Biology subjects

Gao, Y.

Publications and source records attributed to Gao, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2025

Multi-Omics and Machine Learning-Based Profiling of Severity Signatures in Mycoplasma Pneumoniae Infection in Children

Mycoplasma pneumoniae pneumonia (MPP) is a common respiratory infection in children, yet the mechanisms driving its progression to severe disease remain poorly understood. This study employs a comprehensive proteomic and metabolomic approach to elucidate severity-related pathways and identify potential biomarkers for improved diagnosis and targeted therapy. By analyzing blood proteomes from 57 pediatric patients with varying MPP severities alongside 10 healthy controls, and integrating multi-omics data from bronchoalveolar lavage fluid (BALF), we uncovered key severity-associated proteins and metabolites linked to inflammatory and metabolic dysregulation. Notably, alterations in L-arginine metabolism, influenced by APAF1 and SERPINB5, were found to modulate the efferocytosis pathway, while ERCC1 and MLH1, crucial components of the Fanconi anemia pathway, were associated with changes in plasmid acid metabolites affecting fatty acid elongation. Machine learning analysis further identified three critical biomarkers--TNFRSF10B, SAT1, and 4-nitrophenol-- that accurately distinguished between mild and severe MPP cases with high sensitivity (0.8) and specificity (1). These findings provide novel insights into the molecular mechanisms underlying severe MPP, highlighting efferocytosis and fatty acid metabolism as key pathways. The identification of severity-specific biomarkers offers a foundation for enhanced diagnostic precision, improved disease stratification, and the development of targeted therapeutic strategies to optimize the management of severe MPP in pediatric patients. HighlightsO_LIIdentified severity signatures in Mycoplasma pneumoniae infection in children. C_LIO_LIConducted the multi-omics analysis of bronchoalveolar lavage fluid (BALF) in children with varying severities of Mycoplasma pneumoniae infection. C_LIO_LIDiscovered biomarkers that effectively distinguish mild from severe Mycoplasma pneumoniae infection. C_LIO_LIFindings offer potential targets to improve the diagnosis and treatment of severe Mycoplasma pneumoniae C_LIO_LIinfection in children. C_LI

microbiology↗

bioRxiv2025

Adolescents with major depression featured by sensory-association subtyping show divergent information dynamics and streams

Adolescent major depressive disorder (MDD) exhibits complex and heterogeneous alterations of brain functional organization. To understand the neurobiological basis of adolescent MDD, we adopted resting-state functional MRI data and used various matrix decomposition approaches to obtain the organization gradients, temporal dynamics, and information streams. With clustering sensory-association gradient features in our exploratory sample (NMDD = 250 and NControls = 203), we identified two MDD subtypes. Subtype 1 was characterized by sensory contraction and subtype 2 was associated with association expansion. In addition, two subtypes showed divergent bottom-up and top-down information flows in sensory and association areas using temporal dynamics analysis. These subtypes exhibit distinct age-related changes and reorganization trajectories along sensory-association and auditory-visual axes, highlighting that cortical information flow patterns systematically vary and relate differently to sensory integration, cognitive complexity, and aging. These network distinctions are linked to clinical severity and molecular mechanisms. Subtype 1 is predominantly associated with early neurodevelopmental abnormalities and emotional regulation deficits, while Subtype 2 is more related to synaptic dysfunction and reduced neuronal excitability. These results could be largely replicated in another independent sample (NMDD = 73 and NControls = 28). We therefore construct a sensory-association dual functional framework to characterize MDD heterogeneity in adolescent MDD. Itl integrates cortical hierarchy, developmental trajectories, and genetic influences, offering novel insights into MDD pathophysiology and providing a theoretical foundation for precision psychiatry, facilitating personalized diagnosis and intervention strategies.

neuroscience↗

bioRxiv2025

Neural signatures of flexible temporal orienting under spatial and motor uncertainty

