Biology subjects

Mi, J.

Publications and source records attributed to Mi, J..

14 recordsLinked to original sources

bioRxiv2026

SpatialOmicsLab: an integrated research environment for AI co-scientists in spatial transcriptomics

Spatial profiling is moving from method development into a central platform for biological discovery and clinical translation, but analyzing such complex data has become the bottleneck of scientific discovery. Translating spatial transcriptomic measurements into biological insight requires reproducible workflows that integrate diverse analytical methods. Although language-model agents can plan and execute multistep analyses, fragmented data and software ecosystems hinder their use as reliable research assistants. In this study, we introduce SpatialOmicsLab, an integrated research environment for spatial transcriptomics comprising 113 curated computational tools, 63 reference datasets and 4,614 task specifications. We also introduce ST-Coscientist, an AI co-scientist that uses this environment to assemble, execute and refine spatial transcriptomic analyses. Within SpatialOmicsLab, ST-Coscientist outperformed expert-led workflows and other scientific agents across six benchmark settings spanning spatial clustering, cell-type deconvolution and spatially variable gene detection. It constructed alignment-aware workflows for three-dimensional MERFISH data and addressed biological questions by selecting and analysing relevant reference datasets. Procedural memory increased the success rate of integrating and validating additional analytical tools from 48% to 95%. Together, SpatialOmicsLab and ST-Coscientist establish an extensible ecosystem for reproducible spatial transcriptomic research, enabling AI co-scientists to address evolving biological questions with an expanding analytical repertoire.

bioinformatics↗

bioRxiv2025

Cholangiocytes contribute to hepatocyte regeneration after partial liver injury during growth spurt in zebrafish

The livers regenerative ability depends on injury extent. Minor injuries are repaired by hepatocyte self-duplication, while severe damage triggers cholangiocyte involvement in hepatocyte recovery. This paradigm is well-documented for adult animals but is less explored during rapid growth. We design two new partial liver injury models in zebrafish, which were investigated during growth spurts: 1) partial ablation, killing half the hepatocytes; and 2) partial hepatectomy, removing half a liver lobe. In both injuries, de novo hepatocytes emerged alongside existing ones. Single-cell transcriptomics and lineage tracing with Cre-driver lines generated by genome editing identified cholangiocytes as the source of de novo hepatocytes. We further identify active mTORC1 signalling in the uninjured liver of growing animal to be a regulator of the enhanced plasticity of cholangiocytes. Our study suggests cholangiocyte-to-hepatocyte transdifferentiation as the primary mechanism of liver regeneration during periods of rapid growth.

developmental biology↗

bioRxiv2025

Deciphering the zebrafish hepatic duct heterogeneity and cell plasticity using lineage tracing and single-cell transcriptomics

Despite the livers recognized regenerative potential, the role of the hepatic ductal cells (a.k.a. biliary epithelial cells), its heterogeneity, and functionality remain incompletely understood in this process. This study provides a comprehensive examination of the molecular and cellular mechanisms underpinning liver ductal development and liver regeneration in zebrafish, with a spotlight on the functional roles of her family genes in these processes. Using state-of-the-art knock-in zebrafish models and single-cell transcriptomics we reveal the differential expression patterns of the different her genes, of which her2, her6, and her9, were identified as specific molecular signatures for distinguishing different ductal cell types with unique morphology and spatial distribution. Particularly, her9 serves as a pan-ductal marker and shows responsiveness to the synergistic effect of Notch and BMP signaling. By analyzing multiple single-cell RNA-seq datasets, we identify numerous ductal markers which are functional proteins for ductal integrity, and most notably CRISPR mutagenesis demonstrates that her9 is essential for hepatocyte recovery. Using multiple transgenic and knock-in zebrafish lines and genetic fate mapping, we provide a detailed characterization of the ductal remodeling process under development and extreme loss of intra-hepatic duct, highlighting the remarkable ductal cell plasticity. Single-cell transcriptomics of lineage-traced her9-expressing liver ducts in static and regenerative states uncover distinct cell clusters with unique molecular signatures and morphology, reflecting the livers regenerative dynamics and highlight relevant key biological processes that could be leveraged to expedite liver regeneration.

developmental biology↗

bioRxiv2024

DWARF14 and KARRIKIN INSENSITIVE2 mediate signaling of the apocarotenoid zaxinone in Arabidopsis

