Biology subjects

Liao, Y.

Publications and source records attributed to Liao, Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Oncolytic Newcastle disease virus promotes tumor cell apoptosis through SUMO-1-dependent PRKN-mediated degradation of c-Myc

The oncogenic transcription factor c-Myc is aberrantly upregulated in many cancers and plays a central role in tumor cell proliferation and survival. However, direct pharmacological targeting of c-Myc remains challenging because of its intrinsically disordered structure. Newcastle disease virus (NDV) is an oncolytic virus with selective antitumor activity, but the molecular mechanisms by which NDV disrupts oncogenic signaling remain incompletely understood. Here, we show that NDV induces apoptosis in multiple tumor cell lines and suppresses tumor growth in an A549 xenograft model. NDV infection markedly reduced c-Myc protein levels in tumor cells in a time- and dose-dependent manner, and c-Myc knockdown further enhanced NDV-induced intrinsic apoptosis. Mechanistically, NDV promoted ubiquitin-proteasome-dependent degradation of c-Myc through ubiquitination at Lys142. Screening of candidate E3 ubiquitin ligases identified PRKN as a key mediator of NDV-induced c-Myc degradation. NDV infection induced SUMO-1-dependent nuclear translocation of PRKN, allowing PRKN to interact with nuclear c-Myc and promote its degradation. Disruption of this pathway by SUMO-1 or PRKN knockdown impaired PRKN nuclear accumulation, restored c-Myc stability, and attenuated NDV-induced apoptosis. Functionally, expression of the degradation-resistant c-Myc K142R mutant or restoration of c-Myc in c-Myc-knockdown cells protected tumor cells from NDV-induced apoptosis. Together, these findings identify a SUMO-1-PRKN-c-Myc signaling axis that mediates NDV-induced tumor cell apoptosis and reveal c-Myc destabilization as an important mechanism underlying the oncolytic activity of NDV.

cell biology↗

bioRxiv2026

Global biogeography of geckos (Squamata: Gekkota) reveals Old-World origins and region-specific heterogeneity in diversification

Aim Investigating the biogeography and diversification dynamics of global radiations to understand how Earth history has influenced lineage proliferation has long been a goal of macroevolutionary biology. Gecko lizards, being an ancient and globally distributed hyperdiverse lineage, are an excellent system to elucidate how certain regions and events have shaped observed diversity. In this study, we attempt to identify: 1) The heterogeneity in diversification rate across geckos; 2) the ancestral region of geckos; 3) if diversification rate is tied to biogeographic region; and 4) potential mass extinction events in geckos. We generated a massive supermatrix of geckos from Sanger data and, after combination with phylogenomic data, estimate the most comprehensive phylogenetic estimate of geckos to date with 1,783 species. We performed fossil informed ancestral area reconstructions to evaluate the impact of fossils. We performed both state-dependent and state-agnostic diversification analyses to access diversification dynamics. Lastly, we tested for clade-wide mass extinction events. Our divergence date estimates suggested a Jurassic origin for pan-Gekkota and a Cretaceous origin for crown Gekkota. We recovered an Old-World origin for crown Gekkota with high uncertainty and an African origin for the families Phyllodactylidae, Sphaerodactylidae, and Gekkonidae with high confidence. Our results suggest differential diversification dynamics between pygopodoid (Australasian) and gekkonoid lineages (cosmopolitan), with the latter experiencing overall higher rates and more heterogeneity. Our results further suggest Africa being a biodiversity refugia while Eurasia acted as a diversification hotspot for geckos. Lastly, we find no evidence that crown geckos experienced any mass extinctions despite surviving the K-Pg event and major climatic oscillations during the Cenozoic. Our study provides an important global view for the biogeographic and diversification patterns of a morphologically and ecologically distinct lineage of lizards, setting the stage for studies placing clade-specific histories in a global context.

evolutionary biology↗

bioRxiv2026

scRBP infers cell-specific RNA-binding protein regulons from single-cell transcriptomes at gene and isoform resolution

