Biology subjects

Dong, Y.

Publications and source records attributed to Dong, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Astrocytic D1 Dopamine-Signaling Regulates Synaptic Remodeling and Cocaine Seeking

D1-type receptor (D1R)-mediated dopaminergic signaling within the nucleus accumbens shell (NAcSh) is essential for forming adaptive circuit changes that embed persistent memories associated with drug seeking and craving. While D1R is expressed in both NAcSh neurons and astrocytes, the specific contribution of astrocytic D1R to drug-related circuit plasticity remains poorly understood. Here, we demonstrate in mouse NAcSh slices that D1R agonists increase astrocytic Ca2+ activity, an effect that is attenuated by astrocyte-specific D1R knockdown. Furthermore, selective knockdown of astrocytic D1R in the NAcSh prior to cocaine self-administration inhibits cocaine-induced generation of silent synapses, therefore hampering the associated remodeling of NAcSh circuits. Behaviorally, knockdown of NAcSh astrocytic D1R expedites the extinction of cocaine seeking and reduces cue-induced reinstatement. These results identify astrocytic D1R as a fundamental component of NAcSh dopamine signaling during cocaine experience that remodels synaptic connections and neural networks underlying drug seeking and relapse.

neuroscience↗

bioRxiv2026

A workflow for the identification of oligomeric structures on tilted sample planes in Cryo-SMLM

We introduce a workflow to identify oligomeric structures that are recorded with single-molecule localization microscopy (SMLM) under cryogenic conditions. Typically, these oligomers are assumed to consist of protomers arranged as equilateral two-dimensional polygons and every protomer is labeled with a dye molecule for visualization. Unlike previous work, we consider scenarios in which the sample plane has an unknown orientation relative to the focal plane. Our contribution is a high-precision plane-fitting algorithm to determine the sample plane, combined with geometrical transformations and two circle-fitting algorithms to identify the oligomeric structures. Our simulations on synthetic data demonstrate that the proposed workflow achieves high accuracy in estimating both the unknown tilted plane and the oligomer size.

biophysics↗

bioRxiv2026

Integrated RNA-seq analysis identifies ABC transporters mediating taxane export in Taxus species

RNA-seq datasets from medicinal yews are crucial for studying paclitaxel biosynthesis. However, cross-study data analyses are hindered by pronounced batch effects. Here, we compiled 45 RNA-seq samples from three studies across four tissues (bark, leaf, root, stem) and assessed 35 preprocessing pipelines combining six normalization strategies with five batch-effect correction approaches. Unsupervised clustering (HCA, k-means, Grade-of-Membership), evaluated using Jaccard and Adjusted Rand indices, revealed significant variability in batch effect removal. Supervised classification of tissue and project labels (Random Forest and linear/radial SVM) demonstrated improved accuracy in tissue type prediction, highlighting the effectiveness of correction methods. The processed data facilitated the identification of 189 putative ABC transporters across samples, six of which showing a strong correlation to the gene encoding 10-deacetylbaccatin-III-10{beta}-O-acetyltransferase, a key biosynthetic enzyme in the taxol pathway. High expression levels in leaf and bark further support their role in taxane intermediates trafficking in taxol biosynthesis. Structural analysis and molecular docking further supported the selection of these candidates, and the agreement between transcriptomic ranking and docking-based prioritization suggests that these transporters may participate in taxane intermediate recognition, trafficking, or export. These findings demonstrate the importance of normalization and batch effect correction in RNA-seq analysis to advance gene discovery in Taxus species and, more broadly, in plant research. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/723993v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1469162org.highwire.dtl.DTLVardef@1f2c4deorg.highwire.dtl.DTLVardef@15ad821org.highwire.dtl.DTLVardef@123676d_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2026

Patient CACNA1A variant uncouples calcium channel conductance from synaptic output

