Biology subjects

He, Y.

Publications and source records attributed to He, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

Alphaviral nonstructural protein-host RBP co-condensation as a mechanism to sustain virus replication

It has long been recognized that the intracellular replication of alphaviruses critically relies on several key host RBPs, including G3BP1/2 and FXR1/FXR2/FMR1, but how these RBPs modulate alphaviral replication and whether it would be possible to target these RBPs for antiviral treatment are less explored. Here, using SFV as a model, we report that SFV nsP3 exploits G3BP for its condensation and transforms antiviral stress granules into proviral nsP3-G3BP co-condensates. The gel-like co-condensates of nsP3 and G3BP enrich and protect viral genomic RNAs from host RNase degradation and serve as viral translational hubs to promote viral replication. The mode of nsP3-RBP co-condensation is prevalent across alphaviruses, and disruption of nsP3 condensates is an efficient antiviral approach. Thus, these findings uncover a general anti-alphavirus strategy based on the conserved reliance of nsP3-RBP co-condensation.

cell biology↗

bioRxiv2025

Evaluate and simulate the reproduction and survival of a reintroduced population in an endangered bird species Crested ibis (Nipponia nippon)

O_LIReintroduction programs are critical for restoring endangered species. However, scientific assessments and management recommendations based on comprehensive vital rates across the entire life cycle remain limited for such programs. The Crested ibis (Nipponia nippon), once nearly extinct, has been the focus of intensive conservation efforts, including reintroduction into its historical range. Here, we systematically evaluate the success of a Crested ibis reintroduction population by integrating long-term field monitoring with population dynamic modeling. C_LIO_LIWe conducted a systematic, multi-year (2023-2025) demographic study of a reintroduced Crested ibis population in Dongzhai National Nature Reserve, China. From 2013 to 2023, a total of 133 captive Crested ibises were released in seven batches within the nature reserve. By 2025, the wild population had exceeded 500. Based on the combination of field monitoring (n = 176 pairs) and GPS telemetry (n = 74 GPS tags, the longest monitoring time lasting 4 years), we quantified reproductive output and mortality rates across six life stages: nest building, incubation, offspring provisioning, fledgling (< 1 year), sub-adult (1-2 years), and adult (> 2 years). C_LIO_LIThe results show that the average clutch size of this population is 3.24 {+/-} 0.08, and each pair of parent birds can rear 1.31 {+/-} 0.12 nestlings to fledging each year. We found that high mortality during the incubation (32.5%, n = 425 eggs), offspring provisioning (34.1%, n = 287 chicks), and fledgling stages (38.6%, n = 63 birds). Key causes included unfertilized eggs, predation, starvation, and human disturbance. On the other hand, the mortalities in the nest building (9.1%, n = 176 pairs), sub-adult (9.8%, n = 28 birds) and adult stage (21.3%, n = 15 birds) were relatively low. Stage-structured matrix model shows a positive population growth of this reintroduced population (growth rate {lambda} = 1.053), with the population expected to increase 13-fold over 50 years (6,858 individuals). Sensitivity analysis indicates that adult survival had the strongest influence on population growth. Correspondingly, we predict that by 2075, its distribution range will expand 13-fold in tandem with population growth, exceeding 51,000 km{superscript 2} and covering several surrounding cities. C_LIO_LIOur comprehensive monitoring, evaluation, and simulation across the full life-cycle confirm that the reintroduced population is successfully established and self-sustaining. This finding addresses a critical research gap: the lack of a scientific and systematic framework for assessing population reintroductions in endangered species. Furthermore, we identified key conservation practices to enhance population growth and stability, including predator control, supplemental feeding, the rescue of weak chicks, and reducing human disturbance through public engagement. To ensure long-term viability, we also recommend implementing genetic management to avoid inbreeding. The resulting framework provides a practical model for improving reintroduction success and promoting species recovery in other endangered species. C_LI

ecology↗

bioRxiv2025

Integrative spatial multi-omics reveals prognostic tumor niches in female genital tumors

