Biology subjects

Wu, D.

Publications and source records attributed to Wu, D..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Transcranial direct current stimulation combined cognitive training modulates risk-taking behavior in older adults

Risk-taking behavior is a complex cognitive function that often declines with aging, contributing to impaired decision-making and reduced quality of life. While transcranial direct current stimulation (tDCS) has shown promising effects in modulating cognitive function, its influence on ecologically valid, complex behaviors like risky decision-making in older adults remains poorly understood. We investigated whether a single-session stimulation over the medial orbitofrontal cortex (MOFC) combined with cognitive training could enhance decision-making in healthy older adults. In a randomized, sham-controlled study, bilateral MOFC stimulation (left/anode, right/cathode) was applied during a training task based on the Iowa Gambling Task. Pre- and post-intervention assessments utilized conventional behavioral measures and the Values-Plus-Perseveration computational model, alongside task-related fMRI to examine MOFC network changes. Compared to sham, tDCS significantly enhanced the ability to distinguish advantageous from disadvantageous options. Modeling analysis revealed stimulation-induced changes in multiple latent components, such as learning rate, loss aversion, and perseveration decay. Generalized Psychophysiological Interaction analysis showed that tDCS reconfigured the MOFC network by reducing fronto-frontal hyper-connectivity and enhancing fronto-striatal connectivity. These behavioral improvements were specifically associated with the left MOFC network targeted by anodal stimulation. Our results provide causal evidence that tDCS can mitigate age-related impairments in risk-taking by reconfiguring MOFC-related networks. These findings advance the mechanistic understanding of tDCS in aging and highlight its potential as an intervention to prevent age-related decline in decision making.

neuroscience↗

bioRxiv2026

A long-read human pangenome initiative for comprehensive interpretation of nuclear-embedded mitochondrial DNA

Nuclear-embedded mitochondrial DNA segments (NUMT) preserve a record of ongoing mitochondrial-to-nuclear DNA transfer during evolution, with important implications for disease mechanisms and genome organization. Here, we developed a Pangenome Graph-based NUMT Detection (PG-NUMT) approach to improve NUMT detection sensitivity by 2.52-fold compared to short-read based approaches and comprehensively resolved seven concatenated mega-NUMTs with a maximum length of 127.7 kbp. We generated a high-resolution human NUMT map comprising 774 fixed, 280 polymorphic, and 123 pericentromeric NUMTs, alongside 74 superpopulation-stratified NUMTs. Both fixed and polymorphic NUMTs are hypermethylated and enriched within segmental duplications, whereas fixed NUMTs preferentially localize to intergenic regions and avoid transposable elements. Interestingly, NUMTs derived from the 3-end of the mtDNA D-loop are less frequently fixed in human genomes and exhibit potential cis-regulatory activity in the nuclear genome. These observations suggest that selective pressures shape the genomic features of fixed NUMTs. Seven NUMTs associated with gene expression or alternative splicing were further identified, suggesting potential modulatory functions of common NUMTs. Using 20 complete non-human primate genomes, we identified variable NUMT insertion rates across primate lineages (1.5-18.7 insertions per million years), with particularly high rates in the Pan lineage. Notably, we uncovered two NUMT-derived variable number tandem repeats (VNTRs), establishing NUMTs as a novel source of VNTRs. In summary, the integrated analysis enhances our understanding of NUMT genomic architecture, population dynamics, and evolutionary implications in human and non-human primates, establishing NUMTs as dynamic genomic components of biomedical relevance.

