Biology subjects

Qian, H.

Publications and source records attributed to Qian, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Mesaconic acid delivery via biomaterials and engineered probiotics to the gut reduces inflammation in Crohn's Diseases mouse models

Mesaconate (MES, an immunosuppressive metabolite) but not itaconate is upregulated in stool of Crohns Disease (CD) patients, albeit below therapeutic levels.. However, colonic MES level is difficult to maintain because of its high absorption rate, limiting its therapeutic potential for CD. Herein, we developed two strategies that elevate MES level and suppress inflammation: EcN-CAD, an engineered probiotic Escherichia coli Nissle 1917 (EcN) that overexpresses cis-aconitate decarboxylase (CAD, produces itaconic acid that is converted to MES); and MES+Zn, a Zinc-MES ionically crosslinked formulation. Mechanistically, MES modulates T cell function by downregulating glycolytic and mitochondrial activity and decrease ROR{gamma}t expression. In preclinical SAMP1/YitFC dexamethasone-withdrawal model and TNFDARE model, MES+Zn decreased gut permeability significantly compared to controls and reduced myeloperoxidase (MPO, an inflammatory marker) 1000-fold compared to controls. EcN-CAD probiotics decreased ROR{gamma}t expression in CD4+ and CD8+ T cells, gut permeability and inflammation in preventive SAMP1/YitFC model, and SAMP1/YitFC dexamethasone-withdrawal model. Overall, MES rewires T cell responses and technologies that enhance MES levels can be effective in gut-related inflammatory diseases.

immunology↗

bioRxiv2026

Temperature governs fitness effects of transgenes on plants non-monotonically: a global meta-analysis

The global expansion of genetically modified plants supports modern food and ecological security1, yet whether the fitness cost--widely assumed to limit their spread after escape--actually operates in the wild has remained unclear, with empirical evidence remaining mixed2-4. Here, a global meta-analysis of 518 experiments across 48 species reveals that this safety brake is real in the laboratory (fitness cost: [~]13%) but is largely attenuated in the worlds most intensively cultivated croplands. A phylogenetically robust, hump-shaped relationship between mean annual temperature and fitness effect is defined, with fitness benefits emerging specifically within 9.9-22.8{degrees}C. This buffer window overlaps the productive croplands5, where the high-risk proportion (HRP; the area-weighted posterior probability of non-negative fitness effect) consistently exceeds that in natural vegetation and expands with global warming (cropland: +18.4% versus natural vegetation: +8.3% under SSP5-8.5). Notably, constitutive expression or dual-resistance (resist to both abiotic and biotic stressors) transgene can effectively compress the HRP below 30%, providing a quantitative baseline for management. These findings establish a framework for climate-smart deployment that balances agricultural productivity with ecological safety.

ecology↗

bioRxiv2026

APOE4 disrupts the central dogma by arresting neuronal proteome dynamics

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimers disease and promotes neuronal dysfunction through incompletely understood mechanisms. Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic APOE3 and APOE4 human iPSC-derived neurons and found that APOE4 fundamentally impairs neuronal proteome renewal. Although transcriptional changes were modest, APOE4 disrupted ribosome occupancy, altered translational dynamics, and uncoupled protein abundance from transcript levels. Proteome-wide turnover measurements revealed a global extension of protein half-lives and widespread accumulation of long-lived proteins. Functional proteomic analyses demonstrated concurrent lysosomal and proteasomal impairments associated with reduced proteasome activity and increased association of APOE with neuronal proteasomes. Longitudinal proteomics further showed that protein accumulation emerges during neuronal maturation and precedes a senescence-like cellular stress state. Together, these findings identify impaired proteome renewal as a central mechanism underlying neuronal vulnerability to APOE4 and establish defective proteostasis as an early pathogenic event in Alzheimers disease.

