Biology subjects

Li, S.

Publications and source records attributed to Li, S..

At least 325 records · Page 18Linked to original sources

bioRxiv2025

Population-level super-pangenome reveals genome evolution and empowers precision breeding in watermelon

Pangenomes are increasingly critical for harnessing crop genetic diversity, yet their resolution and utility are often limited by insufficient sampling of high-quality genome assemblies. Here, we report a population-level watermelon super-pangenome constructed from 138 reference-grade assemblies, including 135 newly generated near-gapless genomes representing all seven watermelon species. The super-pangenome captures approximately one million structural variants (SVs), enabling accurate variant genotyping across ~900 watermelon accessions and substantially expanding variant discovery both across and within species. Broader sampling within the pangenome provides insights into genome evolution among watermelon species and sheds light on the origin of cultivated watermelon. SV-inclusive genome-wide association studies enhance trait mapping resolution and identify a copy number variation upstream of ClFCI1 that regulates flesh color intensity in a dosage-dependent manner. Leveraging this comprehensive variation map, we developed high-accuracy genomic prediction models for 18 agronomic traits. Together, our findings and genomic resources establish a foundational framework for dissecting complex traits and accelerating precision breeding in watermelon, while offering a valuable model for SV-resolved pangenomics in crop species.

plant biology↗

bioRxiv2025

Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1.

Nerves have been shown to regulate cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified Ntn1 upregulation, and then verified its in vivo upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the Kras mutation and {beta}-adrenergic signaling, in part, through the MAPK pathway. Ex-vivo culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the Pdx1-Cre;LSL-KrasG12D/+ model, Ntn1 knockout decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant NTN1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In Pdx1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+mice, Ntn1 knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of PDAC (pancreatic ductal adenocarcinoma), treatment with a NTN1-neutralizing antibody or tumoral knockdown of Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, Ntn1 overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the NTN1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the NTN1/NEO1 axis could represent a potential therapeutic approach for PDAC. Statement of SignificanceNTN1 promotes pancreatic tumorigenesis and metastasis directly and indirectly through nerves, highlighting the importance of tumor cell-nerve crosstalk in cancer. NTN1 blockade could represent a promising strategy for treating PDAC liver metastasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/666009v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@ca611corg.highwire.dtl.DTLVardef@ad9264org.highwire.dtl.DTLVardef@1661c00org.highwire.dtl.DTLVardef@b86798_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Identification of Pesticides Associated with an Increased Risk of Parkinson's Disease using a Multi-Screen Approach

Parkinsons Disease (PD) is a progressive neurodegenerative disease characterized by aggregation and transmission of alpha-synuclein (-syn) protein and loss of dopaminergic neurons. The etiology of PD is multifactorial involving both genetic and environmental factors. Pesticide exposure has been associated with PD, but it is still unclear which of the hundreds of chemically and structurally diverse pesticides confer this association. While there are numerous pesticides currently registered for use in the United States, in this study, we focused on 62 pesticides used in the California Central Valley. We used 2 cell-based screens and a recently developed pesticide-wide association study (PWAS) analysis to identify candidates that increase the risk of PD. One cell-based screen tested for pesticides that alter autophagy and the other tested for their effect on -syn transmission. To establish biological plausibility, pesticides that were positive in all 3 screens were tested for dopaminergic neurotoxicity in an in vivo zebrafish (ZF) model. The autophagy screen resulted in a total of 22 hits for alterations to either autophagosomes (16 hits) and lysosomes (14 hits) out of the 62 pesticides tested. The -syn transmission screen resulted in 29 hits, and the PWAS resulted in 34 hits. Six pesticides were positive in all 3 screens and four of these pesticides induced aminergic neuron loss in ZF larvae. The majority of the pesticides identified in our screens have not previously been implicated as risk factors for PD but should be considered in future studies.

