Biology subjects

Meng, F.

Publications and source records attributed to Meng, F..

At least 19 recordsLinked to original sources

bioRxiv2026

Disease-associated NK-cell state remodeling reveals transcriptional profiles predictive of clinical phenotypes

Natural killer (NK) cells adapt their cellular states to diverse tissue and inflammatory environments, yet how this plasticity manifests across pathological contexts and relates to patient-level disease phenotypes remains poorly defined. Here we established the Human NK-cell Atlas (HNKA) from over 1 million NK cells, including samples from 1,632 donors spanning 50 diseases. Within a shared NK-cell state architecture, analyses of state abundance and matched-reference exceedance distinguished disease-biased redistribution from transcriptional displacement. Fine-grained analyses localized disease-associated remodeling to specific NK-cell states, including CD56dim NK ISG15 in infection and autoimmunity and CD56bright NK ITM2C in tumors. These patterns were accompanied by recurrent interferon responses and state-specific regulatory activity. Cytokine perturbations recapitulated key transcriptional features of disease-associated NK-cell states. We developed NKceiver, a model based on state-specific NK-cell expression profiles for patient-level prediction. It distinguished 18 diseases and predicted COVID-19 severity and response to immune checkpoint inhibitors, with predictive performance retained in unseen patients and studies. Collectively, our results reveal that disease-associated remodeling within the diverse NK-cell state repertoire resolved by HNKA is biologically interpretable and clinically informative, supporting disease discrimination and prediction of clinical phenotypes.

immunology↗

bioRxiv2026

NEIL2 regulates RNA polymerase II dynamics to suppress transcription replication conflicts in pancreatic cancer

Transcription replication conflicts (TRCs) arise from spatiotemporal interference between replication and transcription machinery and contribute to genome instability in cancer cells. In pancreatic ductal adenocarcinoma (PDAC) cells, oncogenic KRAS drives TRC formation, and base excision repair (BER) contributes to TRC resolution as an adaptive response. Here, we show that TRCs are enriched in pancreatic tumor sections from patients and are associated with malignant progression. We identify NEIL2, a bifunctional DNA glycosylase in the BER pathway, as a critical regulator of TRCs in PDAC cells. Mechanistically, NEIL2 loss causes aberrant RNA polymerase II (RNAPII) occupancy at transcription start sites and downstream of transcription end sites. Dysregulated RNAPII dynamics promote R-loop-dependent and -independent TRCs contributing to replication stress, DNA damage, and impaired cancer cell proliferation. Notably, the DNA-binding motif of NEIL2 necessary for canonical BER function is dispensable for TRC regulation. Together, these findings reveal an unrecognized role for NEIL2 in regulating RNAPII dynamics and mitigating TRCs in pancreatic cancer cells.

molecular biology↗

bioRxiv2026

A telomere-to-telomere genome of Holstein cattle resolves chromosome-end architecture and the genetic basis of telomere length

Telomeres safeguard chromosome-end integrity, yet population-scale dissection of telomere-length genetics has been largely restricted to humans. Here, we report a 3.01-Gb telomere-to-telomere (T2T) genome of Holstein cattle that resolves repeat-rich chromosome ends and centromeres and enables telomere-length quantification at single-chromosome-end resolution. Holstein chromosome ends show marked telomere-length asymmetry and end-specific variation in telomere variant repeats, subtelomeric tandem repeats, GC/CpG composition, and DNA methylation. Using sequencing-depth-corrected telomere-length phenotypes from 9,591 cows, teloGWAS identifies major loci encompassing RTEL1, CTC1, and TERT, while multi-tissue eQTL, sQTL, TWAS, and co-expression analyses prioritize CTC1 and implicate DNA replication, DNA repair, and stress-response networks. Together, these findings extend population-scale telomere genetics beyond humans and establish a sequence-resolved framework for chromosome-end biology and telomere-informed livestock genomics.

genomics↗

bioRxiv2026

Sphingolipid metabolism-related genes as key regulatory hubs in white smoke inhalation induced lung injury