genomics↗

bioRxiv2026

UBE3C retrofits the proteasome to enforce degradation of ultra-stable folds

Neurodegeneration and proteinopathies arise from mutated or misfolded proteins that form ultra-stable, proteotoxic aggregates that evade proteasomal degradation despite ubiquitylation1-8. These conditions are exacerbated by the deubiquitylase USP14 that can prematurely rescue substrates9-11. To counter these obstacles to effective proteolysis, eukaryotes evolved the highly conserved HECT-type E3 ligase UBE3C--dysregulated in neurodegeneration12,13 and overexpressed in cancers14-17--to reprogram the 26S proteasome toward heightened activity via unknown mechanisms18-25. Here we visualized functional dynamics of the human UBE3C-retrofitted proteasome enforcing degradation of a re-engineered superfolder GFP that normally escapes proteolysis, using time-resolved cryo-electron microscopy. A continuum of non-equilibrium conformations, comprising fourteen proteasome conformers orthogonally combined with four UBE3C states or three USP14 states, reveals a cryptic UBE3C-receptor site in the proteasomal lid and captures key intermediates of ubiquitin-chain elongation and branching at four linkage-specific ubiquitin-binding sites. Remarkably, UBE3C creates an extreme shortcut for ubiquitin shuttling that bypasses USP14, promotes USP14 recycling and allosterically strengthens substrate-unfolding forces of the AAA-ATPase unfoldase to ultimately surmount the unfolding energy barrier of ultra-stable proteins. These findings define the complete functional cycle of the UBE3C-reprogrammed proteasome, illuminating how UBE3C simultaneously controls USP14 and the proteasome to enforce clearance of ultra-stable folds, and establish crucial mechanistic foundations for proteolysis-targeting therapeutic discovery.

biochemistry↗

bioRxiv2026

Z-RNA-ZBP1 axis drives Tau-mediated neurodegeneration

Although the causes of Tau aggregates vary, once Tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimers disease (AD) being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting neurotoxicity of Tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in Tau-related neurodegeneration. Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements (TEs) that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from Heterochromatin Protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in AD patients was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged Tau-transgenic mice (24-month-old), highlighting the therapeutic potential of ZBP1 inhibition to strive against neurodegeneration in tauopathies.

neuroscience↗

bioRxiv2026

Modular DNA nanosensors enable state-aware multiplexed single-molecule mass photometry in complex media

Proteins exist in diverse biochemical states, including oligomers, complexes, heterogeneous proteoforms and shed fragments that encode functional and regulatory information. Yet, these molecular states remain difficult to resolve with existing analytical techniques, which typically require labelling, immobilisation or amplification and collapse this information into a single readout. Here, we introduce a modular platform that integrates programmable DNA nanostructures with single-molecule mass photometry for rapid, label-free and multiplexed protein analysis in native and complex media, without washing, enrichment or immobilisation, making native biochemical states observable directly in serum and plasma. DNA nanostructures act as nanosensors whose mass and mobility on supported lipid bilayers provide orthogonal identifiers for target identity and biochemical state, thereby decoupling recognition from readout. We define the analytical specificity and response window, demonstrate quantitative affinity determination, and resolve oligomeric and proteoform differences under native conditions. The nanosensors are rapidly reprogrammable to new targets, support multiplexed detection with internal controls for non-specific interactions, and enable selective resetting via strand displacement. Together, these capabilities establish nanoscale programmability as a route to state-resolved single-molecule protein profiling adaptable to both diagnostic and mechanistic applications.

biophysics↗

bioRxiv2026

IBDkb: an AI-enhanced integrative knowledge base for inflammatory bowel disease research and drug discovery

IBDkb (Inflammatory Bowel Disease Knowledge Base; https://www.biosino.org/ibdkb) is a freely accessible, integrated web-based platform that systematically curates and harmonizes multi-source data related to inflammatory bowel disease (IBD). To address the fragmentation and therapeutic gaps in existing specialized resources, IBDkb establishes a unified framework featuring advanced full-text search, interactive visualizations, cross-module knowledge graphs, and AI-powered utilities for real-time literature retrieval, trend analysis, text/PDF interpretation, and domain-specific conversational assistance. The platform currently integrates 98,453 research articles, 3,390 clinical trials, 200 investigational drugs, 200,606 bioactive compounds, 103 therapeutic targets, 77 experimental models, 12 pathogenesis summaries, and 15 treatment strategies. These integrated tools facilitate efficient exploration of complex associations among drugs, targets, trials, and mechanisms, thereby accelerating hypothesis generation and translational research in IBD. The platform is openly available without registration and supports data downloads. A case study on structure-aware drug comparison further demonstrates its utility in facilitating cross-disease drug repositioning hypotheses.