Single-cell regulatory network inference remains dominated by transcription factors, despite RNA-binding proteins (RBPs) orchestrating major aspects of transcriptional regulation. We present scRBP, a framework that infers motif-supported RBP regulons from short- and long-read single-cell transcriptomes at gene and isoform resolution, resolves targets by transcript region (5'UTR, CDS, intron, 3'UTR), scores regulon activity in individual cells, and tests common- and rare-variant association against matched empirical nulls. From 20,746 motifs for 616 RBPs, scRBP recovered experimentally defined targets across 223 ENCODE eCLIP datasets at gene and isoform level. Across 30 tissues, transcript-region preferences separated 3'UTR-associated stability factors from intron-dominant splicing regulators. In published genome-scale CRISPRi Perturb-seq data, scRBP-inferred targets were over-represented among genes responding to RBP knockdown (1.4-2.5-fold across 161 RBPs; FDR<2x10-4). Across 6.2 million cells and 50 traits, scRBP prioritized cell-specific post-transcriptional programs linking human genetic risk to development and disease.

genetics↗

bioRxiv2026

A Human Genome-wide CRISPR-Cas9 Screen Reveals Host Factors That Support Epstein-Barr Virus B cell infection

Epstein-Barr virus (EBV) infects 90% of the population worldwide and is associated with multiple malignancies, including Burkitt, Hodgkin and post-transplant lymphomas, nasopharyngeal and gastric carcinoma. EBV also triggers autoimmune diseases, including multiple sclerosis and systemic lupus erythematosus. While host factors important for EBV B-cell entry have been defined, including CD21/CR2, MHC class II and R9AP, much remains to be learned about host factors that support post-entry steps of EBV infection. To gain insight, we conducted a human genome-wide CRISPR-Cas9 screen. In addition to known EBV B cell receptors/co-receptors, we identified multiple new factors and pathways essential for EBV B cell infection. These included multiple B cell signaling pathways, actin cytoskeleton and nuclear import factors. Knockout of CD19, its tetraspanin chaperone CD81 or karyopherin subunit alpha 1 (KPNA1, also called importin-5) significantly impaired establishment of EBV infection. EBV and CD19 co-localized at early stages of EBV infection, and the CD19 cytoplasmic tail was important for EBV infection, suggesting CD19 signaling supports EBV uptake. Depletion of KPNA1 significantly impaired establishment of EBV infection, but did not impair production of infectious EBV upon reactivation of latently infected B cells. Together, these results provide insights into pathways that support EBV B cell infection and identify potential therapeutic targets.

microbiology↗

bioRxiv2026

Autism genes converge on three functional programs organized by neuronal subclass, developmental timing, and cortical patterning

Our companion sequencing study uncovered 253 genes robustly associated with autism spectrum disorder (ASD), yet the biological programs they impact, and the cellular, developmental, and spatial contexts in which they converge, remain unresolved. Here we systematically contextualize genes associated with ASD across neurodevelopment and cortical areas, integrating developmental single-cell and spatial atlases with gene- and isoform co-expression, regulatory, proteomic, and synaptic networks. Genetic burden concentrates within temporally-resolved neuronal subclasses: newborn excitatory neurons, immature interneurons, and maturing intratelencephalic lineages. Genes associated with ASD converge on three functional programs--gene regulation, neuronal morphogenesis, and synaptic transmembrane signaling machinery--resolved from 28 ASD-associated networks, several of which are directly regulated by ASD genes including MEF2C, SOX11, and FOXP2. These programs are spatially patterned, with risk genes exhibiting an increasing anterior-to-posterior cortical expression gradient, anchored in the primary visual cortex and driven by excitatory neuron gene-regulatory programs. Finally, ASD risk genes associated with more severe developmental phenotypes show broader excitatory neuron enrichment and less interneuron involvement. Together, these findings anchor ASD genetic vulnerability to specific neurodevelopmental lineages, epochs, and molecular substrates, and delineate the features that distinguish ASD from comorbidities with broader developmental impacts.

genomics↗

bioRxiv2026

Plant-adapted OTO staining improves ultrastructural imaging by transmission electron microscopy

Transmission electron microscopy (TEM) is widely used to examine plant cellular ultrastructure, but sample preparation remains challenging because polysaccharide-rich cell walls, large vacuoles and complex membrane systems compromise staining and structural preservation. Here, we developed a plant-adapted TEM preparation method based on a modified osmium-thiocarbohydrazide-osmium (OTO) staining workflow combined with optimized washing, dehydration and resin infiltration. Using tomato roots and leaves, we show that the optimized method produces cleaner backgrounds, better-defined cellular boundaries and improved preservation of cellular morphology compared with conventional preparation. Fine membrane-associated structures, including mitochondrial cristae, chloroplast grana and stroma lamellae, nuclear membranes and other endomembrane structures, were more clearly resolved, while staining-related precipitates and diffuse background artifacts were reduced. This method provides a practical approach for high-contrast TEM imaging of plant tissues and ultrastructural analysis of plant cells and organelles.