Channelopathies are a class of neurodevelopmental disorders with often devastating consequences, and effective therapies depend on understanding how patient variants alter channel function. These effects are typically assessed by biophysical characterization in heterologous expression systems. Mutations in CACNA1A, which encodes the P/Q-type calcium channel CaV2.1, underlie a spectrum of neurological disorders in which symptoms are generally classified as loss-of-function (LoF) or gain-of-function (GoF). However, some patients present with overlapping phenotypes that defy this binary framework. Here we describe a CACNA1A variant for which heterologous assays fail to capture a key in vivo functional effect. We characterize a de novo variant of a highly conserved residue, D1634N, identified in a patient with a mixed clinical presentation that includes both LoF- and GoF-associated symptoms. Biophysical characterization in HEK293T cells supports a classic and severe LoF effect, including reduced current density and a right-shifted current-voltage relationship. In contrast, in vivo analysis of the corresponding endogenous variant in the C. elegans homolog reveals a paradoxical increase in spontaneous synaptic vesicle release, despite reduced channel expression. Molecular dynamics simulations predict that the mutation prolongs dwell time in a partially open state, potentially increasing calcium influx at rest. This model is supported by biophysical recordings of the human channel showing increased current at hyperpolarized potentials and by rescue of the C. elegans phenotype through genetic elevation of resting membrane potential. Together, these findings reconcile the patients clinical presentation by describing a complex, mixed-function variant, highlight the importance of cellular context in variant interpretation and therapeutic development, and establish C. elegans as a powerful in vivo platform for evaluating the functional consequences of pathogenic ion channel variants.

neuroscience↗

bioRxiv2026

Prenatal THC exposure disrupts mitochondrial respiratory gene programs and delays medium spiny neuron maturation in the nucleus accumbens

Prenatal cannabis exposure (PCE) is increasingly prevalent and has been associated with adverse neurodevelopmental outcomes, yet its molecular impact on brain reward circuitry remains poorly defined. Here, we investigated transcriptional and epigenomic alterations in the nucleus accumbens (NAc) following prenatal {Delta}9-tetrahydrocannabinol exposure in a rat model using snRNA-seq and snATAC-seq analyses. PCE markedly suppressed the expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in the NAc on postnatal day 24 (P24), indicating reduced mitochondrial respiration capacity. This disrupted mitochondrial respiratory gene programming was accompanied by coordinated alterations in ribosomal and proteasomal pathways regulating protein homeostasis in NAc medium spiny neurons (MSNs), suggesting coupled disruption of cellular metabolism and neuronal maturation. snATAC-seq analysis revealed altered chromatin accessibility at promoter regions enriched for Nrf1 and Yy2 binding motifs, implicating Hrf1- and Yy2-associated transcriptional regulation of mitochondrial genes in MSNs following PCE. Moreover, an acute THC challenge in PCE offspring at P24 further exacerbated the suppression of genes involved in mitochondrial OXPHOS and MSN maturation. Together, these findings define a transcriptional and epigenetic framework through which PCE may perturb mitochondrial function and impair MSN maturation trajectories in the NAc, providing mechanistic insights into how PCE may alter the development of reward circuitry.

neuroscience↗

bioRxiv2026

Tetrahydrocurcumin Suppresses Bladder Carcinogenesis via Reprogramming O-GlcNAcylation-Phosphorylation Crosstalk

Bladder cancer exhibits high recurrence rates and limited therapeutic options in advanced stages. Although post-translational modifications (PTMs) are critical regulators of tumor biology, their systems-level remodeling during bladder carcinogenesis remains insufficiently defined. Using a BBN-induced murine bladder cancer model combined with tumor-derived organoids and bladder cancer cell lines, we observed a consistent global elevation of protein O-GlcNAcylation across tumor-associated contexts. Site-resolved quantitative proteomics revealed that this increase reflected selective redistribution rather than uniform accumulation, with differential O-GlcNAc sites nearly evenly divided between up-and down-regulated events. Integrated analyses demonstrated preferential enrichment of up-regulated O-GlcNAcylation within cytoskeleton-adhesion modules and Notch-related domains, whereas down-regulated events were more closely associated with structural maintenance and homeostatic programs. Approximately half of differentially O-GlcNAcylated proteins exhibited concurrent phosphorylation changes, indicating coordinated multi-layer PTM remodeling. Pharmacological inhibition of O-GlcNAc transferase suppressed bladder cancer cell proliferation and organoid growth, supporting a functional association between elevated O-GlcNAcylation and tumor growth. Tetrahydrocurcumin (THC) reduced global O-GlcNAcylation and induced directional remodeling of BBN-associated O-GlcNAc patterns. Cross-comparative analyses identified subsets of sites exhibiting opposite regulation trends following THC intervention. Collectively, these findings define a spatially and functionally organized PTM remodeling landscape in bladder cancer and suggest that THC exerts anti-tumor effects in part through coordinated reprogramming of O-GlcNAcylation and phosphorylation networks.

