging due to limited understanding of sequence-structure- activity relationships under acidic conditions. Here, we propose ACENet, a graph neural network that predicts enzyme pHmin by integrating surface features of protein structures with evolutionary representations derived from the large-scale protein language model ESM-2. ACENet achieved a Pearson correlation coefficient of 0.85 on the test dataset, significantly outperforming other deep learning baseline models and maintains stable pHmin predictions under various conditions. Even on a subset of the dataset with less than 20% homology, the PCC remains above 0.5, with an RMSE (Root mean square error) less than 1.4. ACENet also present excellent performance in the annotation of pHmin for homologous proteins and the predictive screening of minimal active pH in protein mutants. Remarkably, ACENet could identify the catalytic region as key determinants of acid activity through residue-level interpretability analysis. Overall, ACENet accelerates the development of highly efficient biocatalysts for diverse applications where acidic conditions predominate.

bioinformatics↗

bioRxiv2026

Funneliformis mosseae and Pseudomonas putida-symbiotic interaction promote drought resilience in Citrus reticulata

Climate change and increasing drought conditions significantly impedes citrus productivity in subtropical and tropical regions. This study explores the potential of combining arbuscular mycorrhizal fungi (AMF) Funneliformis mosseae and plant growth-promoting rhizobacteria (PGPR) Pseudomonas putida to mitigate drought resilience in Citrus reticulata (Red tangerine). AMF-mediated drought tolerance has been extensively documented; however, the collegial influence of PGPR and AMF on phytohormone signaling, photosynthetic efficiency, nutrient acquisition, and gene expression remains largely unexplored in citrus. We conducted a greenhouse experiment under both well water and drought stress conditions to assess the physiological and molecular responses to individual and co-inoculation with PGPR and AMF. Drought-stressed citrus plants, inoculated with AMF and PGPR, demonstrated significantly improved leaf water potential, stomatal conductance, carbon assimilation, and antioxidant defense. PGPR-AMF co-inoculation enhanced chlorophyll stability, osmotic adjustment, and nutrient uptake, while significantly reducing lipid peroxidation and ROS accumulation. The turquoise module emerged from transcriptomic and gene co-expression network analysis (WGCNA) as a potential key regulator of stress adaptation, revealed key regulatory transcription factors, e.g., CrMYB4, CrZFP8, CrSOS5, CrRGFR2, and CrQUA1, that were upregulated under combined inoculation, highlighting their potential role in stress adaptation. Our findings demonstrate that the synergistic PGPR-AMF interaction improves antioxidant enzyme activities and modulates gene expression to promote drought tolerance, providing new insights into the microbiomes role in plant resilience. These results offer a potential strategy to boost citrus growth and yield under water scarcity, with broad implications for agricultural resilience to climate change.

plant biology↗

bioRxiv2026

Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance

Activating mutations in KRAS drive pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Although mutant-selective KRAS inhibitors and pan-RAS inhibitors provide clinical benefits, the development of resistance limits durable response. Transcriptomic and proteomic analyses reveal that, despite effective suppression of mutant KRAS signaling, resistant cells sustain cell cycle progression. Distinct orthogonal mitogenic pathways are engaged in a context-dependent manner to bypass KRAS inhibition. While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling. Combinatorial drug screens and genome-wide CRISPR-Cas9 screens reveal that perturbing cell cycle nodes via targeting cyclin dependent kinases CDK4/6 and CDK2 could restore sensitivity to KRAS/RAS inhibitors. Co-targeting CDK4/6 induces G1 arrest and suppresses E2F-regulated proteins across all resistant models. In contrast, co-targeting CDK2 exerts a broader effect by impairing DNA replication, inducing G2 arrest, preventing mitotic entry, and yielding a more durable cytostatic response that delays cellular outgrowth after drug withdrawal. Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yields durable tumor control in vivo in xenografts derived from acquired resistant models. In conclusion, our findings identify sustained cell cycle activity as a defining feature of resistance to KRAS-directed therapies and establish cell cycle co-targeting as an effective strategy to overcome KRAS/RAS inhibitor resistance.