pharmacology and toxicology↗

bioRxiv2025

Loss of vitamin C biosynthesis protects from a parasitic infection

The ability to synthesize essential molecules is sometimes lost in evolution. A classic example is ascorbate (Vitamin C), which is synthesized in most animals by L-Gulonolactone Oxidase (GULO), an enzyme lost multiple independent times in animal evolution. This event is thought to be evolutionarily neutral, however, GULO-deficient animals including humans need to obtain ascorbate from their diet and are susceptible to ascorbate deficiency and scurvy. We therefore hypothesized that this disadvantage of GULO loss is offset by physiological benefits. Here we show that ascorbate deficiency protects mice from schistosomiasis, a debilitating parasitic disease which afflicts 250 million people. Schistosoma mansoni worms required host ascorbate to produce eggs in vivo. Consequently, ascorbate-deficient mice were protected from schistosomiasis pathologies and transmission. Intermittent ascorbate deficiency protected Gulo-deficient mice from both scurvy and schistosomiasis mortality. The effects of ascorbate on schistosome reproduction were mediated by ascorbate-dependent histone demethylation which promoted vitellocyte development in female schistosomes. We propose that vitamin deficiencies are not always detrimental but can protect animals from pathogens which need to obtain vitamins from their host.

biochemistry↗

bioRxiv2025

Complementary role of frontal theta and parietal alpha activity in resolving visual competition

Attention plays a central role in selecting information for conscious perception. Because natural environments are structured, prior knowledge about relevant and irrelevant features can guide this selection. However, prior knowledge about distractors can enhance their neural representation, raising the question of how the brain prevents such enhancement from interfering with behavior. We addressed this question by combining a binocular rivalry paradigm with frequency-tagged stimuli to independently track target and distractor signals during sustained perceptual competition. We identified a sequential pattern of oscillatory dynamics underlying stable perception. Early parietal alpha activity (8-12 Hz) was associated with the segregation of competing inputs without altering sensory gain. This was followed by frontal theta activity (3-7 Hz), which was linked to the reactive suppression of distractors representations. Importantly, alpha-mediated gating effects are most pronounced under high perceptual uncertainty, where they facilitated the stabilization of weak target signals and promoted their access to conscious awareness. Together, these findings demonstrate that perceptual competition is resolved through a coordinated sequence of proactive gating and reactive suppression.

neuroscience↗

bioRxiv2025

Synaptic sign switching mediates online dopamine updates

In the mammalian brain, excitatory and inhibitory synapses are generally distinct and have fixed synaptic signs. Therefore, unlike in artificial neural networks, learning in biological networks is thought to be manifested by plasticity mechanisms that modify synaptic weights but not signs. Here, we demonstrate experience-dependent sign switching at synapses between glutamate and GABA co-releasing neurons of the entopedunculus (EP) and their targets in the lateral habenula (LHb). Pairing of reward or punishment with activation of EP co-releasing neurons makes EP-LHb synapses relatively more inhibitory or excitatory, respectively. Synaptic sign switching modulates downstream dopaminergic signaling, correlates with recent dopamine updates, and contributes to reinforcement learning. These data unveil a plasticity mechanism that alters both synaptic signs and weights to rapidly update dopamine release and drive learning.

neuroscience↗

bioRxiv2025

Complexes between Netrin G Ligands and Chiral Nanoparticles Promote Axons Regeneration under Near-Infrared Illumination

Chiral nanoparticles combine functionalities of inorganic materials and large biomacromolecules enabling stimulation of neurons. However, multiple challenges remain in their use for central nervous system including identifying suitable cell signaling pathways and traversing the blood-brain barrier. In this study, we show that glutathione-coated Ni(OH)2 nanoparticles form nanoscale complexes with netrin-G1 ligands (NGL-1), critical for neuronal regeneration. NGL-1 features a semispherical pocket with a 2.5 nm radius of curvature, fitting well with nanoparticles sized 3 {+/-} 1.2 nm. D-NPs with D-glutathione surface ligands activate D-glutathione receptors on epithelial cells, facilitating their transport into the brain. When illuminated with 980 nm light, the nanoparticle-protein complex stimulates axon regeneration through localized IGF-1 production. This approach successfully regenerated (a) hippocampal neurons in Alzheimers disease mice and (b) dorsal root ganglion neurons in spinal cord-injured mice. The nanoparticles were thoroughly tested for safety and excreted intact. The local, rather than systemic, IGF-1 upregulation minimizes its side effects.

