Biology subjects

Zhang, J.

Publications and source records attributed to Zhang, J..

At least 379 records · Page 21Linked to original sources

bioRxiv2025

Cognitive effects of placebo antipsychotics: Investigating their mechanisms using event-related potentials (ERPs) in a cognitive test and a self-referential task

Placebos modulate neurocognitive processes. We examined whether a fully deceptive antipsychotic-placebo changes cognition not only by enhancing arousal and attention but also by changing self-representations, namely, by adding that of being under a treatment related to psychosis and by weakening the binding of experience to reality. Drug-naive healthy participants (N = 83) were split into a group (N = 40) who took a pill described as an antipsychotic and a no-pill control group (N = 43). Participants performed a cognitive test (CogTest), that is, a semantic categorization task and a self-referential role judgment task (SRT). Behavioral responses and event-related potentials (ERPs) were recorded. In the CogTest, placebos showed faster response times and higher accuracy than no-pills. This cognitive improvement was associated with more negative occipito-temporal early ERPs (OTEEs), larger central P2s (CentP2s), and larger late positive potentials (LPPs), with the latter correlating with response times. As in the literature, CentP2s were maximal in the SRT, possibly because it maximally stimulates the binding of the stimulus to long-term self-representations. The larger CentP2s and LPPs for placebos than for no-pills in the CogTest were thus tentatively related to the binding of the stimulus with egocentric self-representations, temporarily enriched by the addition of the representation of being on drug. On the contrary, the more negative OTEEs were related to a weaker binding to allocentric ones, preventing a strong binding of experience with reality. The smaller N400s observed for placebos than for no-pills in both tasks were related to greater openness to new experiences.

neuroscience↗

bioRxiv2025

Transcranial focused ultrasound induces source localizable cortical activation in resting state humans when applied concurrently with transcranial electric stimulation

The effects of transcranial focused ultrasound (tFUS) on the human brain are poorly understood. Currently, the field is at odds with whether tFUS is subthreshold modulating the brains excitability towards other stimuli, producing suprathreshold neural stimulation on its own, or if it even has a spatially specific non-auditory induced affect. Herein, we investigated the ability of tFUS, transcranial direct current stimulation (tDCS) and a novel combination of the two (transcranial electro-acoustic stimulation; tEAS) to evoke cortical target-location specific activity in 27 resting state humans with whole brain electroencephalography recordings. In none of the exogenous event related potentials did tFUS or tDCS result in location-specific activations. However, the co-modulatory combination of tEAS did, providing evidence that tFUS has a location-specific subthreshold modulatory effect. We propose a minimally modified Hodgkin Huxley model that explains our results and provides a unifying framework for the field-wide observed effects (or lack thereof) of tFUS.

neuroscience↗

bioRxiv2025

RBM15 promotes lung adenocarcinoma progression and palbociclib sensitivity via m6A-mediated STIL activation and downstream cyclin D1/CDK4 signaling

RNA-binding motif protein 15 (RBM15), an N6-methyladenosine (m6A) methyltransferase, plays a crucial role in the progression of lung adenocarcinoma (LUAD); however, the underlying mechanisms remain insufficiently defined. In this study, we investigated the contribution of RBM15-mediated m6A modification to LUAD pathogenesis. Our data showed that RBM15 was highly expressed in LUAD tissues and cell lines. Notably, its expression levels were positively correlated with tumor TNM staging and negatively correlated with differentiation status. The overexpression of RBM15 enhanced cell proliferation, migration, invasion, and cell cycle progression, while simultaneously inhibiting apoptosis. Conversely, RBM15 knockdown reversed these phenotypes and induced G2/M-phase arrest. In vivo experiments further confirmed that RBM15 knockdown led to the suppression of tumor growth. RNA sequencing, MeRIP sequencing, and bioinformatics analyses identified STIL as a gene directly regulated by RBM15 through m6A modification, a finding subsequently validated by luciferase reporter assays. Western blot and rescue experiments demonstrated that RBM15 and STIL cooperatively activate the cyclin D1/CDK4 signaling pathway, thereby promoting LUAD progression. However, this effect was markedly attenuated by CDK4/6 inhibitor application. Collectively, these findings indicated that the RBM15-STIL-cyclin D1/CDK4 axis represents a promising therapeutic target for LUAD.