Objective White smoke inhalation injury (WSI) causes severe acute lung damage with no specific therapy currently available. Sphingolipid metabolism is implicated in pulmonary inflammation, but its transcriptional regulatory landscape in WSI remains unexplored. This study aimed to identify key sphingolipid metabolism related genes and evaluate their regulatory roles and therapeutic potential in WSI. Methods We established a rat model of WSI and performed integrated bulk RNA sequencing, weighted gene coexpression network analysis (WGCNA), and single-cell RNA sequencing (scRNAseq) to screen for differentially expressed sphingolipid metabolism-related genes (DESRGs). Protein-protein interaction (PPI) network with four centrality algorithms was used to prioritize hub genes. In silico gene knockout and molecular docking were conducted to assess regulatory functions and identify potential drug candidates. Results We identified 22 DESRGs that were predominantly enriched in DNA replication and cell cycle pathways rather than canonical sphingolipid metabolic processes. PPI consensus prioritized three hub genes--Top2a, Ttk, and Ccna2--with Top2a exhibiting the highest expression in epithelial cells and significant downregulation after smoke exposure. ScRNAseq revealed immune cell infiltration and epithelial differentiation trajectories. Virtual knockout showed that Top2a depletion affected the largest transcriptomic fraction (~0.4%) and was enriched in lysosome biogenesis, innate immunity, phagocytosis, and lipid catabolism. Molecular docking identified thalidomide as a high affinity ligand for Top2a (Vina score: -8.5 kcal/mol). Conclusion Our multiomics integrative framework identifies Top2a as a central regulatory hub linking sphingolipid associated inflammation to epithelial responses in WSI, and nominates thalidomide as a potential drug repurposing candidate. These findings provide prioritized targets for future translational investigation.

bioinformatics↗

bioRxiv2026

Human Cytomegalovirus Infects and Remodels 3D-biofabricated Skin Equivalents

Viral infection, including for the prototypical betaherpesvirus human cytomegalovirus (HCMV) is typically studied in two-dimensional monocultures, which provide experimentally tractable systems for measuring viral replication but do not reproduce the biologically accurate multicellular organization or interactions, nor the three-dimensional (3D) architecture of stratified epithelial tissues. Here, we evaluated a biofabricated 3D skin model containing fibroblasts and keratinocytes as a system to study HCMV infection. The model is generated using a fibrin-based matrix and spatially organization deposition of keratinocytes in combination with fibroblasts, followed by cellular differentiation controlled by calcium conditions. Cultures were infected with a GFP-expressing clinical strain of HCMV (TB40/E-GFP) and compared to traditional monolayer cultures or single cell type 3D cultures. HCMV infection was detectable by GFP expression in an MOI-dependent and longitudinal manner. Infectious virus was recovered from both the cellular associated and released into the extracellular space of the model, demonstrating that the model supports productive viral infection. Transit of infectious virus is reduced in both multicellular and single type 3D cultures, suggesting that the matrix composition influences viral kinetics. Treatment with the antiviral Ganciclovir suppressed virus production in both fibroblast monolayer cultures and 3D skin cultures. These findings establish a tractable, longitudinal observable, multicellular 3D system that supports productive HCMV infection and provides a reliable platform for investigating viral replication in a spatially organized tissue context.

microbiology↗

bioRxiv2026

Evolutionary Origins and Synthetic Reconstruction of Gingerols

How new enzymatic activities become integrated with existing metabolic networks to generate lineage-restricted plant chemistry remains a central question in metabolic evolution, exemplified by gingerol biosynthesis in Zingiberaceae, whose complete enzymatic basis has remained elusive. Here, we resolve this problem by elucidating the evolutionary origins and the full biosynthetic pathway of gingerol through single-cell transcriptomics, functional screening, structural biology, comparative genomics and pathway reconstruction. A coordinated metabolic program operates in ginger oil cells, thereby guiding the identification of diketide-CoA synthases, gingerol synthases (GS) and gingerol reductases that together constitute the complete pathway. GS remodels the conserved type III polyketide synthase scaffold to organize a fatty acyl-CoA and a phenylpropanoid-derived intermediate for gingerol formation. Furthermore, GS arose through duplication and limited active-site remodeling of a curcumin synthase-like enzyme, accompanied by coordinated recruitment of precursor-supply and reduction pathways. Translating these principles into yeast achieves the first de novo microbial production of 6-gingerol from glucose at 12.4 mg/L. These findings reveal the evolutionary logic by which plants recruit and coordinate novel enzymatic activities to establish lineage-restricted metabolic program, providing a framework for understanding and engineering specialized metabolism across the plant kingdom.