cancer biology↗

bioRxiv2026

Complete genome-derived metabolic interactions reveal impact of gut ecology on human health

Metabolic interactions govern gut microbiome assembly, yet functional rules remain obscured by genomic incompleteness and fragmentation. Here, we leverage 1,150 complete genomes to construct genome-scale metabolic models, demonstrating that draft genomes introduce systemic artifacts missing critical transport functions. We observe that metabolic interactions are intrinsically driven by genomic traits and niche specialization rather than random association. We stratifies strains into four ecological groups, including active players, resource predators, utilizers, and contributors, each of which exhibits distinct metabolite exchange/competition signatures. This functional architecture is strongly coupled to secondary metabolism. Applying this framework to inflammatory bowel disease revealed distinct temporal dynamics of ecological groups across disease subtypes, where group-specific dysbiosis predicted clinical phenotypes better than whole community profiles. Furthermore, integrating metabolic and co-occurrence networks to identify keystone for classifiers as features significantly improved disease diagnosis. Our study provides novel insights into gut metabolic interaction landscape, bridging the gap between genomic potential and clinical utility for precision microbiome therapeutics.

microbiology↗

bioRxiv2026

Complete Genomes of Cultivated Gut Bacteria Reveal Mobile Genetic Element-Driven Functional Diversity with Therapeutic Implications

Cultivated bacterial isolates are essential for elucidating gut microbiota functions, yet reliance on fragmented draft genomes and limited mobile genetic element (MGE) annotation has constrained high-resolution analyses. Here, we present the Cultivated Complete Genome Reference (CCGR), a comprehensive compendium of 1,150 fully circularized human gut bacterial genomes. Overcoming draft limitations, CCGR achieves chromosome-scale resolution and reveals distinct evolutionary strategies shaping gene topological organization in response to bacterial growth. Furthermore, we decode the dynamic landscape of MGEs, demonstrating that broad-host-range phages follow strict positional patterns by integrating at conserved chromosomal hotspots flanked by nutrient transporter loci. Importantly, we provide mechanistic in vivo evidence that accessory genomic elements drive strain-level functional heterogeneity. Specifically, the plasmid-encoded scrK gene in Levilactobacillus brevis involved in fructose catabolism is required to mitigate fructose-diet-exacerbated colitis. Collectively, CCGR establishes a framework linking chromosomal architecture and MGEs to bacterial evolution and host health, enabling precise, strain-resolved functional investigations.

microbiology↗

bioRxiv2026

Unbiased Single-Cell Transcriptome-Proteome Co-Profiling Reveals Malignant Dormancy and Post-Transcriptional Buffering of CTCs

Leptomeningeal metastasis is driven by rare cerebrospinal fluid circulating tumor cells (CSF-CTCs). However, the mechanisms underlying their adaptation to chemotherapeutic stress remain elusive, primarily because transcriptomics alone poorly predicts functional protein states. Here, we present scMAPS, a single-cell multi-omics method that employs magnetic-assisted partitioning cell lysates to enable unbiased transcriptome-proteome co-profiling without loss-prone physical splitting and precision device. By coupling scMAPS with our custom CLEAP (CTC Label-free Enrichment and Accurate Picking) system, we performed the first deep multi-omics profiling of rare clinical CSF-CTCs before and after localized chemotherapy, detecting an average of 2,547 proteins and 7,821 genes per cell. The integrated CLEAP-scMAPS pipeline reveals a coordinated prioritizing survival over proliferation malignant dormancy phenotype and identified post-transcriptional buffering as the primary driver of treatment resistance. Our platform enables the comprehensive molecular phenotyping of rare clinical specimens, providing a highly versatile framework for decoding complex post-transcriptional regulatory networks.