neuroscience↗

bioRxiv2026

SOX8-USP7-PGC-1α axis enhances thermogenesis in brown adipocytes

Obesity is one of the most prevalent diseases worldwide. Increasing thermogenesis to enhance energy expenditure has emerged as a promising therapeutic strategy. In an effort to identify new regulatory targets in thermogenic adipocytes, we found that SOX8 is correlated with obesity and serves as a novel marker of classical brown adipocytes in both humans and mice, upregulating during acute cold exposure. Functional studies further demonstrated that adipocyte-specific knockdown of SOX8 leads to obesity and metabolic dysfunction in mice. Mechanistically, SOX8 directly interacts with USP7 and stabilizes PGC-1 by reducing its K48-linked polyubiquitination. AAV-Rec2-mediated SOX8 overexpression initially enhanced energy expenditure, improved insulin sensitivity, and alleviated metabolic dysfunction in HFD-fed mice. However, prolonged SOX8 overexpression induced compensatory metabolic maladaptation, characterized by reduced energy expenditure, impaired glucose homeostasis, and mitochondrial structural disruption. These findings reveal a novel SOX8-USP7-PGC-1 regulatory axis in brown adipocytes, and reveal a previously unrecognized time-dependent effect of sustained thermogenic activation, highlighting SOX8 as a promising therapeutic target for obesity and metabolic syndrome.

cell biology↗

bioRxiv2026

SigBridgeR: An Integrative Framework and Toolkit for Comprehensive Screening and Benchmarking of Phenotype-Associated Cell Subpopulations in Single-Cell Transcriptomics

Single-cell RNA sequencing has revolutionized our understanding of cellular heterogeneity, yet linking specific cell subpopulations to clinically relevant phenotypes remains a persistent challenge. Although multiple computational methods have been developed to bridge this gap, they are typically implemented as standalone packages with heterogeneous preprocessing pipelines, incompatible parameter conventions, and divergent output formats, thereby hindering rigorous cross-method benchmarking and reproducible multi-method workflows. Here, we present SigBridgeR, an extensible R framework and comprehensive toolkit that currently unifies eight state-of-the-art phenotype-associated cell screening algorithms within consistent workflows. We conducted a systematic benchmarking study across four cancer types HER2-positive breast cancer, triple-negative breast cancer, lung adenocarcinoma, and ovarian cancer using both binary phenotypes and patient survival endpoints. Our evaluation incorporated positive and negative control assessments based on differentially expressed genes and randomly selected marker panels, alongside quantitative accuracy comparisons using ground-truth cell labels. Building upon these insights, SigBridgeR provides standardized preprocessing for scRNA-seq and bulk transcriptomic data, unified algorithmic interfaces through a registry-based architecture, ensemble analysis via weighted voting, and comprehensive visualization utilities for multi-method comparison. By lowering technical barriers and promoting methodological standardization, SigBridgeR facilitates reliable discovery of phenotype-relevant cell subpopulations and enhances the translational potential of single-cell omics research.

bioinformatics↗

bioRxiv2026

Molecular basis of quorum-sensing signal transduction by CqsS and its inhibition by CqsA the autoinducer synthase

Vibrio bacteria possess multiple quorum-sensing systems, each of which conveys information into the cell concerning the cell density and species composition of the vicinal community. Germane to the present work is the CqsA-CqsS quorum-sensing pathway that vibrios use for intra-genus communication. CqsA is the synthase for the autoinducer (S)-3-hydroxytridecan-4-one (CAI-1), and CqsS, a bi-functional two-component kinase-phosphatase, is the CAI-1 receptor. Here, we determine the cryo-EM structures of the full-length Vibrio harveyi CqsS dimer in the apo- and ATP{gamma}S-bound states. Our structures reveal the molecular basis for the initiation of the phosphorylation cascade, which we support through biochemical and genetic analyses. Autophosphorylation of CqsS occurs in cis at the conserved histidine residue (H1), whereas phospho-transfer to the conserved aspartate residue (D1) in the C-terminal receiver domain occurs in trans. By co-expressing CqsS and CqsA to capture CqsS bound to CAI-1, we unexpectedly discover a tight interaction between the CqsS intracellular domain and CqsA. In the complex, the CqsS H1 residues are positioned away from the catalytic cavity, and CqsS kinase activity is inhibited. Cryo-EM analysis, focused on the transmembrane domain of CqsS in this complex, reveals the presence of two CAI-1 molecules. CAI-1 binding induces an obvious movement of transmembrane helix 6, disrupting its extension into the cytosol, providing a structural basis for how CAI-1 binding in the periplasm is coupled to signal transduction into the cytoplasm. Together, our findings advance the understanding of CqsS-CAI-1-mediated quorum-sensing signal transduction, an activity that underpins the coordination of group behaviors in vibrios.