synthetic biology↗

bioRxiv2026

An Integrated Preclinical Platform for Lethal Neuroendocrine Prostate Cancer from Rapid Autopsy Bone and Liver Metastases.

Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant disease arising in up to 20% of castration resistant prostate cancers, yet robust biologically relevant preclinical models remain scarce. Here, we describe a technical blueprint for establishing an integrated platform of patient-derived models from visceral and bone metastases collected through a prostate cancer rapid autopsy program (PC RAP). We report the establishment and characterization of patient-derived xenograft (PDX) models from liver metastasis tissue, liver and bone metastasis-derived organoid lines (PDOs), and corresponding patient-derived organoid xenograft (PDOX) models. In addition, we established, to our knowledge, the first mesenchymal stem cell (MSC) cultures derived from neuroendocrine prostate cancer (NEPC) bone metastases. The PDOs preserved intratumoral heterogeneity, displaying both CRPC-NE and CRPC-adenocarcinoma features. These organoids retained neuroendocrine identity across multiple passages, with transcriptomic profiles concordant with the original patient tissue and matched PDX models generated at our institution and at the National Cancer Institute (NCI Patient-Derived Models Repository). To model the bone metastatic microenvironment, we generated novel organoid-based New Approach Methodologies (NAMs) by co-culturing PDOs with iPSC-derived bone marrow organoids, establishing a physiologically relevant vascularized organotypic model of PC bone metastasis. To extend our studies in vivo, we established preclinical models using the liver and bone metastasis-derived organoid models. The PDOX models were tumorigenic and developed spontaneous lymph node metastases, providing clinically relevant models for investigating lethal NEPC biology. Together, these complementary patient-derived models provide a robust and versatile platform for investigating NEPC biology, metastatic progression, and evaluating new therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/740121v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1c641f1org.highwire.dtl.DTLVardef@113696aorg.highwire.dtl.DTLVardef@16dcc72org.highwire.dtl.DTLVardef@1898d9f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINovel preclinical models of visceral and bone metastases established from a prostate cancer rapid autopsy program. C_LIO_LIThis study is the first to establish mesenchymal stem cell cultures from NEPC bone metastases. C_LIO_LIPDOs preserve heterogeneity, showing both CRPC-NE and CRPC-Adeno features, with transcriptomic profiles concordant with originator tissue and PDX models. C_LIO_LIPC RAP-derived organoids are tumorigenic in vivo and generate spontaneous lymph node metastases. C_LI

cancer biology↗

bioRxiv2026

Morula complementation restores fetal kidneys in xenocompatible SALL1 null sheep

To meet the global shortage of organs, extensive genome modifications have been performed to "humanize" livestock tissues for xenotransplantation. However, residual immune rejection remains a problem, prompting alternative approaches that explore the use of animals as hosts for growing human organs. This requires genome editing to disable organogenesis in the host and embryo complementation with suitable donor cells to fill the empty organ niche in chimaeric animals. Pigs have been the predominant livestock species investigated for this approach. Here, we used domestic sheep as hosts for donor-derived kidney formation. Spalt-Like Transcription Factor 1 (SALL1) was targeted in male fibroblasts lacking xenoantigens CMAH and GGTA1, using either one gRNA within zinc finger cluster (ZFC) 2 or two gRNAs to remove all ZF domains. Following somatic cell cloning and embryo transfer of triple knockout strains, fetuses were collected on gestational day 48 to analyze the SALL1 KO phenotypes. Single gRNA editing produced a hypomorph with different degrees of metanephric hypoplasia, while the dual-gRNA deletion resulted in a null allele which completely abolished nephrogenesis. Female donor cells carrying high vs low copy numbers of an mCherry transgene, as well as CMAH and GGTA1 edits, were used for morula complementation. Fetal kidney development was anatomically and histologically restored in sex-chimaeric hosts, providing proof-of- concept for using sheep as a new model species for in vivo organ generation.