cancer biology↗

bioRxiv2025

Guidance receptor-mediated mechanocompliance of GBM cells facilitates immune-silent invasion

The lethality of glioblastoma (GBM) stems from diffuse infiltration and immune evasion, two hallmarks traditionally studied separately. Here, we identify as unifying mechanism how GBM cells utilize guidance receptors Plexin-D1 and Plexin-B2 to gain mechanocompliance, i.e., the ability to deform and remodel membrane/cytoskeleton during confined migration without triggering immune activation. We show that PLXND1 upregulation marks invasive fronts and predicts poor survival of glioma patients. Through live-cell imaging in microchannels, intracranial xenografts, single-nucleus transcriptomics, and lipidomics we demonstrate that Plexin-D1/B2 enable GBM cells to retract tumor microtubes (TMs), traverse constrictions, and escape microglial surveillance. Single and especially double deletion of PLXND1 and B2 resulted in TM overgrowth, membrane instability, and susceptibility to cell fragment shedding, leading to impaired migration and a shift to activation of tumor-associated myeloid cells. Our findings thus reveal a molecular strategy used by GBM cells to penetrate through interstitial space while escaping immune surveillance. SIGNIFICANCEPlexin-mediated mechanocompliance underlies the invasive yet immune-silent behavior of GBM cells, exposing a vulnerability that could be therapeutically exploited by forcing invading tumor cells into a mechanically fragile, immunogenic state.

cancer biology↗

bioRxiv2025

Computational design of CYP102A1 variants for the biosynthesis of a next-generation antiplatelet drug DT-678

Clopidogrel is a widely used antiplatelet prodrug to treat acute coronary syndromes. However, its clinical efficacy is hampered by ineffective bioactivation to produce the pharmacologically active metabolite (AM), leading to variability in antiplatelet response among different ethnic groups. To overcome the shortcomings of clopidogrel, DT-678 was developed by conjugating the AM to 3-nitropyridine-2-thiol via a mixed disulfide bond. It has been challenging to produce the conjugate in high yield by chemical synthesis. Here, we report the first de novo biosynthesis of DT-678 using engineered CYP102A1 variants. We applied structure-based computational design using UniDesign to generate three variants (UD4, UD5, and UD6) that enhanced the catalytic activity and selectivity toward DT-678 synthesis. Among them, UD6 demonstrated the highest total turnover number and DT-678-specific productivity under optimized conditions. Mechanistic analysis revealed that rapid enzyme inactivation, driven by reactive oxygen species (ROS) such as superoxide and hydrogen peroxide, limited overall yield. Remarkably, we found that ascorbic acid significantly protected CYP102A1 variants from inactivation and hence increased production yield. This work establishes a scalable enzymatic strategy for DT-678 biosynthesis and highlights the importance of combining protein engineering with redox control to overcome limitations in CYP-catalyzed reactions.

biochemistry↗

bioRxiv2025

Mapping the Glycogen Synthase 1 Interactome in Brown Adipocytes

Brown adipose tissue (BAT) is distinguished by its ability to dissipate energy through thermogenesis, a process with considerable therapeutic potential for obesity, type 2 diabetes, and related metabolic disorders. Although glycogen represents a relatively minor energy reserve in adipocytes compared with liver and muscle, emerging evidence shows that glycogen turnover increases sharply during metabolic transitions and is required for full thermogenic activation in brown adipocytes. The rate-limiting enzyme glycogen synthase 1 (GYS1) catalyzes glycogen chain elongation, and adipose-specific Gys1 deletion impairs adaptive thermogenesis, highlighting the importance of GYS1 in coordinating glucose and lipid metabolism; however, the mechanisms regulating GYS1 in BAT remain poorly defined. To address this gap, we used an unbiased proximity-labeling strategy in brown adipocytes by fusing GYS1 to the biotin ligase TurboID and identifying biotinylated proteins through mass spectrometry, revealing 425 putative interactors. These included canonical glycogen-handling proteins such as glycogenin and glycogen phosphorylase, validating the approach, while gene ontology analysis uncovered broader enrichment in cytoskeletal remodeling, vesicle trafficking, and transcriptional regulation, suggesting previously unrecognized roles for GYS1 beyond glycogen synthesis. Notably, we identified several novel candidate interactors, including CAST, PDAP1, and CCDC102A. Together, these findings define the most comprehensive GYS1 interactome reported to date and provide new insights into the molecular mechanisms linking glycogen metabolism to thermogenic function in BAT.