plant biology↗

bioRxiv2026

Ancient tandem duplication of CYCLOIDEA is associated with the evolution of capitulum development in Asteraceae

Asteraceae is one of the largest and most diverse families of flowering plants. Much of their evolutionary success is attributed to their unique inflorescence structure-the capitulum. Despite their profound adaptive and taxonomic significance, the evolutionary genetic mechanisms underlying Asteraceae capitulum diversification remains poorly understood. We integrated comparative genomic analyses of 35 Asteraceae genomes with developmental transcriptome profiling of ray and disc florets. Our results uncovered a deeply conserved CYC2e-CYC2c-CYC2d-CYC2g-CYC2b tandem gene cluster that is prevalent across the Asteraceae family. We demonstrated that this tandem cluster arose during the early evolutionary diversification of Asteraceae. Subsequent lineage-specific gene retention and loss events have reshaped the composition of this cluster across different Asteraceae lineages. Notably, key members of this cluster, particularly CYC2c, CYC2d, and CYC2g, are preferentially retained in lineages with ray florets, which is consistent with their roles in regulating the ray floret development. Collectively, our findings establish a mechanistic link between the evolutionary divergence, spatiotemporal expression differentiation of the CYC2 tandem cluster as a key genetic driver underlying the morphological diversification and evolutionary success of Asteraceae.

evolutionary biology↗

bioRxiv2026

An AI System for Autonomous Algorithm Evolution in Drug Development

Artificial intelligence (AI) is increasingly permeating the drug development pipeline. Numerous algorithms for accelerating this multi-stage and multi-task process have been constructed, which depends heavily on expert design and labor-intensive task-specific optimization. Given that AI-driven acceleration of drug development is recognized as a cumulative, often synergistic, effect across multiple stages, the autonomous evolution of existing algorithms across the entire pipeline is demanded to achieve a holistic advancement. Here, we present DrugEvolve, a multi-role large language model system for systematic and autonomous algorithm evolution in drug development. DrugEvolve realizes a closed-loop evolution process by incorporating Researcher, Engineer, and Analyst domains, and enables an iterative design, implementation, evaluation, and refinement of algorithm by leveraging scientific knowledge and accumulated evolutionary experience. Across eleven representative tasks spanning target identification, drug discovery, preclinical study, and clinical trial, DrugEvolve autonomously evolved the corresponding task-specific algorithms and achieved substantial performance enhancement on 120 benchmark test sets. Moreover, it showed robust generalizabilities across heterogeneous data modalities (ranging from biological sequence and graph to molecular topology and textual language), and realized gains in both predictive and generative tasks. Collectively, this AI system can serve not only as an algorithmic infrastructure for drug development, but also as a transferable paradigm for broader scientific domains.

pharmacology and toxicology↗

bioRxiv2026

Single-cell lineage tracing of human neuromesoderm organoids reveals TBX6-mediated posterior mesoderm fate diversification

Neuromesodermal progenitors (NMPs) drive vertebrate posterior axis elongation, but the lineage hierarchy of human NMP derivatives remains poorly defined. Here, we integrated a CRISPR/Cas9-based single-cell lineage tracing system with paired multiomics profiling--including scRNA-seq and scATAC-seq--in human pluripotent stem cell-derived neuromesodermal organoids (NMOs) to reconstruct high-resolution lineage relationships spanning 50 days of differentiation. Our data analysis reveal that intermediate mesoderm (IM) and paraxial mesoderm (PM) originate from a shared presomitic mesoderm (PSM) progenitor downstream of NMPs, whereas lateral plate mesoderm (LPM) segregates early from committed mesodermal progenitors. Notably, TBX6 ablation disrupts both IM and somite development, demonstrating that TBX6 functions as an upstream regulator of these two lineages. Mechanistically, TBX6 loss arrests PSM at the progenitor stage and abolishes activation of development programs required for IM maturation. We further delineate neural crest differentiation pathways from NMPs, identifying pre-bifurcation molecular signatures that predict neural crest fate. This work provides a clonal-resolution lineage map of human NMP differentiation and advances our understanding of human posterior trunk development and the etiology of TBX6-associated congenital disorders affecting both the spine and the kidney.