bioinformatics↗

bioRxiv2026

Molecular and Cellular Underpinnings of Spatial Heterogeneity in Fetal Cortical Folding

Cortical folding is a defining feature of human brain development, yet the molecular and cellular mechanisms that produce regionally specific cortical folding remain incompletely understood. Here we combined high-resolution in-utero T2-weighted and diffusion MRI atlases (23-38 weeks of gestational age) with prenatal transcriptomic profiles to map regional macrostructural and microstructural features of cortical folding to underlying gene expression. We found genes whose expression patterns correlated with cortical curvature were enriched for neurogenesis, progenitor proliferation and radial glia guided neuronal migration, and localized to ventricular zone/subventricular zone progenitor cell subtypes, supporting for the protomap hypothesis of areal specification. By contrast, cortical microstructural markers-associated gene sets were implicated in myelination, cell adhesion and extracellular matrix remodeling, and mapped to astrocyte and endothelial cell programs. The microstructure-related gene expression peaked in the early postnatal period and remained high throughout childhood, while the curvature-associated gene expression reduced with age. Several of these cortical folding-related genes overlapped with autism spectrum disorder risk loci (e.g., SCN2A, STXBP1, DVL3). Collectively, these cross-modal findings outline a sequential developmental architecture--early progenitor driven patterning followed by myelin and extracellular matrix consolidation. In addition, we released a high-resolution fetal labeling atlas to facilitate further imaging-genetic studies of early cortical development.

neuroscience↗

bioRxiv2026

GARD: Genomic Data based Drug Repurposing in Head and Neck Cancer with Large Language Model Validation

Background/ObjectivesHead and neck cancer (HNC) represents the seventh most common cancer diagnosis globally, yet current treatments, including surgery, radiation, and immunotherapy, have shown limited improvement in outcomes. Drug repurposing offers a cost-effective strategy to identify new therapeutic options by leveraging existing medications with known safety profiles. Within this study we developed the GARD pipeline (Genomic Alteration-based Repurposing for Drugs), designed to uncover repurposing candidates for HNC using genomic and network-based approaches. MethodsGARD integrates multi-omics data from The Cancer Genome Atlas (TCGA), including copy number variation (CNV) and somatic mutations (SOM). The cohort was stratified by human papillomavirus (HPV) status. Risk-associated genes were identified and then expanded via high-confidence protein-protein interaction (PPI) networks. Top candidate genes were filtered through comprehensive analysis of publicly available literature data in PubMed using LLM to validate the relationship between the identified genes and HNC. The validated top risk genes and their network-expanded neighbors were mapped against DrugBank, and through statistical significance testing, established significant drug-gene associations. ResultsSignificant genes associated with HNC, inferred by genomics alteration, were identified across HPV-positive and HPV-negative subgroups, such as PIK3CA, SOX2, TP53, EIF4G1, TLR7, CLDN1, PRKCI, and EPHA2. Further expansion through the PPI network identified other targetable genes such as EGFR, ERBB2, and the FGFRs. Literature based validation efforts ensured provided confidence in the gene-disease association. Drug-gene mapping revealed candidates spanning already in clinical trials for HNC (e.g. Afatinib, Cabozantinib, Dasatinib, Brigatinib, Lenvatinib, Capivasertib, Erdafitinib) and emerging or repurposing candidates (Amuvatinib, XL765 (Voxtalisib), Golotimod, Artenimol, Quercetin, and Acetylsalicylic Acid), offering opportunities for precision repurposing. ConclusionsThe GARD pipeline demonstrates a genomics-driven, network-informed framework for systematic drug repurposing in HNC. HPV stratification enhances precision, literature-based validation strengthens confidence, and integrated drug mapping enables refinement of existing therapies and discovery of novel candidates for personalized treatment strategies. Code AvailabilityThe full implementation of the GARD pipeline, including preprocessing scripts, statistical analysis modules, and visualization tools, is publicly available on GitHub at: https://github.com/pvtanike/Genomic-Landscape-Based-Drug-Repurposing.git Simple SummaryHead and neck cancer (HNC) is among the most prevalent and challenging cancers world-wide. Developing new drugs is expensive and time-consuming, so this study explored a faster, cost-effective approach utilizing existing medications with established safety profiles: drug repurposing. We developed the GARD pipeline (Genomic Alteration-based Repurposing for Drugs), which utilizes large-scale genomic data from The Cancer Genome Atlas (TCGA) to identify key genomics changes in HNC. These genes are expanded through protein-protein interaction networks to capture related pathways and then validated using evidence from thousands of PubMed articles extracted by large language model (LLM) tools. Finally, validated genes are matched with drugs using the DrugBank database. This approach uncovered both known cancer drugs and promising new candidates. These included targeted therapies such as Fostamatinib, Nintedanib, Brigatinib, Regorafenib, and Lenvatinib, as well as emerging compounds like Artenimol, Quercetin, and Acetylsalicylic Acid (Aspirin). Through a combination of genomic analysis, network expansion, and literature validation, the GARD pipeline offers a powerful way to accelerate personalized cancer treatments while reducing cost and development time.