Female genital tumors (FGTs), including ovarian, endometrial, and cervical cancers, pose a major global health challenge, yet their spatial and molecular determinants of progression and therapy resistance remain poorly understood. Here we present a large-scale integrative spatial and multi-omics atlas of FGTs, combining exome, transcriptome, methylome, and miRNA sequencing with high-resolution Visium HD spatial transcriptomics, profiling over 62 million cells from 100 tumors. We show that HPV-driven suppression of TGF{beta} signaling in cervical cancer disrupts myofibroblast (myCAF) formation and reshapes immune infiltration, while serous tumors exhibit extensive oncogene amplifications that activate MYC and PI3K pathways, linking chromosomal instability (CIN) to proliferative, immune-cold phenotypes. In high-grade serous ovarian cancer, we identify a previously unrecognized malignant domain, the Proliferating Core Desert (PCD) niche, defined by CIN-high epithelial enrichment, immune exclusion, stromal protection, and chemotherapy resistance, maintained through crosstalk with macrophages and fibroblasts. Finally, we develop POWER, a pathology foundation model that predicts PCD niche abundance from routine H&E slides, enabling robust stratification of prognosis and anti-angiogenic therapy response.

genomics↗

bioRxiv2025

A stress-dependent TRIM28-ALKBH2 feedback loop modulates chemotherapy response

Chemoresistance to DNA-damaging agents, including platinum and alkylating compounds, limits treatment efficacy in non-small cell lung cancer (NSCLC) and is frequently associated with elevated DNA repair activity. Here, we identify a stress-responsive feedback loop between the E3 ligase TRIM28 and the demethylase ALKBH2. TRIM28 binds ALKBH2 and promotes its K48-linked polyubiquitination and proteasomal degradation, whereas ALKBH2 enhances TRIM28 transcription and protein levels, forming a feedback loop. Notably, alkylation stress induces a biphasic response: acute MMS exposure enhances TRIM28-ALKBH2 association and accelerates ALKBH2 degradation, whereas prolonged exposure promotes TRIM28 degradation, leading to ALKBH2 stabilization and transcriptional upregulation. Clinically, ALKBH2 is frequently elevated in lung adenocarcinoma and is associated with worse survival, whereas TRIM28 exhibits prognostic value specifically in chemotherapy-treated patients. Functionally, MMS-cisplatin co-treatment increased DNA damage and reduced clonogenic survival by counteracting ALKBH2-dependent alkylation tolerance, linking the TRIM28-ALKBH2 loop to chemoresistance in NSCLC.

biochemistry↗

bioRxiv2025

Emergence of Individualized Functional Topography in the Neonatal Brain

The early postnatal period represents a critical phase for establishing the brains fundamental architecture. However, how individualized functional topography emerges and shapes long-term cognition remains unknown. Using multimodal neuroimaging data from 419 neonates, we map personalized functional topographies in the first weeks of life and reveal their association with 18-month neurocognitive outcomes. Unique and stable functional topographies are already present at birth, with interindividual variability organized along a conserved sensorimotor-to-association hierarchy. These individualized maps encode early brain maturity and robustly predict cognitive, language, and motor outcomes at 18-month of age, with predictive features concentrated at network boundaries. This functional refinement is structurally anchored by concurrent maturation in cortical myelination and sulcal depth. Preterm birth results in distinctive topographic alterations characterized by accelerated maturation of association networks. Our work establishes a foundation for precision models of early brain development and elucidates its significance for long-term neurocognitive outcomes.

neuroscience↗

bioRxiv2025

Candling analysis of egg development in an endangered bird species Crested ibis (Nipponia nippon)

Identifying key factors influencing the survival of animals, particularly rare and endangered species is crucial to biodiversity conservation. In birds, hatching failure is pronounced in endangered species. Accurate assessment of egg development and the ability to distinguish non-viable eggs are essential prerequisites for identifying the causes of hatching failure and applying appropriate conservation practices. The Crested ibis (Nipponia nippon), a flagship endangered species, has a long history of captive breeding, which has contributed to population recovery. However, little is known about the specific process and characteristics of its egg development. In this study, we provided the first comprehensive description of normal egg development in the Crested ibis, including both the changes observed in unfertilized eggs during incubation and embryonic development via candling (n = 106 eggs, with 1,423 candling images), a commonly used non-invasive method for assessing egg fertility and embryonic status, and offered a practical reference for assessing fertilization status and embryo viability. In addition, we estimated the timing of embryo mortality and found that most deaths occurred during mid-incubation (Day 7[~]15) (n = 12, 60.0%) and shortly before hatching (Day 23[~]29) (n = 7, 35.0%), highlighting these critical periods that require particular attention. This species-specific documentation of egg development provides a valuable reference for accurately assessing embryonic progress, evaluating environmental effects on survival, and guiding adaptive management, benefiting both captive breeding programs and field conservation efforts.