cancer biology↗

bioRxiv2026

PRMT5-Mediated Arginine Methylation of HSP90AA1 Drives Esophageal Squamous Cell Carcinoma Progression

Dysregulated HSP90AA1 chaperone activity is a hallmark of multiple human cancers, yet its post-translational modifications in esophageal squamous cell carcinoma (ESCC) are poorly defined. Here, we identify a PRMT5-driven modification of HSP90AA1, symmetric dimethylation at arginine 182 (R182), as a pivotal switch that fuels ESCC progression. HSP90AA1 physically associates with PRMT5, and genetic or pharmacologic PRMT5 blockade diminishes HSP90AA1-R182 methylation and downstream oncogenic signaling. Functionally, HSP90AA1 loss suppresses ESCC cell proliferation, migration, and invasion; enforces cell cycle arrest and reverses epithelial-mesenchymal transition (EMT). Re-expression of wild-type HSP90AA1 rescues cancer cell growth and EMT in vitro and in vivo, whereas the methylation-deficient R182A mutant does not. Furthermore, clinically oriented analysis shows HSP90AA1 overexpression in ESCC tissues and indicates moderate prognostic utility. Moreover, dual targeting of the PRMT5/HSP90AA1 axis is therapeutically attractive, and combined PRMT5/HSP90AA1 inhibition acts synergistically to exert anti-tumor activity, markedly reducing clonogenicity, invasion, and tumor burden in both cell-derived and patient-derived xenograft models. These findings demonstrate that PRMT5/HSP90AA1 serve as mechanistic drivers and actionable biomarkers in ESCC and provide a rationale for biomarker-guided co-inhibition of PRMT5/HSP90AA1 in translational studies.

cancer biology↗

bioRxiv2026

Digital Twin Brain simulation and manipulation of a functional brain network underlying mental illness

Linking synaptic-level perturbations to distributed brain-network dynamics remains a central challenge for understanding and treating mental illness. Although recent whole-brain models can reproduce individual brain activity patterns, they largely function as descriptive simulators rather than mechanistic, intervention-capable systems. Here we present an intervention-capable digital twin of the human brain, integrating individual neuroanatomy and task-evoked dynamics within a neuronal-scale framework. Individualised digital twin brains recapitulate a participant-specific compact cortico-subcortical network phenotype that captures transdiagnostic psychopathology across population and clinical cohorts. In silico modulation of excitatory and inhibitory synaptic conductance produces bidirectional, heterogeneous network responses across individuals. Population-scale simulations stratify individuals and predict longitudinal symptom trajectories from DTB-derived response profiles. Independent pharmacological functional MRI data further validate the predicted baseline-dependent network responses in vivo. Together, these findings establish digital brain models as experimental platforms for mechanistic perturbation, behavioural prediction and stratification, providing a foundation for precision neuroscience and psychiatry.

neuroscience↗

bioRxiv2026

Molecular Glue-Induced Homodimerization Drives Targeted CRBN Autodegradation

Molecular glue degraders (MGDs) offer a sophisticated, proximity-based approach to protein modulation. In this study, we introduce LJY-3-60, a novel proximity-inducing agent that unexpectedly triggers the potent and selective autodegradation of CRBN. Evidence from CRISPR-Cas9 screening and IP-MS reveals that this degradation process is strictly governed by the intrinsic CRL4CRBN machinery, independent of any extrinsic E3 recruitment. Through a combination of cellular and biophysical characterizations, we demonstrate that LJY-3-60 acts as a molecular bridge to template CRBN homodimerization. This mechanism is unequivocally elucidated by the atomic-resolution co-crystal structure of the CRBNMidi-LJY-3-60 complex. The structure explicitly delineates the homodimerization interface, revealing how the ligand reorganizes the protein surface to stabilize a non-canonical architecture that drives trans-autoubiquitination and subsequent proteasomal degradation. Furthermore, LJY-3-60 serves as a highly effective, controllable off-switch to mitigate PROTAC-induced toxicity. Ultimately, this work delivers a robust chemical tool for modulating CRBN stability. By demonstrating how a small molecule can functionally mimic an endogenous E3 substrates degron to catalyse targeted autodegradation, this study establishes a rational structural framework for designing the next generation of self-destructive modulators in targeted protein degradation (TPD) therapeutics.

