Biology subjects

Li, P.

Publications and source records attributed to Li, P..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

IFN-inducible Human Phospholipid Scramblase 1 (PLSCR1) ProteinRestricts HIV-1 Infection by Inhibiting Membrane Fusion

Human phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that inhibits viral infections through various mechanisms. Here, we identify PLSCR1 as a host restriction factor that inhibits HIV-1 entry by impairing membrane fusion mediated by the envelope glycoprotein (Env). Using multiple cell types including the human SupT1 T cell line and purified CD4+ T cells, we demonstrate that PLSCR1 inhibits the replication of HIV-1 with diverse tropisms and subtypes, as well as HIV-2 and SIV. Mechanistically, we find that PLSCR1 blocks viral entry and cell-to-cell transmission by restricting HIV-1 virion-cell and cell-cell fusion without affecting CD4 or CXCR4 expression or virus binding to the cell surface. Notably, PLSCR1-mediated restriction of viral entry is independent of type I interferon signaling. Collectively, these findings establish PLSCR1 as a broad-spectrum lentiviral restriction factor that acts at the membrane fusion stage, thereby expanding our understanding of ISG-mediated antiviral defense.

microbiology↗

bioRxiv2025

Clade V MLO proteins are bona fide host susceptibility factors required for powdery mildew pathogenesis in Arabidopsis

Obligate biotrophic powdery mildew (PM) fungi strictly require living host to survive. To search for host factors or processes essential for PM pathogenesis, a tailored genetic screen was conducted with the immuno-compromised eds1-2/pad4-1/sid2-2 (eps) triple Arabidopsis mutant. This led to the identification of five allelic disruptive mutations in Mildew Locus O 2 (MLO2) to be responsible for the compromised-immunity-yet-poor infection (cipi) mutant phenotype upon challenge from an adapted PM isolate. Moreover, the eds1/pad4/sid2/mlo2/mlo6/mlo12 (eps3m) sextuple mutant display near complete immunity to the adapted PM fungus without sign of defense activation, demonstrating that these three clade V MLOs in Arabidopsis are bona fide host susceptibility factors of PM fungi. Confocal imaging revealed focal accumulation of MLO2-GFP in the peri-penetration peg membranous space, implicating MLO2 in repairing and stabilizing the damaged host plasma membrane, which may be co-opted by PM fungi for haustorium differentiation. Results from domain-swapping analysis between MLO1 and MLO2 suggest a bipartite functional configuration for MLO2: its C-terminus determines where and when MLO2 functions, while its N-terminal seven transmembrane domain region executes the cellular function that is critical for PM pathogenesis. Genetic studies further demonstrate that, unlike MLO7 in synergids, focal accumulation of MLO2 does not depend on FERONIA (FER) and its five other family members, nor does it require phosphatidylinositol 4,5-bisphosphate produced from phosphatidylinositol 4-phosphate 5-kinase 1 (PIP5K1) and PIP5K2. Together, these findings define clade V MLOs as host factors co-opted by obligate biotrophic PM fungi for successful host colonization.

plant biology↗

bioRxiv2025

Evolutionary Genomics Guides Scalable Coral Probiotics for Climate Resilience

A universal bottleneck limiting probiotic efficacy in medicine, aquaculture, agriculture, and wildlife conservation is uncertain long-term colonization, necessitating repeated administration. We present an evolution-guided framework for probiotic identification based on genomic hallmarks of emerging host dependency, including widespread pseudogenization and insertion sequence proliferation driving genomic restructuring. Applied to coral reefs, we screened over 1,200 coral-associated bacterial isolates and identified Ruegeria MC10 as exhibiting these signatures. Its presence was associated with increased thermal tolerance of a model cnidarian. Following nursery application, MC10 persisted in reef corals for an 8-month monitoring period through a natural bleaching event, improving color retention and retaining algal photosynthesis performance. This work establishes a predictive, scalable pipeline for selecting persistent probiotics, directly addressing a central constraint on microbiome-based interventions across host systems.