cell biology↗

bioRxiv2026

STN-DBS frequency-tuned beta subband dynamics are associated with speech tempo in Parkinson's disease

In Parkinsons disease, subthalamic nucleus deep brain stimulation (STN-DBS) frequency modulates narrow beta subbands, with low-frequency stimulation (LFS) selectively attenuating 15-23 Hz power. The negative association between this subband and speech tempo, together with the LFS-related improvement in articulatory rate, suggests that 15-23 Hz subband dynamics may serve as a candidate neural marker associated with speech tempo modulation.

neuroscience↗

bioRxiv2026

Deconstructing a behavioral state: parallel neural integrators control distinct features of an aversive behavioral state in C. elegans

Transient sensory stimuli can trigger long-lasting changes in behavior and cognition. For example, repeated aversive experiences can lead to persistent changes in arousal and mood. Specialized integrator circuits can store information about recent experiences, but how they are embedded within the architecture of the brain to control internal brain states remains poorly understood. We find that C. elegans accumulates evidence of past aversive experiences over minutes to generate a scalable behavioral state consisting of multiple behavioral changes. Using a brain-wide imaging screen, we identified a set of neurons that integrate aversive sensory stimuli over different timescales, from seconds to minutes. Neuronal perturbations show that these integrator neurons are critical for the aversive behavioral state. They control distinct behavioral features, such as changes in locomotion speed or increased responsiveness to subsequent aversive stimuli. Moreover, the integrator neurons function in parallel to one another, utilize different mechanisms to generate persistent neural activity, and signal through different transmitters. Our result show how a behavioral state can be decomposed into distinct behavioral features that map onto different neural integrators that act in parallel. Combined action of the integrators then generates the full set of behaviors that comprise the global state.

neuroscience↗

bioRxiv2026

The Par complex regulates apical-basal cell polarity through modulation of FAK signaling homeostasis

Cell polarity complexes are essential for embryogenesis, but their regulatory mechanisms during early developmental transitions remain incompletely understood. Here, we individually deleted the Crumbs, Par, and Scrib polarity complexes in mouse embryonic stem cells (mESCs). While loss of any single complex did not affect pluripotency or proliferation, deletion of Par complex disrupted the naive-to-primed transition and impaired subsequent differentiation, particularly lumen formation in neural tube organoids. Mechanistically, Par complex deficiency led to hyperphosphorylation of focal adhesion kinase (FAK) at the primed stage, driving a morphological shift from flat monolayer clusters to dome-shaped colonies. FAK inhibition rescued the aberrant morphology. Upstream, Par complex loss increased AKT phosphorylation, which remodeled extracellular matrix (ECM) and regulated integrin signaling via FURIN-LEFTY, ultimately modulating FAK activity. In addition, conditioned medium from wild-type cells partially rescued differentiation defects in Par knockout cells in a LEFTY-dependent manner. These phenotypes were consistently observed in naive-to-primed transition, neural stem cell differentiation, embryoid body formation, teratoma assays, and neural tube organoid differentiation. Together, these findings establish a Par complex-AKT-FURIN-LEFTY-ECM-integrin-FAK signaling cascade that links apical-basal polarity to early lineage specification and morphogenesis, providing a mechanistic framework for how polarity cues are translated into developmental outcomes. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/722465v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@179e0adorg.highwire.dtl.DTLVardef@8d83bdorg.highwire.dtl.DTLVardef@c425fforg.highwire.dtl.DTLVardef@19a8ee5_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementThis study elucidates the molecular mechanism by which the Par complex regulates the establishment of cell polarity. The authors demonstrate that the Par complex promotes the expression of the protein convertase FURIN via AKT signaling, thereby enhancing the maturation and secretion of LEFTY protein. This process remodels the ECM and modulates integrin signaling, ultimately regulating FAK activity and controlling the establishment of cell polarity. These findings reveal how polarity cues govern early lineage specification and morphogenesis, with implications across multiple developmental contexts.

