Biology subjects

Zheng, B.

Publications and source records attributed to Zheng, B..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

DEC1 Regulates Human β Cell Functional Maturation and Circadian Rhythm

Stem cell-derived islet (SC-islet) organoids offer hope for cell replacement therapy in diabetes, but their immature function remains a challenge. Mature islet function requires the {beta}-cell circadian clock, yet how the clock regulates maturation is unclear. Here, we show that a circadian transcription factor specific to maturing SC-{beta} cells, DEC1, regulates insulin responsiveness to glucose. SC-islet organoids form normally from DEC1-ablated human pluripotent stem cells, but their insulin release capacity and glucose threshold fail to increase during in vitro culture and upon transplant. This deficit reflects downregulation of maturity-linked effectors of glucose utilization and insulin exocytosis, blunting glycolytic and oxidative metabolism, and is rescued by increasing metabolic flux. Moreover, DEC1 is needed to boost SC-islet maturity by synchronizing circadian glucose-responsive insulin secretion rhythms and clock machinery. Thus, DEC1 links circadian rhythms to human {beta}-cell maturation, highlighting the essential role of circadian control in generating fully functional SC-islet organoids.

developmental biology↗

bioRxiv2025

Nitrogen deposition reshapes plant nutrient acquisition strategies: a meta-analysis within the root economics space

Global nitrogen (N) deposition has fundamentally reshaped plant nutrient acquisition by altering mechanistic trade-offs between root exploration-exploitation strategies and mycorrhizal symbiosis. Through a meta-analysis of 135 studies spanning 153 sites, we demonstrate that N deposition stimulates root exploration (+84.6% root length density) and exploitation (+13.2% nitrogen content and +8.5% root biomass) while suppressing mycorrhizal dependence (-32.8% biomass, -18.73% colonized root length, -7.55% hyphal length), indicating a systemic shift toward root-autonomous nutrient acquisition. Divergent responses emerged between plant lifeforms: woody plants prioritize exploitation (+13.2% nitrogen content) over exploration capacity (-7.9% root length density), whereas herbaceous species exhibit synergistic enhancement of both strategies (+88% root length density, +13.2% nitrogen content and +71.3% root biomass). In contrast to N-only effects, Combined nitrogen and phosphorus additions reversed mycorrhizal suppression (+41.9% biomass), highlighting their persistent role in phosphorus acquisition under elevated nutrient conditions. The root economics space framework demonstrates predictive power, with plants possessing lower specific root length (SRL) and higher nitrogen content exhibiting stronger positive responses to N deposition, while those possessing higher SRL and lower nitrogen content showed reduced investment in root systems. These trait-mediated thresholds in carbon-nutrient tradeoffs refine our capacity to model belowground ecological responses to anthropogenic nitrogen perturbation, establishing a mechanistic basis for projecting ecosystem trajectories under global change.

plant biology↗

bioRxiv2025

Genetic basis of partner choice

Previous genetic studies of human assortative mating have primarily focused on searching for its genomic footprint but have revealed limited insights into its biological and social mechanisms. Combining insights from the economics of the marriage market with advanced tools in statistical genetics, we perform the first genome-wide association study (GWAS) on a latent index for partner choice. Using 206,617 individuals from four global cohorts, we uncover phenotypic characteristics and social processes underlying assortative mating. We identify a broadly robust genetic component of the partner choice index between sexes and several countries and identify its genetic correlates. We also provide solutions to reduce assortative mating-driven biases in genetic studies of complex traits by conditioning GWAS summary statistics on the genetic associations with the latent partner choice index.

genetics↗

bioRxiv2025

Sequestration of SerRS through LLPS Impairs Localized Translation and Contributes to Antibiotic Persistence

Antibiotic-tolerant persisters contribute to the emergence of resistance, posing a significant challenge to the efficacy of antibiotic therapies. Despite extensive research, the mechanisms underlying persistence remain inadequately understood. By tracking the evolution of exponential-phase bacterial populations subjected to intermittent high-dose ertapenem exposure, we characterized the evolved strains in terms of tolerance. Mutant strains, harboring mutations in the seryl-tRNA synthetase gene (serS), exhibited abrupt growth arrest upon serine depletion during exponential growth, resembling the persistence phenotype induced by serine hydroxamate (SHX). Under serine starvation, the mutated SerRS protein was sequestrated into liquid-liquid phase separation (LLPS)-driven condensates, disrupting their composition and impairing localized translation. This event precipitated growth arrest and dormancy in the SerST strain, triggering persistence. Our findings reveal an unrecognized role for aminoacyl-tRNA synthetases (aaRSs) in modulating bacterial condensates and provide insights into the molecular mechanisms underlying bacterial persistence. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/630848v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1a69521org.highwire.dtl.DTLVardef@188b087org.highwire.dtl.DTLVardef@fd897forg.highwire.dtl.DTLVardef@14e1b6a_HPS_FORMAT_FIGEXP M_FIG SerRS Recruitment Disrupts Localized Translation in DeaD-marked Condensates. Upon serine starvation, SerRST partitions into LLPS-driven DeaD-marked condensates, impairing their localized translation activity and suggesting mechanisms underlying persistence arising during exponential phase. These evolutionarily conserved condensates orchestrate a robust translation program to enable stress responses and instruct cell fate decisions in bacterial populations. C_FIG

microbiology↗

bioRxiv2024

Activation of hypothalamic-pontine-spinal pathway promotes locomotor initiation and functional recovery after spinal cord injury in mice