zoology↗

bioRxiv2025

Integrated Bioinformatics analysis and Metabolomic Responses in finding novel therapeutic approach to treat viral myocarditis

BackgroundMyocarditis is one of the most common health problems in young people. Despite imaging techniques and endomyocardial biopsies advancing, there is still inadequate for myocarditis characterization. Some studies have shown that myocarditis is closely associated with mitochondrial dysfunction. Therefore, this study was aimed to identify mitochondrial-related biomarkers and gene regulatory networks in myocarditis and potential therapeutic targets. MethodsWe downloaded GSE95368 dataset from GEO to get myocarditis gene expression profiles, then used EdgeR and AI algorithm for bioinformatics analysis of DEGs functions. Established CVB3-induced mouse myocarditis model via intraperitoneal injection, and assessed energy metabolism differences using targeted metabolomics. CVB3 stimulus induced myocarditis in H9C2 cells. We assessed mitochondrial dysfunction (ATP, MMP) with commercial kits, MAPK8 release via ELISA, and MAPK8, p-PI3K, p-AKT levels by western blot. Furthermore, a total of 8 patients primarily diagnosed with myocarditis were enrolled, and levels of MAPK8 and CK in serum were detected. SP600125, an inhibitor of MAPK8, was administrated to CVB3-infected mice to study its potential protective effect in viral myocarditis. ResultsWe obtained 77 DEGs enriched in myocarditis. Analysis yielded 11 modules, MEpurple module genes linked to myocarditis progression were identified via WGCNA. MAPK8, NAMPT and ALB are associated with mitochondrial function. CVB3-infected mice showed cardiac inflammation and high MAPK8 expression in serum or heart tissues.The target metabolism results indicated altered central carbon metabolism distinguished CVB3 group from control, with higher D-Glucose-1-phosphate and D-Glucose-6-phosphate and lower L-Cystine, dCMP, IMP and Xylulose-5-phosphate levels. CVB3 treatment caused mitochondrial dysfunction in H9C2 cells (decreased ATP, MMP), and increased MAPK expression. Western blot showed MAPK8 consolidated the levels of p-PI3K and p-AKT. CK activity was notably higher in myocarditis patients than healthy individuals. MAPK8 levels in myocarditis patients serum also exceeded those in healthy individuals. Pearson analysis indicated that MAPK8 and CK may contribute to myocarditis progression via distinct mechanisms. In CVB3-infected mouse model with SP600125 treatment, cardiac inflammation and MAPK8, p-PI3k, p-AKT expression were reduced, confirming MAPK8s crucial role in viral myocarditis. ConclusionOur study identified MAPK8 as a key biomarker of myocarditis, and it may be a potential therapeutic target for myocarditis.

pathology↗

bioRxiv2025

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

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

pharmacology and toxicology↗

bioRxiv2025

Xanthomonas type III effector XopN targets scaffold protein OsRACK1B to suppress rice immunity

Bacterial leaf streak (BLS), caused by Xanthomonas oryzae pv. oryzicola (Xoc), is a major bacterial disease that poses a substantial threat to rice production. Although Xoc deploys a variety of effectors to subvert host defenses, the mechanistic basis of how these effectors modulate plant immune signaling remains largely unclear. Here, we show that XopN suppresses rice immune responses and physically interacts with the rice scaffold protein OsRACK1B. Notably, OsRACK1B expression is induced following Xoc infection in a type III secretion system (T3SS)-independent manner. Functional analyses indicate that OsRACK1B overexpression enhances Xoc resistance, whereas loss-of-function mutants exhibit heightened susceptibility. This increased susceptibility is characterized by compromised immunity, including reduced callose deposition, diminished reactive oxygen species (ROS) accumulation, and attenuated expression of defense-related genes such as OsPBZ1 and OsPAL1. Furthermore, we demonstrate that XopN competes with OsRap2.6 for binding to OsRACK1B, thereby disrupting the formation of the OsRACK1B-OsRap2.6 immune complex. These findings reveal a novel virulence strategy in Xoc and identify promising gene targets for developing disease-resistant rice varieties.