The goal-dependent use of temporal expectations enhances visual performance, even without concurrent spatial or motor predictions, yet the underlying neural mechanisms remain unclear. To identify the stages of stimulus processing influenced by temporal orienting of attention, we recorded EEG while participants performed a visual identification task manipulating relevance and temporal predictability of targets. Colored targets appeared in one of two simultaneous visual streams. One color appeared unpredictably while two others appeared predictably early or late. Targets appeared in either stream and required a localization response using the corresponding hand. On each trial, one target was cued as task-relevant. Behaviorally, participants used temporal expectations flexibly to optimize processing of goal-relevant targets. The target-defining cue elicited a contingent negative variation (CNV), modulated by the temporal predictability of anticipated early vs. late targets. Target-related event related potentials (ERP) showed strong modulation by target relevance at multiple stages. Modulations impacted target-selection (N2pc), motor preparation (LRP), and late decision-related factors (P300). Interestingly, only the P300 was additionally modulated by the temporal predictability of targets. The findings reveal how temporal attention can impact multiple stages of stimulus processing through the relevance and temporal predictability of targets even without spatial or motor certainty.

neuroscience↗

bioRxiv2025

Time-lapse tryptic digestion: a proteomic approach to improve sequence coverage of extracellular matrix proteins

The extracellular matrix (ECM) is a complex and dynamic meshwork of proteins providing structural support to cells. It also provides biochemical signals governing cellular processes, including proliferation, adhesion, and migration. Alterations of ECM structure and/or composition have been linked to many pathological processes, including cancer and fibrosis. Over the past decade, mass-spectrometry-based proteomics has become the state-of-the-art method to profile the protein composition of ECMs. However, existing methods do not fully capture the broad dynamic range of protein abundances in the ECM. They also do not permit to achieve the high coverage needed to gain finer biochemical on ECM proteoforms (e.g., isoforms, post-translational modifications) and topographical information critical to better understand ECM protein functions. Here, we present the development of a time-lapsed proteomic pipeline using limited tryptic proteolysis and sequential release of peptides over time. This experimental pipeline was combined with data-independent acquisition mass spectrometry and the assembly of a custom matrisome spectral library to enhance peptide-to-spectrum matching. This pipeline shows superior protein identification, peptide-to-spectrum matching, and significantly increased sequence coverage against standard ECM proteomic pipelines. Exploiting the spatio-temporal resolution of this method, we further demonstrate how time-resolved 3-dimensional peptide mapping can identify protein regions differentially susceptible to trypsin, which may aid in identifying protein-protein interaction sites.

biochemistry↗

bioRxiv2025

FMR1 KH0-KH1 Domains Coordinate m6A Binding and Phase Separation in Fragile X Syndrome

The Fragile X Mental Retardation Protein (FMR1) regulates neurodevelopment via m6A RNA interactions, but domain-specific roles of KH0 and KH1 in RNA binding and pathology remain unclear. Through mutagenesis and AlphaFold3 modeling, we demonstrate that KH1 serves as the primary m6A-binding interface, whereas the KH0 domain (e.g., Arg138) modulates liquid-liquid phase separation (LLPS). Pathogenic mutations in KH0 disrupt RNA binding and enhance LLPS aggregation, while m6A RNA suppresses LLPS at KH0. Structural simulations reveal synergistic cooperation between KH0 and KH1 through hydrophobic and electrostatic networks. These dual-domain interactions establish a mechanistic link between m6A dysregulation, aberrant phase separation, and Fragile X syndrome pathogenesis. Our findings propose KH0 as a therapeutic target for RNA-driven neurodevelopmental disorders.

cell biology↗

bioRxiv2025

GSK-3 regulates CD4-CD8 cooperation needed to generate super-armed CD8+ cytolytic T cells against tumors

