Biology subjects

Yang, X.

Publications and source records attributed to Yang, X..

At least 73 records · Page 4Linked to original sources

bioRxiv2026

MMMAS: A Mendelian Mismatch Matrix Analysis System for Deterministic Pre-Screening of Germplasm Collections

Pedigree errors, duplicate accessions, and undocumented kinship limit the effective use of large genebank collections. Existing tools such as CERVUS and COLONY require allele-frequency estimates and return relationship-level assignments, providing no collection-wide view of Mendelian consistency. We developed the Mendelian Mismatch Matrix (MMM) framework and its open-source implementation, MMMAS (Mendelian Mismatch Matrix Analysis System). We applied MMM to apple (Malus x domestica; 1,085 accessions, 15 SSRs) and sweet cherry (Prunus avium; 383 accessions, 13 SSRs) datasets from the German Fruit Genebank. MMM converts pairwise Mendelian mismatch numbers (Mmn) into an N x N symmetric matrix, from which we derive four collection-scale indices (Mmin, the Mendelian minimum mismatch number; Mavg, the Mendelian average mismatch number; Mzmp, the Mendelian zero-mismatch partner number; Mmmd, the Mendelian mismatch-mode duplication index) and the Mendelian Exhaustive Stratification (MES) grading system. Apple showed a gradient-type structure (Mendelian Grade-gap Index, MGI = 0.125), sweet cherry a broken-type structure (MGI = 0.545). The Mmin-Mavg strategy identified 20 and 10 distinct accessions in apple and sweet cherry, including the scab-resistance donor Malus x floribunda 821 (Rvi6) and the fire-blight donor M. x robusta 5. The Mmmd index flagged one literature-confirmed pair of duplicate genotypes in sweet cherry. Of CERVUS-confirmed parent-offspring pairs, 97.31% in apple and 100% of high-confidence pairs in sweet cherry fell within Mmn <= 1. Mzmp rankings matched documented breeding history, with 'Cox Orange' (Mzmp = 57) and 'Luebecker Bunte' (Mzmp = 49) ranking first in each species. The complete end-to-end analysis of all 588,070 apple pairwise comparisons took 7.24 s on an ordinary workstation. This deterministic pre-screening framework, with a parameter-free core, supports routine quality assessment in germplasm collections.

genetics↗

bioRxiv2026

Reconstructing lineage-constrained gene-program dynamics with PhyloFM

Cell-fate dynamics are defined not only by where cells end, but by when fate programs emerge, diverge, and reshape population structure. Much recent effort has been devoted to reconstructing these dynamics from temporally resolved single-cell RNA-seq and spatial transcriptomics. However, it is difficult because these measurements only provide destructive snapshots instead of continuous molecular histories. On the other hand, a diverse set of lineage-tracing methods are now available which could serve as temporal constraints to connect the dots. The challenge is how to utilize and unify these diverse ancestry records in the reconstruction of a continuous cell state dynamics. Here we introduce PhyloFM, a lineage-constrained flow-matching framework that maps heterogeneous lineage information onto a cell-fate-anchor topology and learns a continuous velocity field together with relative cell-abundance changes on a topology-regularized latent geometry. From the same integrated trajectories, PhyloFM predicts population transport, future fate probabilities, commitment timing and branch-resolved projected gene- and module-level dynamics. We tested PhyloFM across five lineage-tracing settings spanning C. elegans embryogenesis, LARRY hematopoiesis, pandaCREST ventral-midbrain development, zebrafish heart regeneration and spatial eTracer tumours. In C. elegans, our method improved population transport by 17.3% and lineage-grounded dynamic error by 16.3% relative to state-of-the-art dynamical baselines, with transport error reduced by 26.6% relative to additional lineage-aware control. Independent EPIC GFP reporter traces support the inferred timing of proneural, ciliated-neuron and late-selector programs, with 67% of matched reporter genes showing Pearson r > 0.6. On the spatial eTracer tumour benchmark, PhyloFM increased clone-grounded fate accuracy by 70.4% relative to the best spatial baseline. Together, these analyses show that diverse lineage records can serve as biological constraints for reconstructing continuous, interpretable molecular fate dynamics from single-cell snapshots.