microbiology↗

bioRxiv2025

A modular lentiviral system for multiplexed gene perturbation and functional analysis reveals interdependence of hormone receptors in breast cancer growth in vivo

Precise and flexible control of gene expression is essential for dissecting gene function in complex biological systems. Although recent developments in genetic engineering and CRISPR/Cas9 technology have expanded tools for gene activation, suppression and editing, their application in physiologically relevant models remains challenging, time consuming, and expensive. Here, we present a modular, doxycycline-inducible vector system that integrates gene overexpression, shRNA-mediated knockdown, and CRISPR/Cas9-mediated regulation within a single, lentivirus-compatible system. The modular design allows rapid exchange of selection markers, epitope tags, and reporters via Gateway cloning, providing broad adaptability across experimental settings. In addition to standard fluorescent and luminescent reporters, the system includes advanced sensors, such as Fucci cell cycle reporters, to enable monitoring of cellular processes. By combining fluorescence barcoding with combinatorial genetic perturbations, the platform supports multiplexed analysis of gene function and genetic interactions through phenotypic characterization by fluorescence imaging or flow cytometry. We demonstrate its utility in vivo with breast cancer intraductal xenografts, which suggest that ER+ breast cancer cells (MCF7) rely on androgen (AR), estrogen (ER) and progesterone receptors (PR) for in vivo growth. This versatile gene perturbation system provides tight temporal control, streamlined implementation, and high-content phenotyping capacity facilitating efficient in vitro and in vivo studies while reducing the use of animals in in vivo validation experiments. It thus expands the experimental repertoire for dynamic, multigene interrogation in complex systems.

molecular biology↗

bioRxiv2025

Spatial transcriptomics reveals injury responsive compartments and coordinated immune fibrotic signaling in ANCA associated renal vasculitis

ANCA-associated vasculitis (AAV) often presents with rapidly progressive glomerulonephritis, yet how immune and stromal programmes are organised within kidney tissue remains unclear. We applied spatial transcriptomics to renal cortex biopsies from patients with AAV of varying disease severity and normal-histology controls, generating a spatial map that localizes disease programmes in situ. Four disease-responsive compartments--immune/interstitial fibroblasts (IM/Fib), glomeruli, myofibroblasts, and vascular compartments--showed distinct compartment-specific signatures that correlated with histopathology at the patient level. We also identify coordinated immune-fibrotic signaling linked to severity. Within IM/Fib, the CXCR4-CD74 receptor complex co-localised with IgM cells, and lumican (LUM) co-localised with collagen I/III; both were validated by immunofluorescence and associated with fibrotic injury. These tissue-anchored signatures constitute candidate diagnostic/prognostic biomarkers, and show the utility of this foundational spatial transcriptomics map to generate testable hypotheses which will guide validation in larger, stratified, treatment-annotated cohorts.

