Biology subjects

Jing, Z.

Publications and source records attributed to Jing, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Targeting cancer-associated cell surface RNAs with oligonucleotide-drug conjugates enables broad antitumor activity

Recent studies have revealed the presence of RNAs on mammalian cell surfaces, yet the linkage of cell surface RNAs (csRNAs) to cellular states and their potential as extracellular accessible drug targets remains unexplored. Here we develop Cell-surface and Intracellular RNAs Co-mapping (CIRCmap), a highly multiplexed in situ profiling approach that simultaneously detects thousands of cell-surface and intracellular RNAs at single-cell resolution. Using CIRCmap, we uncover that csRNA distributions are correlated with cellular states and identified cancer-associated csRNAs. Integrative analysis of cell-surface and intracellular RNAs within the same cells implies that the csRNAs undergo endocytosis and endolysosomal trafficking, which is further supported by perturbation experiments and co-localization visualization. We design oligonucleotide-drug conjugates (ODCs) that target cancer-associated csRNAs for endocytic delivery of cytotoxic payloads selectively to cancer cells. ODCs exhibit broad antitumor activity in cell lines and an in vivo mouse tumor model, opening a promising new avenue for targeted cancer therapy.

cell biology↗

bioRxiv2025

Dual functions of apigenin in suppressing Phytophthora capsici and shaping the pepper microbiome

BackgroundPlant resistance to soil-borne pathogens is shaped by the interactions among host genetics, root exudates, and rhizosphere microbiomes. Flavonoids are widely recognized for their antimicrobial and signaling functions, yet their role in mediating metabolite-microbiome-pathogen interactions in pepper (Capsicum frutescens) remains poorly understood. ResultsThrough integrated microbiome, transcriptome, and metabolome analyses, we compared resistant (CA53) and susceptible (CA476) pepper cultivars under challenge by Phytophthora capsici. Resistant plants maintained relatively stable transcriptional and metabolic profiles, whereas susceptible plants exhibited a pronounced suppression of the flavonoid biosynthesis pathway, with a marked decline in apigenin levels. Exogenous application of apigenin significantly enhanced pepper resistance by disrupting sporangial cell membrane integrity and thereby inhibiting zoospore release. In addition, apigenin functioned as a central hub metabolite, selectively enriching disease-suppressive rhizosphere microbes and reinforcing host protection. ConclusionOur findings uncover a dual role of apigenin in pepper resistance: directly inhibiting pathogen propagation and indirectly reinforcing the recruitment of protective microbiota. These insights highlight the ecological functions of root-derived metabolites in shaping plan-microbiome interactions and provide potential avenues for metabolite-informed strategies in sustainable crop protection.

microbiology↗

bioRxiv2025

ETS1 Orchestrates a Hybrid EMT Program Driving in vivo Metastasis and Immune Evasion

Transcriptional Intratumoral heterogeneity (ITH) is a hallmark of aggressive cancers, yet how transcriptional ITH programs drive tumor metastasis and immune evasion in upper aerodigestive squamous cell carcinoma (UASCC) remains unclear. Through single-cell RNA sequencing analysis of UASCC cells and patient tumors, we uncovered a hybrid epithelial mesenchymal transition (hEMT) ITH program linked to metastatic dissemination. The transcription factor ETS1 was identified as a master regulator of the hEMT program, directly activating pro-metastatic genes and promoting distant spread in vivo. Unexpectedly, ETS1 also orchestrated an immune-cold tumor microenvironment by transcriptionally activating both STAT1 and PD-L1 (CD274) genes, suppressing T lymphocyte infiltration, and elevating immune checkpoint molecules. Clinically, ETS1-high tumors strongly correlated with poor survival and resistance to immune checkpoint blockade across multiple cohorts. Leveraging drug screens, we discovered that ETS1-high cancers are vulnerable to HSP90 inhibitors (e.g., Alvespimycin), which suppress ETS1 by disrupting HIF1A-mediated transcriptional activation. Together, our work reveals ETS1 as a dual driver of tumor distal metastasis and immune evasion in UASCC, while nominating HSP90 inhibition as a tailored treatment strategy for ETS1-driven tumors. These findings provide a roadmap for targeting aggressive ITH subsets and overcoming immunotherapy resistance.

cancer biology↗

bioRxiv2025

ROMO1 loss in cholinergic neurons induces mitochondrial ultrastructural damage and ALS-like neuromuscular degeneration