neuroscience↗

bioRxiv2025

Harnessing DNA Foundation Models for Cross-Species Transcription Factor Binding Site Prediction in Plant Genomes

Accurate prediction of transcription factor binding sites (TFBSs) is crucial for understanding gene regulation. While experimental methods such as ChIP-seq and DAP-seq are informative, they are labor-intensive and species-specific. Recent advancements in large-scale pretrained DNA foundation models have shown promise in overcoming these limitations. This study evaluates the performance of three such models--DNABERT-2, AgroNT, and HyenaDNA--in predicting TFBSs in plants. Using DAP-seq data from Arabidopsis thaliana and Sisymbrium irio, we benchmark their accuracy against specialized approaches, including a motif-based method and two deep learning models, DeepBind and BERT-TFBS. Our results demonstrate that foundation models, particularly HyenaDNA, offer superior predictive accuracy and computational efficiency, highlighting their potential for scalable, genome-wide TFBS prediction in plants.

bioinformatics↗

bioRxiv2025

Correlated protein-RNA associations reveal a requirement for HNRNPU in long-range Polycomb recruitment by the lncRNAs Airn, Kcnq1ot1, and Xist

The lncRNAs Airn and Kcnq1ot1 recruit Polycomb Repressive Complexes (PRCs) and repress genes over multi-megabase genomic intervals, but how they interact with proteins to direct repression remains poorly understood. We conducted formaldehyde-linked RNA-immunoprecipitations of 27 proteins from trophoblast stem cells, using a protocol exhibiting similar signal-to-noise and post-lysis reassociation ratios as CLIP and CLAP. Patterns of protein associations across Airn and Kcnq1ot1 were more similar to each other than to nearly all other transcripts and partitioned to extents that mirrored degree of repression each lncRNA induced, implying connections to mechanism. Indeed, HNRNPU, an essential protein that helps Xist localize to chromatin, was enriched within and required to direct PRC-catalyzed modifications by Airn and Kcnq1ot1, without being required for their localization. Our study provides insights into the role of HNRNPU in lncRNA-mediated gene regulation and reports architectures of protein association across Airn and Kcnq1ot1 relative to the transcriptome at large. Author summaryMammalian genomes express thousands of long noncoding RNAs (lncRNAs). While most remain functionally uncharacterized, a handful are known to regulate genes via epigenetic pathways. Whether or not these known regulatory lncRNAs operate through shared or divergent mechanisms remains unclear. To gain insight, we compared RNA-protein associations across three known regulatory lncRNAs -- Airn, Kcnq1ot1, and Xist -- relative to the broader transcriptome, using a protocol to immunoprecipitate RNA from formaldehyde-crosslinked cells. Benchmarking of our RNA-immunoprecipitation protocol against methods called CLIP and CLAP revealed similar results and complementary strengths among methods. We discovered similarities in RNA-protein associations between Airn and Kcnq1ot1 that nominated them as mechanistically important. One such protein, HNRNPU, was required for Airn and Kcnq1ot1 to coordinate long-range recruitment of Polycomb complexes, without giving the appearance of being required to tether either lncRNA to chromatin, as HNRNPU has been proposed to do for Xist. Our study identifies RNA-protein associations that correlate with long-range gene regulation by lncRNAs and provides new perspectives on the potential mechanisms through which HNRNPU participates in lncRNA-mediated epigenetic control. We also benchmark a protocol to recover RNA-protein interactions that is simple to execute and has complementary strengths relative to other methods.