bioinformatics↗

bioRxiv2025

Bodily Self in Macaque Monkeys and Human Infants

Whether monkeys possess the concept of bodily self remains controversial. We found that macaque monkeys trained for mirror self-recognition (MSR) could spontaneously recognize themselves when viewing video images of their back from a third-person perspective (3PP), but this generalization required a few minutes of "exploration". In contrast, through visual-tactile synchronization training similar to that used in human out-of-body studies, naive monkeys could recognize themselves from 3PP back images and demonstrated MSR within seconds. Interestingly, in human infants, we found that 3PP back self-recognition developed spontaneously several months after MSR. These results demonstrate the existence of hierarchical bodily self in macaques and similar stepwise development of bodily self in human infants, offering insights into the emergence and manifestation of bodily self in natural and artificial intelligence.

neuroscience↗

bioRxiv2025

Generalized brain-state modeling with KenazLBM

The large-scale functional state of a human brain remains difficult to characterize, much less predict. Regardless, techniques have been engineered to electrically neuromodulate the brain to treat a subset of neurologic and psychiatric disorders with moderate efficacy. Accurate characterization of a brains instantaneous functional state has stymied the development of more effective neuromodulation paradigms. Advanced computational methods are required to address this gap and enable large-scale neuroscience. Here we define the concept of generalized brain-state modeling across humans as Large Brain-State Modeling (LBM) and present KenazLBM as the worlds first example. KenazLBM can instantaneously characterize the functional state of a persons brain with raw iEEG data, and predict future brain-states. KenazLBM was trained on over 17.9 billion unique multichannel tokens from people undergoing intracranial electroencephalography (iEEG) recordings, and has learned to interrelate brain-states between people into a common interpretable topology. Most importantly, the model generalizes to unseen subject data with significant recording channel heterogeneity from the training set. We offer KenazLBM as a first generalized brain-state model to serve as a new paradigm of basic neuroscience inquiry and potential translation into neuromodulation therapeutics.

neuroscience↗

bioRxiv2025

Human growth plates house resting zone sub-populations with features of quiescent stem cells

Incomplete mapping of gene expression within human (epiphyseal) growth plates contributes to the challenges of diagnosing and treating patients with skeletal growth disorders. To address this issue, we applied spatially resolved transcriptomics to rare growth plate biopsies obtained from healthy adolescents. In addition to identifying novel markers of each zone of the human growth plate, spatial profiling revealed that the expression of genes associated with poorly understood growth disorders, including NKX3-2, SGMS2 and WNK4, is restricted to specific human growth plate zones. By elaborating on the low transcriptional activity of resting zone chondrocytes, we found that a subset of these cells exists in a functionally quiescent state in vivo, as determined by their predominantly nuclear mRNA, abundant heterochromatin, and ability to exit the G0 phase under specific conditions - features shared with skeletal stem cells in mouse growth plates. Additionally, we identified distinct and overlapping sub-populations of human resting zone chondrocytes; an exploration of their hierarchy determined that CHRDL2 and/or SFRP5-positive sub-populations are among the least quiescent resting zone cells. In summary, we generated the most comprehensive gene expression characterization of the human growth plate, which revealed novel zone-specific markers, new primary growth disorders, candidate pharmacological targets, and led us to uncover sub-populations of resting zone chondrocytes with features of quiescent stem cells. These results contribute to a better understanding of the cellular and molecular mechanisms governing human height and can facilitate improved diagnosis and treatment strategies of patients with skeletal growth disorders.

molecular biology↗

bioRxiv2025

Development of itaconate polymer microparticles for intracellular regulation of pro-inflammatory macrophage activation