The natural growth regulator zaxinone increases the levels of the phytohormones strigolactone (SL) and abscisic acid in Arabidopsis (Arabidopsis thaliana) via unknown mechanisms. We demonstrate that parts of the effects of zaxinone in Arabidopsis depend on the SL receptor DWARF14 (AtD14), the karrikin receptor KARRIKIN INSENSITIVE2 (AtKAI2), and the F-Box protein MORE AXILLARY BRANCHING2 (AtMAX2) that mediates the signaling of SLs and karrikins. Binding assays and co-crystallization revealed zaxinone as an additional ligand of AtD14 and an SL antagonist that interrupts the interaction of AtD14 with AtMAX2. Zaxinone also bound to AtKAI2. These findings unveil a perception mechanism for zaxinone in Arabidopsis and demonstrate the capability of AtD14 and AtKAI2 to bind signaling molecules, other than strigolactones or karrikins, and mediate their transduction.

plant biology↗

bioRxiv2024

Self-adjusting Engineered Probiotic for Targeted Tumor Colonization and Local Therapeutics Delivery

Engineered bacteria have demonstrated great potential for treating a broad array of tumors. However, the precision and safety of controlling the performance of engineered bacteria in vivo remains a central challenge. Here, we utilized genetic circuit programming strategy to construct an engineered Escherichia coli Nissle 1917 with accurate targeted colonizing and on-demand payloads releasing ability. The engineered probiotic survives only in the presence of more than 5 mM L-lactate by employing an improved lactate-sensing system, which leads to preventing the growth outside the permissive environments in mice. Meanwhile we introduce an expressing -hemolysin (SAH) circuit based on quorum-sensing system to augment anti-tumor effect. Furthermore, coagulase induced by high-level lactate creates the closure to deprive tumor of nutrients and oxygen and prevents leakage of bacteria and SAH, which enhances the therapeutic effectiveness and biosafety. This self-adjusting living biotherapeutics significantly inhibits tumor proliferation and prolongs the survival time of colorectal tumor-bearing mice. Together, our work takes a step towards safer and more effective application of living bacteria for tumor treatment in practice.

synthetic biology↗

bioRxiv2023

Systems genetics identifies the association between Enc1 and cognitive function in the hippocampus

Ectodermal-Neural Cortex 1 (ENC1) is expressed in multiple regions of the brain, including the hippocampus. However, knowledge about its function has been well explored only in the context of peroxidative stress and cancer. In this study, we investigated the association of hippocampal Enc1 with cognitive function in BXD mice. We performed Pearson correlation, phenotype-wide association analysis (PheWAS), expression-Based PheWAS, pathway enrichment, and protein interaction networks on Enc1 and BXD phenotypes/transcriptome of the hippocampus, and the results indicated that Enc1 is inextricably linked to cognitive performance. In addition, we found that most of the Enc1 co-expressed genes were highly expressed in GABAergic neuronal cells. Expression quantitative trait loci analysis indicated that Enc1 was cis-regulated in the hippocampus of mice as well as human. Genome-wide association analysis revealed ENC1 to be significantly associated with cognitive-related traits, including age-related cognitive changes etc. In conclusion, our findings demonstrated that Enc1 is involved in cognitive functions mainly in hippocampal GABAergic neuronal cells through neurogenesis, synaptic signaling, and CGMP-PKG signaling pathways, and interacts with the neurological function-related genes.

genetics↗

bioRxiv2023

β-ionone regulates Arabidopsis thaliana transcriptome and increases its resistance against Botrytis cinerea

Carotenoids are isoprenoid pigments vital for photosynthesis. Moreover, they are the precursor of apocarotenoids that include the phytohormones abscisic acid (ABA) and strigolactones (SLs), and retrograde signaling molecules and growth regulators, such as {beta}-cyclocitral and zaxinone. The apocarotenoid {beta}-ionone ({beta}-I) was previously reported to exert antimicrobial effects. Here, we showed that the application of this scent to Arabidopsis plants at micromolar concentrations caused a global reprogramming of gene expression, affecting thousands of transcripts involved in stress tolerance, growth, hormone metabolism, pathogen defense and photosynthesis. These changes, along with modulating the levels of the phytohormones ABA, jasmonic acid and salicylic acid, led to enhanced Arabidopsis resistance to Botrytis cinerea (B.c.), one of the most aggressive and widespread pathogenic fungi affecting numerous plant hosts and causing severe losses of postharvest fruits. Pre-treatment of tobacco and tomato plants with {beta}-I followed by inoculation with B.c. confirms the conserved effect of {beta}-I and induced immune responses in leaves and fruits. Moreover, there was reduced susceptibility to B.c. in LYCOPENE {beta}-CYCLASE- expressing tomato fruits possessing elevated levels of the endogenous {beta}-I, indicating beneficial biological activities of this compound in planta. Our work unraveled {beta}-I as a further carotenoid-derived regulatory metabolite and opens up new possibilities to control B.c. infection by establishing this natural volatile as an environmentally friendly bio-fungicide.