bioinformatics↗

bioRxiv2026

Development of Integrin α5β1-targeted PET/NIR imaging probes for glioblastoma intraoperative navigation and intracavity targeted radionuclide therapy

Incomplete extent of tumor resection is the major factor of glioblastoma recurrence, leading to its poor prognosis. Developing therapies that enable the minimal tumor cell remnant during surgical resection is a major challenge to combat this aggressive cancer. This study develops a glioblastoma integrin 5{beta}1-selective peptide binder through series strategy screening and labeling it with 68Ga, indocyanine green (ICG), or 177Lu for efficacious multimodal treatment. This strategy combines positron emission tomography (PET) imaging for preoperative diagnosis, intraoperative NIR-II fluorescence-guided surgery for maximal tumor resection, and followed by intracavity targeted radionuclide therapy for elimination of residual tumor cells. We identified GR, with five arginine mutation, exhibiting superior integrin 5{beta}1 binding affinity and brain penetration. [68Ga]GR demonstrated substantial tumor uptake and prolonged retention time in both mouse models and tissues from glioblastoma patients. The guidance of ICG-GR achieved accurately intraoperative tumor imaging and maximal tumor resection in orthotopic mouse glioblastoma models. Notably, combining intracavity administration of [177Lu]GR following ICG-GR guiding resection markedly inhibited tumor growth and reduced possibility of tumor recurrence compared with surgery alone (unguided or ICG-GR-guided) or unguided surgery followed by [177Lu]GR. Therefore, we have reported the integrin 5{beta}1-targeted radionuclide and optical agents for maximal elimination of tumor cells during surgical resection in glioblastoma patients. HIGHLIGHTSO_LIGR is a glioblastoma-specific peptide with both favorable binding affinity superior brain penetration. C_LIO_LIICG-GR is a glioblastoma-targeted NIR probe enabling maximal surgical resection. C_LIO_LIICG-GR-guided surgery with [177Lu]GR-based adjuvant therapy allows robust elimination of tumor cells. C_LI

cancer biology↗

bioRxiv2026

Intramolecular loops control SARS-CoV-2 nucleocapsid protein self-association and nucleic acid binding dependent on phosphorylation