microbiology↗

bioRxiv2025

Whole chloroplast genomes reveal a complex genetic legacy of lost lineages, past radiations and secondary contacts in the dominant temperate deciduous tree genus Fagus

Background--Major northern temperate tree genera emerged in the Eocene and now have vast ranges across the Northern Hemisphere. Here we undertake a multi-discipline study to provide novel insights into the formation and biogeographic history of a dominant, yet understudied temperate tree genus, Fagus L. Data and methodology--A whole chloroplast genome phylogeny (eighty-two chloroplast genomes) with multi-accessions of most species was determined and contrasted with the timing of lineage diversification inferred from three different nuclear and chloroplast gene time-calibrated phylogenies using 101 fossils as age priors. Main results--Five deeply diverged chloroplast lineages were revealed that, with the exception of a Eurasian lineage, underwent divergence decoupled from speciation predating modern species lineages by up to 28 million years (Ma). The geographic distribution of chloroplast lineages reflects a complex history of genetic admixture during past contact between extinct and modern species including between different subgenera in East Asia and long-term persistence particularly in Japan which is the hotspot of plastome diversity. Conclusion--Modern Fagus forests are the consequence of 62 million years of evolution, migration, genetic exchange and species extinction with most modern species harbouring a mosaic of genetic material, a legacy of multiple admixture events in deep time.

evolutionary biology↗

bioRxiv2025

Engineering a mouse-adapted SADS-CoV and establishing a neonatal mouse model to study its infection

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is an emerging bat-origin alphacoronavirus causing severe disease in neonatal piglets, with significant economic losses to the swine industry as a consequence. The virus exhibits a broad species tropism, infecting cells derived from pigs, humans and mice, highlighting its potential for cross-species transmission. Due to drawbacks associated with the use of young piglets, there is a need for an appropriate small animal model to study SADS-CoV biology. Here we established a mouse infection model based on a murinized mutant of the virus, mSADS-CoV, in which the ectodomain of the viral spike protein was replaced by that of the murine coronavirus mouse hepatitis virus (MHV). This chimeric virus, generated through targeted RNA recombination, replicated efficiently in murine cell cultures and exhibited an age-dependent infection in neonatal mice that was lethal in 2-day-old BALB/c mice affecting various organs, notably the intestine. We validated our infection model by successfully verifying the efficacy of the RNA-dependent RNA polymerase inhibitor remdesivir (RDV). The model will serve as a valuable tool for studying SADS-CoV pathogenesis and for elucidating the roles of host factors in viral replication as well as for preclinical evaluation of vaccine candidates and antiviral compounds targeting the viral replication machinery. Author SummarySADS-CoV poses a dual threat to the swine industry and public health because of its broad species tropism and potential for cross-species transmission. The emergence of other bat-derived coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV), underscores the need for robust models to study these pathogens. The successful rescue of mSADS-CoV and the development of a mouse infection model represent significant advancements in SADS-CoV research. This model not only enables the evaluation of antiviral therapeutics such as RDV but also provides a powerful platform for investigating viral replication mechanisms and host-pathogen interactions, offering critical insights for pandemic preparedness.

microbiology↗

bioRxiv2025

The XPF-like domain in SHOC1 required for homologous recombination and safeguarding autosome from meiotic silencing of unsynapsed chromatin