developmental biology↗

bioRxiv2026

Significantly Improved Mouse and Rat Genome Annotation Using Sequence Read Archive RNA-seq Data

To detect currently unannotated genes with low expression levels with high sensitivity and accuracy, we developed a new exon->gene->transcript annotation pipeline that can identify previously undetected multi-exon transcripts using large volumes of RNA-Seq data. Our pipeline incorporates three new algorithms: 1) model-based spliced exon detection, 2) exon-to-gene assignment across multiple tissue/datasets through exon community discovery, and 3) ranking top transcripts by a stepwise minimum flow procedure. The design of our pipeline allowed us to leverage hundreds of Tbases of public RNA-seq data as input to improve mouse and rat genome annotation. Using this data, our pipeline identified close to 15K and 21K unannotated genes in GENCODE M37 and ENSEMBL 114 for mouse and rat, respectively. Each species also gained over 200K predicted transcripts containing at least one new exon, although most were transcripts from GENCODE/ENSEMBL annotated genes with newly assigned exons. To make our genome annotation available for common use, we have packaged this new annotation in standard file formats for the analysis of bulk and single cell RNA-seq data (GTF, 10X genome files). We have also provided two use examples which demonstrate the utility of our newly annotated genes in functional analyses, showing that their expression can be differentially regulated in relationship to cell type and selective breeding. Due to the efficiency provided by our pipeline, we expect that as new RNA-seq data become available in the coming years it will significantly benefit rat gene/transcript annotation, eventually enabling us to approach the target of complete gene and transcript annotation.

genomics↗

bioRxiv2026

TRIM32-UBQLN2-p62 axis promotes TDP-43 inclusion formation and amyloid aggregation through shuttle condensates

Aberrant protein aggregation is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which share overlapping genetic and pathological features. Similar aggregates are increasingly recognized in Alzheimers disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, it remains unclear whether a shared molecular pathway drives this pathological aggregation. Here, we report that the E3 ubiquitin ligase TRIM32, together with the shuttle factor UBQLN2 and the autophagy adaptor p62/SQSTM1, form condensates that depend on E3 ligase activity and a network of intermolecular interactions. These condensates act as scaffolds that capture UBQLN2 client proteins, including TDP-43 and ANXA11, and modulate their mobility. A unique hydrophobic loop within TRIM32s substrate-binding domain mimics low-complexity motifs in ANXA11 and TDP-43, enabling selective retention via competitive binding mediated by UBQLN2 STI1 domain. Moreover, TRIM32 condensates promote amyloid aggregation of TDP-43, an effect that is exacerbated by pathogenic UBQLN2 mutation. In brains from individuals with diverse neurodegenerative diseases, TRIM32 co-localizes with pathological phospho-TDP-43 (pTDP-43) inclusions, supporting a model in which TRIM32-driven condensates function as selective proteostasis sorting compartments that broadly contribute to TDP-43 proteinopathy.

neuroscience↗

bioRxiv2026

The genome of an aneuploid cultivar facilitates elucidating the genetic bases of trait polymorphisms in Phalaenopsis orchids

As an important ornamental crop, Phalaenopsis orchids exhibit extraordinary trait diversity with unclear genetic bases. Here, we present a haplotype-resolved, chromosome-level genome for an aneuploid cultivar Santiago. We reveal pervasive variation in the number and sequence among homoeologous genes. When serving as a reference, this genome facilitates the genetic understanding of trait variation in a hybrid population that is highly representative in trait polymorphisms. Specifically, nucleotide polymorphisms in a potential long-distance enhancer and the consequential expression variation of PsAGL6-2, presence/absence of PsMYB12 and b-type homoeologous gene of PsMYB2 determine lip morphology variation, presence/absence of venation-associated stripes and background pink color, respectively. Diverse functions of PsMYBx1 in repressing anthocyanin accumulation across different cultivars further enhances the color patterning diversity in Phalaenopsis. Our study provides a practical framework for using a highly heterogeneous, haplotype-resolved genome to decode phenotypic diversity and has the potential to promote marker-assisted breeding in Phalaenopsis.