The hypothalamus is critical for regulating behaviors essential for survival and locomotion, but how it integrates internal needs and transmits locomotion commands to the spinal cord (SC) remains unclear. We found that glutamatergic neurons in lateral hypothalamic area (LHA) are essential for regulating motivated locomotor activity. Using single-neuron projectome analysis, trans-synaptic tracing, and optogenetic manipulation, we showed that LHA facilitates motivated locomotion during food seeking via pontine oral part (PnO) projection neurons, rather than direct SC projections or indirect stress signaling via medial septum and diagonal band. Activating PnO-SC projection neurons also initiated locomotion. Importantly, LHA-PnO projection neurons were crucial for regulating locomotor recovery following mouse spinal cord injury (SCI). Closed-loop deep brain stimulation (DBS) of LHA via gating by motor cortex signals markedly promoted long-term restoration of hindlimb motor functions after SCI. Thus, we have identified a hypothalamic-pontine- spinal pathway and the stimulation paradigm for potential therapeutic intervention after SCI.

neuroscience↗

bioRxiv2024

Physics-Informed Ellipsoidal Coordinate Encoding Implicit Neural Representation for high-resolution volumetric wide-field microscopy

Wide-field fluorescence microscopy through axial scanning provides a simple way for volumetric imaging of cellular and intracellular activities, but the optical transfer function (OTF) of wide-field microscopy suffers from axial frequency deficiencies, leading to strong interference from out-of-focus fluorescence signals and reduced imaging quality. Richardson-Lucy (RL) deconvolution and its variants are commonly employed to reduce inter-plane signal interference of wide-field microscopy. However, these methods are still affected by the "missing cone" issue inherent in the OTF, compromising both the axial resolution and optical sectioning capability. Existing deep learning methods could realize high-fidelity 3D image stack restoration, but relying on high-quality paired datasets or specific assumptions about sample distributions. Here, we propose a novel method named physics-informed ellipsoidal coordinate encoding implicit neural representation (PIECE-INR), to tackle the challenges of background signal interference and resolution loss in axial scanning image stacks using the wide-field microscopy. In PIECE-INR, we integrate the wide-field fluorescence imaging model with the self-supervised INR network for high-fidelity reconstruction of 3D fluorescence data without the need of additional ground truth data for training. We further design a novel ellipsoidal coordinate encoding based on the systems OTF constraints and incorporate implicit priors derived from the physical model as the loss function into the reconstruction process. Our approach enables block-wise reconstruction of large-scale images by using localized physical information. We demonstrate state-of-the-art performance of our PIECE-INR method in volumetric imaging of live HeLa cells, large-volume C. elegans whole-embryo, and mitochondrial dynamics.

cell biology↗

bioRxiv2024

A CXCR4 partial agonist improves immunotherapy by targeting polymorphonuclear myeloid-derived suppressor cells and cancer-driven granulopoiesis

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that potently impair immunotherapy responses. The chemokine receptor CXCR4, a central regulator of hematopoiesis, represents an attractive PMN-MDSC target1. Here, we fused a secreted CXCR4 partial agonist TFF2 to mouse serum albumin (MSA) and demonstrated that TFF2-MSA peptide synergized with anti-PD-1 to induce tumor regression or eradication, inhibited distant metastases, and prolonged survival in multiple gastric cancer (GC) models. Using histidine decarboxylase (Hdc)-GFP transgenic mice to track PMN-MDSC in vivo, we found TFF2-MSA selectively reduced the immunosuppressive Hdc-GFP+ CXCR4hi tumor PMN-MDSCs while preserving proinflammatory neutrophils, thereby boosting CD8+ T cell-mediated anti-tumor response together with anti-PD-1. Furthermore, TFF2-MSA systemically reduced PMN-MDSCs and bone marrow granulopoiesis. In contrast, CXCR4 antagonism plus anti-PD-1 failed to provide a similar therapeutic benefit. In GC patients, expanded PMN-MDSCs containing a prominent CXCR4+LOX-1+ subset are inversely correlated with the TFF2 level and CD8+ T cells in circulation. Collectively, our studies introduce a strategy of using CXCR4 partial agonism to restore anti-PD-1 sensitivity in GC by targeting PMN-MDSCs and granulopoiesis.

cancer biology↗

bioRxiv2024

Auditory Cortex Learns to Discriminate Audiovisual Cues through Selective Multisensory Enhancement