bioinformatics↗

bioRxiv2026

Switch-TRIBE: Lineage-specific high-resolution profiling of endogenous RNA-protein interactions

RNA-binding proteins (RBPs) play vital roles in regulation of cell fate and function. Here, we introduce Switch-TRIBE, which conditionally tags endogenous RBPs with the adenosine deaminase catalytic domain to detect physiological RBP-RNA interactions. We apply Switch-TRIBE to the TRIM-NHL RBPs, BRAT and MEI-P26, essential regulators of Drosophila neurogenesis. Single-cell Switch-TRIBE in neural stem cell lineages defines cell-type specific targets and identifies novel neurogenesis regulators. Beyond target identification, Switch-TRIBE highlights the complex interplay between co-regulating RBPs, uncovering distinct binding site topographies. Our analysis uncovers a potential strategy used by BRAT and MEI-P26 to regulate lineage growth through direct binding of transcripts that encode the core metabolic and translation machineries. Switch-TRIBE provides a robust tool for characterizing RBP-RNA interactions in complex systems without compromising biological fidelity.

genomics↗

bioRxiv2026

Hidden genetic diversity in 320 nearly-complete East Asian genome assemblies

East Asian populations, representing over 20% of the global population, remain critically underrepresented in human genomic studies, limiting our understanding of population-stratified genetic variation and its implications for health and disease. Here we present the first phase of the Asian Pan-Genome project (APG), comprising 320 nearly complete, fully phased haploid genome assemblies from 160 East Asian individuals. These assemblies achieve unprecedented quality, with an average contig N50 of 144.3 megabase pairs and an average quality value of 64.5. Leveraging these superior assemblies, we reveal previously uncharacterized diversity in human repeatome, including population-stratified patterns in centromere satellites and rDNA arrays. Compared to existing global human genome assemblies, the newly generated genomes supplement 152 million base pairs of novel sequences, 355 gene gains, 18,300 structural variation loci and 26 large euchromatic inversions missing from current human pangenomes. We perform population stratification analyses of structural variations, and further resolve the structural haplotypes of complex genomic regions such as Major Histocompatibility Complex and Survival Motor Neuron loci across global pangenomes, exemplifying tandem-duplicate and inversion-rich complex locus architectures in the human genome, respectively. This resource provides a critical foundation for human genetic studies, especially for East Asian populations, promoting more accurate variant discovery, reducing bias, and ultimately advancing the equity and efficacy of genomic medicine.

genomics↗

bioRxiv2026

LIFU-Responsive Nanocomplexes Deliver PDGF-BB mRNA for Plaques Stabilization via Neovascularization Modulation