molecular biology↗

bioRxiv2025

Dosing and Serostatus Shape the Efficacy of Adenovirus, mRNA, and Protein Vaccines

Despite the widespread use of adenovirus, mRNA, and protein-based vaccines during the COVID-19 pandemic, their relative immunological profiles and protective efficacies remain incompletely defined. Here, we compared antigen kinetics, innate and adaptive immune responses, and protective efficacy following Ad5, mRNA, and protein vaccination in mice. Ad5 induced the most sustained antigen expression, but mRNA induced the most potent interferon responses, associated with robust antigen presentation and costimulation. Unlike Ad5 vaccines, which were hindered by pre-existing vector immunity, mRNA vaccines retained efficacy after repeated use. As a single-dose regimen, Ad5 vaccines elicited superior immune responses. However, as a prime-boost regimen, and particularly in Ad5 seropositive mice, mRNA vaccines outperformed the other vaccine platforms. These findings highlight strengths of each vaccine platform and underscore the importance of host serostatus in determining optimal vaccine performance.

immunology↗

bioRxiv2025

An activator of a two-component system controls cell separation and intrinsic drug resistance in Mycobacterium tuberculosis

Unlike commonly studied rod-shaped bacteria, mycobacteria grow from their poles, requiring precise coordination between division and initiation of new pole growth. The mechanisms that mediate this transition are largely unknown, but likely represent a rich source of drug targets for the treatment of mycobacterial infections, including tuberculosis. Here, we identify TapA (MSMEG_3748/Rv1697) as a key regulator of this transition. TapA interacts with the sensor kinase MtrB at the septum to initiate a signaling cascade that ultimately results in the expression of the essential peptidoglycan hydrolases RipAB, amongst others, at the end of division. Loss of TapA disrupts division, dysregulates pole formation, and sensitizes Mycobacterium tuberculosis and other mycobacteria to several first and second-line TB antibiotics, establishing TapA as a potential therapeutic target, and defining a new link between cell cycle progression, envelope remodeling, and intrinsic antibiotic resistance in mycobacteria.

microbiology↗

bioRxiv2025

Assessing large-scale genomic language models in predicting personal gene expression: promises and limitations

Large-scale genomic language models (gLMs) hold promise for modeling gene regulation, yet their ability to predict personal gene expression remains largely unexplored. We developed a framework, gLM2X-Tower, to benchmark gLMs and sequence-to-function (S2F) models on this task with paired personal genome-transcriptome data. With individual-level training, we found that similar to S2F models (e.g., AlphaGenome), gLMs (e.g., Evo2) remain incapable of predicting the inter-person variability on held-out genes. However, such training improves prediction for seen genes in new individuals, particularly by gLMs, highlighting the potential applications in few-shot settings like for rare variants

bioinformatics↗

bioRxiv2025

Thioredoxin-1 inhibits granulosa cell ferroptosis to rescue ovarian aging through mitophagy-dependent activation of BNIP3L

Ovarian aging is closely associated with a decline in fertility and an increase in reproductive dysfunction. Ovarian granulosa cells (GCs) support oocyte homeostasis and development, yet insight into GC dysfunction during aging is limited. Here, we show that aged GCs of humans and mice have indications of elevated ferroptosis, including increased ferroptosis-related metabolites, lipid peroxidation, and iron accumulation. The ferroptosis inhibitor Ferrostatin-1 reversed ovarian impairment and fertility of aged mice in vivo. We show that the age-related reduction in the expression of TXN (thioredoxin) leads to ferroptosis in human and mouse GCs by blocking BNIP3L-dependent mitophagy. Exogenous activation of TXN could promote mitophagy, thereby clearing excessive ROS and inhibiting ferroptosis. These results suggest that anti-ferroptosis-related treatments may assist in treating aging-related reproductive disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/664497v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1b97e8forg.highwire.dtl.DTLVardef@123f8d0org.highwire.dtl.DTLVardef@a44c61org.highwire.dtl.DTLVardef@92b32e_HPS_FORMAT_FIGEXP M_FIG C_FIG Key pointsO_LIFerroptosis signatures are upregulated in aged GCs from human and mouse ovaries C_LIO_LITXN is deregulated in aged GCs, leading to mitochondrial and ROS metabolic dysfunction C_LIO_LITXN binds to DNA to regulate autophagy and mitophagy genes, including BNIP3L C_LIO_LIInhibition of ferroptosis can ameliorate GC dysfunction C_LI