cell biology↗

bioRxiv2026

APEX1 Protects Cardiomyocytes Against Oxidative Stress by Regulating p53 Protein Stability

Withdrawal statementThe authors have withdrawn this manuscript because the preprint was uploaded to bioRxiv before all co-authors had been fully informed and had provided their explicit consent to make the manuscript publicly available as a preprint. Following internal discussions, the authors have reached a consensus that they do not wish this version to be publicly available. We therefore kindly request that this preprint be withdrawn on the bioRxiv platform. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

molecular biology↗

bioRxiv2026

Refinement of Nucleus Accumbens Neuronal Dynamics During Cocaine Self-Administration Training

Drug addiction is an acquired motivational-behavioral state that begins with drug taking, which is comprised of a series of phases, including initial acquisition, stabilization, habituation, and maintenance. In rodent models of cocaine self-administration, the forebrain region nucleus accumbens (NAc) has been critically implicated in the acquisition-maintenance process of drug taking and seeking behaviors. However, it remains unknown how NAc neurons shift their activity patterns in response to these phasic transitions during cocaine taking. To examine this, we used GCaMP6m-based in vivo Ca2+ imaging to monitor activities of principal medium spiny neurons (MSNs) in the NAc across eleven days of cocaine self-administration. Behaviorally, mice exhibited progressive stabilization of operant responding and locomotion across 11 days of cocaine self-administration. During the early training days, we detected a portion of NAc neurons--a potential neuronal ensemble--that exhibited increased activities temporally contingent to the lever-press for cocaine. The number of NAc neurons exhibiting contingent activity increased progressively over the first three training days and then decreased gradually during the later training days, exhibiting expansion-refinement dynamics that may correspond to the acquisition and subsequent stabilization/maintenance of cocaine self-administration. Using a neuron-tracking technique, we found that the lever-press-contingent NAc ensemble exhibited substantial compositional dynamics, with neurons dropping into and out across training days. These activity features of lever-press-contingent neurons may represent key circuit dynamics of the NAc that transition the acquisition toward the maintenance of cocaine-taking behavior.

neuroscience↗

bioRxiv2026

Cell Ploidy Modulates Nucleolar Size via Dosage of Nucleolar Organizing Regions

Abnormal nucleolar morphology is a pathognomonic histologic feature of cancer cells. Nucleoli are biomolecular condensates and cytogenetic entities that form around nucleolar organizing regions (NORs), located on the short arms of acrocentric chromosomes. Given that aneuploidy is pervasive in human cancers and can involve NOR-bearing chromosomes, we investigated how aneuploidy-driven changes in NOR dosage impact nucleolar morphology. We used reversine, a spindle assembly checkpoint inhibitor, to induce chromosomal instability and complex aneuploidy in DLD1 colorectal cancer cells (near-euploid) and normal human colon organoids (colonoids, euploid). High resolution 3D imaging and quantitative analyses of reversine-treated cells showed overall doubling of total nucleolar volume per nucleus. Reversine-associated nucleolar enlargement occurred independently of global protein synthesis, and thus was not solely driven by increases in biosynthetic demand. The volume of individual nucleoli showed a direct linear correlation with the number of associated NORs, as revealed by 3D co-localization with NOR-specific FISH probes. These findings establish NOR dosage as a determinant of nucleolar morphology and metric of genomic instability, providing a new paradigm by which aneuploidy can modulate spatial chromosomal constraints and nuclear architecture in cancer. Significance statementCancer cells often show enlarged and abnormal nucleoli. We show that aneuploidy, a common feature of cancer, can directly reshape nucleolar morphology by altering the copy number of acrocentric chromosomal regions around which nucleoli form, NORs. Using high-resolution 3D imaging in cell lines and patient-derived colonoids, we find that nucleolar number and volume directly correlate with NOR number, independent of overall protein synthesis. Individual nucleolar volume scales with the number of 3D NOR associations, and prominent single nucleoli arise when NORs accumulate. These results provide evidence that aneuploidy can lead to aberrant nucleolar morphologies seen in many human cancers.