BackgroundPathological intraplaque neovascularization, vascular leakage, and fibrous cap thinning contribute to vulnerable atherosclerotic plaque rupture. Platelet- derived growth factor-BB (PDGF-BB) has been shown to promote pericyte recruitment, thereby stabilizing the microvascular structure, and to induce phenotypic modulation of vascular smooth muscle cells (VSMCs), which enhances fibrous cap thickness and reinforces plaque stability. Nevertheless, systemic protein delivery is limited by rapid clearance and potential off-target effects. MethodsWe developed PDGF-BB mRNA-loaded lipid nanoparticle-poly(lactic-co- glycolic acid) nanobubble complexes (LNPmRNA@PLGA) and used low-intensity focused ultrasound (LIFU) to enhance plaque-targeted delivery. Cellular uptake, PDGF- BB expression, vascular mural-cell responses, plaque histology, hemodynamics, and proteomic changes were evaluated in vitro and in ApoE-/-Fbn1C1041G+/- mice. ResultsLIFU enhanced nanocomplex uptake and PDGF-BB expression, promoted vascular smooth muscle cell proliferation, migration, and phenotypic switching, and increased pericyte coverage. In vivo, LIFU plus LNPmRNA@PLGA reduced the plaque vulnerability index by 78.2% and the neovascularization area by 67.3% compared with controls, while increasing collagen deposition and improving carotid hemodynamics. ConclusionsLIFU-responsive delivery of PDGF-BB mRNA stabilized vulnerable plaques by promoting neovessel maturation and strengthening the fibrous cap. This strategy provides a spatially controlled framework for therapeutic remodeling of high-risk atherosclerotic plaques. Research Perspective What New Question Does This Study Raise?O_LICan spatially controlled PDGF-BB mRNA delivery simultaneously mature intraplaque neovessels and reinforce the fibrous cap without the systemic effects associated with recombinant PDGF-BB? C_LI What Question Should Be Addressed Next?O_LIFuture studies should define the therapeutic window, durability, and long-term safety of LIFU-triggered PDGF-BB mRNA delivery in large-animal models that more closely reproduce human plaque rupture. C_LI

pharmacology and toxicology↗

bioRxiv2026

Pan-Peroxisome Proliferator-Activated Receptor Agonist IVA337 Alleviates Secondary Lymphedema via Inhibiting TGFβ/SMAD2/3 Signaling Pathway

Lymphedema is a chronic disease characterized by impaired lymph drainage and accumulation of protein-rich interstitial fluid, which progresses to develop irreversible fibrosis. Importantly, effective therapies and treatments are lacking to alleviate and mitigate the disease. The pathological inflammation and fibrogenesis underlying lymphedema prompted us to evaluate a preclinical medicine IVA337, a pan-peroxisome proliferator-activated receptor (PPAR) agonist that improves liver fibrosis in patients with metabolic dysfunction-associated steatohepatitis (MASH) by activating three PPAR isoforms (, {beta}/{delta}, {lambda}), which play critical roles in lipid metabolism, anti-inflammation responses, and anti-fibrogenesis. Here, we investigate the therapeutic effects of IVA337 during the early stage of surgery-induced secondary lymphedema in mice and explored the underlying mechanisms. IVA337 administration alleviated lymphedema progression, improved lymphatic drainage, reduced dermal thickness, and resolved lymphatic vessel dilation. Mechanistically, IVA337 suppressed the TGF{beta}/SMAD2/3 signaling pathway, reduced immune cells infiltration, and improves lymphatic vessels integrity. In human dermal lymphatic endothelial cells (HDLECs), IVA337 attenuated TGF{beta} induced SMAD2/3 phosphorylation and preserved the expression of cell junction Claudin5, reduced VE-Cadherin-stained cell-cell gaps. Collectively, our findings demonstrate that IVA337 protects against early stage lymphedema by inhibiting TGF{beta}/SMAD2/3-mediated inflammatory and fibrotic responses. This study provides a potential therapeutic strategy to improve lymphatic function during the early phase of lymphedema and prevent progressive fibrosis in patients with lymphedema and related disorders.

pathology↗

bioRxiv2026

Multidimensional variation and population stratification across 8000 complete human centromeres

