Biology subjects

Li, Q.

Publications and source records attributed to Li, Q..

At least 163 records · Page 9Linked to original sources

bioRxiv2025

Modular mRNA lipid nanoparticle platform rescues diverse genetic male infertility

Genetic male infertility arises from diverse mutations that disrupt spermatogenesis, yet therapeutic strategies capable of restoring germ-cell function remain limited. Messenger RNA (mRNA) therapeutics offer a programmable and non-integrating approach, but their functional compatibility in structured and immune-privileged tissues remains unclear. Here we identify a temporal mismatch between mRNA delivery kinetics and the progression of spermatogenesis as a key barrier to functional rescue. We show that delivery efficiency does not predict outcome: formulations with high peak expression but short duration fail to support spermiogenesis, whereas sustained expression aligned with developmental timing enables recovery. Guided by this principle, we establish a testis-targeted mRNA delivery platform that restores spermatogenesis across multiple genetic models and generates functional sperm capable of supporting embryo development and multigenerational inheritance. The approach is modular, extends to human seminiferous tubules ex vivo, and is supported by comprehensive safety analyses. Together, these findings define a design constraint for RNA therapeutics in structured tissues: functional rescue requires temporal alignment between delivery kinetics and the therapeutic window defined by tissue-specific biological programs.

bioengineering↗

bioRxiv2025

Acute Myeloid Leukemia Relapse after Bromodomain Inhibitor Treatment or Chemotherapy is Characterized by Myc-Ras Transcriptional Remodeling

Adult and pediatric acute myeloid leukemias (AMLs) harbor distinct mutational profiles, including a higher incidence of RAS and other signaling mutations in young patients. Here we show that the BET inhibitor PLX51107 potently suppresses the growth of NRAS-mutant AML cell lines, and that these activities are enhanced by co-treatment with the MEK inhibitor PD0325901. Controlled preclinical trials in primary mouse Nras-mutant AMLs revealed single agent efficacy of PLX51107 that was enhanced by PD0325901. Leukemias that relapsed during treatment developed intrinsic drug resistance characterized by transition to a more primitive state, up-regulation of Myc target genes, and down-regulation of Ras-associated transcriptional programs. AMLs that relapsed after frontline chemotherapy showed similar transcriptional remodeling. These studies demonstrate transcriptional plasticity in primary AMLs that relapse following in vivo treatment with either targeted agents or chemotherapy, and support evaluating BET inhibition in leukemias with monocytic differentiation and RAS mutations.

cancer biology↗

bioRxiv2025

Agentic Lab: An Agentic-physical AI system for cell and organoid experimentation and manufacturing

Reproducibility in biological research and manufacturing remains constrained by the complexity of multi-step protocols, fragmented data-analysis pipelines, and the intrinsic variability of experimental execution. Here, we present Agentic Lab, an agentic-physical AI platform that unifies large language model and vision language model (LLMs/VLMs)-driven reasoning with real-world laboratory operations. Agentic Lab uses multi-agent orchestration architecture, comprising of specialized subagents for knowledge retrieval, protocol design, multimodal data analysis, and training-free segmentation and representation learning for intrinsically explainable single-cell and organoid phenotyping. These agents operate under the orchestration of a virtual principal investigator MolAgent that is linked to an augmented reality (AR)-based physical AI interface, which can bridge digital reasoning with human physical execution. Agentic Lab perceives real-world experimental activities, provides context-aware instructions, identifying procedural errors in real time for humans to correct, and continuously evolves with its long-term memory database expanding through the accumulation of experimental data logs from human scientists. This interaction allows scientists and AI agents to collaborate and co-evolve dynamically, closing the loop between planning, action, and analysis in the traditional cell and organoid research lifecycle. We demonstrate Agentic Lab in organoid differentiation from human pluripotent stem cells, where it autonomously generates protocols, monitors culture procedures, and identifies subtle morphological heterogeneity linked to growth conditions. The system interprets these phenotypes, grounds them in literature, and proposes targeted instructions for improving differentiation efficiency. By combining multi-agent reasoning with physical laboratory awareness, Agentic Lab transforms experimentation and biomanufacturing from a static workflow into an adaptive, feedback-driven, bidirectional process that integrates agentic AI into the research lifecycle. This framework establishes a foundation for intelligent laboratories that integrate design, execution, and interpretation within a unified agentic-physical system.