biochemistry↗

bioRxiv2026

Multi-omic profiling of human and mouse dorsal root ganglia enables targeted gene delivery to nociceptors

Chronic pain conditions are often driven by hyperexcitability of nociceptors, the peripheral sensory neurons that detect noxious stimuli. Recent single-cell transcriptomic studies have begun to clarify the molecular identity of distinct peripheral sensory neuron subtypes, but tools that restrict transgene expression to nociceptors while sparing other dorsal root ganglion (DRG) subtypes remain limited. Here, we combined single-nucleus multi-omic profiling of human and mouse DRG with in vivo AAV enhancer screening to identify cis-regulatory elements that drive biased AAV expression in mouse DRG nociceptors and human iPSC-derived nociceptors. We then validated that an enhancer AAV designed to express Kir2.1 preferentially in nociceptors reduces DRG neuronal excitability. Leveraging these multi-omic datasets, we trained a sequence-based model to decode the cis-regulatory logic of nociceptors, enabling both the prioritization of native candidate elements and the design of synthetic enhancers with a range of nociceptor targeting properties. Together, these cross-species multi-omic resources define conserved DRG regulatory programs and provide a viral toolkit for pain research with potential translational applications for patients with refractory pain.

neuroscience↗

bioRxiv2026

A sequence motif for DNA double-strand break and telomere healing during programmed DNA elimination

Programmed DNA Elimination (PDE) is an exception to the paradigm of genome integrity, removing selected DNA sequences during development. PDE is observed in dozens of metazoan species from diverse phyla, but its molecular mechanisms and biological significance in most metazoa remain largely unknown. During PDE in the nematode Oscheius tipulae, DNA double-strand breaks (DSBs) are generated at subtelomeric regions, followed by the loss of DNA at chromosome ends and the healing of the DSBs by de novo telomere synthesis. DSBs occur at a 29-bp degenerate palindromic Sequence For Elimination (SFE) motif. We determined the sequence requirement for DSB generation and demonstrated that the conserved GGC/GCC sites are used for neotelomere formation. Introducing the SFE into a retained DNA region adjacent to a native SFE induces DNA cleavage, telomere healing, and loss of additional DNA between the two SFEs. Moreover, insertion of the SFE in the middle of the sex chromosome splits it into two functional somatic chromosomes, demonstrating that the function of SFE is not necessarily constrained by its genomic location. Overall, our data show that the SFE motif is both necessary and sufficient for the generation of DSBs and healing of DSB ends via telomere addition, providing molecular insights into the mechanisms of metazoan PDE.

genetics↗

bioRxiv2026

Mechanistic Basis for the Selective Recognition of the Fcγ Receptor IIa by Monoclonal Antibody IV.3

The monoclonal antibody IV.3 selectively binds the platelet Fc{gamma} receptor IIa (Fc{gamma}RIIa), potently blocking immune complex engagement without cross-reacting with the closely-related Fc{gamma}RIIb. This specificity has made IV.3 invaluable for dissecting Fc{gamma}RIIa-mediated activation in diverse conditions, including infection, autoimmunity, thromboinflammation, and platelet-mediated thrombosis. We combined cryogenic electron microscopy, surface plasmon resonance, alchemical free energy calculations, and molecular dynamics simulations to elucidate IV.3s binding sites on Fc{gamma}RIIa and the mechanistic basis of IV.3 specificity. We find that IV.3 engages a broader Fc{gamma}RIIa epitope than previously recognized, extending beyond residues H/R134 and L135 (R and S in Fc{gamma}RIIb). Simulations of Fc{gamma}IIa-R134 variants bearing either L135 or S135 reveal that IV.3 specificity arises from hydrophobic stabilization mediated by L135 and disruption of an R134-specific interaction network in the presence of S135. These findings provide a mechanistic framework for rational design of Fc{gamma}RIIa-targeted therapeutics.