While immune checkpoint blockade (ICB) has revolutionized cancer treatment, the key T-cell signaling pathways responsible for its potency remain unclear. GSK-3 is an inhibitory kinase that is most active in resting T-cells. In this study, we demonstrate that GSK-3 facilitates PD-1 blockade, an effect seen by modulating CD4 T-cell help for CD8+ CTL responses against ICB resistant tumors. We show that GSK-3 controls metabolic reprogramming towards glycolysis and synergizes with PD-1 to induce a transcriptional program that reduces suppressive CD4+ Treg numbers while generating super-armed effector-memory CD8+ CTLs that express an unprecedented 7/9 granzymes from the genome. Crucially, we found that GSK-3 cooperates with PD-1 blockade to determine the dependency of CD8+ CTLs on help from CD4+ T-cells. Our study unravels a novel cooperative PD-1 blockade-dependent signaling pathway that potentiates CTL responses against tumors, offering a new strategy to overcome immunotherapy resistance by modulating CD4+ helper and CD8+ cytotoxic functions. SignificanceThis study demonstrates for the first time that GSK-3 controls the crosstalk between CD4+ and CD8+ T cells, synergizing with anti-PD-1 therapy to overcome resistance to checkpoint blockade and to generate super-armed CD8+ effector cells in cancer immunotherapy. This newly uncovered GSK-3-dependent CD4-CD8 T-cell crosstalk mechanism presents a new approach to enhance anti-PD-1 immunotherapy.

immunology↗

bioRxiv2025

Characterization of the gut mycobiome in patients with non-alcoholic fatty liver disease and correlations with serum metabolome

BackgroundThe relationship between the gut mycobiome and non-alcoholic fatty liver disease (NAFLD) is largely unexplored. MethodsIn this study, we used a publicly available shotgun metagenomic sequencing dataset of fecal samples to compare the gut fungal communities of 90 NAFLD patients with those of 90 healthy controls. We examined their correlations with gut bacterial communities, host serum metabolite s, and the interactions of key taxa within these networks. ResultsOur results revealed a remarked dysbiosis in the gut mycobiome of NAFLD patients, cha racterized by a significant increase in four fungal taxa, including Pseudopithomyces sp. c174, Muc or sp. c176, Aspergillus sp. c25, and uncultured Ascochyta c213. Multi-omics analysis showed that the gut mycobiome significantly contributes to the host serum metabolome. Pseudopithomyces s p. c174 was notably associated with some beneficial blood metabolites, such as glycoursodeoxycholic acid and alpha-linolenic acid, whereas the NAFLD-enriched pro-inflammatory phenylacetic acid was linked to Aureobasidium sp. c170 and Basipetospora sp. c193. Network analysis revealed significant alterations in the gut microbiome of NAFLD patients, highlighting the potential roles of Alternaria alternata c42, Penicillium sp. c5, and uncultured Malassezia c303. Moreover, predictive models that integrated both bacterial and fungal taxa improved prediction accuracy, emphasizing the crucial role of gut fungi in NAFLD. ImportanceNon-alcoholic fatty liver disease (NAFLD) is a widespread liver condition with limited treatments. While gut bacteria have been extensively studied in NAFLD, the role of gut fungi (the mycobiome) remains poorly understood. This study fills that gap by characterizing gut fungal communities in NAFLD patients and linking these changes to their blood metabolite profiles. We found that NAFLD patients show distinct fungal imbalances, which correlate with key metabolic alterations in the host. These findings expand our understanding of NAFLD by spotlighting gut fungi as important contributors to disease progression. This insight opens new avenues for potential biomarkers and therapies targeting the gut-liver axis. ConclusionsOur findings provide a comprehensive understanding of the link between the gut mycobiome and NAFLD progression, which is essential for guiding future therapeutic research.

microbiology↗

bioRxiv2025

The stress response factor SigH mediates intrinsic resistance to multiple antibiotics in Mycobacterium abscessus