Itaconate (IA) is an endogenous metabolite and a potent regulator of the innate immune system. Its use in immunomodulatory therapies has faced limitations due to inherent challenges in achieving controlled delivery and requirements for high extracellular concentrations to achieve internalization of the highly polar small molecule to achieve its intracellular therapeutic activity. Microparticle (MP)-based delivery strategies are a promising approach for intracellular delivery of small molecule metabolites through macrophage phagocytosis and subsequent intracellular polymer degradation-based delivery. Toward the goal of intracellular delivery of IA, degradable polyester polymer-(poly(itaconate-co-dodecanediol)) based IA polymer microparticles (IA-MPs) were generated using an emulsion method, forming micron-scale ([~] 1.5 {micro}m) degradable microspheres. IA-MPs were characterized with respect to their material properties and IA release kinetics to inform particle fabrication. Treatment of murine bone marrow-derived macrophages with an optimized particle concentration of 0.1 mg/million cells enabled phagocytosis-mediated internalization and low levels of cytotoxicity. Flow cytometry demonstrated IA-MP-specific regulation of IA-sensitive inflammatory targets. Metabolic analyses demonstrated that IA-MP internalization inhibited oxidative metabolism and induced glycolytic reliance, consistent with the established mechanism of IA-associated inhibition of succinate dehydrogenase. This development of IA-based polymer microparticles provides a basis for additional innovative metabolite-based microparticle drug delivery systems for the treatment of inflammatory disease.

bioengineering↗

bioRxiv2025

Frontoparietal activity related to neuropsychological assessment of working memory

Executive functions, including working memory, are typically assessed clinically with neuropsychological instruments. In contrast, computerized tasks are used to test these cognitive functions in laboratory human and animal studies. Little is known of how neural activity captured by laboratory tasks relates to ability measured by clinical instruments and, by extension, clinical diagnoses of pathological conditions. We therefore sought to determine what aspects of neural activity elicited in laboratory tasks are predictive of performance in neuropsychological instruments. We recorded neural activity from intracranial electrodes implanted in human epilepsy patients as they performed laboratory working memory tasks. These patients had completed neuropsychological instruments preoperatively, including the Weschler Adult Intelligent Scale and the Wisconsin Card Sorting test. Our results revealed that increased high-gamma (70-150 Hz) power in the prefrontal and parietal cortex after presentation of visual stimuli to be remembered was indicative of lower performance in the neuropsychological tasks. On the other hand, we observed a positive correlation between high-frequency power amplitude in the delay period of the laboratory tasks and neuropsychological performance. Our results demonstrate how neural activity around task events relates to executive function and may be associated with clinical diagnosis of specific cognitive deficits.

neuroscience↗

bioRxiv2024

A Palette of Bridged Bicycle-Strengthened Fluorophores

Organic fluorophores are the keystone of advanced biological imaging. The vast chemical space of fluorophores has been extensively explored in seek of molecules with ideal properties. However, within the current molecular constraints, there appears to be a trade-off between high brightness, robust photostability, and tunable biochemical properties. Herein we report a general strategy to systematically boost the performance of donor-acceptor-type fluorophores by leveraging SO2 and O-substituted azabicyclo[3.2.1] octane auxochromes. These bicyclic heterocycles give rise to a collection of Bridged dyes (BD) spanning the UV and visible range with top-notch quantum efficiencies, enhanced water solubility, and tunable cell-permeability. Notably, these azabicyclic fluorophores showed remarkable photostability than its tetramethyl or azatidine analogue, at the same time completely resistant to oxidative photobluing rendered by the Bredts rule. Functionalized BD dyes are tailored for applications in single-molecule imaging, super-resolution imaging (STED and SIM) in fixed or live mammalian cells and plant cells, and live zebrafish imaging or chemigenetic voltage imaging. Synergizing with advanced imaging methods, the bridge bicycle dyes represent a versatile palette for biological researches.

biophysics↗

bioRxiv2024

Vascular endothelial growth factor-D improves lung vascular integrity during acute lung injury