Mitochondrial dysfunction is strongly associated with the pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motor neuron degeneration. However, it remains obscure whether mitochondrial abnormities are sufficient to drive ALS development. Here, we show that selective depletion of reactive oxygen species modulator 1 (ROMO1), an inner mitochondrial membrane-delimited protein, in cholinergic neurons leads to adult-onset, progressive locomotor deficits in mice that closely resemble ALS pathology. ROMO1 ablation in cholinergic neurons induces ALS-like neuromuscular degeneration, as evidenced by age-dependent motor neuron loss, axon degeneration, disrupted cholinergic transmission, neuromuscular junction denervation, and the resultant muscle atrophy. Notably, ROMO1 loss induces early and progressive mitochondrial cristae deformation in motor neurons, preceding the onset of ALS-like syndromes. Our findings support that mitochondrial impairment in vulnerable motor neurons is a sufficient contributor to ALS etiology, positioning mitochondria as a potential therapeutic target.

neuroscience↗

bioRxiv2024

Three-dimension transcriptomics maps of whole mouse embryo during organogenesis

Understanding mammalian development heavily relies on classical animal models like the house mouse (Mus musculus). Advanced spatial transcriptomics has enabled biologists to break new ground in studies of molecular dynamics and cellular patterning during embryonic development with spatiotemporal resolution. To construct a comprehensive developmental trajectory, current three-dimensional (3D) spatial transcriptomic profiling leverages mouse embryos from gastrulation (E5.5) to organogenesis (E13.5) in continuity. However, a crucial phase for early organogenesis between E9.5 and E11.5 was deficient. To unveil the mystery of this stage, we present the 3D transcriptomics of mouse embryos at E9.5 and E11.5, with a widely applicable reconstruction workflow that bypasses sophisticated bioinformatic calculations. As our 3D atlas is generated at single-cell resolution, we demonstrate how organogenetic processes can be interpreted at different levels of granularity, from local cellular interactions to whole embryonic regionalization. We release the open-access database MOSTA3D (Mouse Organogenesis Spatiotemporal Transcriptomic Atlas in Three-dimensional) and hope a broader community will contribute to extending this framework from conception to senility in the near future.

developmental biology↗

bioRxiv2024

Poxvirus A52 is a host range factor for modified vaccinia virus Ankara (MVA) and promotes viral replication by disturbing the formation of autolysosomes

Many members of the poxvirus family are important zoonotic pathogens that pose a significant threat to human and animal health worldwide. Autophagy is a multi-step degradation pathway within cells, and one of its primary biological functions includes the clearance of invading viruses. Nevertheless, the interplay between poxviruses and host cell autophagy has not been fully elucidated. Here, we demonstrate that vaccinia virus (VACV) and lumpy skin disease virus (LSDV) induce incomplete autophagy and inhibit the fusion of autophagosomes and lysosomes, while modified vaccinia virus Ankara (MVA), an attenuated strain of VACV unable to replicate in almost all human cells, does not. Additionally, we screened and identified the VACV protein A52 as a key factor that obstruct the formation of autolysosomes. Mechanistically, A52 interacts with SNAP29 and inhibits its interaction with STX17 and VAMP8, both of which are binding partners of SNAP29 and are essential for complete autophagy. Moreover, A52 promotes the proteasomal degradation of SNAP29, which facilitates viral replication. We further revealed that SNAP29 functions as a restriction factor for MVA, as the suppression of SNAP29 allowed the replication of MVA in human cells. In summary, our data present a molecular mechanism by which poxviruses manipulate the cellular autophagic machinery and provide additional explanation for the restriction of MVA in human cells.

microbiology↗

bioRxiv2024

Perceptual tri-stability, measured and fitted as emergent from a model for bistable alternations

The human auditory system in attempting to decipher ambiguous sounds appears to resort to perceptual exploration as evidenced by multi-stable perceptual alternations. This phenomenon has been widely investigated via the auditory streaming paradigm, employing ABA_ triplet sequences with much research focused on perceptual bi-stability with the alternate percepts as either a single integrated stream or as two simultaneous distinct streams. We extend this inquiry with experiments and modeling to include tri-stable perception. Here, the segregated percepts may involve a foreground/background distinction. We collected empirical data from participants engaged in a tri-stable auditory task, utilizing this dataset to refine a neural mechanistic model that had successfully reproduced multiple features of auditory bi-stability. Remarkably, the model successfully emulated basic statistical characteristics of tri-stability without substantial modification. This model also allows us to demonstrate a parsimonious approach to account for individual variability by adjusting the parameter of either the noise level or the neural adaptation strength.