Human centromeres are indispensable for the faithful segregation of chromosomes during cell division, yet their highly repetitive nature has historically precluded comprehensive characterization, leaving fundamental questions about their sequence diversity, evolution trajectories and function dynamics unresolved. Here, we generated 6,312 complete human centromere sequences from 320 phased genome assemblies in Asian Pan-Genome project phase 1. By integrating the assemblies from the Human Pangenome Reference Consortium (HPRC) and Human Genome Structural Variation Consortium (HGSVC), we constructed a multidimensional genetic variation map encompassing over 8,000 gapless centromeres. Centromeric satellite arrays account for 4.19% to 6.01% of the whole genome, with substantial variations in size and architecture across chromosomes. Using a refined alpha satellite clustering approach that captures global diversity, we identified 195 higher-order repeat (HOR) arrays, 56.4% of which are absent from the T2T-CHM13 reference genome. Extensive structural variations across multiple dimensions exhibit population stratification, including centromeric haplotypes (CenHaps), ultra-large pericentric inversions spanning up to 36.6 Mbp, and inter-chromosomal HOR sharing that reflects sequence exchange among chromosomes. Integrating CENP-A CUT&Tag experiments and long-read-based DNA methylation profiles, we demonstrate that 16.8% of centromeres harbor multiple potential kinetochore assembly sites, and CenHap-specific local HOR homogenization is associated with kinetochore positioning. Despite global suppression of recombination at centromeres, we observed asymmetric linkage disequilibrium flanking centromeres and an ancient recombination event within the centromere of chromosome 19. Furthermore, contrary to the prevailing assumption of high mutation rates in centromeres, our estimates based on stringent orthology reveal no significantly higher single-base substitution rates for centromeres relative to flanking pericentromeric regions with substantial variations across chromosomes, despite extraordinary structural plasticity. Collectively, these multi-scale centromeric variations provide a global view of human centromere diversity and population stratification, fundamentally redefine centromere evolution through a dual-track model balancing structural innovation with mutational constraint, and establish an essential resource for investigating centromere biology and a baseline reference for diagnosing centromere-associated disorders.

genomics↗

bioRxiv2026

A dual-layer computational framework for prioritising therapeutic candidates targeting extracellular vesicle-mediated immune escape in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterised by a highly immunosuppressive tumour microenvironment and limited therapeutic responses. Tumour-derived extracellular vesicles (EVs) contribute to PDAC progression by transferring immunomodulatory molecules and tumour-associated signals, suggesting EV-associated processes as potential intervention opportunities. However, the heterogeneity of EV biology and the complexity of tumour-immune interactions make single-target intervention strategies challenging. Here, we developed a computation-driven dual-layer candidate-prioritisation framework to identify potential modulators associated with PDAC EV-mediated immune escape through complementary production-side and action-side strategies. For the production-side layer, we focused on upstream processes related to EV biogenesis, cargo regulation, inflammatory signalling, and tumour-associated pathways. An 88-gene PDAC EV-associated target framework was integrated with cell-type-resolved prognosis annotations from ctPANDA and predicted targets of 18 natural products derived from Scutellaria baicalensis, Epimedium spp., and Cornus officinalis to prioritise natural-product candidates with disease relevance and potential chemical tractability. In parallel, key targets with experimentally resolved ligand-binding structures were subjected to pocket-guided de novo small-molecule design based on co-crystal ligand-defined binding sites, followed by structural, docking-based, and physicochemical screening of generated compounds. For the action-side layer, VHH and scFv binders were computationally designed and screened against extracellular regions of MET and CD81 to prioritise candidates potentially suitable for EV recognition and capture. This study provides a computational strategy for narrowing candidate spaces across both EV-associated production pathways and released vesicle recognition. The resulting small molecules, antibody-like binder models, and screening workflows provide a resource for future experimental validation of strategies targeting PDAC EV-associated immune regulation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/740294v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@11829b0org.highwire.dtl.DTLVardef@158efb5org.highwire.dtl.DTLVardef@1e17cc5org.highwire.dtl.DTLVardef@c69696_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Crystal structures of a far-red photoreceptor in different light-absorbing states: insights into spectral tuning and light signaling