bioengineering↗

bioRxiv2025

Analysis of SIV Spatiotemporal Dissemination Patterns in Rhesus Macaques During Early Rectal Transmission Demonstrates Systemic Infection Does Not Require Viral Local Amplification at the Entry Portal

Receptive anal sex is a dominant mode of HIV-1 (HIV) transmission, especially among men who have sex with men (MSM). However, the early events during HIV rectal transmission are not well understood and many questions remain, such as, does virus local amplification at the entry portal require for viral distal seeding? What is the spatiotemporal dissemination pattern across whole body? How do three viral forms, i.e., cell-free virus (VCF), cell-associated virus (VCA), and follicular dendritic cell-trapped virus (VFDC), evolve during early infections? To close this knowledge gap, we comprehensively examined rectum, draining lymph nodes (dLN) and distal lymph nodes (disLN), as well as non-lymphoid organs of brain, lungs, and liver of Indian rhesus macaques (RMs) at the early time points following intrarectal SIVmac251 inoculation (1, 2, 3, 4, 6, 10 14, 28 day post inoculation, dpi). Our findings demonstrated SIV rapidly disseminates to distant tissues and organs (<=1 dpi) and virus local amplification in rectum and dLN is not required for viral distal seeding for the establishment of systemic infection, viral forms shift from VCF and VCA to VFDC accompanying from T cell zones into B cell follicles. Collectively, these findings indicate that an effective HIV vaccine needs to induce immune protection both locally at sites of viral entry and systemically.

immunology↗

bioRxiv2025

Decorin promotes nascent proteoglycan retention in cartilage matrix by strengthening collagen II-aggrecan integration

Cartilage extracellular matrix (ECM), a hydrated collagen II-aggrecan composite, undergoes dynamic turnover during both normal homeostasis and disease-associated remodeling. This study elucidates a crucial role for decorin in promoting the retention and stability of nascent aggrecan within this matrix. By applying bio-orthogonal click-labeling, we demonstrate that loss of decorin accelerates the release of nascent aggrecan under both physiological and inflammatory conditions, without affecting its preferred localization to the pericellular matrix. Conversely, supplementation with exogenous decorin mitigates inflammation-induced loss of nascent aggrecan, supporting its potential as a therapeutic target. At the molecular level, decorin exhibits strong binding affinity for aggrecan, and enhances aggrecan-aggrecan and aggrecan-collagen II interactions, reinforcing its direct role in integrating cartilage matrix constituents. Also, by binding to collagen II, decorin stiffens the collagen II fibril network, thereby strengthening the confinement effect that limits the diffusive loss of entrapped aggrecan. Notably, decorin does not alter chondrocyte transcriptomic profiles in vivo, emphasizing its primary role in maintaining matrix integrity through biophysical mechanisms rather than cell signaling. Together, these findings provide a mechanistic foundation for developing decorin-based biomaterials or gene therapies aimed at preserving or regenerating the cartilage matrix for improved outcomes in osteoarthritis.

biophysics↗

bioRxiv2025

R-loops orchestrate the maternal-to-zygotic transition by harnessing RNA polymerase II pause release