neuroscience↗

bioRxiv2023

Expanding RNA editing toolkit using an IDR-based strategy

RNA base editors should ideally be free of immunogenicity, compact, efficient and specific, which has not been achieved for C>U editing. Here we first describe a compact C>U editor entirely of human origin, created by fusing the human C>U editing enzyme RESCUE-S to CIRTS, a tiny, human-originated programmable RNA binding domain. This editor, CIRTS-RESCUEv1 (V1), was inefficient. Remarkably, a short Histidine-Rich Domain (HRD), which is derived from the Internal Disordered Region (IDR) in the human CYCT1, a protein capable of liquid-liquid phase separation (LLPS), enhanced V1 editing at on-targets as well as off-targets, the latter effect being minor. The V1-HRD fusion protein formed puncta characteristic of LLPS, and various other IDRs (but not an LLPS-impaired mutant) could replace HRD to effectively induce puncta and potentiate V1, suggesting that the diverse domains acted via a common, LLPS-based mechanism. Importantly, the HRD fusion strategy was applicable to various other types of C>U RNA editors. Our study expands the RNA editing toolbox and showcases a general method for stimulating C>U RNA base editors.

molecular biology↗

bioRxiv2023

Spatially resolved molecular and cellular atlas of the mouse brain

A comprehensive atlas of genes, cell types, and their spatial distribution across a whole mammalian brain is fundamental for understanding function of the brain. Here, using snRNA-seq and Stereo-seq techniques, we generated a mouse brain atlas with spatial information for 308 cell clusters with single-cell resolution involving over 6 million cells as well as for 29,655 genes. We have identified new astrocyte clusters, and demonstrated that distinct cell clusters exhibit preference for cortical subregions. In addition, we identified 155 genes exhibiting regional specificity in the brainstem, and 513 long non-coding RNA exhibited regional specificity in the adult brain. Parcellation of brain regions based on spatial transcriptomic information showed large overlap with that by traditional method. Furthermore, we have uncovered 411 transcription factor regulons with spatiotemporal specificity during development. Thus, our study has discovered genes and regulon with spatiotemporal specificity, and provided a high-resolution spatial transcriptomic atlas of the mouse brain.

neuroscience↗

bioRxiv2023

Fine-tuning spatial-temporal dynamics and surface receptor expression support plasma cell-intrinsic longevity

Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, the factors that control LLPC specification and survival remain poorly resolved. Using intra-vital two-photon imaging, we find that in contrast to most plasma cells in the bone marrow (BM), LLPCs are uniquely sessile and organized into clusters that are dependent on APRIL, an important survival factor. Using deep, bulk RNA sequencing, and surface protein flow-based phenotyping, we find that LLPCs express a unique transcriptome and phenotype compared to bulk PCs, fine tuning expression of key cell surface molecules, CD93, CD81, CXCR4, CD326, CD44 and CD48, important for adhesion and homing. Conditional deletion of Cxcr4 in PCs following immunization leads to rapid mobilization from the BM, reduced survival of antigen-specific PCs, and ultimately accelerated decay of antibody titer. In naive mice, the endogenous LLPCs BCR repertoire exhibits reduced diversity, reduced somatic mutations, and increased public clones and IgM isotypes, particularly in young mice, suggesting LLPC specification is non-random. As mice age, the BM PC compartment becomes enriched in LLPCs, which may outcompete and limit entry of new PCs into the LLPC niche and pool. HIGHLIGHTSO_LILLPCs have reduced motility and increased clustering in the BM C_LIO_LILLPCs accumulate in the BM PC pool, with mouse age C_LIO_LILLPCs have unique surfaceome, transcriptome, and BCR clonality C_LIO_LICXCR4 controls maintenance of PCs and antibody titers C_LI

immunology↗

bioRxiv2022

Spateo: multidimensional spatiotemporal modeling of single-cell spatial transcriptomics

Cells do not live in a vacuum, but in a milieu defined by cell-cell communication that can be measured via emerging high-resolution spatial transcriptomics approaches. However, analytical tools that fully leverage such data for kinetic modeling remain lacking. Here we present Spateo (aristoteleo/spateo-release), a general framework for quantitative spatiotemporal modeling of single-cell resolution spatial transcriptomics. Spateo delivers novel methods for digitizing spatial layers/columns to identify spatially-polar genes, and develops a comprehensive framework of cell-cell interaction to reveal spatial effects of niche factors and cell type-specific ligand-receptor interactions. Furthermore, Spateo reconstructs 3D models of whole embryos, and performs 3D morphometric analyses. Lastly, Spateo introduces the concept of "morphometric vector field" of cell migrations, and integrates spatial differential geometry to unveil regulatory programs underlying various organogenesis patterns of Drosophila. Thus, Spateo enables the study of the ecology of organs at a molecular level in 3D space, beyond isolated single cells.