The nucleocapsid protein of SARS-CoV-2 scaffolds genomic RNA into ribonucleoprotein complexes (RNP) for assembly in the virion, but also fulfills critical intracellular functions in replication and the suppression of host defense. It is comprised of a folded nucleic acid binding domain (NTD) and a dimerization domain, connected by a disordered linker containing a serine/arginine-rich (SR) region and a leucine-rich sequence (LRS). The switch between intracellular and assembly functions of N-protein is controlled by phosphorylation of the SR region, but the molecular details are unclear. Here we describe a model in which two mutually exclusive intramolecular loops bind the NTD and dynamically control self-association and nucleic acid binding properties dependent on the SR linker phosphorylation state. The model is supported by biophysical properties and interactions of full-length protein, point mutants, and peptide fragments. We find SR linker phosphorylation compacts the protein and inhibits nucleic acid binding and RNP formation, while enhancing self-association through promotion of transient coiled-coils in the LRS of the linker. These changes shift the nucleocapsid protein to a configuration poised for multi-valent interactions that support intracellular functions.

biophysics↗

bioRxiv2026

Cysteine reactive chloroalkane probe enables HaloTag ligation for downstream chemical proteomics analysis.

Chemical proteomics is a powerful method to track proteins labelled by reactive small molecules in living cells on proteome-wide scale. The strategy relies on reactivity and specificity of bioorthogonal click reactions. Although a variety of bioorthogonal reactions have been developed to facilitate chemical proteomics, their reactivity and specificity might not be comparable with enzymatic reactions. Here we describe an iodoacetamide chloroalkane cysteine reactive probe that is, upon the reaction with nucleophilic cysteine of thioredoxin (TrxA), efficiently and specifically conjugated with HaloTag protein. The TrxA-HaloTag conjugate is utilized for downstream chemoproteomics analysis including in-gel shift assay and mass spectrometry-based proteomics. The TrxA-HaloTag conjugation in whole cell lysate allows fast and efficient pull-down of labelled protein on anti-HaloTag nanobeads resulting in low background after mass spectrometric analysis. The main advantage of the system is its high efficiency and complete biorthogonality due to enzymatic reactivity that is characteristic for HaloTag ligation. The study demonstrates the utility of chloroalkane small compound probes for chemoproteomics applications.

biochemistry↗

bioRxiv2025

Post-weaning social isolation impairs the orbitofrontal cortical circuit subserving contagious pain and prosocial behaviors

Empathic behaviors are sensitive to environmental factors like post-weaning social isolation (SI), yet the mechanisms by which SI affects empathy remain unclear. Here, we show that mice subjected to SI exhibit marked impairments in contagious pain and prosocial behaviors, including allo-grooming and allo-licking toward cagemates experiencing inflammatory pain. Mechanistically, we identify the glutamatergic projection from the ventromedial thalamic nucleus (VM) to the orbitofrontal cortex (OFC) as critical for these empathy-like responses. SI induces hypoexcitability of OFC glutamatergic neurons and attenuates excitatory synaptic transmission within the VM[->]OFC pathway. Remarkably, chemogenetic activation of OFC neurons or the VM[->]OFC projection restores empathic behaviors in SI mice. Furthermore, we uncover a molecular basis for SI-induced OFC hypoexcitability: the downregulation of Grik3, encoding a kainate-type glutamate receptor subunit. These findings reveal a previously uncharacterized thalamocortical mechanism through which early-life social deprivation disrupts empathic behaviors, offering insights into the underpinnings of social-affective dysfunction.

neuroscience↗

bioRxiv2025

Small molecule inhibitor of PPARγ acetylation promotes insulin sensitization and browning of white adipose tissue with improved safety