During meiosis, a group of evolutionarily conserved ZMM proteins plays essential roles in stabilizing the recombination intermediates and promoting crossover (CO) formation. In mice, SHOC1 forms a trimeric complex with the other two ZMM proteins, SPO16 and TEX11, to bind recombination intermediates after strand invasion. Although genetic variants of SHOC1 are clinically associated with meiotic arrest and male infertility, their precise molecular mechanisms and evolutionarily conserved functions in human gametogenesis remain enigmatic. Here, we delineated species-specific divergences between human and mouse SHOC1 complex, and identified a missense variant within the XPF-like domain in SHOC1 (c.A1769G:p.Q590R) that was associated with meiotic arrest and non-obstructive azoospermia (NOA). The disorder of the XPF-like domain in SHOC1 impaired DNA double-strand breaks repair by compromising its ability to bind branched DNA structures and the recruitment of M1AP, REDIC1, and ZMM factors to recombination intermediates, ultimately abolishing CO formation. Furthermore, the variant disrupted dynamic 3D chromatin structure in pachytene spermatocytes and induced defects in homologous chromosome synapsis. More importantly, the XPF-like domain in SHOC1 was revealed to prevent autosome intrusion into the sex body compartment, thereby safeguarding critical autosomal loci from meiotic silencing of unsynapsed chromatin (MSUC). Overall, our study demonstrated that the XPF-like domain in SHOC1 is required for homologous recombination and safeguarding autosome from MSUC in meiosis.

developmental biology↗

bioRxiv2025

Phylogenomics of Aristolochia subg. Siphisia (Aristolochiaceae) reveals widespread incomplete lineage sorting and supports a novel pollinator-filtering hypothesis

Aristolochia subgenus Siphisia constitutes a monophyletic lineage of predominantly lianescent species, with occasional shrubs or herbs, and is characterized by remarkable diversity in perianth morphology. Members of Siphisia serve as larval hosts for endangered Lepidoptera and are widely used in traditional medicine. Despite its ecological and ethnobotanical significance, Siphisia systematics remains unresolved due to limited genomic resources and insufficient phylogenetic signal across previously sampled loci. Here, we present a phylogenomically informed framework for Siphisia, integrating 46 newly collected accessions and seven public datasets across 44 taxa. Using genome skimming ([~]30x coverage) and HybPiper, we recovered Angiosperms353 nuclear loci, including supercontigs, for phylogenetic reconstruction via concatenation and coalescent approaches. The resulting species trees resolve seven strongly supported monophyletic clades, each defined by distinct biogeographic patterns and morphological synapomorphies. Comparative plastome analyses from de novo assemblies explored quadripartite structure, plastid phylogeny, GC content, and gene synteny. Cytonuclear discordance was concentrated in species-rich Asian clades, while hybridization signals were rare and limited to deep backbone nodes in North American lineages. These results indicate that incomplete lineage sorting, rather than introgression, accounts for most gene-species tree conflicts and likely reflects strong reproductive isolation following speciation. We also revise a previously taxonomically ambiguous complex--the now well-supported A. versicolor species group--based on integrated phylogenomic and morphological evidence. Within this group, we describe five previously unrecognized cryptic species and identify a novel pollination syndrome involving floral adaptations for pollinator filtering. This syndrome may contribute to prezygotic isolation and recent diversification, and it challenges the prevailing assumption that Aristolochia pollination is universally governed by a trapping-release mechanism--suggesting this model may not apply to subg. Siphisia.

evolutionary biology↗

bioRxiv2025

Cognitive and Synaptic Impairment Induced by Deficiency of Autism Risk Gene Smarcc2 and its Rescue by Histone Deacetylase Inhibition

SMARCC2, which encodes BAF170, a core subunit of chromatin remodeling BAF complex, is one of the top-ranking risk genes for autism spectrum disorder (ASD). However, the mechanisms linking SMARCC2 haploinsufficiency to ASD remain poorly understood. Genome-wide RNA-seq analysis revealed that SMARCC2 was significantly diminished in iPSC-derived neurons from idiopathic ASD patients. ChIP-seq of SMARCC2 demonstrated its binding to many other ASD risk genes involved in transcriptional regulation. Smarcc2 deficiency in prefrontal cortex (PFC) of adolescent mice led to impaired working memory, with largely intact social and anxiety-like behaviors. Significant downregulation of genes enriched in synaptic transmission were found in PFC of Smarcc2-deficient mice by RNA-seq and qPCR profiling. In parallel, electrophysiological recordings uncovered the significant impairment of GABAergic and glutamatergic synaptic currents in Smarcc2-deficient PFC pyramidal neurons. Smarcc2 bound to HDAC2, and Smarcc2 deficiency led to the reduced global histone acetylation and H3K9ac enrichment at synaptic gene Slc1a3 (EAAT1), Slc6a1 (GAT1), and Slc32a1 (VGAT) promoters. Treatment of Smarcc2-deficient mice with romidepsin, a class I HDAC inhibitor, restored histone acetylation, working memory and some synaptic gene expression. These findings highlight the critical role of Smarcc2 in regulating cognitive and synaptic function, suggesting that targeting HDAC could alleviate deficits in Smarcc2-associated neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