Cyanobacteriochromes (CBCRs) are bilin-binding photoreceptors with remarkable spectral versatility. Using phycocyanobilin (PCB) as a chromophore, CBCRs regulate diverse light-dependent processes in cyanobacteria, ranging from photosynthesis to chromatic acclimation. Although extensive studies have uncovered multiple spectral tuning mechanisms in bilin-binding proteins, recent structural studies of far-red CBCRs suggest the existence of additional tuning strategies in both the 15Z and 15E states. Here we report crystal structures of the representative far-red CBCR Anacy_2551g3 in three distinct light-absorbing states, all of which adopt a compact all-syn PCB conformation. These structures demonstrate that 15Z/15E photoisomerization in Anacy_2551g3 involves minimal chromophore rotation relative to the GAF domain, in stark contrast to other characterized bilin-based photoreceptors. To investigate the molecular basis of its far-red absorption, we examined the protonation and tautomeric states of PCB in the Pfr state using resonance Raman (RR) spectroscopy and quantum mechanics/molecular mechanics (QM/MM) calculations. Comparisons of experimental and calculated RR spectra support a bilin lactam as the predominant tautomeric form in the Pfr state. Integrating structural, spectroscopic, computational and mutational analyses, we propose that specific protein-chromophore interactions play critical roles in modulating chromophore conjugation beyond bilin coplanarity. Structural analyses further suggest a signaling model in which light regulation by Anacy_2551g3 is mediated through reversible switching between a high-affinity Pfr state and a low-affinity Po state that does not involve large chromophore motions. Together, these results provide new insights into how protein-chromophore coupling governs spectral tuning and light signaling in bilin-based photoreceptors. Significance statementBilins are widespread biological pigments that mediate photoreception, light harvesting, and photosynthesis across diverse light environments. In a phenomenon known as spectral tuning, the optical properties of bilin-binding proteins are profoundly influenced by protein-chromophore interactions. Mechanistic understanding of spectral tuning and light signaling is important not only for advancing fundamental knowledge of light-sensitive proteins but also for developing new engineering strategies in synthetic biology and biotechnology. Recently discovered cyanobacteriochromes (CBCRs) exhibit remarkable spectral diversity and structural versatility, providing excellent model systems for dissecting the mechanisms of bilin-based photoreceptors. By integrating crystallography, spectroscopy and computational methods, this work examines three distinct light absorbing states of a representative far-red CBCR. Our findings reveal previously unrecognized mechanisms of spectral tuning and light signaling, highlighting the critical roles of protein-chromophore coupling and electrostatic interactions in regulating photoreceptor function.

biochemistry↗

bioRxiv2026

AI-enabled reconstruction of 3D spatial multi-omics at single-cell resolution

Three-dimensional (3D) spatial multi-omics provides unparalleled insights into biological activities, yet remains technically prohibitive. Here, we introduce Histo3D-MO, a hybrid experimental-computational pipeline for reconstructing single-cell-resolution 3D spatial multi-omics maps. Notably, Histo3D-MO integrates sparse, omics-disjoint spatial measurements with dense Hematoxylin and Eosin (H&E) histology through SPatial multi-Omics from h&E imaGEs (SPONGE), achieving cell-level 3D mapping across multiple omics layers. Validated using held-out slices, SPONGE substantially outperforms existing omics prediction methods. We further developed an algorithmic suite for 3D cell-type propagation and tissue-domain annotation, enabling whole-volume characterization of the tumor microenvironment. Applied to the in-house hepatocellular carcinoma data, Histo3D-MO revealed spatially organized patterns of translation efficiency, volumetric decoupling between malignant cells and monocytes, and depth-associated monocyte differentiation trajectories. Together, these results establish Histo3D-MO as a scalable framework for reconstructing single-cell-resolution 3D spatial multi-omics and interrogating tissue organization across complex biological systems.