biochemistry↗

bioRxiv2025

GPR34 regulation of disease-associated microglial states and responses to physiological stimuli

Expression of the G protein coupled receptor GPR34 is highly enriched in microglia and has been reported to be downregulated in several brain disease contexts, including Alzheimers disease (AD) and multiple sclerosis (MS). GPR34 function is poorly understood, as is its role in regulation of microglial states. Using RNA-sequencing, we find that microglia from Gpr34 knockout (KO) mouse brains exhibited a transcriptomic shift toward disease-associated microglia (DAM) and inflammatory profiles, partially resembling the microglial phenotype seen in 5xFAD AD model mice. Moreover, when Gpr34 KO mice were crossed with 5xFAD mice, the DAM transcriptional profile of microglia and glial pathology were further enhanced beyond the already robust DAM signature driven by 5xFAD alone. This occurred without affecting amyloid plaque burden. Human stem cell-derived microglia (iMGLs) lacking GPR34 showed reduced calcium (Ca{superscript 2}) and phosphorylated ERK (pERK) signaling in response to stimulation with known GPR34 agonists (lyso-phosphatidylserine (lysoPS) and myelin), as well as transcriptomic changes in immune regulation and cell proliferation related pathways. Interestingly, GPR34 KO iMGLs were selectively impaired in phagocytosis of myelin but not amyloid-{beta} (A{beta}) or E. coli, and showed a diminished transcriptional response elicited by myelin. Together, these findings suggest that GPR34 is important for maintaining microglia in a homeostatic state, promotes phagocytosis of and transcriptional response to myelin, and limits microglial activation in neurodegenerative disease conditions.

neuroscience↗

bioRxiv2025

Amyloid-β 42-carrying extracellular vesicles are associated with neurodegeneration and neuroinflammation in Alzheimer's disease

Alzheimers disease (AD) is the most common form of dementia, characterized by progressive amyloid-{beta} (A{beta}) accumulation and neurodegeneration. Extracellular vesicles (EVs) have been implicated in AD pathology, but their relationship to disease progression and the cerebrospinal fluid (CSF) proteome remains poorly understood. In this study, we analysed plasma-derived A{beta}42-containing EVs from participants of the Alzheimers Disease Neuroimaging Initiative (ADNI) and calculated the ratio between the percentage of A{beta}42-positive peripheral EVs and CSF A{beta}42 (rA{beta}42). This ratio was elevated in AD and positively correlated with amyloid pathology as measured by PET. Longitudinal analyses revealed that higher rA{beta}42 values predicted accelerated hippocampal atrophy and cognitive decline, independent of CSF A{beta}42 concentrations. Proteomic profiling of CSF using the SomaScan platform showed that rA{beta}42 was associated with an inflammatory signature characterized by myeloid activation and type II interferon-related signalling pathways. Together, these findings indicate that A{beta}42-carrying EVs reflect an active and inflammatory component of AD pathology and may represent a novel class of biomarkers for disease progression. Understanding the mechanisms that link A{beta}42-positive EVs to neuroinflammatory signalling could open new avenues for pathway-specific diagnostics and therapeutic strategies in AD.

neuroscience↗

bioRxiv2025

Flexible Skull-Conformal Phased Array for Aberration-Corrected Transcranial Focused Ultrasound Therapy