plant biology↗

bioRxiv2025

TMEM100 attenuates NF-κB activation via disrupting the PRDX1-GNAI2 complex to alleviate acute lung injury

Acute lung injury (ALI) is a severe and diffuse inflammatory disorder of interstitial lung. Emerging evidence suggests that TMEM100 is closely associated with lung development and function. However, its role in ALI remains unclear. In this study, we observed a significant downregulation of TMEM100 expression in both mouse lung tissues with ALI and lipopolysaccharide (LPS)-induced pulmonary vascular endothelial cells (PVECs). Overexpression of TMEM100 markedly attenuates LPS-induced lung injury and inflammation, while also restoring the imbalance between proliferation and apoptosis in PVECs. Mechanistically, TMEM100 interacts with both PRDX1 and GNAI2, disrupting the PRDX1-GNAI2 complex and thereby inhibiting LPS-induced NF-{kappa}B activation, which contributes to its anti-inflammatory effects. These findings highlight the protective role of TMEM100 in endotoxin-induced ALI and provide a theoretical basis for understanding its biological functions and potential applications in ALI gene therapy.

immunology↗

bioRxiv2025

Pan-cancer analysis reveals that tumor microbiomes generate specific epitopes through transcriptional reprogramming

The therapeutic promise of tumor microbial peptides faces a critical safety paradox: tumors and peritumor tissues harbor compositionally similar microbiomes, yet safe immunotherapy demands tumor-specific targeting. We performed comprehensive transcriptomic analysis of microbial communities from 1,868 tumor and peritumor samples across 11 cancer types. Although 88.5% of microbial species are present in both tissue types, tumor and peritumor tissues exhibit profound transcriptional divergence: only 34.1% of microbial genes are expressed in both tissue types, and merely 18.2% of predicted HLA-binding peptides overlap. This transcriptional divergence represents microbial transcriptional reprogramming (MTR) in tumor tissues, through which microbes activate distinct genomic regions while adapting to tumor microenvironmental pressures, thereby generating tumor-specific peptide repertoires. Using Microbial Transcriptional Reprogramming Index (MiTRI) to quantify MTR, we found that higher MiTRI values correlate with expanded immunogenic peptide repertoires. Mass spectrometry-based immunopeptidomics confirmed that 25% of naturally presented microbial peptides originate from MTR regions. Crucially, in microsatellite-stable colorectal cancer, neo-adjuvant therapy responders exhibited significantly higher MiTRI values. T cell receptors (TCRs) recognized MTR-derived epitopes at 2.10-fold higher rates than genome-wide epitopes, accounting for 79.1% of clonally expanded TCRs. These findings establish MTR as the principle that ensures the tumor-specificity and safety of micorbiome-directed immunotherapy.

cancer biology↗

bioRxiv2025

Cell cycle-driven epigenetic resetting maintains stem cell fate for shoot branching

Adult mammalian stem cells typically maintain stem cell identity through proliferative quiescence. In contrast, we demonstrate that stem cell maintenance in Arabidopsis bud precursor cells requires active cell-cycle progression. Inhibiting division silences the shoot meristem marker gene SHOOT MERISTEMLESS (STM) and promotes differentiation. Whereas proliferation dilutes H3K27me3 levels to counteract silencing. Meanwhile, we identified two classes of transcription factors recruiting polycomb repressive complex 2 (PRC2) to epigenetically silence STM. The balance between these forces establishes a cell cycle-coupled epigenetic "Sisyphus" mechanism that maintains pluripotency. This cell fate switch is bistable; modeling and experimental data confirm that prolonged quiescence triggers irreversible differentiation. We propose that sequence-dependent PRC2 recruitment in plants enables precise silencing of fate-determining genes, while cell proliferation sustains pluripotency by resetting epigenetic marks.

plant biology↗

bioRxiv2025

Lymphatics unload VEGFR3 in response to the endothelial stress upon VEGFR2 insufficiency