DeepAden: an explainable machine learning for substrate specificity prediction in nonribosomal peptide synthetases

Microbial non-ribosomal peptides (NRPs) exhibit remarkable structural diversity and serve as valuable sources of lead compounds for clinical drug development. The biosynthesis of NRPs relies on non-ribosomal peptide synthetases (NRPSs), in which adenylation (A) domains play a pivotal role in defining the core structure by selectively recognizing and activating amino acid substrates. Accurately predicting the substrate specificities of A-domains is thus essential for understanding the core structural and biosynthetic logic of NRPs. Here, we present DeepAden, a two-stage deep learning framework. In the first stage, a graph attention network (GAT)-based model localizes 27-residue binding pockets within 6 [A] of bound substrates and convert these into pocket representations. In the second stage, pocket representations are then encoded alongside substrate information using pretrained language models, and aligned using contrastive learning. In addition, we introduce a SHapley Additive exPlanations (SHAP)-guided data augmentation strategy to mitigate class imbalance and improve robustness, particularly for nonproteinogenic substrates. DeepAden achieves competitive performance compared with state-of-the-art tools on a benchmark dataset, and enabled the identification of two Streptomyces NRPS gene clusters through accurate A-domain substrates specificity predictions. DeepAden offers a powerful tool for precise pocket localization and robust substrate prediction, accelerating the discovery and characterization of novel NRP natural products for future work. The DeepAden web server is available at https://deepnp.site/.

bioinformatics↗

bioRxiv2025

Testicular mRNA-LNP Delivery: A Novel Therapy for Genetic Spermatogenic Disorders

Uniform testicular maturation arrest is a severe form of male infertility characterized by the presence of germ cells that do not complete spermatogenic development. It is usually caused by meiotic arrest with genetic variants and difficult to treat via drugs or surgery. mRNA-lipid nanoparticle (LNP) delivery is a promising therapeutic option for maturation arrest with monogenic variants via protein replacement therapy. Herein, a spermatocytes-tropic LNP (Pool1-LNP3) was identified via a library of 30 ionizable lipids screening. And in vivo delivery of this novel LNP composition using rete testis microinjection was showed to be high spermatocytes targeting with high transfection efficiency. Thereafter, it was revealed that in vivo delivery of Pool1-LNP3 encapsulating Msh5 mRNA could promote crossover formation and restore spermatogenesis in Msh5D486Y/D486Y mouse models with DSB recombination defects. Notably, the offspring without genomic integration was born using intracytoplasmic sperm injection (ICSI) derived from rescue of Msh5D486Y/D486Ymouse and embryo transfer. Furthermore, no obvious inflammation and histologic damage in any tissue were detected after in vivo delivery of mRNA-LNP. In addition, it was demonstrated that Maps mRNA-LNP3 recovered spermatogenesis in Maps KO mouse with meiotic arrest. Altogether, these findings suggested that this spermatocytes-tropic mRNA-LNP delivery could become a viable and broad applicable strategy for treatment of spermatogenic disorders with genetic defects, providing a foundation for future clinical application.

molecular biology↗

bioRxiv2025

Microbially-mediated halogenation and dehalogenation cycling of organohalides in the ocean