Mycobacterium abscessus (Mab) causes pulmonary diseases with limited treatment options due to its high level of intrinsic resistance to available drugs. Mab possesses complex and poorly understood drug resistance mechanisms. Identifying new drug targets and gaining a deeper understanding of drug resistance mechanisms are essential for discovering novel therapeutic alternatives. Here, we investigated the role of a putative sigma factor SigH in intrinsic multi-drug resistance in Mab. Mab SigH shares an 84% peptide sequence identity with Mycobacterium tuberculosis (Mtb) SigH, a well-known stress response protein and global transcriptional regulator. We constructed a sigH gene deletion strain of Mab ({Delta}sigH) and complemented strains by expressing either Mab sigH (CPMabsigH) or Mtb sigH (CPMtbsigH) in {Delta}sigH. The {Delta}sigH strain exhibited hypersensitivity to a broad range of antibiotics, including levofloxacin, moxifloxacin, tigecycline, tetracycline, amikacin, vancomycin, and rifabutin and all complemented strains restored the drug resistance phenotype. Additionally, {Delta}sigH showed increased sensitivity to oxidative and heat stress compared to the wild-type Mab and complemented strains. Transcriptomic analysis revealed that deletion of sigH disrupted the balance of gene expression, primarily elevating the expression of genes encoding YrbE and MCE family proteins and downregulating genes expressing ABC-type transporters, sigma and anti-sigma factors and other genes associated with antimicrobial resistance. Collectively, our findings indicate that SigH is a key regulator of global gene expression in response to environmental stresses, including antimicrobial treatment, and is crucial for the intrinsic drug resistance of Mab. SigH represents a promising target for the development of novel therapeutic strategies against Mab infections.

molecular biology↗

bioRxiv2025

Re: Concerns Regarding the Validation of ZYS-1 as a Bona Fide ADAR1 Inhibitor

Wang et al. in Nature Cancer report ZYS-1 as an ADAR1 inhibitor and present biochemical and cellular evidence to support ZYS-1s direct interaction with and inhibition of ADAR1, including enzymatic assays, surface plasmon resonance (SPR), drug affinity responsive target stability (DARTS), and cellular thermal shift assays (CETSA). We raise critical methodological concerns regarding the validation of ZYS-1 as a bona fide ADAR1 inhibitor. Our primary concern relates to the misuse of an adenosine deaminase (ADA) activity assay kit for ADAR1 enzymatic activity characterization. Using established biochemical assays with direct inosine quantification, we evaluated ZYS-1s inhibitory activity against ADAR1 using physiologically relevant RNA substrates. The compound showed no inhibitory activity at concentrations up to 1 mM. We demonstrate that the ADA assay kit used by Wang et al. does not reflect ADAR1-specific activity, and ZYS-1 is unable to inhibit ADAR1 in well-validated biochemical assays. We urge for further validation using ADAR1-specific assays to establish ZYS-1 as a genuine ADAR1 inhibitor.

pharmacology and toxicology↗

bioRxiv2025

The relationship of white matter tract orientation to vascular geometry in the human brain

The white matter of the human brain exhibits highly ordered anisotropic structures of both axonal nerve fibers and cerebral vasculature. Separately, the anisotropic nature of white matter axons and white matter vasculature have been shown to cause an orientation dependence on various MRI contrasts used to study the structure and function of the brain; however, little is known of the relationship between axonal and vascular orientations. Thus, the aim of this study is to compare the orientation between nerve fibers and vasculature within the white matter. To do this, we use diffusion MRI and susceptibility weighted imaging acquired in the same healthy young adult volunteers and analyze the alignment between white matter fibers and blood vessels in different brain regions, and along different pathways, to determine the degree of alignment between these structures. We first describe vascular orientation throughout the brain and note several regions with consistent orientations across individuals. Next, we find that vasculature does not necessarily align with the dominant direction of white matter in many regions, but, due to the presence of crossing fiber populations, does align with at least some white matter within each MRI voxel. Even though the spatial patterns of blood vessels run in parallel to several white matter tracts, they do not do so along the entire pathway, nor for all pathways, suggesting that vasculature does not supply/drain blood in a tract-specific manner. Overall, these findings suggest that the vascular architecture within the white matter is closely related to, but not the same as, the organization of neural pathways. This study contributes to a better understanding of the microstructural arrangement of the brain and may have implications for interpreting neuroimaging data in health and disease.