genomics↗

bioRxiv2026

Neurons in the Human Substantia Nigra Respond to Cognitive Boundaries and Predict Memory

Segmenting mnemonic episodes from continuous experience is a key aspect of human episodic memory. The brain constantly forms predictions about what will happen next based on previous experience and knowledge, and prediction errors are thought to signal when a new event begins (cognitive boundaries). Dopamine has been closely linked to prediction error signals, yet it remains unknown how human midbrain neurons are modulated by cognitive boundaries and how their responses influence memory. To address these questions, we recorded activity of individual neurons in the human substantia nigra, a critical brain structure for dopamine production and regulation, while participants undergoing deep brain stimulation surgery watched a series of clips embedded with cognitive boundaries and performed a recognition memory task. We found that neural activity in the substantia nigra was robustly modulated by cognitive boundaries during clip viewing. Moreover, a subset of these boundary-responsive neurons also differentiated novel from familiar images during recognition, and their firing rates were indicative of participants memory success. These findings reveal that neurons in the human substantia nigra carry boundary- and novelty-related signals consistent with prediction error mechanisms that influence the encoding and retrieval of episodic memories.

neuroscience↗

bioRxiv2026

All-in-one Single-Cell Proteomic Analysis of Protein Alterations in Human Oocytes Undergoing in Vitro Aging

Study questionWhat specific proteomic changes and molecular markers associated with in vitro aging occur in human oocytes? Summary answerSingle-cell proteomic analysis revealed the protein dynamics during the in vitro aging of oocytes. Subsequent functional analysis highlighted key biological processes affected in aged oocytes and identified several genes as candidate key factors for oocyte and early embryo quality. What is known alreadyOvulated oocytes undergo a time-dependent degradation process if fertilization does not occur within a specific window. This aging process leads to morphological, molecular, and epigenetic changes that can compromise oocyte quality and subsequent embryo development. In previous studies, transcriptome sequencing in humans and mice has revealed serial changes in aging oocytes including oxidative stress, mitochondrial dysfunction, DNA damage, and alterations in cell cycle regulation. These changes can lead to apoptosis, chromosomal abnormalities, and epigenetic modifications, all of which negatively affect oocyte quality. However, research regarding protein level changes and regulatory mechanisms in human oocytes during in vitro aging remains unclear. Study design, size, durationUtilizing "All-in-one" single-cell proteomics, we investigated the protein expression levels in human oocytes at the germinal vesicle (GV) stage and metaphase II (M II) stage following 24 hours of in-vitro aging. We analyzed four groups of oocytes: fresh GV (n=8), in vitro-aged GV (n=9), fresh M II (n=11), and in vitro-aged M II (n=11). This approach allowed for a detailed comparison of proteomic changes associated with in vitro aging in oocytes at different developmental stages. Participants/materials, setting, methodsOocytes at GV and MII stage were collected for "All-in-one" single-cell quantitative proteomic respectively. Differentially expressed genes were analyzed using the R package DESeq2 or DEP (filtered with q-value[≤]0.05 and Foldchange[≥]1.5). EGSEA package was used to perform pathway analysis. Main results and the role of chanceThe proteomic analysis of fresh and in vitro-aged human GV and MII oocytes identified 3,268 proteins. In GV oocytes, compared to fresh samples, 73 proteins were upregulated and 90 were downregulated. Gene Ontology (GO) enrichment analyses revealed these DEPs were involved in key biological processes such as lysosome organization, spindle assembly and oxidative stress response. Gene Set Enrichment Analysis (GSEA) revealed a significant down regulation of genes associated with protein translation initiation and methylation pathways, while those in the apoptosis mitochondrial changes were upregulated. In MII oocytes, 63 proteins were upregulated and 69 were downregulated. GO analysis highlighted their involvement in cytoplasmic translation, ribosome biogenesis and oocyte development. GSEA showed that aged MII oocytes exhibited a downregulation of gene sets in protein translation but an upregulation in membrane fusion pathways compared to fresh oocytes. Furthermore, we identified proteins with consistent expression trends across both GV and MII stages, including MRFAP1 and MT2A, as candidate biomarkers for human oocyte aging in vitro. Limitations, reasons for cautionSingle cell proteomic techniques may not fully capture the dynamic range of proteins present within oocytes, leading to potential underrepresentation of low-abundance proteins that could play crucial roles. Furthermore, the heterogeneity within oocytes introduces variability that can obscure the identification of consistent proteomic signatures associated with oocyte quality or aging. Wider implications of the findingsThese findings not only provide an understanding of the protein changes underlying the in vitro aging of human oocytes but also offer potential biomarkers and intervention targets for future research and clinical applications in assisted reproductive technologies. Study funding/Competing interest(s)This project received funding from the National Natural Science Foundation of China (NO.82471693, 22574175); the Natural Science Foundation of Hunan Province (NO. 2024JJ4100), the Hunan Provincial Grant for Innovative Province Construction (2019SK4012), the Hundred Youth Talents Program of Hunan Province (to S.Z.), the Major Scientific Program of CITIC Group (No. 2023ZXKYB34100) and Scientific Research Foundation of Reproductive and Genetic Hospital of CITIC-XIANGYA (YNXM-202313, YNXM-202319, YNXM-202211). The authors have no conflicts of interest to declare.