systems biology↗

bioRxiv2022

Emerging Evidence for Poxvirus-Mediated Unfolded Protein Response: Lumpy Skin Disease Virus Maintains Self-replication by Activating PERK and IRE1

The cytoplasmic replication of poxviruses requires extensive protein synthesis, challenging the capacity of the endoplasmic reticulum (ER). However, the role of the ER in the life cycle of poxviruses is unclear. In this study, we demonstrate that infection with the lumpy skin disease virus (LSDV), a poxvirus, causes ER stress in vivo and in vitro, further facilitating the activation of the unfolded protein response (UPR). Although UPR activation aids in the restoration of the cellular environment, its significance in the LSDV life cycle remains unclear. Furthermore, the role of ER imbalance for viral replication is also unknown. We show that LSDV replication is hampered by an unbalanced ER environment. In addition, we verify that the LSDV replication depends on the activation of PERK-eIF2 and IRE1-XBP1 signaling cascades rather than ATF6, implying that global translation and XBP1 cleavage are deleterious to LSDV replication. Our findings suggest that LSDV engages all UPR signaling sensors, and that activation of PERK and IRE1 sensors is indispensable to maintaining its own replication. IMPORTANCEAlthough numerous viruses cause ER stress and employ endogenous UPR components to control viral growth, there is no such evidence for poxviruses. Recent real-world epidemics of poxviruses such as monkeypox and LSDV indicated a lack of available coping strategies. Our findings show that LSDV encoding up to 156 open reading frames (ORFs) causes pressure to the stabilization of ER, triggers ER stress, and further promotes the activation of all three UPR signaling pathways. However, inhibiting PERK-eIF2 and IRE1-XBP1 was not conducive for LSDV replication. Since LSDV efficiently utilizes UPR components to assist its own replication, signal-blocking agents of PERK and IRE1 may be useful in the treatment of LSDV. More evidence for the efficacy of such therapy for LSDV, even monkeypox, could come from a clearer characterization of the ER stress-mediated viral replication process.

microbiology↗

bioRxiv2022

Structural basis of a two-antibody cocktail exhibiting highly potent and broadly neutralizing activities against SARS-CoV-2 variants including diverse Omicron sublineages

SARS-CoV-2 variants of concern (VOCs), especially the latest Omicron, have exhibited severe antibody evasion. Broadly neutralizing antibodies with high potency against Omicron are urgently needed for understanding working mechanisms and developing therapeutic agents. In this study, we characterized previously reported F61, which was isolated from convalescent patients infected with prototype SARS-CoV-2, as a broadly neutralizing antibody against all VOCs including Omicron BA.1, BA.1.1, BA.2, BA.3 and BA.4 sublineages by utilizing antigen binding and cell infection assays. We also identified and characterized another broadly neutralizing antibody D2 with epitope distinct from that of F61. More importantly, we showed that a combination of F61 with D2 exhibited synergy in neutralization and protecting mice from SARS-CoV-2 Delta and Omicron BA.1 variants. Cryo-EM structures of the spike-F61 and spike-D2 binary complexes revealed the distinct epitopes of F61 and D2 at atomic level and the structural basis for neutralization. Cryo-EM structure of the Omicron-spike-F61-D2 ternary complex provides further structural insights into the synergy between F61 and D2. These results collectively indicated F61 and F61-D2 cocktail as promising therapeutic antibodies for combating SARS-CoV-2 variants including diverse Omicron sublineages.

biochemistry↗

bioRxiv2022

CD169+ macrophages orchestrate plasmacytoid dendritic cell arrest and retention for optimal priming in the bone marrow of malaria-infected mice