Microbially mediated organohalide cycling in the ocean has profound implications for global element cycles and climate, but the phylogeny, coding potential, and distribution of the halogenation-dehalogenation cycling microorganisms remain unknown. Here, we construct an organohalide-cycling database (HaloCycDB) to explore the global atlas of halogenation-dehalogenation cycling genes and microorganisms in the ocean from 1,473 marine metagenomes. FlaHase and HyDase/RDase as predominant halogenase- and dehalogenase-encoding genes account for 80.24% of all potential organohalide-cycling activities. We identify 80.91% RDase and 91.35% RDase-containing prokaryotes as unknown organohalide-cycling genes and microorganisms, respectively, which greatly expand the diversity of dehalogenation phylogeny and coding potential. Further integration of microbial cultivation with protein structure prediction and molecular docking elucidates 4 unique "microorganism-enzyme-organohalide" patterns for organohalide dehalogenation in the ocean. Our results provide the first insight into microbial halogenation-dehalogenation cycling of organohalides and associated yet-to-be-explored resources in the ocean.

ecology↗

bioRxiv2025

Exercise Related microRNAs in C. elegans Regulate Calcium Homeostasis and Mitochondrial Dynamics: Conserved pathways, Divergent mircoRNAs

Exercise can help mitigate age-related muscle atrophy, promoting mitochondrial function, Ca2+ homeostasis and regulating gene expression. MicroRNAs (miRs) are crucial post-transcriptional regulators of gene expression, fine tuning protein levels to maintain cellular homeostasis. In C. elegans, a 5-day swimming regimen increased mitochondrial content, lifespan and fitness. Small RNA sequencing identified exercise specific miRs, including increased levels of cel-miR-57-5p and cel-miR-249-3p, and decreased cel-miR-72-3p and cel-miR-77-5p. mir-57 and mir-249 mutant strains had enhanced fertility, survival and lifespan, whereas mir-72 and mir-77 mutant strains had diminished fertility, survival and lifespan. Interestingly both miR-77 and mir-249 mutant strains had disrupted mitochondrial morphology and reduced fitness following exercise. The exercise related miRs identified in C. elegans did not have conserved mammalian orthologs. Exercise regulated mammalian miRs were identified from the literature including mmu-miR-181a-5p, mmu-miR-199a-5p and mmu-miR-378a-3p. Treatment of murine myoblasts with mmu-miR-181a-5p and mmu-miR-378a-3p enhanced mitochondrial content, autophagy markers and myogenesis, while mmu-miR-199a-5p impaired these processes. Exercise related miRs identified in C. elegans target genes regulating Ca2+ homeostasis such as ipp-5 (inositol Polyphosphate-5-phosphatase), sca-1 (Ca2+ transporting ATPase) and ncx-2 (mitochondrial Na+/Ca2+ antiporter). It was also confirmed that mmu-miR181a-5p (miR181) targets Inpp5a and antogmiR-181 (AM181) treatment decreased Ca2+ handling in myotubes. Similarly, mmu-miR-378a-3p and cel-miR-249-3p target Kinase Suppressor of Ras (Ksr1)/ksr-2, involved in the MAPK pathway. Despite direct conservation of exercise related miRs from nematodes to mammals there are common regulatory pathways, contributing to exercise-induced adaptations. Graphical abstractThe exercise related microRNAs (cel-miR-77-5p and cel-miR-249-3p) identified in C. elegans following a 5-day swimming protocol are not conserved in mammalians. However, the microRNAs identified share common gene targets regulating Ca2+ homeostasis and mitochondrial function, with previously identified exercise related microRNAs in murine models. The results highlight conserved regulatory adaptive mechanisms in response to exercise. O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/653755v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1da431forg.highwire.dtl.DTLVardef@6cdb70org.highwire.dtl.DTLVardef@ba9d76org.highwire.dtl.DTLVardef@1b7b481_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Actin Depolymerization Factors (ADFs) Moonlighting: Nuclear Immune Regulation by Interacting with WRKY Transcription Factors and Shaping the Transcriptome