Transcranial focused ultrasound (tFUS) is a promising non-invasive tool for precise deep-brain interventions, including neuromodulation, blood-brain barrier opening, and drug delivery. However, conventional rigid tFUS arrays suffer from poor skull conformity, compromising patient comfort and targeting precision, while skull-induced aberrations degrade focal accuracy and efficiency. To address these challenges, we present the first flexible, skull-conformal aberration-corrected phased array (F-SCAPA), a transformative solution integrating mechanical adaptability with advanced acoustic correction. The 0.5-MHz array--comprising 8x8 elements--features an optimized fabrication process that enhances material efficiency, ensures flexibility and stretchability, and maintains uniform electrical performance. Coupled with CT-based skull modeling and time-reversal aberration correction, F-SCAPA dynamically conforms to cranial anatomy while compensating for phase distortions. Transcranial validation in a human skull demonstrates precise focusing at 36 mm depth, achieving an axial full width at half maximum (FWHM) of 8.9 mm. This breakthrough overcomes existing limitations by combining mechanical adaptability with high-resolution transcranial focusing, establishing F-SCAPA as a robust, patient-compatible platform for next-generation non-invasive brain therapies.

bioengineering↗

bioRxiv2025

Non-invasive modulation of brain activity and behavior by transcranial radio frequency stimulation

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSAchieving non-invasive, targeted modulation of deep brain tissue remains a major challenge in neurotechnology. Current non-invasive brain stimulation methods--such as transcranial electrical (TES), magnetic (TMS), and focused ultrasound (TFUS) stimulation--suffer from limitations in spatial focality, penetration depth, or skull-related distortions. Radio frequency (RF) energy, which penetrates biological tissue effectively, offers an alternative avenue for neural modulation. This study introduces Transcranial Radio Frequency Stimulation (TRFS) as a novel, contactless neuromodulation technique that leverages RF-induced thermal effects to modulate neural activity in vivo. MethodsWe developed a custom RF stimulation system using 945 MHz stub antennas optimized for localized brain heating in mice. Using our unique experimental setup, we developed and tested two operational modes of TRFS: Pristine mode: RF stimulation applied to intact brain tissue. RF-genetics mode: RF stimulation applied to brain regions virally transduced to overexpress the thermosensitive TRPV1 ion channel. Neural activity was recorded using metal-free one-photon fiber photometry with GCaMP calcium indicators. Behavioral effects were assessed through a rotational test in freely moving mice after MK-801-induced hyperlocomotion. Local temperature changes were monitored by optical thermometry. ResultsIn pristine mode, RF exposure induced temperature rises leading to dose-dependent suppression of cortical parvalbumin (PV) interneuron activity. This neural suppression translated behaviorally into a unilateral rotational bias ipsilateral to the stimulated hemisphere in hyperlocomotive freely moving mice. In RF-genetics mode, RF stimulation of TRPV1-overexpressing regions produced temperature-dependent excitation of neural activity once local change in temperatures exceeded {Delta}T {approx} 1.5 {degrees}C. Behaviorally, this excitation reversed the direction of rotation in hyperlocomotive freely moving mice, yielding a contralateral bias. ConclusionsTRFS represents a conceptual advance in neuromodulation, uniting the inherent capability of RF energy to target deep brain tissue with the biophysical reliability of thermal modulation. TRFS applications are bimodal, capable of influencing the pristine brain by suppressing the activity of specific neuronal populations in targeted regions, or of exciting selectively transfected neural ensembles expressing thermosensitive TRPV1 ion channels. The latter modality, first introduced here, represents a novel concept termed "RF-genetics." TRFS represents a promising platform for next-generation non-invasive brain stimulation with potential translational applications in treating various neurological and psychiatric disorders.

neuroscience↗

bioRxiv2025

NanoporeDB: A Structural Resource Of Multimeric Protein Nanopores In Single-Molecule Sensing