plant biology↗

bioRxiv2023

Massive expansion of the pig gut virome based on global metagenomic mining

The pig gut virome plays a crucial role in the gut microbial ecosystem of pigs, yet a comprehensive reference database is still lacking. To address this gap, we established the Pig Virome Database (PVD) of the gut that comprises 5,566,804 viral contig sequences from 4,650 publicly available gut metagenomic samples using a pipeline named "metav" developed in this study. The majority of viral operational taxonomic units (vOTUs) were identified as Caudoviricetes (65.36%). By clustering sequences, we identified 48,299 vOTU genomes, of which 92.83% were not found in existing major databases. The PVD database contains a total of 18,161,503 protein-coding genes that can be used to explore the functional potential of the pig gut virome. Our study showed that the PVD can improve the detection of viruses that carry antibiotic/metal resistance genes, mobile genetic elements, virulence factor genes, and quorum sensing systems. These findings highlight the extensive diversity of viruses in the pig gut and provide detailed insight into host-virus interactions.

microbiology↗

bioRxiv2022

Efficient knock-in method enabling lineage tracing in zebrafish

The CRISPR-Cas9 system aids generation of knock-in zebrafish lines, but it has been hard to integrate large constructs and avoid disrupting the targeted genes. Here we devised a 3 knock-in strategy of PCR-amplified dsDNA, which coded for fluorescence proteins and Cre recombinase in frame with the endogenous gene but separated from each other by self-cleavable peptides. Primers with 5 AmC6 end-protections generated improved PCR amplicons harboring either short or long homologous arms, which were co-injected with pre-assembled Cas9/gRNA ribonucleoprotein complexes for early integration. We targeted four genetic loci (krt92, nkx6.1, krt4, and id2a) and generated ten knock-in lines, which function as reporters for the endogenous gene expression. The knocked-in iCre or CreERT2 were used for lineage tracing, which suggested nkx6.1+ cells are multipotent pancreatic progenitors that gradually restrict to bipotent duct; while id2a+ cells are multipotent in both liver and pancreas and gradually restrict to ductal cells. Additionally, hepatic id2a+ duct show progenitor properties upon extreme hepatocyte loss. Thus, we present an efficient knock-in technique with widespread use for both cellular labelling and lineage tracing.

genetics↗

bioRxiv2022

Nitrogen competition is the general mechanism underlying cnidarian-Symbiodiniaceae symbioses

Symbiotic associations with Symbiodiniaceae have evolved independently across a diverse range of cnidarian taxa including reef-building corals, anemones and jellyfish, yet the molecular mechanisms underlying their regulation and repeated evolution are still elusive. Here we show that despite their independent evolution, cnidarian hosts employ the same mechanism of symbiont control in which symbiont-derived glucose is used to assimilate nitrogenous waste via amino acid biosynthesis to limit the availability of nitrogen to the symbionts. In this metabolic interaction, glucose significantly reduces symbiont density while ammonium promotes symbiont proliferation. We show that glucose-derived 13C and ammonium-derived 15N are co-incorporated into amino acids by the hosts. Metabolic differences between the hosts further suggest that corals are more susceptible to environmental stress and symbiosis breakdown due to their increased energy demands to satisfy calcification. Our results reveal the general metabolic interaction underlying these symbioses and provide a parsimonious explanation for their repeated evolution.

ecology↗

bioRxiv2022

The Arabidopsis D27like1 is a novel Isomerase that Contributes to SL Biosynthesis and Negatively Impacts ABA Level

The enzyme DWARF27 (D27) catalyzes the reversible isomerization of all-trans- into 9-cis-{beta}-carotene, initiating strigolactone (SL) biosynthesis. Genomes of higher plants encode two D27-homologs, D27-like1 and -like2, with unknown functions. Here, we investigated the enzymatic activity and biological function of the Arabidopsis D27-like1. In vitro enzymatic assays and Expression in Synechocystis sp. PCC6803 revealed a yet not reported 13-cis/15-cis/9-cis- and a 9-cis/all-trans-{beta}-carotene isomerization. Although disruption of AtD27-like1 did not cause SL deficiency phenotypes, overexpression of AtD27-like1 in the Atd27 mutant restored the more-branching phenotype, indicating a contribution of AtD27-like1 to SL biosynthesis. Accordingly, generated Atd27 Atd27like1 double mutants showed more pronounced branching phenotype, compared to Atd27. The contribution of AtD27-like1 to SL biosynthesis is likely due to its formation of 9-cis-{beta}-carotene that was present at higher levels in AtD27-like1 overexpressing lines. In contrast, AtD27-like1 expression correlated negatively with the content of 9-cis-violaxanthin, a precursor of abscisic acid (ABA), in shoots. Consistently, ABA levels were higher in shoots and also in dry seeds of the Atd27like1 and Atd27 Atd27like1 mutants. Transgenic lines expressing {beta}-glucuronidase (GUS) driven by the AtD27LIKE1 promoter and transcript analysis performed with hormone-treated Arabidopsis seedlings unraveled that AtD27LIKE1 is expressed in different tissues and regulated ABA and auxin. Taken together, our work revealed a cis/cis-{beta}-carotene isomerase activity that affects the content of both cis-carotenoid derived plant hormones ABA and SLs.