Vascular endothelial growth factor receptor 2 (VEGFR2) is a key target for regulating the endothelial cell lineage and angiogenesis. It is also expressed by lymphatic endothelial cells (LEC) while its participation in the process of lymphangiogenesis remains inadequately characterized. We show in this study that VEGFR2 is highly expressed in dermal initial lymphatic vessels and valves. The induced deletion of pan-endothelial Vegfr2 at the neonatal stage produced a potent suppression of dermal lymphatic growth, including the thinner lymphatic diameter, the decrease of LEC number and lymphatic valves. Mechanistically, the VEGFR2 insufficiency led to a dramatic decrease of lymphatic VEGFR3, a key regulator mediating signals for lymphatic growth and remodeling. The RNA sequencing analysis revealed that GO terms enriched for the downregulated genes included biological processes related to the EC development while pathways related to the hematopoiesis and immune responses were upregulated in the skin of Vegfr2 mutants compared with the littermate controls. This was further confirmed by the RNA-seq analysis of dermal tissues 48 hours after the endothelial Vegfr2 deletion. Consistently, an inhibitory effect on the dermal lymphatic growth was also observed by targeting Vegfr2 in PROX1+ cells, manifesting a similarly altered transcriptome signature. The alteration of lymphatic gene expression was further validated by the siRNA mediated knockdown of Vegfr2 in primary lymphatic endothelial cells, showing a transcriptional trend of LEC to hematopoietic transition. Findings from this study imply that VEGFR2 is required for the maintenance of endothelial identity and its insufficiency may trigger the alteration of lymphatic transcriptional programs to diminish the VEGFR3-mediated lymphangiogenesis.

developmental biology↗

bioRxiv2025

A Population-scale Single-cell Spatial Transcriptomic Atlas of the Human Cortex

The genetic and spatial determinants of cell type diversity in human cerebral cortices remain poorly defined. Here, we present a population-level single-cell spatial transcriptomic atlas of human cortices from 71 donors across the lifespan. We identified 906 layer-specific genes showing conserved and divergent laminar expression patterns between humans and other species. Spatial analysis revealed neuronal vulnerability and glial activation during aging, together with a decline in the proportion of superficial SST neurons and their interactions with other cells. Disease-associated genes exhibited high cell-type and layer-specific expression, implicating the pathogenic role of spatially specific gene expression. Spatial cis-eQTL analysis identified regulatory variants linked to genes related to diseases like Tourette syndrome. Cross-species comparison demonstrated glial expansion in the human cortex, accompanied by enhanced neuron-glia communication via the neuregulin signaling. Together, we provide a comprehensive single-cell atlas of the human cortex that is essential for understanding aging, evolution, and disease pathogenesis.

neuroscience↗

bioRxiv2025

Dopamine and its receptor DcDop2 are involved in the mutualistic interaction between 'Candidatus Liberibacter asiaticus and Diaphorina citri

Candidatus Liberibacter asiaticus (CLas), the causal agent of citrus huanglongbing, is transmitted by the Asian citrus psyllid Diaphorina citri. While CLas-positive (CLas+) females exhibit increased fecundity and metabolic demands, their neuroendocrine regulation mechanisms remain unclear. We propose CLas manipulates dopamine (DA) signaling to enhance psyllid fecundity and CLas proliferation. Metabolomics revealed elevated DA in CLas+ females. Silencing DA synthesis genes and receptor DcDop2 via RNAi reduced lipid reserves, fecundity, and ovarian CLas titers. Through combined in vivo and in vitro experiments, we demonstrated that the microRNA miR-31a suppresses DcDop2 expression by binding to its 3 untranslated region. Overexpression of miR-31a resulted in decreased DcDop2 expression and CLas titers in the ovaries, eliciting phenotypic defects akin to DcDop2 knockdown. Furthermore, DcDop2 knockdown and miR-31a overexpression reduced juvenile hormone (JH) levels and adipokinetic hormone (AKH) signaling in fat bodies and ovaries. Consequently, CLas regulates the DA-DcDop2 signaling axis to improve D. citri lipid metabolism and fecundity, while simultaneously promoting its replication. These findings reveal a coevolution between CLas proliferation and ovarian development in the insect host. This discovery enhances our understanding of the molecular interplay between plant pathogens and vector insects and offers novel targets and strategies for HLB field management.

ecology↗

bioRxiv2025

Proteome Landscapes Decode Organelle Vulnerabilities in cortical and dopaminergic-like induced neurons Across Lysosomal Storage Disorders

Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy, and by recycling building blocks for organelle biogenesis. Lysosomal Storage Disorders (LSDs) comprise a group of diseases affecting diverse lysosomal functions. To facilitate molecular phenotyping across diverse LSD gene classes, we are developing a library of human embryonic stem cells engineered to lack individual LSD genes as a resource for the field. Here, we report our initial stem cell toolkit lacking one of 23 LSD genes, including the majority of genes associated with sphingolipidoses and neuronal ceroid lipofuscinoses, and its use in the generation of a proteomic resource for induced cortical-like and midbrain dopaminergic-like neurons In-depth abundance and correlation profiling across organelles and sub-organelle components revealed potential vulnerabilities that reflect distinct patterns of proteome alterations across both genotypes and neuronal cell types. We characterize alterations in the mitochondrial proteome associated with GBA1 and ASAH1 deficiency and identify synaptic and mitochondrial defects in ASAH1-/- induced neurons that correlate with defects in neuronal firing rates. Moreover, we developed an informatic pipeline for proteome-wide identification of individual protein interactions and protein complexes that may be disrupted as a result of LSD gene deficiency. Finally, we visualized structural alterations of ASAH1-deficient endolysosomes in situ using cryo-electron tomography, revealing swollen organelles that were largely devoid of dense internal membranes characteristic of wild-type cells, but containing numerous intralumenal vesicle compartments. This toolkit and associated proteomic landscapes provide a resource for defining molecular signatures associated with LSD gene dysfunction and organelle vulnerability.

cell biology↗

bioRxiv2025

ANTIDOTE: A Metadata-Driven Neural Network for Improving CryoEM 3-D Particle Sorting

Despite the maturation of cryogenic electron microscopy (cryoEM) methodologies, generating high-resolution three-dimensional (3-D) reconstructions from micrographs is a time-intensive process involving iterative rounds of subjective data curation and hyperparameter optimization. Current approaches to particle classification are often unable to remove all low-quality particles from particle stacks, largely due to the low signal-to-noise ratio, the high dimensionality of particle images, and the multiple degrees of freedom associated with each particles unknown rotation, orientation, and class assignment. The retention of low-quality particles negatively affects the overall quality of the final EM density and continued efforts to eliminate their deleterious contributions are warranted. Here, we present ANTIDOTE (A Neural network Trained In Deleterious Object deTection and Elimination), a neural network framework that discriminates between constructive and deleterious particles using per-particle metadata generated during 3-D classification in RELION. Using benchmark and real-world cryoEM datasets, we demonstrate that ANTIDOTE paired with RELION 3-D classification achieves higher particle classification accuracy than conventional data processing approaches alone, yielding improvements in reconstruction quality, global and local resolution, and map interpretability while reducing time-consuming hyperparameter optimization. We additionally detail practical use-case scenarios for ANTIDOTE and demonstrate its versatility in increasing particle curation accuracy for high-quality cryoEM reconstruction.

biophysics↗

bioRxiv2025

Cellular and Spatial Drivers of Unresolved Injury and Functional Decline in the Human Kidney

Building upon a foundational Human Kidney resource, we present a comprehensive multi-modal atlas that defines spatially resolved versus unresolved repair states and mechanisms in human kidney disease. Homeostatic interactions between injured kidney epithelium and its surrounding milieu determine successful repair outcomes, while pathogenic signaling promotes unresolved inflammation and fibrosis leading to chronic disease. We integrated multiple single-cell and spatial modalities across [~]700 samples from >350 patients ([~]250 research biopsies), analyzing [~]1.7 million cells alongside complementary mouse multi-omic profiles spanning acute-to-chronic injury and aging (>300,000 cells) and spatial transcriptomic analysis of >150 human biopsies. This cross-species atlas delineates functional pathways and druggable targets across the nephron and defines gene regulatory networks and chromatin landscapes governing tubular, fibroblast, and immune cell transitions from injury to either recovery or failed repair states. We identified distinct cellular states associated with specific pathological features that show dynamic distributions between acute kidney injury (AKI) and chronic kidney disease (CKD), organized within unique spatial niches that reveal progression mechanisms from early injury to unresolved disease. Gene regulatory analyses prioritized key transcription factor activities (SOX4, SOX9, NFKB1, REL, KLFs) and their target networks establishing disease states and tissue microenvironments. These regulatory programs were directly linked to clinical outcomes, identifying molecular signatures of recovery and secreted biomarkers predictive of AKI-to-CKD progression, providing a key resource for therapeutic development and precision medicine approaches in kidney disease.

molecular biology↗