Plasmacytoid dendritic cells (pDC) are the most potent producer of type I interferon (IFN), but how pDC are primed in vivo is poorly defined. Using a mouse model of severe malaria, we have previously established that upon priming by CD169+ macrophages (MP), pDC initiate type I IFN-I secretion in the bone marrow (BM) of infected mice via cell-intrinsic TLR7 sensing and cell-extrinsic STING sensing. Herein we show that CD169+ MP and TLR7-sensing are both required for pDC arrest during priming, suggesting CD169+ MP are the source of TLR7 ligands. We establish that TLR7 sensing in pDC and chemotaxis are both required for pDC arrest and functional clustering with CD169+ MP in the BM. Lastly, we demonstrate that STING-sensing in CD169+ MP control pDC initiation of type I IFN production while also regulating pDC clustering and egress from the BM. Collectively, these results link pDC acquisition of type I IFN secreting capacity with changes in their motility, homing and interactions with CD169+ MP during infection. Thus, targeting this cellular interaction may help modulate type I IFN to improve outcomes of microbial infections and autoimmune diseases.

immunology↗

bioRxiv2022

Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth

One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)2 design (14-H-06) but not the CrossMAb design (14-crs-06) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.

microbiology↗

bioRxiv2021

Construction of a potent pan-vaccine based on the evolutionary tendency of SARS-CoV-2 spike protein.

SARS-CoV-2 continued to spread globally along with different variants. Here, we systemically analyzed viral infectivity and immune-resistance of SARS-CoV-2 variants to explore the underlying rationale of viral mutagenesis. We found that the Beta variant harbors both high infectivity and strong immune resistance, while the Delta variant is the most infectious with only a mild immune-escape ability. Remarkably, the Omicron variant is even more immune-resistant than the Beta variant, but its infectivity increases only in Vero E6 cells implying a probable preference for the endocytic pathway. A comprehensive analysis revealed that SARS-CoV-2 spike protein evolved into distinct evolutionary paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance, resulting in a narrow spectrum of the current single-strain vaccine. In light of these findings and the phylogenetic analysis of 2674 SARS-CoV-2 S-protein sequences, we generated a consensus antigen (S6) taking the most frequent mutations as a pan-vaccine against heterogeneous variants. As compared to the ancestry SWT vaccine with significantly declined neutralizations to emerging variants, the S6 vaccine elicits broadly neutralizing antibodies and full protections to a wide range of variants. Our work highlights the importance and feasibility of a universal vaccine strategy to fight against antigen drift of SARS-CoV-2.

microbiology↗

bioRxiv2021

Spatially-resolved transcriptomics analyses of invasive fronts in solid tumors

Solid tumors are complex ecosystems, and heterogeneity is the major challenge for overcoming tumor relapse and metastasis. Uncovering the spatial heterogeneity of cell types and functional states in tumors is essential for developing effective treatment, especially in invasive fronts of tumor, the most active region for tumor cells infiltration and invasion. We firstly used SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq) with a nanoscale resolution to characterize the tumor microenvironment of intrahepatic cholangiocarcinoma (ICC). Enrichment of distinctive immune cells, suppressive immune microenvironment and metabolic reprogramming of tumor cells were identified in the 500{micro}m-wide zone centered bilaterally on the tumor boundary, namely invasive fronts of tumor. Furthermore, we found the damaged states of hepatocytes with overexpression of Serum Amyloid A (SAA) in invasive fronts, recruiting macrophages for facilitating further tumor invasion, and thus resulting in a worse prognosis. We also confirmed these findings in hepatocellular carcinoma and other liver metastatic cancers. Our work highlights the remarkable potential of high-resolution-spatially resolved transcriptomic approaches to provide meaningful biological insights for comprehensively dissecting the tumor ecosystem and guiding the development of novel therapeutic strategies for solid tumors.

cancer biology↗

bioRxiv2021

MyD88 Mediates Colitis- and RANKL-induced Microfold Cell Differentiation

Intestinal microfold (M) cells are critical for sampling antigen in the gut and initiating the intestinal mucosal immune response. In this study, we found that the differentiation efficiency of M cells was closely related to the colitis severity. The expression levels of M cells differentiation-related genes were synchronized with the kinetics of pro-inflammatory cytokines expression originated from dextran sulfate sodium (DSS) induction and Salmonella infection. Compared with wild-type (WT) mice, MyD88-/- mice exhibited significantly lower expression levels of M cells differentiation-related genes. However, DSS could induce colitis in MyD88-/- mice but failed to promote M cells differentiation. Furthermore, the receptor activator of the Nuclear Factor-{kappa}B ligand (RANKL) induced M cells differentiation in murine intestinal organoids prepared from both WT and MyD88-/- mice. However, less M cells differentiation were found in MyD88-/- mice as compared with WT mice. Hence, we concluded that myeloid differentiation factor 88 (MyD88) is an essential molecule for colitis- and RANKL-related M cells differentiation.

cell biology↗