cancer biology↗

bioRxiv2026

A Lightweight Dual-Attention Neural Network for In-Situ Hyperspectral Classification of Microalgae

Accurate monitoring of microalgae is essential for assessing marine ecological health and preventing harmful algal blooms in ocean engineering. Current in situ identification methods often suffer from limited discriminative feature extraction and inadequate adaptation to complex underwater imaging conditions. This study introduces a lightweight dual-attention neural network, termed ANMM, designed for real-time, in situ hyperspectral classification of microalgae within integrated underwater monitoring systems. The model strengthens a deepened AlexNet backbone with multi-head latent attention (MLA) and multi-head self-attention (MSA) mechanisms, which jointly enhance local feature refinement and global spectral dependency modeling. An early-stopping strategy is further incorporated to prevent overfitting and ensure robust generalization. Evaluated on a custom dataset of field-collected fluorescence spectra, the model achieves a classification accuracy of 98.91%, outperforming several state-of-the-art deep-learning counterparts. With a compact parameter size of 16.34 M and low-latency inference on edge hardware, the system demonstrates strong potential for deployment on embedded underwater sensing platforms. This work provides a practical and efficient AI-driven solution for continuous marine microalgae monitoring, supporting advances in ocean observation technology and ecological engineering.

microbiology↗

bioRxiv2026

Minute-scale coupling of chromatin marks and transcriptional bursts

Histone modifications are often described as stable epigenetic marks that contribute to maintaining gene-expression programs during development and environmental responses 1-5. However, transcription of many genes is intermittent, switching between transcriptionally active and inactive episodes within minutes 6-10. Whether chromatin marks around individual genes change on these rapid timescales remains unclear. Here we show that local chromatin modification signals around endogenous genes in mouse embryonic stem cells fluctuate reversibly with transcriptional state, using live imaging of individual genes together with fluorescent probes that report histone modifications11-16. Activation-associated acetylation and methylation marks increased in association with transcriptional activation and decreased with inactivation, whereas a Polycomb-associated repressive mark behaved oppositely. Transcriptional coactivators and both histone acetyltransferase and deacetylase complexes were enriched during transcriptionally active state, consistent with opposing enzymatic activities shaping local acetylation levels 17,18. Inhibiting histone deacetylases altered the durations of active and inactive events, supporting a role for deacetylation in regulating transcriptional state transitions. Thus, histone modifications undergo reversible, minute-scale changes coupled to transcriptional activity. This framework helps explain how stochastic transcriptional bursts can occur with stable gene regulation over longer timescales.

molecular biology↗

bioRxiv2026

The genetic repertoire of the deep sea: from sequence to structure and function

The deep sea as the largest and maybe most hostile environment on Earth is still underexplored especially regarding its genetic repertoire. Yet, previous work has revealed significant habitat-specific deep-sea biodiversity. Here, we present an integrated deep-sea genetic dataset comprising 502 million nonredundant genes from 2,138 samples and 2.4 million predicted structures, and used it to link specific protein structures with genetic variants associated with life in the deep sea and to assess their biotechnology potential. Combining global sequence analysis with biophysical and biochemical measurements revealed unprecedented sequence diversity, yet substantial structural conservation of proteins. Especially proteins involved in replication, recombination, and repair were identified to be under rapid evolution and with specialized properties. Among these, a structurally divergent helicase exhibited advantages in controlling nanopore sequencing speed. Thus, our work positions the deep sea as a unique evolutionary engine that generates and hosts genetic diversity and bridges genetic knowledge with biotechnology.

bioinformatics↗

bioRxiv2026

Organoid-Based Transcriptomics Indicate IFIT-Associated Immune Modulation during Cryptotanshinone Treatment in Bladder Cancer