developmental biology↗

bioRxiv2026

Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

Internal tandem duplication mutations in FLT3 (FLT3ITD) occur in approximately 30% of patients with acute myeloid leukemia (AML) and are among the most common genetic alterations in this disease. FLT3ITD is a major driver of AML and is associated with poor clinical outcomes. Although FLT3 inhibitors (FLT3is) have significantly improved outcomes for patients with FLT3ITD+ AML, acquired resistance remains a major barrier to durable clinical benefit. Reactivation of RAS/MAPK signaling, often driven by activating NRAS mutations, is a major mechanism of FLT3i resistance in AML; however, effective strategies to overcome this resistance remain lacking. Here, we identify ribonucleotide reductase (RNR) as a critical therapeutic vulnerability in NRAS-driven FLT3i-resistant FLT3ITD+ AML. Activation of RAS signaling through SPRY3 loss or oncogenic NRAS mutations confers robust resistance to FLT3is, whereas pharmacologic inhibition of RNR with multiple inhibitors, as well as siRNA-mediated RNR suppression, reverses FLT3i resistance and restores FLT3i sensitivity across multiple FLT3ITD+ AML models in vitro. In vivo, clofarabine, an FDA-approved RNR inhibitor (RNRi), significantly overcomes NRAS mutation-driven FLT3i resistance. In combination with FLT3 inhibition, clofarabine markedly suppresses the progression of FLT3i-resistant AML and significantly prolongs survival in cell line-derived xenograft (CDX) models. Importantly, the therapeutic efficacy of the gilteritinib/clofarabine combination was independently validated in two genetically distinct patient-derived xenograft (PDX) models harboring different NRAS mutations, demonstrating robust reduction of leukemia burden and confirming the generalizability of RNR inhibition in primary FLT3i-resistant AML. Together, these findings identify a previously unrecognized therapeutic vulnerability in FLT3i-resistant FLT3mut+ AML and establish RNR inhibition as an effective strategy to overcome FLT3i resistance, providing a strong rationale for the clinical evaluation of RNRis in combination with FLT3is in patients with resistant AML. SignificanceAlthough FLT3 inhibitors (FLT3i) are an important therapeutic advance in FLT3ITD+ AML, resistance commonly develops. We identified ribonucleotide reductase (RNR) as a new key vulnerability in NRAS-driven FLT3i-resistant AML and demonstrated that multiple RNRis, including the FDA-approved agent clofarabine, restore FLT3i sensitivity and enhance antileukemic activity, supporting a clinically actionable combination strategy.

cancer biology↗

bioRxiv2026

Tracing the 'Panda of the Sea': Species-Specific qPCR Assays for eDNA Monitoring of Critically Endangered Bahaba taipingensis in the Pearl River Estuary

Chinese Bahaba (Bahaba taipingensis, Sciaenidae) is a Critically Endangered, Grade I state-protected marine fish in China. Reliable, non-invasive monitoring tools are urgently needed to inform conservation and restocking efforts. We developed and validated three TaqMan probe-based qPCR assays targeting mitochondrial 12S rRNA, ND5, and control region (D-loop) loci for species-specific detection of B. taipingensis. Primer-probe sets were designed from complete mitochondrial genomes and evaluated in silico against GenBank and in vitro against tissue DNA from B. taipingensis and closely related sciaenids, plus positive eDNA samples; sensitivity was quantified using serial dilutions of synthetic target DNA. All three assays showed high specificity and consistent amplification; 12S rRNA assay (Bhb_12S) was selected for field screening based on superior low-copy sensitivity and minimal by-products. We applied the Bhb_12S assay to 414 seawater samples collected from 23 sites in western Hong Kong during 2025 surveys, detecting B. taipingensis eDNA in the September samples (0.71-2.85 copies per L; mean 2.05), with positive detections confirmed by Sanger sequencing. Overall, these validated qPCR assays provide a robust molecular toolkit for non-invasive monitoring of B. taipingensis and will aid conservation planning, restocking evaluation, and long-term biodiversity assessments in the Pearl River Estuary and adjacent coastal waters.

ecology↗

bioRxiv2026

Coronavirus papain-like protease antagonizes innate immunity by cleaving Importin α1 to disrupt nuclear transport