cell biology↗

bioRxiv2025

HER2; p53 Co-mutated Cancers Show Increased Histone Acetylation and are Sensitive to Neratinib plus Trastuzumab Deruxtecan.

In metastatic breast cancer, HER2-activating mutations often co-occur with TP53 mutations, a combination linked to poor response to neratinib and worse prognosis. To model this clinical challenge, we bred HER2 V777L transgenic mice with two TP53 mutant alleles: TP53 R172H (the murine homolog of human TP53 R175H) and TP53fl/fl, which mimics p53 truncations common in human tumors. TP53 mutations accelerated tumor development and reduced survival in HER2-mutant mice. These co-mutant tumors were resistant to neratinib but remained sensitive to exatecan, the topoisomerase I (TOP1) inhibitor payload in trastuzumab deruxtecan (T-DXd). Mechanistically, TP53 mutant tumors exhibited upregulation of histone acetylation, hypertranscription of DNA repair factors, increased chromatin accessibility, and rendered cells more susceptible to TOP1 inhibitors via G2/M arrest and apoptosis. This vulnerability is dependent on transcriptional activity of TP53 mutations, highlighting a novel strategy to treat HER2;TP53 co-mutant breast cancers using TOP1-targeted therapies. Statement of SignificanceTP53 mutations sensitize HER2-mutant cancers to TOP1 inhibitors via chromatin accessibility and hyper-transcription, supporting combination therapy with neratinib and T-DXd in TP53/HER2 co-mutant breast cancers.

cancer biology↗

bioRxiv2025

EED Maintains the Small Cell Lung Cancer Neuroendocrine Phenotype and Drives Lung Cancer Histological Transformation

Lung cancer histological subtypes include lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC). While typically distinct, combined LUAD/SCLC histology tumors occur, and LUAD can transform into SCLC as a resistance mechanism to targeted therapies, especially in EGFR-Mutant LUADs with RB1/TP53-inactivation. Although PRC2 complex expression increases during this transformation, its functional role has remained unclear. Using CRISPR-based autochthonous immunocompetent GEMMs, we demonstrate that inactivation of EED, the core PRC2 scaffolding subunit, impairs SCLC tumorigenesis and drives histological transformation from ASCL1-positive SCLC to LUAD through a transient NEUROD1-positive intermediate state. Mechanistically, EED loss de-represses bivalent genes co-marked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes, to promote transformation to LUAD. Consistently, these same signaling genes are bivalently repressed in human SCLC patient-derived xenograft (PDX) tumors, suggesting a conserved PRC2-dependent mechanism to repress LUAD lineage oncogenic signaling to maintain the SCLC neuroendocrine identity. In a complementary EGFR-mutant LUAD GEMM with RB1/TP53 inactivation, EED was required for LUAD-to-SCLC transformation and distant metastasis upon EGFR withdrawal. These findings identify the PRC2 complex as a key epigenetic enforcer of SCLC neuroendocrine identity and nominate EED inhibition as a potential strategy to block SCLC transformation in high-risk LUAD.

cancer biology↗

bioRxiv2025

Musculoskeletal architecture of the shoulder: A comparative anatomy study in bats and mice informing human rotator cuff function