R-loops, ubiquitous three-stranded nucleic acid structures abundant in the mammalian genome, play pivotal roles in diverse biological processes1-3. However, the dynamics and functions of R-loops during mammalian preimplantation embryonic development remain poorly understood. Here we optimized an innovative, ultra-sensitive RIAN-seq method capable of mapping genome-wide R-loop landscape using ultra-low cell numbers to investigate R-loop dynamics in mouse gametes and early embryos. Our findings reveal the widespread presence of AT-rich R-loops during early mouse embryonic development and highlight their critical roles in orchestrating transcription machinery during zygotic genome activation (ZGA). We demonstrate that the stability and inheritance of R-loops through developmental stages are governed by their sequence composition, with GC-rich R-loops exhibiting greater stability. Notably, R-loops, particularly AT-rich R-loops, inhibit DDX21 helicase activity on the 7SK/HEXIM1 snRNP complex, thereby reducing CDK9 release. This, in turn, modulates the phosphorylation of Ser2 at C-terminal domain (CTD) of RNA polymerase II (RNAPIIS2p) at the promoters of major ZGA and maternal genes. Furthermore, R-loops promote RNAPII accumulation at major ZGA gene promoters, preventing RNAPII from premature release and ensuring timely activation of major ZGA genes. Conversely, R-loops enhance the retention of stalled RNAPII at maternal gene promoters, effectively repressing their expression and facilitating the maternal-to-zygotic transition. In summary, our study unveils a key role for R-loops in regulating the maternal-to-zygotic transcription transition and early embryonic development in mice.

developmental biology↗

bioRxiv2025

Effects of carbon dioxide enrichment and environmental factors on photosynthesis, growth and yield and their interaction in cucumber: a meta-analysis

Despite the ongoing increase in atmospheric carbon dioxide concentrations, these levels remain well below the optimal threshold for cucumber growth and development. In addressing the challenges posed by climate change to agricultural production, the use of carbon dioxide enrichment (eCO2) has become increasingly widespread in order to meet global demand for cucumbers. Nevertheless, the impact of eCO2 and environmental factors on cucumber growth remains to be elucidated. In this study, we conducted a meta-analysis of 73 research papers on eCO2 in cucumbers was conducted, and their photosynthesis, growth, and yield were analysed. In summary, under conditions of elevated CO2 levels, the net photosynthetic rate, biomass, and yield of cucumbers exhibited a marked increase of 56.31%, 27.75%, and 21.98%, respectively. Concurrently, stomatal conductance and transpiration rate exhibited a decline of 36.07% and 30.42%, respectively. In the context of the implementation of eCO2 at varying levels within a production environment, the prevailing recommendation pertains to the range of 800-1200 ppm. It is advised that this be integrated with elevated light intensity, augmented temperature, suitable humidity levels, and a sufficient supply of fertiliser to achieve a synergistic effect. The findings of this study contribute to enhancement of environmental control in the context of greenhouse cultivation of cucumber in response to climate change, as well as promoting the green and sustainable development of the cucumber industry.

plant biology↗

bioRxiv2025

Core Activation Program and Selective Regional Responsiveness of Microglia in Aging and Parabiosis

Aging is associated with immune dysregulation in brain and is the biggest risk factor for many neurodegenerative diseases whereas rejuvenation interventions can mediate beneficial effects. Microglia are considered as a major player in the development of neurodegenerative disease yet, the molecular changes underlying brain aging and rejuvenation remain poorly understood at the single cell level. We identified and benchmarked several reproducible microglial states and a core set of genes leading to microglia activation in the mice brain. We investigated microglial heterogeneity and studied the impact of aging and parabiosis-mediated exposure of young and old blood on microglia subpopulations across four different brain regions including cerebellum, cortex, hippocampus, and striatum. We revealed region-specific differences in microglia subpopulation composition and age-related changes, with cerebellum and striatum displaying the most distinctive profiles and dynamic shifts compared to other brain regions. We consistently observed cerebellum as the most responsive, while striatum appeared distinctive by its minimal responsiveness to these interventions. Our findings highlighted the role of microglia in brain regional vulnerability and provided a foundation for microglia-targeted treatment for modulating brain aging. HighlightsO_LIDefined the composition of different microglial populations reproducible in aging and parabiosis, benchmarking a reference for the field. C_LIO_LIUncovered an under-appreciated core activation gene signature of microglia shared in all reactive states and regions during normal aging and old blood-induced aging. C_LIO_LIIdentified region-specific gene expression changes and associated biological processes in microglia during aging and parabiosis C_LIO_LIDiscovered microglial regional selectivity in response to aging and parabiosis, showing cerebellum as the most sensitive region and the striatum as the least affected. C_LI

neuroscience↗

bioRxiv2025

A model of apical-out human first trimester trophoblast organoids to study regeneration after syncytial damage