The Importin family, as key mediators of nucleocytoplasmic transport, represents a common target for viral immune evasion. However, whether coronaviruses directly manipulate Importin to disrupt nuclear trafficking and suppress antiviral immunity has remained unclear. In this study, we identify a previously unrecognized mechanism by which coronaviruses from all four genera subvert host innate immunity through the proteolytic inactivation of Importin 1, a key mediator of nuclear import of cargo proteins. We demonstrate that the membrane-associated papain-like protease (PLpro-TM) directly cleaves Importin 1 at specific glycine residues, G129 for PEDV and IBV PLpro, and G119 for MHV and PDCoV PLpro, thereby disrupting its nuclear import function. This cleavage impairs the nuclear translocation of multiple transcription factors (IRF3, STAT1, STAT2, and p65) and suppresses the expression of downstream antiviral genes, including IFN-{beta} and IFN-stimulated genes (ISGs). Importantly, cleavage-resistant mutants of Importin 1 (G129A or G119A) restore nuclear import capability and rescue IFN-{beta} signaling. Consequently, they exert a more potent inhibitory effect on viral replication than the wild-type Importin 1, fulfilling an antiviral role. Our work establishes PLpro-TM-mediated cleavage of Importin 1 as a conserved immune evasion strategy across coronaviruses and highlights this interaction as a potential target for broad-spectrum antiviral intervention. Author summaryThe nuclear transport of transcription factors is a critical checkpoint for the initiation of innate antiviral immunity. Here, we identify the PLpro-TM protein as a pan-coronavirus antagonist of nucleocytoplasmic trafficking and innate immune response. We demonstrate that PLpro-TM from four distinct coronavirus genera directly cleaves Importin 1 at specific glycine residues, thereby disabling its ability to mediate the nuclear import of key transcription factors and subsequent transcription of anti-viral genes. This work reveals a previously unrecognized, evolutionarily conserved immune evasion strategy shared across , {beta}, {gamma}, and {delta} coronaviruses. By uncovering the proteolytic inactivation of Importin 1 targeting by PLpro-TM, our findings not only resolve a long-standing question about how coronaviruses disrupt nuclear trafficking, but also establish PLpro-TM and Importin 1 as promising targets for the development of broad-spectrum antiviral therapeutics against current and emerging coronaviruses.

microbiology↗

bioRxiv2026

Epstein-Barr virus transformation creates a methionine-dependent ferroptosis vulnerability in B cells

Epstein-Barr virus (EBV) causes over 200,000 cancers annually, including immunoblastic lymphomas in immunosuppressed hosts. Most transformed cells arrest, yet survive when deprived of the essential amino acid methionine. We instead find that EBV transformed lymphoblastoid cell lines (LCLs), which model the EBV latency III program-driven B-cell lymphoproliferative diseases of immunosuppressed hosts, rapidly die upon methionine restriction. Methionine restriction elevated LCL lipid reactive oxygen species and triggered ferroptosis. Whereas methionine restriction hypomethylates the EBV genome and triggers viral reactivation in latency I Burkitt cells by lowering the cellular methylation potential, the LCL latency III program instead redirected methionine toward redox defense, without altering the SAM/SAH ratio. Stable-isotope tracing revealed that latency III strongly induces transsulfuration, synthesizing cysteine de novo to support glutathione pools. The EBV oncoprotein LMP2A, which mimics B-cell receptor signaling, supported newly infected human B cell cystathionine-{beta}-synthase and cystathionine-{gamma}-lyase expression and methionine dependence, phenocopied by immunoglobulin crosslinking. In vivo, dietary methionine restriction impaired LCL xenograft outgrowth and depleted tumor cystine. Combined methioninase and cyst(e)inase administration blocked both cysteine sources, collapsed tumor glutathione levels, and triggered ferroptosis. Our results define methionine metabolism as a targetable ferroptosis vulnerability of EBV-transformed B cells. HighlightsO_LIMethionine restriction triggers EBV-transformed lymphoblastoid B cell ferroptosis C_LIO_LIEBV latency III induces transsulfuration to sustain LCL cysteine and glutathione C_LIO_LIMethioninase or dietary methionine restriction strongly impair LCL growth in vivo C_LIO_LIMethioninase plus cyst(e)inase collapses xenograft GSH levels and drives ferroptosis C_LI

biochemistry↗

bioRxiv2026

Real Science Is Harder Than Benchmarks: Evaluating Advanced AI Frameworks on Published Studies. I. Uncertainty Quantification, ML on Therapeutic Data Commons, and Agent-Based Modeling