neuroscience↗

bioRxiv2025

Mesoderm-specific transcript reduces ciliary sphingomyelin levels to promote tendon stem/progenitor cells osteochondrogenesis in traumatic heterotopic ossification

Traumatic heterotopic ossification (tHO) is a musculoskeletal disorder characterized by ectopic bone formation in soft tissues following trauma. However, the etiology and mechanisms of tHO remain unknown, and no treatments are highly effective for tHO. Here, by performing single-cell RNA sequencing (scRNA-seq) on two tHO mouse models, we found that ciliary Hedgehog (Hh) and PI3K-Akt signaling in tendon stem/progenitor cells (TSPCs) is upregulated during tHO development, leading to the activation of GLI family zinc finger 2 (GLI2) transcription factor, which promotes mesoderm-specific transcript (MEST) gene expression. Untargeted lipidomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS) on detached cilia indicated that MEST could reduce ciliary sphingomyelin (SM) levels by inhibiting SM synthesis in TSPCs, creating a positive feedback loop that amplified ciliary Hh signaling, enhancing TSPCs osteochondrogenesis and driving tHO formation. Targeting ciliary genes intraflagellar transport 88 (IFT88) or ADP ribosylation factor like GTPase 3 (ARL3) restored normal TSPCs osteochondrogenesis in vitro and attenuated ectopic bone formation in vivo by suppressing Hh and PI3K-Akt signaling. AAV-mediated MEST inhibition or exogenous SM administration in vivo also alleviates tHO progression. These findings may provide novel insights into tHO pathogenesis and potential therapeutic strategies.

molecular biology↗

bioRxiv2025

The Effect of Arsenic on Mitochondrial Fatty Acid Metabolism via Inhibition of Carnitine Palmitoyltransferase 1B and Choline Kinase Beta in C2C12 Cells

Arsenic can enter the human body through environmental exposure via food, drinking water, and chemotherapy for cancer. Prolonged and excessive exposure to arsenic causes various toxic reactions, leading to diseases that significantly impact health and lifespan. Increasing evidence suggests that arsenic damages skeletal muscle tissue by reducing muscle mass and causing atrophy, thereby contributing to conditions such as respiratory and cardiovascular diseases, as well as diabetes. Fatty acid {beta}-oxidation is the most efficient mechanism for ATP production and serves as a primary energy source for tissues, including the heart and skeletal muscles. However, the metabolic mechanisms underlying arsenics effects on muscle function and pathogenesis remain incompletely understood. In this study, we investigated the role of mitochondrial fatty acid oxidation in arsenic-induced muscular damage using mouse skeletal muscle C2C12 cells. Our results demonstrated a dose-dependent inhibitory effect of sodium arsenite (0-2 {micro}M, 72 hours) on C2C12 cells proliferation, viability, and differentiation (indicated by reduction of myogenic differentiation 1 mRNA expression). Arsenic exposure disrupted mitochondria through increasing reactive oxygen species production, reducing mitochondrial membrane potential, downregulating mitochondrial fatty acid metabolism-related enzymes (carnitine palmitoyltransferase 1B and choline kinase beta mRNA), and decreasing mitochondrial DNA copy number. These findings suggest that arsenic-induced pathological changes in skeletal muscle are associated with impaired mitochondrial membrane function, disrupted fatty acid metabolism, and reduced mitochondrial DNA content in muscle cells.

cell biology↗

bioRxiv2025

Proteome analysis of daily urine samples of pregnant rats unveils developmental processes of fetus as well as physiological changes of mother rats