Remodeling of the actin cytoskeleton is a critical process for plant immunity, essential for the transport, activation, and stabilization of immune-regulatory molecules and organelles. In this process, actin depolymerization factors (ADFs) function as key players through severing and depolymerizing actin microfilaments. However, recent evidence suggests that ADFs may possess non-canonical immune functions inside the nucleus, in addition to the canonic cytosolic role, a phenomenon not adequately explained by the traditional mechanistic model of ADF-actin dynamics. In this study, we demonstrate that Arabidopsis ADFs exhibit a moonlighting function in the nucleus, where they interact with transcriptional machinery to regulate the transcriptome during both the resting state and the immune responses. We show that ADF2/3/4 have redundant functions in defense against virulent and avirulent Pseudomonas syringae. Notably, it is nuclear - rather than cytosolic - ADFs that contribute to defense against P. syringae and mediate pro-immune transcription. Mechanistically, we demonstrate that nuclear ADFs interact with transcription factors, histone complexes, and other components of the transcriptional machinery. Specifically, ADF2/3/4 can form a complex with WRKY transcription factors, such as WRKY22/29/48, thereby directly regulating WRKY activity to shape the pro-immune transcriptome. In summary, our study reveals that ADFs moonlight as direct regulators of transcription factors, mediating a broad range of nuclear-cytoplasmic regulation in plant immunity and potentially other biological processes.

plant biology↗

bioRxiv2025

Improving Thermal and Gastric Stability of Phytase via pH Shifting and Coacervation: A Demonstration of Bayesian Optimization for Rapid Process Tuning

Phytase (phyA) breaks down phytate, which can help with nutrient absorption in a plant-based seed diet or high-phytate food. Unfortunately, it is prone to denaturation at food preparation temperatures and is easily inactivated by pepsin during gastric digestion. To protect phyA for use in high-temperature processes (100 {degrees}C) and gastric digestion, chitosan (CS) was used to complex phyA. Bayesian optimization, a machine learning technique, was used to demonstrate how to expedite the optimization process. Thermal stability of the optimized complex increased from 20% (Control: phyA in the native state) up to 74% at 4:1 CS to phyA (CS-phyA) complex and 52% at the 1:1 CS-phyA complex as measured by phytase activity assay. Chitosan complexation also improved the retention of enzyme activity after thermal and gastric digestion by 13-fold, retaining residual activity at 40% for the 4:1 CS to phyA and 22% for the 1:1 CS-phyA complexes compared to the enzyme itself, which only retained 3% residual activity. Molecular docking and circular dichroism were used to investigate the underlying interaction mechanism between CS and phyA and the secondary structure of the enzyme after heat treatment. Confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) confirmed the complexation of phyA with CS and revealed complex morphology. With improved enzyme stability, there is great potential for efficiently expanding phytase applications in a high plant-based seed food matrix. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/649602v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@889b76org.highwire.dtl.DTLVardef@969ed3org.highwire.dtl.DTLVardef@953e55org.highwire.dtl.DTLVardef@2f5864_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThermal stability of phytase improved from 20% to 74% using chitosan C_LIO_LIpH shifting increased enzyme complexation efficiency and thermal stability (100 {degrees}C) C_LIO_LIBayesian optimization (BO) is a promising optimization tool for complexation conditions C_LI

biochemistry↗

bioRxiv2025

DICAR-JP Regulates Ribosome Migration, a New Theory of Mitochondrial Protein Production