bioinformatics↗

bioRxiv2026

Spatial Glyco-Codes Define Human Liver Pathology and Progression

Glycosylation is a fundamental process regulating cellular function, tissue organization, and disease progression. However, comprehensive glycan profiling at single-cell spatial resolution remains largely inaccessible, particularly in clinical archival tissues. Here we develop spatial-GPT, a multimodal platform for simultaneous profiling of glycans, proteins, and/or transcripts in archival formalin-fixed paraffin-embedded (FFPE) tissues. Using a panel of 30 DNA-encoded lectins recognizing major mammalian glycan motifs and structural classes, sequencing-based spatial-GPT (DBiT-GPT) mapped the spatial glycome, proteome, and transcriptome across 16 human liver specimens encompassing steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), leading to identification of spatial glyco-codes - combinatorial glycan states associated with distinct cellular identities, tissue features, and pathological processes. Unexpectedly, glyco-codes alone were sufficient to resolve major cell types, disease states, and HCC subtypes, revealing a previously unappreciated level of biological information encoded within the tissue glycome. Spatial glycomics uncovered tumor-like glyco-codes in premalignant regions, suggesting that glycan reprogramming may precede overt malignant transformation. Using imaging-based single-cell spatial glycan-protein profiling (CODEX-GP), we track glyco-codes across the whole-tissue architecture of 3 representative HCC samples. We further examined the glyco-codes across more than 300 patient specimens and quantified cell-type- and disease-specific glyco-codes as well as glycan-defined immune-evasion, T-cell-exhaustion, and steato-fibrotic niches. Together, these findings establish spatial glyco-codes as a previously unrecognized layer of tissue organization that encodes cellular identity, tissue function, and disease progression. The ability of glyco-codes to distinguish major liver pathologies across independent patient cohorts further highlights their potential as a new class of molecular histopathology biomarkers.

pathology↗

bioRxiv2026

Natural compounds magnolol and dicoumarol enhance adipogenesis for future food applications

Edible adipose tissue can enhance the sensory and nutritional qualities of cultivated and plant-based meats, yet efficient adipogenic differentiation remains a major bottleneck and synthetic PPAR{gamma} agonists are not approved for use in food production. Here, we report a natural compound screen in 3T3-L1 adipocytes that identifies magnolol and dicoumarol as enhancers of adipogenesis; this combination also robustly promotes lipid accumulation in primary porcine dedifferentiated fat cells and ovine preadipocytes. Transcriptomic analyses show that magnolol and dicoumarol induce adipogenesis in murine and porcine cell systems through canonical adipogenic pathways with a narrower transcriptional footprint than the potent PPAR{gamma} agonist rosiglitazone. These findings support the potential of naturally occurring compounds magnolol and dicoumarol as enhancers of adipogenesis for both mechanistic studies and food-relevant applications. More broadly, our findings establish a generalizable screening framework and identify small-molecule combinations that accelerate adipose tissue engineering across murine, porcine, and ovine culture systems.

bioengineering↗

bioRxiv2026

Transfer learning reveals species-specific olfactory preferences in Diptera and informs pest management strategies

The interaction between volatile organic compounds (VOCs) and odorant receptors (ORs), termed VOI, constitutes the molecular basis for species to recognize chemical information in the environment. Characterization of subtle differences in VOI relationships among closely related species is crucial for understanding the rapid evolution of ORs and for identifying species-specific chemical cues relevant to pest management. However, progress in this field has been constrained by both the scarcity of experimental data and limitations in computational prediction accuracy. To address this, we developed a virtual screening-enhanced transfer learning strategy that integrates large-scale molecular docking data with sparse functional experimental data. The resulting VOI prediction model was validated through functional experiments on the pest species Bactrocera dorsalis, demonstrating its cross-species predictive capacity. Using this model, we investigated the relationship between ecological niches and olfactory sensitivity in Diptera insects from multiple perspectives, with an emphasis on patterns that may inform pest behavioral research. The models predictive reliability was further supported by its consistency with known olfactory trends: it recapitulated the preferential responses of fruit flies and mosquitoes to esters and aromatics, respectively, and reproduced the previously reported negative correlation between olfactory and visual capacities in Drosophila. As a proof-of-concept application, we compared hematophagous and non-hematophagous mosquitoes, revealing overlapping chemical spaces but distinct patterns in their specifically recognized compounds. This study provides a reliable VOI prediction framework that reveals species-level olfactory preference patterns in Diptera, offering a computational pipeline to accelerate the discovery of behaviorally active compounds for species-specific pest monitoring and control.