Significant physiological changes occur in both fetus and mother during pregnancy. Urine proteins have been shown to reflect a wide range of physiological and pathological changes in the body. To comprehensively explore the daily changes in urine proteins during pregnancy, this study employed low-abundance protein-enriched magnetic nanobeads to conduct an in-depth analysis of the daily changes in urine proteins throughout the entire pregnancy of rats. Based on the 3,455 identified urine proteins, fetal and maternal dynamic changes were observed in the pregnancy group compared to the control group, including blastocyst formation and cell division in the early stage of pregnancy, embryonic development and organ morphogenesis in the intermediate and mid-to-late stages of pregnancy, and maternal-specific change such as lactation in the late stage of pregnancy. These results indicate that urine protein can reflect the fetal and maternal dynamic physiological alterations during pregnancy, which suggests the potential value of urine protein analysis in pregnancy health monitoring. It is emphasized that the analysis focuses on the daily variations in the urine proteins, as these daily changes are expected to reveal more dynamic and detailed information about the physiological processes during pregnancy.

developmental biology↗

bioRxiv2025

APV-Sankey: A Comprehensive Toolbox for Aptamer Screening and Visualization

Aptamers, short single-stranded DNA or RNA molecules, have gained prominence as molecular recognition elements in diagnostics and therapeutics. Screening high-performance aptamers from SELEX process is tough due to limited library diversity, PCR bias, and low library enrichment efficiency. The enriched highest frequency sequences often do not have the highest affinity or specificity. Thus, we developed APV-Sankey, a novel and versatile toolbox designed for the rapid aptamer screening and visualization of the enrichment process. Its key feature is the innovative use of Sankey charts for interactive and informative visualizations. These charts facilitate tracing the evolution of K-mers (K-mer is just a sequence of k characters in a string) across SELEX rounds, aiding in the identification and selection of high-affinity sequences containing K-mers while excluding high-frequency sequences without affinity. Besides integrating essential functions for aptamer analysis, we also developed advanced methods including K-mer concatenation and K-mer evolution, combined with Sankey chart visualizations. Using this toolbox to analyze experimentally screened sequences, we successfully identified high-performance candidate aptamers of rapamycin and thrombin.

bioinformatics↗

bioRxiv2025

TinA enables kinesin-14/KlpA to exhibit processive minus-end-directed motility

Kinesin-14 motors contribute to spindle assembly by localizing to spindle poles and anchoring the minus ends of spindle microtubules. Unlike other kinesin-14 motors, KlpA uniquely exhibits plus-end-directed motility on single microtubules as individual homodimers. However, the mechanism by which KlpA achieves minus-end-directed motility on single microtubules remains elusive. Here, we report that TinA, a highly conserved microtubule-anchoring protein, serves as an activator of KlpA for minus-end-directed motility. TinA directly interacts with KlpA to form minus-end-directed complexes that exhibit continuous movement on microtubules with two distinct velocity modes. The assembly of KlpA-TinA complexes depends on TinA binding to the central stalk of KlpA. Furthermore, TinA is a microtubule-binding protein, with its C-terminal region playing a critical role in microtubule interaction. Deletion of the C-terminus of TinA markedly reduces its microtubule-binding ability and severely impairs the formation of KlpA-TinA complexes. Nonetheless, KlpA-TinA complexes formed without the C-terminus of TinA still exhibit minus-end-directed motility, albeit with a single velocity mode. Collectively, these findings provide critical mechanistic insights into how TinA modulates KlpA, enabling the kinesin-14 motor to achieve minus-end-directed motility.

biophysics↗

bioRxiv2025

Effects of One-week Intake of Different Edible Oils on the Urinary Proteome of Rats