Protein nanopores are essential molecular gateways in biology and have inspired transformative technologies in biosensing and single-molecule sequencing. While this technology has transformed genomics and biosensing, the discovery of novel nanopore scaffolds remains limited due to the scarcity of experimentally resolved pore structures. Here, we present NanoporeDB, an open-access structural resource comprising over 6,600 high-confidence multimeric models across four representative pore types. Candidate proteins were systematically mined from large-scale datasets, including the AlphaFold Protein Structure Database, UniRef90, and MGnify90, and assembled using AlphaFold-Multimer and AlphaFold3. We performed membrane embedding, pore axis annotation, and constriction profiling to enable functional interpretation. NanoporeDB features an interactive web interface with 3D visualization and quantitative metrics such as insertion depth, tilt angle, and pore geometry. This resource provides a structural foundation for advancing nanopore-based molecular sensing, precision diagnostics, and synthetic biology.

bioinformatics↗

bioRxiv2025

Direct recruitment of RNA Polymerase II by NANOG to activated target genes

Cell identity relies upon transcription factors (TFs). The concentration of the TF NANOG determines the efficiency of maintenance of mouse embryonic stem cell (ESC) identity. However, the mechanisms by which NANOG acts are not fully understood. Models of mammalian transcription generally propose that TFs bind DNA and connect to the transcriptional machinery indirectly via intermediary proteins. Accordingly, examples of direct contact between cell-type specific TFs and RNA synthesis enzymes in mammalian cells remain elusive. Here we show that NANOG directly contacts RNA Polymerase II (RNAPII) via aromatic residues within the low complexity domains of both proteins. NANOG can localize RNAPII to a specific DNA site, with RNAPII enhancing NANOG DNA affinity. The NANOG-RNAPII complex is dissociated by the transcriptional pause-release enzyme, CDK9. Inhibition of CDK9 enhances NANOG chromatin binding, while induction of NANOG localizes RNAPII to specific NANOG chromatin sites. Induced RNAPII localization is selective for targets activated by NANOG. A NANOG mutant that retains DNA, but not RNAPII binding, cannot stimulate RNAPII localization to chromatin, shows an impaired transcriptional response and does not drive LIF-independent ESC self-renewal. These results identify a novel, regulatable interaction between a cell-type specific TF and RNAPII that can change transcription and alter cell fate.

cell biology↗

bioRxiv2025

Fluctuating flooding motivates the facilitation of a wetland invader: a probe into the stress gradient hypothesis

Stress gradient hypothesis proposes that the plant interaction tends to convert from competition to facilitation when facing accelerating stress. The present study aims to explore the interaction between two co-existing wetland plant invaders - Alternanthera philoxeroides and Myriophyllum aquaticum with exposure to flooding stress. Different plant assemblages including monospecific (single individual per species), homospecific (two individuals of same species) and heterospecific (two individuals of different species) treatments were subjected to different flooding regimes including mesic habitat, constant flooding and fluctuating flooding. The plant interaction was evaluated by biomass accumulation, biomass allocation and relative competition intensity index (RCI). We found that the biomass accumulation and allocation of A. philoxeroides were consistent across different treatments of community assemblage and flooding regime, while the root mass, biomass and root mass allocation of M. aquaticum significantly increased at the presence of A. philoxeroides. Moreover, the RCI of M. aquaticum decreased at the presence of A. philoxeroides. Especially, the RCI of M. aquaticum was 0.06 in the homospecific community, while that of M. aquaticum was -0.82 in the heterospecific treatment under fluctuating flooding condition. Overall, Alternanthera philoxeroides facilitated M. aquaticum, especially under fluctuating flooding condition, which complies with the stress gradient hypothesis. The water level drawdown can benefit the impedance of the growth of M. aquaticum and the deceleration of the co-invasion of A. philoxeroides and M. aquaticum.

ecology↗

bioRxiv2025

From Circles to Signals: Representation Learning on Ultra-Long Extrachromosomal Circular DNA