BackgroundDICAR plays a cardioprotection of diabetic models. DICAR-JP, a short sequence of DICAR, may represent DICARs active functional domain. NAC is necessary for the heart tissue development. Addtionally, OGDHL is a metabolism regulator. In this study, we examine a new mechanism of DICAR via NAC/OGDHL on regulating cardiomyocyte metabolism in DCM. We also sought to elucidate the function of DICAR/DICAR-JP in modulating NAC-dependent production of OGDHL nascent peptides and their mitochondrial translocation, and we also aimed to optimize the DICAR-JP sequence to be better therapy on DCM. MethodsSPR was to investigate the binding interaction between DICAR-JP and NAC. The function of DICAR-JP and DICAR-JP45 on OGDHL nascent peptide transfection was detected by in vitro translation approach. Biotin-DICAR-JP was transfected to study the function of DICAR-JP, NAC and OGDHL. Untargeted metabolomics was utilized to characterize the metabolic reprogramming of cardiomyocytes. AAV9-DICAR-JP and DICAR-JP45 were constructed and administered to db/db mice for 1-2 months to assess their cardioprotective effects detected by Echocardiography confirmed mouse cardiac function. ResultsOur findings demonstrated that DICAR-JP be the functional domain that interacts with NAC to regulate OGDHL nascent peptide expression. Disruption of OGDHL expression reversed the metabolic reprogramming observed in diabetic cardiomyocytes, highlighting its crucial role in maintaining cardiac metabolic homeostasis. DICAR-JP facilitated the translocation of OGDHL nascent peptides from the cytoplasm to the mitochondria, leading us to hypothesize that DICAR-JP plays a key role in regulating ribosomal migration from the endoplasmic reticulum to the mitochondria. We refer to this process as the Ribosome Migration. In our studies using AAV9-mediated DICAR-JP and DICAR-JP45 overexpression in heart tissue. DICAR-JP and DICAR-JP45 both exhibited significant cardioprotective effects against diabetic cardiomyopathy (DCM), comparable to those observed with Empagliflozin. ConclusionsIn a conclusion, we propose a new endogenous nucleic acid candidate drug library, and a new molecular framework, the Ribosome Migration, which implicates the DICAR-JP/NAC/OGDHL nascent peptide axis in metabolic reprogramming related to DCM. This theory constructs a new mitochondrion protein from nuclear original protein. Moreover, DICAR-JP45 shows strong potential as a nucleic acid-based therapeutic candidate for treating DCM. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSDICAR is a new protective circular noncoding RNA for diabetic cardiomyopathy. NAC is located in ribosome and regulates new peptide production, which is also a key factor in heart tissue development. OGDHL can regulate different energy metabolism in mitochondria. What New Information Does This Article Contribute?DICAR-JP is the functional domain that interacts with NAC to regulate OGDHL nascent peptide expression. There is an interaction between DICAR-JP and NAC. DICAR-JP sequence is protected by NAC and NAC function is mediated by DICAR-JP. We called this RNA functional domain. OGDHL expression reversed the metabolic reprogramming observed in diabetic cardiomyocytes, highlighting its crucial role in maintaining cardiac metabolic homeostasis. DICAR-JP takes part in tanscription and translocation of OGDHL nascent peptides from the cytoplasm to the mitochondria via plasma ribosome. We call this process the Ribosome Migration Theory. DICAR-JP and DICAR-JP45 both exhibited significant cardioprotective effects against diabetic cardiomyopathy (DCM), comparable to those observed with Dapagliflozin (DAPA). Our study revealed a novel molecular framework, the Ribosome Migration Theory, which implicates the DICAR-JP/NAC/OGDHL nascent peptide axis in metabolic reprogramming related to DCM. Moreover, DICAR-JP45 shows strong potential as a nucleic acid-based therapeutic candidate for treating DCM.

pharmacology and toxicology↗

bioRxiv2025

Novel Strategy against AML by Rescuing Loss of Phase Separation of Pathogenic NPM1c

Nucleophosmin (NPM1) is a nucleolar protein that participates in many biological processes through phase separation. In acute myeloid leukemia (AML), nearly one-third of cases harbor NPM1c mutations. Previous studies mainly focused on the contribution of the additional NES in NPM1c mislocalization and AML development; however, the mechanisms underlying the relationship between aberrant localization and phase separation of NPM1c remain poorly understood. In this study, we demonstrate that loss of phase separation (LoPS) with RNA is associated with NPM1c mislocalization, which uncovers a new strategy for therapeutic targeting of NPM1c. Leveraging high-throughput screening, we identify a potent small molecule capable of rescuing NPM1c LoPS in vitro and effectively restoring the nucleolar localization of NPM1c within cells. Remarkably, this compound demonstrates anti-leukemia activity in both AML cell lines and patient-derived blasts. Overall, these findings indicate a promising avenue for developing new AML therapies against NPM1c by reinstating its phase separation capabilities. One-Sentence SummaryRescuing the lost phase separation capacity of NPM1c unveils a promising AML therapy.