Artificial Intelligence (AI) frameworks for automating scientific research have shown strong performance on benchmarks, but their capacity to routinely reproduce results from multiple real-life published studies remains largely untested. We evaluated five advanced AI research frameworks (Kosmos, K-Dense, ToolUniverse, BioAgents from bio.xyz, and the AI Scientist-v2 from Sakana AI) on three real-life tasks (including two recently published papers) spanning uncertainty quantification for molecular property predictions, machine learning on Therapeutic Data Commons benchmarks, and agent-based modeling. AI frameworks demonstrated genuine strengths: generating original hypotheses, competently executing routine data acquisition and coding tasks, providing statistical measures of confidence often absent from the original papers, and producing well-formatted final reports. At the same time, our experiments revealed that real-world scientific tasks remain considerably harder than current benchmarks suggest. No AI framework matched the scope or depth of the original studies, results varied across multiple runs of the same framework with the same prompt, and we documented cases of severe hallucinations in final reports, gaps in literature coverage, and overconfident conclusions. Verification of AI outputs required substantial domain expertise. While these three tasks are only partially representative of the broader scientific landscape, they offer a starting point for developing a more rigorous methodology for evaluation of AI performance than what is currently practiced. We conclude that AI frameworks are already valuable for prototyping research directions and stress-testing completed studies, and some of the limitations documented here appear largely tractable through infrastructure improvements and continued development.

bioinformatics↗

bioRxiv2026

Targeting Cellular Pseudo-Senescence to Overcome PARP inhibitors Resistance in BRCA1 -Mutated Breast Cancer

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a mainstay therapy for homologous recombination (HR)-deficient cancers; however, resistance remains a major clinical challenge. Previously, through a genome wide CRISPR screen, we identified ZNF251 haploinsufficiency as a novel driver of PARPi resistance. In BRCA1-mutant (BRCA1mut) cells, ZNF251 deficiency led to HR hyperactivation, conferring PARPi resistance that could be reversed by RAD51 inhibition. In this study, we further show that ZNF251 deficiency induces replication stress and a pseudo-senescence state, in which cells exhibit molecular and phenotypic markers of senescence while retaining proliferative capacity. Because senomorphic and senolytic therapies can target senescent cells, we tested whether these approaches could overcome PARPi resistance in ZNF251-deficient breast cancer cells. Critically, targeting this senescence-like state with either senomorphic agents, such as cytokine inhibitors, or senolytic agents, such as BCL-2 and BCL-XL inhibitors, overcame PARPi resistance ex vivo and in vivo. Importantly, pseudo-senescence was also observed in other PARPi-resistant contexts driven by HR hyperactivation, including 53BP1- and Shieldin-mutant cells, suggesting that it may represent a broader mechanism underlying PARPi resistance in breast cancer. Furthermore, in two olaparib-resistant, BRCA-mutant triple-negative breast cancer organoid models, treatment with DT2216, a BCL-XL-targeting PROTAC, sensitized both models to olaparib. Together, our work defines a novel pathway linking HR hyperactivation, replication stress, and pseudo-senescence, and positions both senomorphic and senolytic therapies as promising strategies to overcome PARPi resistance in BRCA1mut breast cancer. HighlightsO_LIZNF251 deficiency drives PARP inhibitor resistance through HR hyperactivation, replication stress, and pseudo-senescence in BRCA1-mutant breast cancer. C_LIO_LISenomorphic and senolytic therapies overcome PARP inhibitor resistance in vitro, in vivo, and in patient-derived organoid models. C_LIO_LIPseudo-senescence represents a shared vulnerability of HR-hyperactivated PARPi-resistant cancers and can be therapeutically targeted. C_LI

Cancer Biology↗

bioRxiv2026

Steller: a high-resolution platform for spatial clonal tracing of mammalian brain development