The villous syncytiotrophoblast in humans is the interface between maternal blood and the placenta and its functions are essential for a successful pregnancy. The syncytium can be damaged in vivo focally by high-velocity and turbulent maternal blood flow, or more globally by oxidative stress. It then quickly regenerates, a process critical for the maintenance of placental functions including nutrient transfer and protection from infections. To investigate this process, we developed apical-out trophoblast organoids from first-trimester placentas and induced mechanical damage to the syncytium. We observed spontaneous regeneration of syncytiotrophoblast both morphologically and functionally. TNFRSF12A, the TWEAK receptor, was identified as a potential enhancer of syncytiotrophoblast regeneration. Supplementation with recombinant TWEAK in organoids increased the expression of cell proliferation and fusion markers, promoting syncytiotrophoblast formation. The source of TWEAK was found to be macrophages derived from maternal blood monocytes that adhere to sites of syncytiotrophoblast damage in vivo. This in vitro model that allows the exploration of syncytial biology has relevance for important pregnancy disorders including pre-eclampsia, where breaks occur more often, and vertical infections, where maternal monocytes could be a source of transmission.

developmental biology↗

bioRxiv2025

Transplantation of active mitochondria condensed in liquid-liquid phase-separated hydrogels ameliorates myocardial ischemia-reperfusion injury

Mitochondrial dysfunction is a key driver of myocardial ischemia-reperfusion injury (MIRI), which exacerbates cardiac damage following the restoration of blood flow. Although single-phase hydrogel-based mitochondria transplantation therapy (MTT) holds promise for restoring cellular energy metabolism, its effectiveness is limited by extracellular calcium-induced mitochondrial degradation. In this study, we design a thermo-sensitive hydrogel utilizing liquid-liquid phase separation (LLPS), composed of gelatin and polyethylene glycol (PEG), to condense freshly isolated mitochondria. Compared to conventional single-phase hydrogels, the LLPS hydrogel significantly increases the sol-gel transition temperature above physiological levels, allowing it to remain injectable at body temperature while enabling rapid mitochondrial release following transplantation. More importantly, the LLPS structure enhances mitochondrial packing density and protects the activity of condensed mitochondria against calcium toxicity through spatial confinement and gelatin-mediated calcium chelation. In vitro, LLPS hydrogel-condensed mitochondria exhibit improved mitochondrial membrane potential and ATP production ability compared to those delivered via single-phase gelatin hydrogel. In vivo, mitochondria released from the LLPS hydrogel are effectively internalized by cardiomyocytes, resulting in improved cardiac function and reduced tissue damage after MIRI. These findings suggest that LLPS-based hydrogels offer a promising strategy to enhance MTT efficacy for MIRI and other mitochondria-related disorders.

bioengineering↗

bioRxiv2025

Integrated phenotypic and proteomic screening identifies top-tier Alzheimer's disease therapeutic targets

IntroductionAlzheimers disease (AD) is a complex neurodegenerative disorder. Hundreds of therapeutic targets have been nominated through genetic and multi-omic studies, but effective prioritization remains a major bottleneck. MethodsWe applied an integrative screening framework to assess 29 candidate targets from risk-enriched biological domains. Using disease-relevant murine BV2 microglial cell lines with stable Psen2 knockdown, we performed siRNA-mediated perturbations followed by cellular phenotypic assays and quantitative proteomics. ResultsTwenty-five candidate targets significantly altered at least one phenotype, with stronger effects in Psen2 knockdown cells. Integrated proteomic analyses identified several perturbations that reversed AD-associated molecular patterns. Five targets--Ap2a2, Pdhb, Pdha1, Dlat, and Psmc3-- impacted both phenotypes and related proteomic responses. DiscussionWe established a scalable platform for target functional validation that bridges unbiased systems-level assessments of AD risk with experimental evidence. The ESSJ TREAT-AD center will prioritize further resource development for these validated targets.