bioinformatics↗

bioRxiv2026

Reduced LANCL1-AS1 in old human skeletal muscle diminishes mitochondrial activity, shortens mt-mRNA poly(A) tails, and suppresses myogenesis

Regeneration of skeletal muscle preserves muscle mass and function, which decline with age. Here, we sought to identify long noncoding (lnc)RNAs involved in skeletal muscle myogenesis and potentially relevant to muscle aging. Cross-sectional analysis of skeletal muscle transcriptomes from healthy 22-through 89-year-old individuals revealed lncRNA LANCL1-AS1 among the top declining transcripts. Conversely, LANCL1-AS1 increased robustly during skeletal myogenesis and promoted myogenic differentiation in culture. Affinity pulldown by ChIRP followed by mass spectrometry revealed that LANCL1-AS1 associated with the mitochondrial protein LRPPRC, enhancing the formation of the chaperone complex LRPPRC-SLIRP, which maintains longer poly(A) tails of mitochondrial (mt-)mRNAs and stabilizes mt-mRNAs. Importantly, while myoblasts from old rhesus monkey muscle expressed lower levels of LANCL1-AS1 and mt-mRNAs, and displayed lower mitochondrial activity than young monkey myoblasts, overexpressing LANCL1-AS1 in old myoblasts restored mitochondrial activity and myogenesis. We propose that the age-associated reduction in LANCL1-AS1 contributes to impaired mitochondrial function and reduced myogenic capacity in aging skeletal muscle.

molecular biology↗

bioRxiv2026

Neural representation of hedonic valence during narrative listening

Hedonic valence, the intrinsic pleasantness or unpleasantness of an experience, is fundamental to human psychological functioning. Yet, how valence is represented in the brain remains an open question. Functional MRI studies have demonstrated that the brain encodes both positive and negative valence, but this evidence largely stems from experiments using simplified, controlled stimuli, such as images, sounds, or words. As a result, it remains unclear how valence is processed during rich, naturalistic experiences that more closely reflect real life. In addition, most studies adopt a single statistical model, raising concerns about the robustness of their findings. This study used a formal voxel-wise Bayesian model selection approach to test alternative statistical models supporting Bipolarity, Valence-General, and Bivalence hypotheses to identify the most optimal model of valence representation during narrative listening. Our results provide evidence for the Bipolar model. We identified distributed brain regions that selectively encode valence as a bipolar continuum (negative to positive) during narrative comprehension, including classical emotion-related hubs such as ventromedial prefrontal cortex, as well as regions not traditionally associated with emotion processing, such as inferior occipital cortex, supramarginal cortex, inferior frontal cortex, and middle cingulate. Regions selectively encoding arousal and those broadly responsive to both valence and arousal were also identified. These findings highlight the importance of using formal model comparison and naturalistic paradigms in affective neuroscience, advancing our understanding of how valence is represented in the brain during real-world experiences.

neuroscience↗

bioRxiv2026

P-DOpE probes reveal local amplification of phasic noradrenergic release in the hippocampus