cancer biology↗

bioRxiv2025

Tff2 marks gastric corpus progenitors that give rise to pyloric metaplasia/SPEM following injury

In BriefTu et al. show that Tff2+ corpus isthmus cells are TA progenitors, and they, not chief cells, are the primary source of SPEM following injury. Upon Kras mutation, these progenitors directly progress to dysplasia, bypassing metaplasia, highlighting them as a potential origin of gastric cancer. HighlightsO_LITff2+ corpus cells are TA progenitors that give rise to secretory cells. C_LIO_LITff2+ progenitors, not chief cells, are the primary source of SPEM after injury. C_LIO_LIKras-mutant Tff2+ progenitors progress directly to dysplasia, bypassing metaplasia. C_LIO_LIMulti-omics analysis reveals distinct trajectories for SPEM and gastric cancer. C_LI O_FIG O_LINKSMALLFIG WIDTH=191 HEIGHT=200 SRC="FIGDIR/small/647847v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@48a2d1org.highwire.dtl.DTLVardef@b96642org.highwire.dtl.DTLVardef@1e89a4dorg.highwire.dtl.DTLVardef@1ea6a86_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG Pyloric metaplasia, also known as spasmolytic polypeptide-expressing metaplasia (SPEM), arises in the corpus in response to oxyntic atrophy, but its origin and role in gastric cancer remain poorly understood. Using Tff2-CreERT knockin mice, we identified highly proliferative Tff2+ progenitors in the corpus isthmus that give rise to multiple secretory lineages, including chief cells. While lacking long-term self-renewal ability, Tff2+ corpus progenitors rapidly expand to form short-term SPEM following acute injury or loss of chief cells. Genetic ablation of Tff2+ progenitors abrogated SPEM formation, while genetic ablation of GIF+ chief cells enhanced SPEM formation from Tff2+ progenitors. In response to H. pylori infection, Tff2+ progenitors progressed first to metaplasia and then later to dysplasia. Interestingly, induction of KrasG12D mutations in Tff2+ progenitors facilitated direct progression to dysplasia in part through the acquisition of stem cell-like properties. In contrast, Kras-mutated SPEM and chief cells were not able to progress to dysplasia. Tff2 mRNA was downregulated in isthmus cells during progression to dysplasia. Single-cell RNA sequencing and spatial transcriptomics of human tissues revealed distinct differentiation trajectories for SPEM and gastric cancer. These findings challenge the conventional interpretation of the stepwise progression through metaplasia and instead identify Tff2+ progenitor cells as potential cells of origin for SPEM and possibly for gastric cancer.

cell biology↗

bioRxiv2025

A reference genome assembly of the alpine forage grass Elymus nutans

Elymus nutans Griseb. (Poaceae: Triticeae, 2n=6x=42) is a dominant perennial plant species in the Qinghai-Tibetan Plateau in China, which is an important forage resource in high-altitude and cold regions and is the most popular species used for high yield artificial grassland planting because of its rich nutritional value and good palatability for herbivorous ruminant animals. In this study, using advanced sequencing technology, we generated an allohexaploid reference genome for E. nutans, representing the three sets of chromosomes (subgenomes St, Y, and H). This is the first study to our knowledge to confirm the origin of the Y subgenome, which shares a close relationship with the V subgenome. We predict that E. nutans arose via two-step hybridization and that its speciation occurred [~]3.16 MYA. The whole genome in this study will update the Triticeae family genomics information and provide theoretical basis for the evolutionary of its related speicies.

plant biology↗