Disorders in pulmonary vascular integrity are a prominent feature in many lung diseases. Paracrine signaling is highly enriched in the lung and plays a crucial role in regulating vascular homeostasis. However, the specific local cell-cell crosstalk signals that maintain pulmonary microvascular stability in adult animals and humans remain largely unexplored. In this study, we employed single-cell RNA-sequencing (scRNAseq)-based computational pipelines to systematically profile ligand-receptor (L/R) interactions within the lung microvascular niche and identified vascular endothelial growth factor-D (VEGF-D) as a key local factor with previously unrecognized barrier-protective properties in models of acute lung injury. Our scRNAseq data revealed that, under physiological conditions, soluble L/R interactions between mesenchymal cells, in particular alveolar fibroblast, and microvascular endothelial cells are predominantly associated with pathways involved in maintaining vascular integrity as compared to all other cells. Upon treatment with top identified ligands, we found that VEGF-D significantly enhanced endothelial barrier function and conferred protection against inflammatory challenges induced by tumor necrosis factor- (TNF-), interleukin-1{beta} (IL-1{beta}), and thrombin. This barrier-protective effect of VEGF-D was significantly attenuated by inhibition of VEGFR2, either through siRNA knockdown or pharmacological blockade using specific VEGFR2 inhibitors. Intravenous administration of recombinant VEGF-D in lipopolysaccharides (LPS)-induced acute lung injury models significantly reduced vascular permeability (7339 {+/-} 2510 (LPS) v.s. 5350 {+/-} 1821 (LPS + VEGF-D), p < 0.05), immune cell infiltration (0.791 {+/-} 0.199 x 106 WBC/mL (LPS) v.s. 0.540 {+/-} 0.190 x 106 WBC/mL (LPS + VEGF-D), p < 0.01), and the expression of pro-inflammatory markers TNF- and IL-6 in the lung tissue. This effect was abolished in VEGFR2iECKO mice, confirming that VEGF-D mediates its effects via VEGFR2-dependent signaling. This study demonstrates an unexpected protective role for VEGF-D in promoting lung endothelial barrier integrity and suggests that paracrine signaling from the alveolar fibroblast niche contributes critically to lung capillary homeostasis.

molecular biology↗

bioRxiv2024

Toward De Novo Protein Design from Natural Language

Programming biological function-designing bespoke proteins to perform specified molecular tasks-is a foundational goal of molecular engineering. However, current design paradigms remain fundamentally limited: they typically require either natural proteins as starting points for optimization or manual reformulation of functional goals as geometric and sequence-level constraints to guide candidate generation. Here we introduce Pinal, a 16-billion-parameter foundation model that designs candidate proteins from natural-language descriptions of desired function. Trained on 1.7 billion synthetically annotated protein-text pairs, Pinal links functional intent to protein sequence and structure. In computational evaluations, generated candidates combined high predicted foldability with functional-description alignment and sequence diversity, providing a basis for prioritizing experimentally testable designs. We applied Pinal to four distinct design tasks-a fluorescent protein, a polyethylene terephthalate hydrolase, an alcohol dehydrogenase and a metabolic H-protein-and experimentally observed the intended function in each case, including catalytic activity for both designed enzymes. Crucially, without iterative experimental optimization, a Pinal-designed H-protein increased product titer by 1.7-fold relative to the corresponding native E. coli H-protein in a multi-enzyme CO2 fixation pathway. These findings support natural language as a high-level interface for candidate generation in protein design, enabling programmable exploration with reduced reliance on manually specified structural or sequence constraints.