plant biology↗

bioRxiv2021

Manipulation of carotenoid metabolism stimulates biomass and stress tolerance in tomato

Improving yield, nutritional value and tolerance to abiotic stress are major targets of current breeding and biotechnological approaches that aim at increasing crop production and ensuring food security. Metabolic engineering of carotenoids, the precursor of Vitamin-A and plant hormones that regulate plant growth and response to adverse growth conditions, has been mainly focusing on provitamin A biofortification or the production of high-value carotenoids. Here, we show that the introduction of a single gene of the carotenoid biosynthetic pathway in different tomato cultivars simultaneously improved photosynthetic capacity and tolerance to various abiotic stresses (e.g., high light, salt, and drought), caused an up to 77% fruit yield increase and enhanced fruits provitamin A content and shelf life. Our findings pave the way for developing a new generation of crops that combine high productivity and increased nutritional value with the capability to cope with climate change-related environmental challenges.

plant biology↗

bioRxiv2021

The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease

Multiple myeloma (MM) is a fatal hematological malignancy, where the majority of patients are diagnosed with, or develop, destructive and debilitating osteolytic bone lesions. Current treatments for MM bone disease such as the bisphosphonate zoledronic acid can result in deleterious side effects at high doses. In this study, eliglustat, an FDA approved glycosphingolipid inhibitor, was shown to reduce MM bone disease in preclinical models of MM. Mechanistically, eliglustat alters the lipid composition and plasma membrane fluidity and acts as an autophagy flux inhibitor in bone-resorbing osteoclasts (OC). Autophagic degradation of the signaling molecule TRAF3 is key step in OC differentiation; this was prevented by eliglustat in OC precursors. In addition, eliglustat works depend on TRAF3 in vivo. Furthermore, the combination of eliglustat and zoledronic acid was found to have an additive effect to reduce MM bone disease, suggesting the potential for combination therapies that would allow for drug dose reductions. Taken together, this project identifies a novel mechanism in which glycosphingolipid inhibition reduces osteoclastogenesis via autophagy and highlights the translational potential of eliglustat for the treatment of bone loss disorders such as MM. One Sentence SummaryTranslational use of eliglustat as an autophagy inhibitor to limit bone lesions in multiple myeloma.

cell biology↗

bioRxiv2018

Anchorene is an endogenous diapocarotenoid required for anchor root formation in Arabidopsis

Arabidopsis root development is predicted to be regulated by yet unidentified carotenoid-derived metabolite(s). In this work, we screened known and putative carotenoid cleavage products and identified anchorene, a predicted carotenoid-derived dialdehyde (diapocarotenoid) that triggers anchor root development. Anchor roots are the least characterized type of root in Arabidopsis. They form at the root-shoot junction, particularly upon damage to the root apical meristem. Using Arabidopsis reporter lines, mutants and chemical inhibitors, we show that anchor roots originate from pericycle cells and that the development of this root type is auxin-dependent and requires carotenoid biosynthesis. Transcriptome analysis and treatment of auxin-reporter lines indicate that anchorene triggers anchor root development by modulating auxin homeostasis. Exogenous application of anchorene restored anchor root development in carotenoid-deficient plants, indicating that this compound is the carotenoid-derived signal required for anchor root development. Chemical modifications of anchorene led to a loss of anchor root promoting activity, suggesting that this compound is highly specific. Furthermore, we demonstrate by LC-MS analysis that anchorene is a natural, endogenous Arabidopsis metabolite. Taken together, our work reveals a new member of the family of carotenoid-derived regulatory metabolites and hormones.\n\nSignificanceUnknown carotenoid-derived compounds are predicted to regulate different aspects of plant development. Here, we characterize the development of anchor roots, the least characterized root type in Arabidopsis, and show that this process depends on auxin and requires a carotenoid-derived metabolite. We identified a presumed carotenoid-derivative, anchorene, as the likely, specific signal involved in anchor root formation. We further show that anchorene is a natural metabolite that occurs in Arabidopsis. Based on the analysis of auxin reporter lines and transcriptome data, we provide evidence that anchorene triggers the growth of anchor roots by modulating auxin homeostasis. Taken together, our work identifies a novel carotenoid-derived growth regulator with a specific developmental function.

plant biology↗