biophysics↗

bioRxiv2026

Protein Language Modeling and Evolutionary Analysis Reveal an N-terminal Determinant of Functional Divergence in Cytochrome P450s from Sophora. tonkinensis

The N-terminal membrane anchor of cytochrome P450s is essential for function yet exceptionally variable--a paradox resistant to alignment-based analysis. Using an alignment-free protein language model (ESM2) pipeline on 345 Sophora tonkinensis P450s, we show the N-terminal 50 residues evolve under pervasive neutral relaxation (mean dispersion 0.62), punctuated by a single constrained island: a PxxG structural hinge (P21, G24 conserved at 98%/99%). Despite lacking sequence-level constraint, embedding-space decomposition resolves this scaffold into two separable channels. DIVA (unsupervised) captures a topological template encoding membrane-anchoring architecture, validated by physicochemical correlations recapitulating ER signal-anchor insertion and confirmed by DeepLoc- 2.1. PIVOT (supervised ablation) captures a family-associated signal whose peak position distinguishes CYP families ({varepsilon}2 = 0.44, permutation p < 0.0001) despite label-free training. The channels are largely separable: PIVOT peaks lie downstream of DIVA peaks in 84.4% of proteins, with mutually exclusive signal-loss sets. The P450 N-terminus thus integrates membrane-topological and family-identity information within a single relaxed region. Neutral evolution is reframed not as absence of information, but as the condition enabling multiplexed functional encoding--a mechanistic rationale for the functional importance of this variable anchor.

plant biology↗

bioRxiv2026

IRE1 drives a homeostatic response to reduced protein influx into the endoplasmic reticulum

IRE1, alongside ATF6 and PERK, orchestrates the Unfolded Protein Response, a network of signaling pathways that maintains endoplasmic reticulum (ER) homeostasis. Two modes of IRE1 activation are known: i) in response to an accumulation of unfolded proteins in the ER lumen and ii) in response to compositional changes to the ER membrane that alter its physical properties. Here we identify a third, independent mode of IRE1 activation: ER co-translational translocation deficits activate IRE1 through a mechanism that relies on the release of IRE1 molecules from unoccupied translocons. We define this mechanism as TRES for "TRanslocon Engagement Surveillance". TRES leads to spontaneous activation of IRE1 and bypasses its unfolded protein- and ER membrane composition-sensing functions. Inhibiting translation initiation similarly activates IRE1 by TRES, as it leads to a decline in ER protein import, thus linking the Integrated Stress Response to IRE1 signaling. TRES drives IRE1 activation without activating ATF6 or PERK, resulting in a distinct gene expression program that feeds back by boosting the co-translational translocation machinery to rebalance the ER protein load. Our findings thus demonstrate that monitoring and adjusting the rates of protein translocation are critical for maintaining ER homeostasis.

cell biology↗

bioRxiv2026

Evolutionary Divergence of Structure-Function Coupling between Human and Macaque: Spatial Patterns and Transcriptomic Basis