ObjectiveTo explore the effects of different edible oils on the rat body by analyzing the changes in the urinary proteome and post-translational modifications of rats after one-week intake of olive oil, butter, lard, hydrogenated vegetable oil, and rapeseed oil. MethodsSix parallel experiments were set up using male Wistar rats. Group A served as the control group, while groups B - F were administered different edible oils. The daily intakes were calculated respectively according to the "2015 - 2020 Dietary Guidelines for Americans" and the "Dietary Guidelines for Chinese Residents". Urine samples were collected after one week and identified by label - free quantitative proteomics technology of high - performance liquid chromatography - tandem mass spectrometry (LC - MS/MS). Differentially expressed proteins and differential post - translational modifications in the urinary proteome were screened for functional analysis. ResultsAfter the intake of different types of edible oils, rats produced a large number of proteins and biological pathways related to metabolism, but there were few common differentially expressed proteins among different groups. In addition, the olive oil group and the butter group were enriched with many biological pathways related to the nervous system, and the rapeseed oil group produced more differentially expressed proteins and biological pathways related to immunity. ConclusionThe urinary proteome of rats showed significant changes after one-week intake of edible oils, and the effects of various edible oils on the rat urinary proteome were different from each other. This effect is comprehensive and multi-dimensional at the level of the rat body. The changes in post-translational modifications of the proteome were relatively small.

biochemistry↗

bioRxiv2025

Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus

Pathologic T cell-B cell interactions drive disease in systemic lupus erythematosus (SLE). The T cells that activate B cell responses include T peripheral helper (Tph) and T follicular helper (Tfh) cells, yet the developmental and clonal relationships between these B cell-helper T cell populations are unclear. Here we use T cell receptor (TCR) profiling to demonstrate substantial clonal overlap between Tph and Tfh cells in the circulation of patients with SLE. Expanded Tph and Tfh cell clones persist over the course of 1 year in patients with a new diagnosis of SLE, and clones are observed to shift both from Tfh to Tph cells and from Tph to Tfh cells over time. High resolution analysis of cells sorted as Tph cells (CXCR5- PD-1hi) from SLE patients revealed considerable heterogeneity among these cells and highlighted a subpopulation of cells with transcriptomic features of activated B cell-helper T cells. This cell population, marked by expression of TOX and CXCL13, was found in both sorted Tph and Tfh cells, and was clonally linked in these two populations. Analysis of B cell-helper T cells in murine pristane-induced lupus demonstrated similar populations of Tph and Tfh cells in both lung and spleen with strong clonal overlap. T cell-specific loss of Bcl6 prevented accumulation of Tfh cells and reduced accumulation of Tph cells in pristane-treated mice, indicating a role for Bcl6 in the survival and expansion of both populations. Together, these observations demonstrate a shared developmental path among pathologically expanded Tph and Tfh cells in SLE. The persistence of expanded Tph and Tfh cells clones over time may explain the lack of stable tolerance induction by immunosuppressive medications or by B cell depletion.

immunology↗

bioRxiv2025

Mouse Cortical Cellular Diversification Through Lineage Progression of Radial Glia

Cortical radial glia (RGs) sequentially generate pyramidal neurons (PyNs) and glia. In this study, we investigated the cell intrinsic programs underlying cortical cellular diversification using time-series scRNA-seq and snATAC-seq on purified mouse cortical progenitors across embryonic and postnatal stages. Our data revealed that RGs transition from early to late over time, sequentially producing intermediate neuronal progenitors (INPs) and intermediate glial progenitors (IGPs). While INPs expand exclusively to generate PyNs, IGPs progress from young to old, sequentially producing cortical astrocytes, oligodendrocytes, and olfactory bulb interneurons. We constructed comprehensive molecular maps that reflect cell lineage progression. In particularly, we found that chromatin accessibility drives cortical cellular diversification by restricting broadly expressed transcription factors to specific stages and cell types. Developmental changes in chromatin accessibility confine Lhx2-induced neurogenesis to early-stage RGs, leading to the loss of neurogenic competence and the acquisition of gliogenic competence as corticogenesis progresses.

neuroscience↗