The nuclear receptor PPAR{gamma} is a primary therapeutic target for insulin resistance and type 2 diabetes (T2D); however, its thiazolidinedione (TZD) class of PPAR{gamma} agonists have substantial safety concerns in clinical utilization. Genetic inhibition of PPAR{gamma} acetylation at K268 and K293 dissociates the major adverse effects of TZDs from insulin sensitization and other metabolic improvements. We therefore posit that chemical inhibition of PPAR{gamma} acetylation would elicit insulin sensitization with improved safety. Here we describe the identification of a synthetic thiopyrimidine derivative (TPMD) that acts as a small molecule inhibitor of PPAR{gamma} acetylation. TPMD improves insulin sensitivity, promotes brown remodeling of white adipose tissue (WAT), increases energy expenditure, and decreases adiposity in dietary and genetic mouse models of T2D. Importantly, TPMD is deprived of the major side effects of TZDs, including weight gain, fluid retention, cardiac hypertrophy, bone marrow adiposity, and bone loss. X-ray crystallography at 2.0 [A] resolution reveals a unique binding mode of TPMD molecules to the PPAR{gamma} ligand-binding domain and provides structural and molecular basis for the acetylation inhibitory activity of TPMD together with site-directed mutagenesis studies. These findings identify TPMD as a first-in-class compound that specifically targets PPAR{gamma} acetylation and possesses the potential of developing into a safe insulin sensitizer to treat and prevent T2D and obesity.

cell biology↗

bioRxiv2025

Surface phase separation in a confined space

Biomolecular condensates frequently form near surfaces, including lipid membranes. However, the effect of a surface on phase separation within a cell, a confined system, remains elusive. In this work, we study surface phase separation under the constraint of a finite number of molecules in a confined space and identify three wetting states: thin, intermediate, and thick. Notably, the intermediate state, which is unstable in a fixed-chemical-potential system, can be stabilized in confinement below a critical width. Intriguingly, in wider systems, the intermediate solution becomes unstable due to a negative relationship between the chemical potential and the particle number, resulting in partial-wetting or prewetting droplets. Importantly, starting from a homogeneous surface, droplets can form only when the average volume fraction reaches the threshold of the intermediate state. Our theory elucidates the kinetic pathways of droplet formation in a confined system, providing crucial insights into how biomolecular condensates near surfaces respond to cellular events, such as the synthesis of biomolecules.

biophysics↗

bioRxiv2025

Panax notoginseng saponins protect the blood brain barrier against oxidative stress by activating the Akap12/PI3K/AKT/AQP1 signaling axis

Oxidative stress is a key pathological factor that contributes to blood-brain barrier (BBB) disruption during ischemic injury. Panax notoginseng saponins (PNS), the primary bioactive components of Panax notoginseng, possess potent antioxidative and vasoprotective activities. This study aimed to elucidate the molecular mechanisms by which PNS regulate endothelial integrity and BBB permeability under oxidative stress conditions. Mouse brain microvascular endothelial cells (bEnd.3) were treated with hydrogen peroxide to induce oxidative damage, followed by intervention with PNS. Transcriptomic and proteomic analyses revealed that Akap12 (A-kinase anchoring protein 12) and Aquaporin 1 (AQP1) were key molecules involved in PNS-mediated endothelial protection. H2O2 exposure markedly suppressed Akap12 expression and inhibited the PI3K/AKT signaling pathway, leading to elevated AQP1 expression and increased BBB permeability. PNS treatment reversed these effects by restoring Akap12 expression, reactivating PI3K/AKT signaling, and reducing AQP1 levels. Functional validation further showed that AQP1 dysregulation altered the expression balance of tight junction proteins, including Claudin-5 and ZO-1, thereby impairing barrier function. Collectively, these findings demonstrate that PNS protect endothelial cells from oxidative injury by activating Akap12-dependent PI3K/AKT signaling and modulating AQP1-associated tight junction remodeling. This study provides new mechanistic insights into the molecular basis of PNS-mediated BBB protection and suggests potential therapeutic targets for oxidative or ischemic cerebrovascular diseases.

pharmacology and toxicology↗

bioRxiv2025

Streptavidins play a multifunctional role within a biotin-pathway antibiotic network encoded in a biosynthetic supercluster