Bladder cancer (BC), particularly muscle-invasive and metastatic disease, remains a major clinical challenge despite recent advances in immunotherapy. In this study, we aimed to identify a promising antitumor compound from five candidate small molecules and to explore its potential roles in BC progression. Through antiproliferative screening, cryptotanshinone (CTS) was identified as the promising candidate. Using both two-dimensional BC cell lines and three-dimensional bladder tumor organoid models, we comprehensively evaluated the effects of CTS on cell proliferation, migration, apoptosis, and organoid growth. To further explore the underlying mechanisms, transcriptomic sequencing based on bladder cancer organoid models, protein-protein interaction network analysis, and public databases (TCGA-BLCA, TIMER, and TISIDB) were integrated to examine immune-related pathways and potential molecular targets associated with CTS. GeneMANIA network prediction and molecular docking analyses were subsequently performed to investigate upstream regulatory networks and the potential interactions between CTS and key components of the cGAS-STING-IFN-I-JAK-STAT signaling pathway. Integrative analyses suggested that IFIT1, IFIT2, and IFIT3 may function as immune-associated genes potentially linked to BC progression, patient prognosis, immune cell infiltration, and PD-1/PD-L1 expression. Molecular docking results suggested that CTS may interact with core regulatory proteins within the cGAS-STING-IFN-I-JAK-STAT pathway, potentially influencing IFIT transcriptional regulation. Collectively, these findings indicate that CTS exhibits measurable antitumor and immunomodulatory effects, which may be associated with modulation of the cGAS-STING-IFN-I-JAK-STAT-IFIT signaling axis, supporting its potential as a small-molecule candidate for bladder cancer.

cancer biology↗

bioRxiv2026

Ketosis rescues frataxin deficiency and corrects disease phenotypes in an FRDA animal model

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by deficiency of the mitochondrial protein frataxin. Effective therapeutic options remain limited for FRDA. We previously demonstrated that frataxin regulates ketone body metabolism by modulating 3-Oxoacid CoA-Transferase 1 (OXCT1), the rate-limiting enzyme in ketone body catabolism. However, the mechanisms governing frataxin-dependent control of OXCT1 turnover as well as the contribution of frataxin deficiency-induced OXCT1 reduction to FRDA pathogenesis, have remained unclear. Here, we demonstrate that frataxin regulates OXCT1 protein turnover by inhibiting its ubiquitination and subsequent proteasomal degradation. The N-terminal 40 amino acids of frataxin mediate such events, as overexpression of this region alone blocks ubiquitin-proteasome system (UPS)-dependent OXCT1 degradation. To evaluate the impact of OXCT1 deficiency on FRDA phenotypes, we enhanced OXCT1 reduction by introducing a 50% OXCT1 knockout into frataxin-deficient KIKO mice (KIKO/OXCT1/-). While OXCT1 deficiency potentiates cell death in vitro in control and FRDA patient fibroblasts, further OXCT1 reduction in KIKO mice induces ketosis, increases frataxin levels, and improves neurobehavioral performance. The increase in frataxin does not reflect elevated FXN gene transcription but rather enhanced mitochondrial biogenesis, evidenced by increased biogenesis markers, restored mitochondrial morphology and size, and increased mitochondrial gene expression. Fasting-which promotes ketosis-similarly increases frataxin levels and mitochondrial biogenesis markers in older KIKO/OXCT1+/- mice. {beta}-hydroxybutyrate administration in FRDA iPSC-derived cardiomyocytes elevates frataxin levels and mitochondrial biogenesis markers, further supporting the beneficial effect of ketosis on frataxin expression and mitochondrial biogenesis. Collectively, our findings demonstrate that ketosis partially restores frataxin levels and ameliorates FRDA-related phenotypes, providing a potential therapeutic strategy for FRDA.

biochemistry↗

bioRxiv2025

Cross-sectional association study from NHANES between some dietary supplements and anti-HAV antibodies

Background/Objectivesdietary supplements intake is known for its importance in preserving immune system and immune response but we need to estimate if there were direct cross-sectional association between some dietary supplements use 24-hours and anti-HAV antibodies or not. Methodsdata merged from three NHANES three cycles along (2013-2018) were analyzed, representing 29.400 participants across all ages. The data collected were subjected to a logistic regression analysis to assess the relationship between the reported frequency of infections and dietary nutrients consumed including minerals and some vitamins. Resultsthe results in overall verified no significant association between investigated dietary supplements use 24-hours and anti-HAV antibodies. However, vitamin D (p = 0.004) showed a significant positive association. Conclusionsthere were true direct association revealed of vitamin D on anti-HAV antibodies.

immunology↗