Resolving both lineage history and spatial position at single-cell resolution is essential for understanding how tissue assemble, yet simultaneously interrogation of both dimensions remains technically challenging. Here, we present Steller (Spatio-temporal cell lineage tracker), an integrated experimental and computational framework that overcomes the sensitivity bottleneck limiting lineage barcode detection in high-resolution spatial transcriptomics (ST). By co-depositing capture probes alongside conventional poly(T) oligonucleotides on high-density spatial arrays, Steller achieves targeted enrichment of lineage barcodes at spatial single cell resolution. Applied to clonally labeled embryonic day 12.5 (E12.5) mouse forebrain development harvested at postnatal day 4 (P4), Steller increased the proportion of barcode-detectable cells and recovered higher clonal diversity compared with poly(T) chip. Leveraging this enhanced sensitivity, we resolved distinct spatial clonal architectures across three forebrain regions: horizontal or radial-to-horizontal transitions in hippocampal pyramidal neurons, dorsoventrally restricted yet multi-nuclei spread in thalamus, and fate-restricted spiny projection neuron lineages. Steller establishes a generalizable strategy for lineage-enhanced spatial profiling compatible with existing high-resolution spatial transcriptomics platforms and adaptable to diverse biologic process, providing a framewrok for investigating lineage-dependent tissue organization. HighlightsO_LISteller integrates targeted lineage-barcode enrichment with high-resolution spatial transcriptomics C_LIO_LISteller substantially improves clonal detection sensitivity at single-cell resolution C_LIO_LISteller reveals region-specific spatial clonal architectures across the developing mouse forebrain C_LI

Developmental Biology↗

bioRxiv2026

Psychometric Validation of the Education and Assessment of Genetic Literacy (EAGL) Measure

Genetic literacy is an integral measure for examining societys interaction with genetics, but widely-used "genetic literacy" measures lack both knowledge comprehension measures and psychometric validation. To address these issues, we validated the Education and Assessment of Genetic Literacy measure (EAGL) in a sample of 2708 US participants, using both exploratory and confirmatory factor analysis. In addition to standard subjective and objective knowledge subscales, our measures distinct knowledge comprehension subscale focuses on autism as an example of a complex condition. Regression analyses showed a statistically significant interaction when looking at education and personal connection to autism in relation to knowledge comprehension (F=3.68, p=0.003). Separately, those in our sample with a connection to autism scored higher on the subjective knowledge section (F=19.52, p<0.001) only, concurring with previous demonstrations of a subjective-objective knowledge gap in science literacy. We explored geographic location as one potential factor in genetic literacy and found that metropolitan vs non-metropolitan status had no significant main effects on overall levels. After the validation process, we have two multi-domain measures which accurately capture the construct of genetic literacy and are available for wide use: the multi-faceted EAGL-long, which has previously been tested in thousands of participants, or the validated three-factor EAGL-short.

genetics↗

bioRxiv2026

RIPK3 suppresses photoreceptor degeneration in a Stargardt disease mouse model

Autosomal recessive Stargardt disease type 1 (STGD1) is the most prevalent inherited juvenile macular degeneration, ultimately leading to irreversible blindness through photoreceptor cell loss, yet the underlying cell death mechanisms remain poorly defined. Receptor-interacting protein kinase 3 (RIPK3) is a well-established mediator of necroptosis and, under certain circumstances, apoptosis downstream of TNF family ligands, and it was found to be progressively upregulated in the retina of a STGD1 abca4-/-rdh8-/- (DKO) mouse model coinciding with the onset and progression of photoreceptor degeneration. Despite elevated RIPK3 expression, necroptosis was not detectable in this model, as evidenced by the absence of phosphorylated MLKL and unaltered photoreceptor degeneration in abca4-/- rdh8-/-mlkl-/- mice. Intriguingly, genetic ablation of Ripk3 exacerbated photoreceptor loss in DKO mice in both chronic (age-dependent) and acute (light-induced) retinal degeneration paradigms. This detrimental effect was partially ameliorated by pan-caspase inhibition in the acute degeneration model, indicating caspase-dependent apoptosis as the primary executioner. Mechanistically, we demonstrated that RIPK3 suppressed extrinsic apoptosis by attenuating caspase-8 activation downstream of TNF family ligands. Collectively, our findings reveal a non-canonical, protective role of RIPK3 in photoreceptors, as a brake on apoptotic signaling rather than a necroptotic executor, in the context of STGD1. These findings redefine the role of RIPK3 in retinal degeneration and emphasize the contextual plasticity of cell death regulators in neurodegenerative diseases.

neuroscience↗