Structural-functional coupling (SFC) provides critical insights into how the brains structural architecture constrains functional organization for supporting higher-order cognition. Investigating evolutionary differences in SFC between humans and macaques may provide new insights into the neural basis of unique human cognitive abilities. In this study, we analyzed multimodal magnetic resonance imaging data from anesthetized and awake adult rhesus macaques and adult humans to examine cross-species divergences in SFC. Moreover, we integrated transcriptomic data to elucidate the molecular mechanisms underlying evolutionary differences in SFC patterns. We find that humans and macaques exhibit distinct SFC patterns: the human brain shows high SFC in the lateral and medial prefrontal cortex, whereas macaques show high SFC in the sensorimotor cortex. Notably, language-related regions in the human lateral temporal cortex exhibit relatively low SFC. Furthermore, the human whole-brain SFC pattern and the evolutionary differences in SFC between humans and macaques are negatively correlated with cortical evolutionary expansion. By integrating human and macaque transcriptomes, we reveal that the macaque SFC specifically associated genes are primarily involved in basic physiological functions, whereas the human SFC specifically associated genes exhibit evolutionary adaptations in synaptic function, neurotransmitter secretion, and other molecular processes. Moreover, the human-specific genes showing significant overlap with Human Accelerated Regions genes were mainly enriched in cell types of astrocyte and oligodendrocyte and in diseases of schizophrenia and Alzheimers diseases. Overall, these findings advance our understanding of the intricate relationships of SFC in human and macaque brains and provide novel insights in understanding evolutionary conservation and species specificity in cognitive function and gene regulation.

evolutionary biology↗

bioRxiv2026

SPATIALLY PATTERNED PODOCYTE STATE TRANSITIONS COORDINATE AGING OF THE GLOMERULUS

BackgroundWith the US population living longer, the risk, incidence, prevalence and severity for chronic kidney diseases become more abundant. Glomerular diseases are the leading cause for chronic and end-stage kidney disease. Yet, the cellular responses and the underlying mechanisms of progressive glomerular disease, which ultimately leads to glomerulosclerosis and loss of kidney function with advancing age, are poorly understood. MethodsKidneys of young (4 months-old), middle-aged (20 months-old) and aged (24 months-old) mice were separated into outer cortex and juxta-medullary region and processed for single nuclei transcriptomics. Focusing on the aging glomerulus data were analyzed using a state-of-the-art analysis pipeline dissecting out the cellular age- and kidney region-specific responses. ResultsGlobal analysis of the transcriptome reveals regional-specific differences that are detectable across multiple cell types exemplified by the expression of Napsa as a bona-fide juxta-medullary marker. In contrast aging led to rather cell type-specific responses. In the glomerulus, healthy podocytes were characterized by expression of canonical podocyte genes; conversely the senescent, aged podocytes were characterized by the down-regulation of canonical podocyte genes and the emergence of inflammatory and senescent signatures. Interestingly, these senescent podocytes were primarily located in the juxtamedullary region suggesting that juxtamedullary podocytes are more sensitive. Yet, instead of aging being defined by distinct cell states, the profiles, as well as ligand-receptor and pseudotime analyses suggest that podocytes aging is selective and coordinated, not universal degeneration. This was different to the other glomerular cell types, parietal epithelial cells, glomerular endothelial cells and mesangial cells. While they also as existed in different subpopulations, they exhibited little regional-, or age-depended changes. Finally proximal tubular aging manifested itself as discrete cellular states. ConclusionsThe single nuclei transcriptomics of the aging kidney provides a mechanistic explanation for regional susceptibility of nephrons and suggests that the future therapeutic strategies need to consider the cellular and spatial complexity of the glomerulus.

bioinformatics↗

bioRxiv2026

DeepSRFusion: a point cloud deep learning framework for super-resolution particle fusion

Deciphering the spatial organization of macromolecular complexes in their native context is central to structural biology. Particle fusion in single-molecule localization microscopy offers a unique capability for high-resolution structural reconstruction in situ. However, existing methods face significant challenges from large rotational perturbations and sparse labeling, resulting in compromised accuracy and substantial computational cost. We present DeepSRFusion, a self-supervised pretraining framework for three-dimensional super-resolution particle fusion. By representing single-molecule point clouds as Gaussian Mixture Models, DeepSRFusion integrates data-driven feature learning with physical imaging constraints. A two-stage optimization strategy with dynamic template updating enhances robustness, and a novel Clustering Error metric quantifies fusion quality. Nanometer-scale validation on both simulated and experimental datasets demonstrates high reconstruction fidelity and structural consistency with cryo-electron microscopy and AlphaFold3. DeepSRFusion remains effective under challenging imaging conditions, including large 3D rotations, sparse labeling, high localization uncertainty, and limited particle numbers, while achieving over 100-fold speedups compared to current methods. It resolves fine structural features with a measured spatial resolution of 1.60 {+/-} 0.10 nm, sufficient to distinguish ~10 nm spaced protein pairs and visualize tilted internal substructures within macromolecular assemblies. DeepSRFusion provides a powerful tool for high-precision structural analysis in native cellular environments.