Extrachromosomal circular DNA (eccDNA) is a covalently closed circular DNA molecule that plays an important role in cancer biology. Genomic foundation models have recently emerged as a powerful direction for DNA sequence modeling, enabling the direct prediction of biologically relevant properties from DNA sequences. Although recent genomic foundation models have shown strong performance on general DNA sequence modeling, their application to eccDNA remains limited: existing approaches either rely on computationally expensive attention mechanisms or truncate ultra-long sequences into kilobase fragments, thereby disrupting long-range continuity and ignoring the molecules circular topology. To overcome these problems, we introduce eccDNAMamba, a bidirectional state space model (SSM) built upon the Mamba-2 framework, which scales linearly with input sequence length and enables scalable modeling of ultra-long eccDNA sequences. eccDNAMamba further incorporates a circular augmentation strategy to preserve the intrinsic circular topology of eccDNA. Comprehensive evaluations against state-of-the-art genomic foundation models demonstrate that eccDNAMamba achieves superior performance on ultra-long sequences across multiple task settings, such as cancer versus healthy eccDNA discrimination and eccDNA copy-number level prediction. Moreover, the Integrated Gradient (IG) based model explanation indicates that eccDNAMamba focuses on biologically meaningful regulatory elements and can uncover key sequence patterns in cancer-derived eccDNAs. Overall, these results demonstrate that eccDNAMamba effectively models ultra-long eccDNA sequences by leveraging their unique circular topology and regulatory architecture, bridging a critical gap in sequence analysis. Our codes and datasets are available at https://github.com/zzq1zh/eccDNAMamba.

bioinformatics↗

bioRxiv2025

TXNDC5 Governs Extracellular Matrix Homeostasis in Pulmonary Hypertension

BACKGROUNDPulmonary hypertension (PH) is characterized by vascular remodeling without effective treatments. Thioredoxin domain containing 5 (TXNDC5), a member of the protein disulfide isomerases (PDI) family, regulates protein folding and vascular homeostasis, yet its role in PH remains unknown. METHODSLabel-free proteomics profiled protein expression in lungs from PH patients. TXNDC5 was analyzed by single-cell RNA sequencing, immunofluorescence, and Western blot. Endothelial gain- and loss-of-function approaches were applied in Sugen5416/hypoxia (SuHx)-induced rodent PH models. RNA sequencing and protein-protein interaction analysis were used to investigate underlying mechanisms. RESULTSTXNDC5 was significantly upregulated in the lungs of patients with PH and in experimental PH models, with predominant localization in endothelial cells (ECs) of remodeled distal pulmonary arteries. Endothelial TXNDC5 overexpression exacerbated pulmonary vascular remodeling, elevated right ventricular systolic pressure, and promoted right ventricular hypertrophy, whereas global or endothelial-specific TXNDC5 deficiency conferred protection against SuHx-induced PH. Hypoxia-induced factor (HIF)-2 transcriptionally activated TXNDC5 to drive PH development. Single-cell RNA sequencing identified a distinct subpopulation characterized by TXNDC5high extracellular matrix (ECM)-producing ECs. Bulk RNA sequencing combined with protein-protein interaction analysis revealed that TXNDC5 regulated ECM homeostasis through biglycan (BGN). Pharmacological inhibition of TXNDC5 with E64FC26 and endothelial-targeted TXNDC5 gene therapy significantly attenuated PH severity in rats. CONCLUSIONSOur study reveals that TXNDC5 is a main modulator to regulate ECM homeostasis and may serve as a promising target for the treatment of PH.