systems biology↗

bioRxiv2025

MicroRNA-21-3p regulation of NOX4 and VEGFA contributes to hemorrhage in cerebral cavernous malformations

ObjectiveMicroRNAs regulate the brain vascular integrity and are involved in the lesion development of cerebral cavernous malformations (CCM). This study examines the role of microRNA-21-3p in CCM-related cerebral hemorrhage and its underlying mechanisms. MethodsThe expression of miRNA-21-3p and its target genes of NADPH oxidase 4 (NOX4) and vascular endothelial growth factor A (VEGFA) in brain microvascular endothelial cells (BMECs) and pericytes were assessed in cavernous malformation lesions of 20 sporadic CCM patients by fluorescence in situ hybridization. The association of their expression with hemorrhage manifestation was evaluated. Cell proliferation, permeability, reactive oxygen species (ROS), migration, tubule formation, and the expression of NOX4 and VEGFA were assessed in CCM2 gene-depleted human BMECs and pericytes after miRNA-21-3p intervention. Cerebral hemorrhage, vascular permeability, vascular dilation, and angiogenesis after miRNA-21-3p intervention were evaluated in the ccm2 gene-knockdown zebrafish. ResultsDecreased miRNA-21-3p and increased NOX4 and VEGFA were shown in BMECs and pericytes of the CCM lesions compared to peri-lesion normal vessels from epilepsy patients, which were also correlated with the presence of cerebral hemorrhage in CCM patients. Increasing miRNA-21-3p attenuated cell proliferation, permeability, ROS expression, cell migration, and tubule formation by targeting NOX4 and VEGFA in CCM2 gene-depleted BMECs and pericytes. In vivo studies revealed that increasing miRNA-21-3p reduced cerebral hemorrhage, vascular permeability, vascular dilation, angiogenesis, and the overexpression of nox4 and vegfa in ccm2 gene-knockdown zebrafish. ConclusionMiRNA-21-3p can be a novel therapeutic target by regulating NOX4 and VEGFA, thereby stabilizing vascular integrity and reducing cerebral hemorrhage in CCM lesions.

neuroscience↗

bioRxiv2025

DEEPReditor-CMG: A deep-learning-based predictive RNA editor for crop mitochondria genomes

C-to-U RNA editing is a pervasive phenomenon in crop mitochondria, playing a pivotal role in the processing of functional proteins encoded by mitochondrial genes and serving as a crucial regulatory mechanism for nuclear control over mitochondrial gene expression. However, identifying editing sites across the mitochondrial genome with high precision remains a formidable challenge. To address this challenge and uncover the potential regulatory patterns of C-to-U RNA editing, this study compiled a comprehensive dataset of mitochondrial genome sequences from 13 crops, including Arabidopsis thaliana, Lactuca sativa var. Capitata, Oryza sativa Japonica, and Zea mays, among others, annotated with editing sites from NCBI. Utilizing TensorFlow 2.0, we constructed a rigorous hyperparameter optimization framework, which facilitated the development of the DEEPReditor-CMG model, demonstrating superior predictive capabilities. Based on the DEEPReditor-CMG model and three interspecies relationship indices, we discovered that species with closer phylogenetic relationships exhibit more similar C-to-U RNA editing mechanisms, providing valuable insights into the evolutionary conservation of RNA editing mechanisms. We further developed executable programs for predicting C-to-U RNA editing sites in crop mitochondrial genomes, leveraging the conserved nature of the crop RNA editing machinery to maximize prediction reliability and uncover new editing sites with great potential. This research not only deepens our understanding of C-to-U RNA editing and post-transcriptional regulatory mechanisms in crop mitochondria but also paves a novel avenue for investigating RNA editing mechanisms. Experimental data, computational code, and applications are publicly accessible at https://github.com/Qinsidong/DEEPReditor-CMG. HighlightsHigh-precision prediction model for C-to-U RNA editing in crops--DEEPReditor-CMG Three interspecies relationship indices describing C to U RNA editing Prediction tools based on the conservation of crop RNA editing mechanisms Open-sourced experimental data, computational code, and applications