Streptavidin, the well-known biotin-binding protein extensively used in biotechnology, is naturally co-produced in Streptomyces avidinii alongside stravidins--inhibitors of biotin biosynthesis. Here, we uncover and activate a conserved genomic region flanked by two streptavidin genes, revealing multiple biosynthetic gene clusters that produce diverse biotin-related metabolites, including stravidins, acidomycin, -methyl-KAPA, -methyldesthiobiotin, and the novel non-proteinogenic amino acid ANDA. We show -methyldesthiobiotin arises from -methyl-KAPA, illustrating how methylated analogues interfere with distinct steps of biotin biosynthesis. Contrary to the view that streptavidin functions solely by sequestering biotin, our biochemical, structural, and bioactivity analyses demonstrate that it also binds acidomycin, neutralizing its antibacterial activity to protect the producer while likely facilitating compound secretion. The crystal structure of the streptavidin-acidomycin complex reveals the molecular basis for this dual functionality. Our findings establish a multifunctional streptavidin that integrates biotin sequestration and self-resistance to balance an antibiotic network targeting the biotin pathway in microbial competition.

microbiology↗

bioRxiv2025

Resolving Heterogeneity in Major Depression: Overcoupling and Undercoupling Subtypes Exhibit Differential Treatment Response and Molecular Pathways

Major depressive disorder (MDD) exhibits significant heterogeneity whose neurobiological mechanisms remain elusive. Alterations in morphological-functional coupling (MFC) have been observed in MDD. This study aims to investigate MDD subtypes based on MFC alterations and their associations with clinical symptoms and molecular basis. We identified two clinically distinct MDD subtypes in multi-center neuroimaging data (Discovery: 828 MDD/776 healthy controls; Validation: 236 MDD/86 healthy controls) by using a semi-supervised machine learning approach based on MFC changes, which were validated and robustly repeated in the validation dataset. Differences among subtypes were then examined in relation to clinical assessments, gene expression patterns, neurotransmitter and cell density, and treatment response. Subtype I (overcoupling) showed elevated MFC in high-order association cortices, linking to synaptic transmission activity and severe symptoms. Subtype II (undercoupling) demonstrated reduced MFC in primary cortices, associated with cell cycle regulation and treatment resistance. Both subtypes shared molecular signatures (cell types: astrocytes and oligodendrocytes; neurotransmitter systems: serotonergic and GABAergic receptors). Crucially, longitudinal data (33 MDD undergoing Escitalopram monotherapy) revealed that undercoupling subtype exhibited better response, implying a potential mechanism of the drug via increasing the MFC. Our work deciphers MFC-driven MDD phenotypes with distinct molecular profiles and differential treatment outcomes, suggesting potential pathways for personalized diagnosis and treatment strategies in MDD, advancing precision psychiatry.

neuroscience↗

bioRxiv2025

Rewiring protein function through genetically encoded oxidative chemistry

Oxidative chemistry underlies many endogenous signaling pathways but remains underutilized as a programmable strategy for regulating protein function in living cells. Here we establish genetically encoded oxidative chemistry as a tunable framework for modulating diverse proteins by coupling a photosensitizer to defined intracellular contexts. Using miniSOG to generate reactive oxygen species (ROS), we show that controlled intracellular oxidation increases the fluorescence of the redox reporter HyPerRed and activates redox-sensitive TRP ion channels, with strong responses in TRPA1 and TRPV1 but not TRPV4. Pathway-selective scavengers reveal differential coupling of soluble and membrane targets to distinct oxidative processes, supporting selectivity by context rather than uniform oxidative perturbation. Modulation strength and kinetics are quantitatively tunable through illumination parameters, expression ratios, and subcellular localization, with membrane targeting enhancing coupling to membrane effectors. Finally, fusion targeting of miniSOG to TRPV1 and modulation of endogenous TRPA1 in human fibroblasts extend this approach to protein-proximal and native cellular settings. Together, these results position genetically encoded oxidative chemistry as a versatile and spatially organized modality for engineering protein function in living cells within a defined operating regime.

synthetic biology↗