molecular biology↗

bioRxiv2025

Distinct Programs Drive Organ Development and Regeneration

A prevailing paradigm in stem cell and developmental biology posits that regeneration is a recapitulation of embryonic programs, yet the molecular logic underlying these processes remains unclear. Here, using the mammary gland as a model, we identified a novel intermediate cell state essential for basal-to-luminal differentiation during regeneration. The transcription factor Pou2f3 is a master regulator of this state, critical for regeneration but dispensable for organ physiology. Mechanistically, we found that POU2F3 functions as a transcriptional repressor that drives lineage conversion by restricting chromatin accessibility of basal genes rather than by directly activating luminal programs. Furthermore, we uncovered a POU2F3-TNF feedback loop that maintains epithelial homeostasis, where TNF signaling suppresses Pou2f3 to inhibit differentiation, and loss of luminal cells relieves this repression to trigger regeneration. Strikingly, cell fate is governed by signaling pathways essential for cell-cell communication during development, but by Pou2f3-dependent chromatin remodeling for rapid response and injury repair. We validate the regeneration-specific requirement for Pou2f3 in mammary gland and further demonstrate analogous regeneration defects in prostate and pancreas. These findings challenge the long-held assumption that regeneration recapitulates development and establish a framework for understanding context-specific mechanisms of tissue plasticity, with implications for regenerative medicine and epithelial biology.

cell biology↗

bioRxiv2025

A nucleic acid labeling chemistry reveals surface DNA on exosomes

Chemical labeling of nucleic acids is essential to pinpoint the structure, localization, and function of RNA and DNA. Yet, reversible sequence-independent chemistries that can label native RNA and DNA remain poorly developed. Here we describe Reversible Uridine Nitrilium-mediated Addition (RUNA), a reversible covalent chemistry that selectively modifies uridine and thymidine residues via N3 deprotonation and reaction with a nitrilium ion intermediate generated from an aldehyde and an isonitrile. The reaction forms a stable N3 adduct that can be quantitatively reversed by hydrolysis. By using reagents that are either membrane permeable or impermeable, we demonstrate the localization and function of DNA on exosomes. Although exosomes harbor nucleic acids, whether the latter are encapsulated in the exosome lumen or are surface-adhered is unknown. RUNA revealed that exosomes display DNA on their outer surface. The abundance of such surface DNA increases upon DNA-damage accumulation in cancer cells that are treated with a PARP inhibitor. This surface DNA drives exosome uptake by M2-polarized macrophages through scavenger receptors and triggers a shift toward an M1-like pro-inflammatory state. The selective labeling of surface DNA revealed an unexpected mechanism by which exosomes engage innate immune cells. RUNA is a versatile tool to analyze the nucleic acid content and functionality of extracellular vesicles in health and disease. Significance StatementPinpointing the localization of RNA and DNA in cells and organelles is central to deriving insights into their biological functions in health and disease. We describe a new method, RUNA, for labeling nucleic acids that is sequence-independent and reversible. By varying RUNA reagents, we can distinguish between nucleic acids that are located either inside or outside of membrane compartments. Using RUNA, we showed that DNA is associated with the outer surface of exosomes that are secreted by cancer cells. Further, the amount of surface DNA increases when the cancer cells are treated with an anti-cancer drug. This surface DNA promotes the uptake of exosomes by innate immune cells known as macrophages and modulates their inflammatory response.

biochemistry↗

bioRxiv2025

Dynamic interactions in human amygdala subregions support hierarchical processing of fearful faces

Fearful-expression recognition is critical for adaptive responses to potential threats and relies on both rapid threat detection and fine-grained face encoding. Yet how human amygdala subregions differentially support these distinct cognitive components remains unclear. Here, we recorded intracranial EEG from lateral and medial amygdala in epilepsy patients performing an emotional face-matching task and combined multivariate decoding, time-frequency and directed-connectivity analyses with intracranial stimulation. The lateral amygdala exhibited early fear-specific responses, characterized by higher decoding accuracy and increased theta/alpha-band (4-12 Hz) power, and transmitted this fear-related information to the medial amygdala, which showed delayed and sustained activation. By contrast, the medial amygdala encoded face-specific information at later stages in the 2-16 Hz band with superior decoding accuracy and then relayed this information back to the lateral amygdala. Intracranial stimulation produced a double dissociation in behavior, with lateral amygdala stimulation disrupting fear detection, whereas medial amygdala stimulation selectively accelerated neutral-face recognition. Together, these findings reveal a temporal hierarchy in the human amygdala, whereby dynamic bidirectional interactions between subregions implement distinct components of fearful-expression recognition, providing a circuit-level framework for understanding social threat processing.

neuroscience↗