bioinformatics↗

bioRxiv2025

A TCR-mimic bispecific antibody reduces HIV-1 provirus and delays viral rebound in HLA-matched humanized mice

Bispecific antibodies that reroute cytotoxic effectors toward infected cells are promising HIV-1 cure agents, yet existing formats bind Env and are limited by antigenic variation and Env down-regulation. We engineered a TCR-mimic single-chain diabody, HI12, that recognizes a conserved Pol-derived peptide presented by HLA-A*02:01 and evaluated its effect in HLA-matched, HIV-infected humanized mice. When administered during early antiretroviral therapy (ART), HI12 was well tolerated, activated HIV-specific CD8+ T cells and accelerated plasma virus decay. Treatment produced four-to six-fold reductions in intact and total proviral DNA within lymph-node and splenic CD4+ T cells, indicating substantive reservoir clearance. After ART interruption, HI12-treated animals showed a significant delay in viral rebound compared with controls, linking reservoir reduction to improved post-therapy control. These findings provide the first in-vivo evidence that a peptide-HLA-directed bispecific antibody can both shrink the intact HIV reservoir and defer viral recrudescence, supporting further development of TCR-mimic bispecific antibodies for cure strategies. Significance StatementAn HIV-1 cure strategy will require novel therapeutics to facilitate immune-mediated elimination of infected cells and reduction of blood and tissue reservoirs. Here, we demonstrate that an TCR-mimic bispecific antibody that recognizes a conserved Pol epitope can promote CD8+ T cell-mediated clearance of infected cells in HLA-matched, HIV-infected humanized mice. The bispecific antibody therapy reduced HIV-1 proviral DNA in lymph node and splenic tissues and improved post-therapy viral control. This study highlights the potential of developing novel TCR-mimic bispecific antibodies in HIV cure-directed strategies.

immunology↗

bioRxiv2025

RareFoldGPCR: Agonist Design Beyond Natural Amino Acids

Noncanonical amino acids (NCAAs) expand the chemical diversity of peptides beyond the twenty standard residues, offering new opportunities for designing binders with novel interaction modes and functional activity. G protein-coupled receptors (GPCRs) are central to cellular signalling and represent one of the largest classes of therapeutic targets, yet their functional modulation remains challenging. Here, we present RareFoldGPCR (RFG), a GPCR-specialised AI model for structure prediction and design that supports NCAAs. By applying transfer learning on high-resolution GPCR structures, RFG accurately models and rationally designs both linear and cyclic peptides that incorporate NCAAs and modulate GPCR activity. This is achieved without the model ever being trained on NCAA-based GPCR modulators. We showcase the capability of RFG by designing peptide agonists for the glucagon-like peptide-1 receptor (GLP1R) and validating their functional activity experimentally in cell-based assays. We investigate the precise capabilities of generating active agonists by expanding different regions of the native GLP-1 hormone, and further demonstrate the design of cyclic peptide agonists with entirely novel sequences and topologies, creating new agonist modes. We analyse how design metrics relate to pathway specificity, enabling precise modulation of pathway activity, such as activating the cAMP response without recruiting {beta}-arrestin to reduce receptor desensitisation. RFG shows how transfer learning on specific target classes enables generalisation to new chemistry and molecular topology, providing a broadly applicable strategy for designing functional ligands beyond the constraints of natural amino acid chemistry. RFG is freely available: https://github.com/patrickbryant1/RareFoldGPCR

bioinformatics↗

bioRxiv2025

METTL3 Uncouples Chromatin Accessibility from Transcription during Retinal Development