biophysics↗

bioRxiv2026

The structure and catalytic mechanism of new cellular and viral HDV ribozymes

We have determined the molecular structure and investigated the catalytic mechanism of two new ribozymes of the Hepatitis delta virus family, found in the nematode Caenorhabditis briggsae and virus Ackermannviridae. Crystal structures of both conform to the double-pseudoknot architecture adopted by the viral HDV ribozyme. The C. briggsae ribozyme has been determined both pre- and post-cleavage. In the former both nucleotides flanking the scissile phosphate are observed, along with a metal ion, and cytosine 75 N3 bound to the O5 leaving group. The pH dependence of cleavage rate reveals a pKa of 6.6 and together with the inactivity of a C75U mutant provides evidence for its role as general acid. In contrast to other nucleolytic ribozymes that use catalytic metal ions, reaction rate does not depend on the pKa of the divalent metal ion. Limited adjustment of structure of the active center is consistent with direct bonding of the metal ion to the O2 and non-bridging O, suggesting that the ion acts as a Lewis acid to activate nucleophilic attack. This mechanism appears to be general for the HDV ribozyme class, and distinguishes it from the majority of nucleolytic ribozymes that use general base catalysis.

biochemistry↗

bioRxiv2026

SpaMOAL: A spatial multi-omics graph contrastive learning method for spatial domains identification

Recent advances in spatial multi-omics technologies have opened new avenues for characterizing tissue architecture and function in situ, by simultaneously providing multimodal and complementary information--such as spatially resolved transcriptomic, epigenomic, and proteomic features. Current computational approaches face substantial challenges such as effective integration of multi-omics molecular information with spatial information and corresponding high-resolution histology images. To address this challenge, we proposed SpaMOAL (Spatially Multi-Omics graph contrAstive Learning), a graph-based contrastive learning approach for spatial domain identification. SpaMOAL learns clustering-friendly representations from spatial multi-omics data by integrating spatial coordinates, histological image features and molecular profiles, enabling accurate delineation of spatial tissue domains. Benchmarking across multiple recent paired spatial multi-omics datasets demonstrated that SpaMOAL consistently outperforms existing methods. By enabling accurate spatial domain delineation, SpaMOAL provides a powerful framework for interpreting tissue organization and cellular microenvironments.

bioinformatics↗

bioRxiv2026

Neural Control of Autonomic Arousal During Threat Anticipation Revealed by High-Resolution Cardiac Contractility

The sympathetic nervous system prepares the organism for adaptive action by shaping physiological, affective, and behavioral responses to environmental demands. Yet, how sympathetic signals dynamically couple with neural systems supporting emotional experience and behavior remains poorly understood, in part because common indices such as skin conductance responses lack sufficient temporal resolution to track these dynamics. Here, we evaluated trans-radial electrical bioimpedance velocimetry (TREV), a non-invasive measure of beat-to-beat cardiac contractility, and compared it with skin conductance responses during threat anticipation and simultaneous fMRI. Participants (n=60) completed a threat-of-shock paradigm requiring goal-directed action. Cardiac contractility increased during threat anticipation, covaried with skin conductance responses, and independently predicted self-reported emotional intensity. Critically, threat-related increases in contractility--but not skin conductance--tracked threat-related modulation of activation in dorsomedial prefrontal cortex, posterior parietal cortex, and cerebellum, with contractility-modulated cerebellar activation predicting faster motor responses under threat. These findings establish TREV-derived cardiac contractility as a physiological signal linking sympathetic drive with neural responding, emotional experience, and adaptive behavioral mobilization during emotion-guided action.

neuroscience↗