Overhead motion in humans often leads to shoulder injuries, a consequence of the evolutionary trade-off in glenohumeral joint anatomy that balances stability with mobility. Bats consistently engage in overhead motion during flight, subjecting their shoulders to substantial loading throughout their relatively long lifespan. Remarkably, despite the demands placed on a bats shoulder, instability and rotator cuff tears, which could be fatal to bats in short order, are not observed in nature. We were thus inspired to study functional adaptations in the shoulders of bats that enable this overhead motion. Comparative anatomical studies of the shoulders of bats and mice, similarly-sized quadrupeds, were performed and interpreted using a mathematical model. Scapular anatomy indicated a more prominent role for the infraspinatus muscle in the bat compared to the mouse. Measurements of bat and mice shoulders revealed that the bat glenoid had a larger curvature and arc length than that of mice, providing a larger articulating surface area with and deeper enclosing surface of the humeral head. Modeling results predicted that the bat shoulder is stable over a dramatically larger range of angles compared to the mouse shoulder. These results suggested that adaptations to constraints imposed by the bony anatomy and rotator cuff tendons of the shoulder may contribute to the ability of bats to sustain overhead motion in a high stress, repeated loading environment without injury. Results suggest that bats have evolved unique adaptations in their glenohumeral bony anatomy that reduce stress on the supraspinatus, enhance joint stability, and optimize strength across a broad range of motion.

physiology↗

bioRxiv2025

Copper-Containing ROS-Scavenging Nanozyme Paradoxically Drives Alpha-Synucleinopathy by Amplifying Nitrosative Stress

Reactive oxygen and nitrogen species (RONS) are implicated in neurodegeneration, but their specific pathogenic roles remain unclear. Here, we developed a pair of iridium-based nanozymes with opposing functionalities to dissect these pathways. We show that a copper-tuned iridium nanozyme (Ir{square}Cu), despite being a superior ROS scavenger, paradoxically and dramatically exacerbated -synuclein (Syn) pathology in vivo. This pathology was causally linked to its ability to amplify RNS, as pharmacological inhibition of nitric oxide synthase (NOS) with L-NAME completely abrogated the pathology and reversed a human Parkinsons disease (PD)-like transcriptomic signature. In contrast, a copper-free, broad-spectrum RONS-scavenging iridium (Ir) nanozyme demonstrated substantial therapeutic efficacy across diverse brain-first, body-first, and Alzheimers disease with Lewy body co-pathology models. Our findings uncover the importance of the RNS pathway in driving -synucleinopathies and establish a critical design principle for nanomedicine, mandating caution in the use of redox-active copper for neuroprotective applications.

pathology↗

bioRxiv2025

Buffer Valency Engineering Enables High-concentration and Shelf-stable DNA Transfection Particles for Viral Vector Production

Cost-effective and scalable production is critical for advancing the clinical translation of adeno-associated virus (AAV)-mediated gene therapy. The widely used transient transfection method using plasmid DNA (pDNA)-loaded transfection particles for AAV production faces technical challenges due to instability of the particles and the concentration limits for particle preparation, hindering reproducibility and scalability. Here, we report a streamlined and scalable strategy to generate shelf-stable, highly concentrated pDNA/poly(ethylenimine) (PEI) transfection particles. By incorporating trivalent citrate ions in the dilution buffers, we kinetically modulate electrostatic complexation to achieve uniform nanoparticle assembly and prevent aggregation at high concentrations. This enables a tenfold increase in pDNA concentration in stabilized transfection particles from a typical range of 10-20 g/mL to 200 g/mL, while reducing the required dosing volume from 5-10% to 0.5% of the cell culture medium. The particle assembly process is robust to changes in mixing scale and timing and is compatible with standard workflows. We demonstrate equivalent AAV production efficiencies to standard methods and consistent performance in various production scales, which confirms the practical utility of this assembly method in developing robust, scalable, and cost-effective AAV manufacturing processes.

biochemistry↗