METTL3 is a key regulator of RNA metabolism, yet its genomic and epitranscriptomic roles in tissue development are largely unexplored. Using embryonic stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we integrated transcriptome-wide m6A profiling (GLORI), protein-DNA (ChIP-seq and CUT&RUN) and chromatin accessibility (ATAC-seq) mapping, and targeted m6A engineering (dCas13b-FTO) to dissect METTL3 function. Loss of METTL3 nuclear m6A activity disrupted Rx+ retinal anlage formation in vitro, with dCas13b-FTO epitranscriptome engineering revealing that m6A at the Six3 3UTR governs its stability. Surprisingly, while METTL3 loss altered histone modifications and chromatin accessibility, its direct chromatin targets showed little transcriptional correlation. A degron-based METTL3 degradation strategy, paired with protein-RNA interaction profiling, exposed rapid regulatory shifts in RPCs, revealing a METTL3-Ythdf1 protein-RNA axis. Our multi-omics approach establishes METTL3-dependent m6A as a critical epitranscriptomic layer in retinal development, unveiling a genomic paradigm in which chromatin accessibility diverges from transcriptional output.

developmental biology↗

bioRxiv2025

Unveiling The Origin of Human High-Grade Serous Ovarian Cancer Using Bulk and Single-Nucleus RNA Sequencing

High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy, yet its earliest cellular precursors remain incompletely defined. Here, we integrate bulk and single-nucleus RNA sequencing of human fallopian tubes, ovaries, and primary HGSOC tumors to resolve the epithelial hierarchy of the fallopian tube and examine its relationship to malignant states. We identify a rare LGR5/PGR basal population as putative epithelial stem cells and delineate a large pool of OVGP1/RNPC3 progenitors that give rise to both secretory and ciliated lineages. By jointly analyzing normal and malignant transcriptomes, we find that these progenitor populations show the strongest transcriptional and developmental continuity with multiple HGSOC cell states, suggesting that they represent the epithelial compartments most plausibly poised for oncogenic divergence. Transcription factor network reconstruction highlights SPDEF as a key regulator of progenitor identity and NR2F6 as a candidate oncogenic driver, while inferred copy number variations and microenvironmental collagen-integrin signaling further illuminate the genomic and stromal factors that consolidate malignant fate. Together, these findings refine the cellular landscape of the human fallopian tube and identify progenitor-enriched molecular features that could inform earlier detection, improved risk stratification, and new preventive strategies for women at risk of developing HGSOC. One sentence summaryFallopian tube progenitor cells represent a key intermediate state linking normal epithelial hierarchy to the earliest stages of high-grade serous ovarian cancer development.

cancer biology↗

bioRxiv2025

Brawn before bite in endemic Asian mammals after the end-Cretaceous extinction

The first 10 million years (Myr) following the Cretaceous-Paleogene (K-Pg) mass extinction marked a period of global greenhouse conditions and dramatic rise of placental mammals. Because [~]80% of known terrestrial sections capturing post-K-Pg mammal recovery come from North America, a substantial knowledge gap exists in the tempo and mode of recovery in Asia, where only 3% of sites are located and most contain species found nowhere else. We show that isolated Paleocene placental assemblages from China (1) reached high tooth size disparity early in the Paleocene, (2) tracked regional and global environmental changes in their dental shape later in the Paleocene, and (3) achieved maximum dental shape-performance integration near the end of the first 10 Myr post-K-Pg. This brawn before bite transformation, coupled with prolonged dental shape versus performance variability, favors a scenario whereby many living orders of placental mammals were borne out of phenotypically and functionally plastic ancestral assemblages, including those in tropical south China, during the Paleocene.

paleontology↗