Fiber photometry (FP) has become a tool of choice for in vivo monitoring of genetically encoded biosensors. The ability to record and optogenetically manipulate circuits through the same fiber stub is powerful, but limited, as biosensors typically do not sample membrane voltage, leaving the experimenter blind to the direct effects of opsin photoactivation. Here we developed the Photometry Device with Optogenetics and Electrophysiology (P-DOpE) probe, fabricated via a new convergence taper-break (CTB) method that integrates industry-standard silica optical waveguides with low-impedance metal electrodes that can be arranged in experimenter-defined configurations. We demonstrate that chronically implanted P-DOpE probes provide months-long recordings of local field potential, single unit recording, and fiber photometry, with parallel optogenetic circuit perturbation. Conducting fiber photometry with same-site optogenetic stimulation, we identified a robust fluorescence signal that scaled with network activity and survived biosensor antagonism. As this confound could not be eliminated with standard isosbestic controls, we propose a simple correction strategy. As a first application, we used the probe to test a proposed mechanism for focal modulation of noradrenergic signaling in and by cortical circuits receiving afferents from the locus coeruleus. We found that increasing spiking activity in CA1 amplifies noradrenergic signaling evoked by contextual arousal by [~]50%, but does not induce norepinephrine release in the absence of a phasic trigger - thus supporting the central prediction of the glutamate amplifies noradrenergic effects (GANE) hypothesis. The P-DOpE probe thus enables optogenetic manipulation and multimodal readout in a configurable low-cost, scalable, and robust format.

neuroscience↗

bioRxiv2026

HiFi-ST: High-Fidelity Reconstruction of Continuous Spatial Transcriptomic Expression Fields via Conditional Neural Fields

Spatial transcriptomics characterizes tissue-scale gene expression patterns, yet its observations are sparse discrete samples of an underlying continuous molecular field, leading to spatial aliasing and sub-resolution information loss. Existing methods usually formulate this task as spot-level point regression, making it difficult to capture both expression continuity and the regional nature of observation. Here, we propose HiFi-ST, a conditional neural field framework for continuous spatial transcriptomics modeling. HiFi-ST formulates spatial gene expression prediction as continuous expression field learning, models each spot as a regional observation over a finite support domain, approximates local integration through Monte Carlo sampling, and integrates multiscale tissue feature extraction with FiLM-based conditional modulation to improve modeling of complex spatial heterogeneity and consistency with the underlying measurement process. Systematic evaluation on three independent datasets (HER2+, cSCC, and Alex_NatGen) showed that HiFi-ST outperformed mclSTExp, BLEEP, THItoGene, His2ST, and HisToGene on key metrics. On HER2+, HiFi-ST achieved an average PCC improvement of 65.1% and an average MSE reduction of 40.9%; on cSCC, PCC improved by 10.2% and MSE decreased by 51.2%; on Alex_NatGen, PCC improved by 80.0% and MSE decreased by 16.3%. In addition, the learned multiscale tissue representations supported downstream spatial immunoanalysis, including assisted identification of candidate TLS regions. Overall, HiFi-ST provides a unified framework bridging discrete measurements and continuous expression field reconstruction for tumor microenvironment analysis and spatial immune structure characterization.

genomics↗

bioRxiv2026

Heterogeneous flux capacity and oxygen sensitivity lead to subcellular ETC flux gradients in mouse oocytes

Mitochondria are metabolic hubs of the cell that provide energy and metabolites to meet the energetic, biosynthetic and signaling demands of the cell. Mitochondrial activities are characterized by the metabolic fluxes through their internal metabolic pathways. One of the most important mitochondrial metabolic pathways is the electron transport chain (ETC), where electron carriers such as NADH donate their electrons to oxygen to power mitochondrial respiration. Mitochondrial activities are dynamically and spatially regulated during organism development to ensure robust development. Recent work has revealed the existence of a subcellular ETC flux gradient within a single mouse oocyte, where mitochondria closer to the cell membrane display a higher ETC flux, but the mechanism underlying the formation of this gradient is unknown. In this work, we study the origin of the ETC flux gradients by modulating them through perturbations of external oxygen concentration and temperature. Interpreting the data with spatial kinetic modeling of mitochondrial respiration, we discover that the subcellular ETC flux gradient cannot be explained by reaction-diffusion of oxygen alone, but is a result of mitochondrial heterogeneity where mitochondria closer to the cell membrane display larger ETC flux capacity and lower oxygen sensitivity. Our work suggests that kinetically distinct subpopulations of mitochondria are spatially sorted according to their metabolic activities to form intracellular metabolic gradients.

biophysics↗