bioengineering↗

bioRxiv2024

Mesolimbic local field potentials are modulated by motor control

Background and ObjectivesWhile historically cortico-basal ganglia-thalamocortical loops were believed to process limbic and sensorimotor data in parallel, there is now evidence to suggest that the two information streams can be processed in a single open loop. However, the limbic-motor interface remains insufficiently characterized. We sought to further investigate how extrastriatal regions may regulate motor output by examining electrophysiological activity in these areas during a response inhibition paradigm. MethodsWe recorded local field potentials (LFPs) from epilepsy patients implanted with intracranial depth electrodes for seizure localization purposes. Participants performed the stop-signal task, during which they made speeded choice reactions to "go" stimuli and occasionally inhibited their reactions in the incident of a "stop" signal. To compare power during movement and the absence of movement, we applied a Wilcoxon signed-rank test. Additionally, we performed a linear mixed-effects model to relate power in limbic regions to power in the motor cortex. Finally, we implemented exploratory analyses to identify power differences for correct go versus correct stop trials and for correct stop versus incorrect stop trials using cluster-based permutation testing. Results14 patients participated. A comparison between movement and baseline fixation revealed that motor response is associated with reduced beta (15-35 Hz) power in the amygdala, hippocampus, and motor cortex and reduced gamma (35-100 Hz) power in the amygdala and hippocampus. Moreover, average beta and gamma power in the amygdala and hippocampus during motor execution were positively associated with average beta and gamma power in the motor cortex. Additionally, we identified significant differences between correct go and stop trials in delta (1-4 Hz) power for all three regions and in theta (4-8 Hz) power for the amygdala and motor cortex. Likewise, we identified significant differences between correct and incorrect stop trials in delta power for the hippocampus and motor cortex, in theta power for the motor cortex, in alpha (8-15 Hz) and beta power for the amygdala and motor cortex, and in gamma power for all three areas. DiscussionThese correlations between neural oscillations in the hippocampus and amygdala and movement strengthen the notion of mesolimbic modulation of motor activity.

neuroscience↗

bioRxiv2024

Reward Circuit Local Field Potential Modulations Precede Risk Taking

Risk taking behavior is a symptom of multiple neuropsychiatric disorders and often lacks effective treatments. Reward circuitry regions including the amygdala, orbitofrontal cortex, insula, and anterior cingulate have been implicated in risk-taking by neuroimaging studies. Electrophysiological activity associated with risk taking in these regions is not well understood in humans. Further characterizing the neural signalling that underlies risk-taking may provide therapeutic insight into disorders associated with risk-taking. Eleven patients with pharmacoresistant epilepsy who underwent stereotactic electroencephalography with electrodes in the amygdala, orbitofrontal cortex, insula, and/or anterior cingulate participated. Patients participated in a gambling task where they wagered on a visible playing card being higher than a hidden card, betting $5 or $20 on this outcome, while local field potentials were recorded from implanted electrodes. We used cluster-based permutation testing to identify reward prediction error signals by comparing oscillatory power following unexpected and expected rewards. We also used cluster-based permutation testing to compare power preceding high and low bets in high-risk (<50% chance of winning) trials and two-way ANOVA with bet and risk level to identify signals associated with risky, risk averse, and optimized decisions. We used linear mixed effects models to evaluate the relationship between reward prediction error and risky decision signals across trials, and a linear regression model for associations between risky decision signal power and Barratt Impulsiveness Scale scores for each patient. Reward prediction error signals were identified in the amygdala (p=0.0066), anterior cingulate (p=0.0092), and orbitofrontal cortex (p=6.0E-4, p=4.0E-4). Risky decisions were predicted by increased oscillatory power in high-gamma frequency range during card presentation in the orbitofrontal cortex (p=0.0022), and by increased power following bet cue presentation across the theta-to-beta range in the orbitofrontal cortex (p=0.0022), high-gamma in the anterior cingulate (p=0.0004), and high-gamma in the insula (p=0.0014). Risk averse decisions were predicted by decreased orbitofrontal cortex gamma power (p=2.0E-4). Optimized decisions that maximized earnings were preceded by decreases within the theta to beta range in orbitofrontal cortex (p=2.0E-4), broad frequencies in amygdala (p=2.0E-4), and theta to low-gamma in insula (p=4.0E-4). Insula risky decision power was associated with orbitofrontal cortex high-gamma reward prediction error signal (p=0.0048) and with patient impulsivity (p=0.00478). Our findings identify and help characterize reward circuitry activity predictive of risk-taking in humans. These findings may serve as potential biomarkers to inform the development of novel treatment strategies such as closed loop neuromodulation for disorders of risk taking.

neuroscience↗