developmental biology↗

bioRxiv2025

scMOBA: A conversational single-cell Multi-Omics Brain Agent across species

Single-cell and spatial multi-omics are revolutionizing our understanding of the complexity in the developmental, aging, and diseased brain, but integrating this knowledge across modalities and species remains challenging. To bridge this gap, we propose scMOBA, a conversational single-cell Multi-Omics Brain Agent established by a large language model, a gene encoder, and a cross-attention projector. The scMOBA was pre-trained on 130 million single-cell and spatial multi-omics data spanning the entire brain across diverse species, development, aging and diseases. The pre-training utilized a novel multi-omics Feature-Question-Answer (FQA) paradigm, enabling the model to generate biological answers from feature inputs and textual queries. This unique scheme facilitates superior zero-shot inference capabilities without requiring additional fine-tuning. We demonstrate that scMOBA achieves state-of-the-art performance in fine-grained cell type classification across different species and modalities, as well as in batch correction and multi-omics data integration. Furthermore, scMOBA significantly boosts the accuracy of kinds of critical downstream tasks, including cell-type specific aging clock construction and disease status prediction. Overall, scMOBA serves as a powerful scientific discovery engine for multi-omics brain research, advancing the precision prediction and early intervention of neurological aging and diseases.

bioinformatics↗

bioRxiv2025

Selector: A General Python Library for Diverse Subset Selection

Selector is a free, open-source Python library for selecting diverse subsets from any dataset, making it a versatile tool across a wide range of application domains. Selector implements different subset sampling algorithms based on sample distance, similarity, and spatial partitioning, along with metrics to quantify subset diversity. It is flexible and integrates seamlessly with popular Python libraries like Scikit-Learn, demonstrating the interoperability of the implemented algorithms with data analysis workflows. Selector is an operating-system agnostic, accessible, and easily extensible package designed with modern software development practices, including version control, unit testing, and continuous integration. Interactive quick-start notebooks, which are also web-accessible, provide user-friendly tutorials for all skill levels, showcasing applications in computational chemistry, drug discovery, and chemical library design. Additionally, a web interface has been developed that allows users to easily upload datasets, configure sampling settings, and run subset selection algorithms, with no programming required. This paper serves as the official release note for the Selector package, offering a technical overview of its features, use cases, and development practices that ensure its quality and maintainability.

bioinformatics↗