Multisensory object discrimination is essential in everyday life, yet the neural mechanisms underlying this process remain unclear. In this study, we trained rats to perform a two-alternative forced-choice task using both auditory and visual cues. Our findings reveal that multisensory perceptual learning actively engages auditory cortex (AC) neurons in both visual and audiovisual processing. Importantly, many audiovisual neurons in the AC exhibited experience-dependent associations between their visual and auditory preferences, displaying a unique integration model. This model employed selective multisensory enhancement for the auditory-visual pairing guiding the contralateral choice, which correlated with improved multisensory discrimination. Furthermore, AC neurons effectively distinguished whether a preferred auditory stimulus was paired with its associated visual stimulus using this distinct integrative mechanism. Our results highlight the capability of sensory cortices to develop sophisticated integrative strategies, adapting to task demands to enhance multisensory discrimination abilities.

neuroscience↗

bioRxiv2024

Translatome analysis reveals cellular network in DLK-dependent hippocampal glutamatergic neuron degeneration

The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, and neurodegeneration, depending on cell-type and cellular contexts. Emerging evidence implicates abnormal DLK signaling in several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network in the central nervous system remains limited. Here, we investigated the roles of DLK in hippocampal glutamatergic neurons using conditional knockout and induced overexpression mice. We found that dorsal CA1 and dentate gyrus neurons are vulnerable to elevated expression of DLK, while CA3 neurons appear less vulnerable. We identified the DLK-dependent translatome that includes conserved molecular signatures and displays cell-type specificity. Increasing DLK signaling is associated with disruptions to microtubules, potentially involving STMN4. Additionally, primary cultured hippocampal neurons expressing different levels of DLK show altered neurite outgrowth, axon specification, and synapse formation. The identification of translational targets of DLK in hippocampal glutamatergic neurons has relevance to our understanding of selective neuron vulnerability under stress and pathological conditions.

neuroscience↗

bioRxiv2024

Discovery of a Heparan-Sulfate Binding Domain in Monkeypox Virus H3 Protein as a New Anti-poxviral Drug Target

Viral adhesion to host cells is a critical step in infection for many viruses, including monkeypox virus (MPXV). In MPXV, the H3 protein mediates viral adhesion through its interaction with heparan sulfate (HS), yet the structural details of this interaction have remained elusive. Using AI-based structural prediction tools and molecular dynamics (MD) simulations, we identified a novel, positively charged -helical domain in H3 that is essential for HS binding. This conserved domain, found across orthopoxviruses, was experimentally validated and shown to be critical for viral adhesion, making it an ideal target for antiviral drug development. Targeting this domain, we designed a protein inhibitor, which disrupted the H3-HS interaction, inhibited viral infection in vitro and viral replication in vivo, offering a promising antiviral candidate. Our findings reveal a novel therapeutic target of MPXV, demonstrating the potential of combination of AI-driven methods and MD simulations to accelerate antiviral drug discovery.

biophysics↗

bioRxiv2023

Prognostic implications and biological roles of EMT-related lncRNAs in lung squamous cell carcinoma: an in-depth analysis utilizing a novel prognostic signature and classification system

BackgroundLung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer (NSCLC), a leading contributor to cancer-related mortality. Epithelial-mesenchymal transition (EMT)-associated genes have been implicated in poor survival and metastatic gene expression in LUSC. Long non-coding RNAs (lncRNAs) are known to facilitate tumor progression and metastasis via EMT regulation. However, the prognostic significance and biological functions of EMT-associated lncRNAs in LUSC remain to be elucidated. MethodsIn this study, we aimed to develop an EMT-related lncRNA prognostic signature (EMT-LPS) utilizing RNA transcription data from LUSC patients in The Cancer Genome Atlas (TCGA) database, along with corresponding clinical characteristics. Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and Cox regression were employed to validate and assess the model. Furthermore, we confirmed the independent prognostic value of key genes in EMT-LPS using Gene Expression Profiling Interactive Analysis (GEPIA). Additionally, we proposed a novel LUSC classification system based on EMT-related lncRNA expression patterns, evaluating the prognostic profile, tumor microenvironment, and immunotherapy sensitivity of each subtype. ResultsA prognostic signature comprising twelve genes was constructed, and patients were stratified into high and low-risk groups according to their risk scores. Cox regression analysis revealed that the risk score served as an independent prognostic factor. A nomogram was generated to predict LUSC patient survival rates. Distinct subtypes exhibited varying tumor purity, immunogenicity, and immunotherapy drug sensitivity. ConclusionsOur findings underscore the relevance of EMT-related lncRNAs in LUSC and their potential utility in guiding immunotherapy strategies. The EMT-LPS and novel LUSC typing scheme provide a new perspective for understanding the biological functions and prognostic role of EMT-related lncRNAs in LUSC.

bioinformatics↗

bioRxiv2023

Lymphotoxin-β Promotes Bone Colonization and Osteolytic Outgrowth of Indolent Bone Metastatic cells of Breast Cancer

Bone metastatic relapse is a lethal consequence of breast cancer, occurring years after initial diagnosis. By analyzing single-cell transcriptomes of bone-seeding tumor cells and in vivo barcoded cDNA library screening, LT{beta} (lymphotoxin-{beta}) is identified as a key factor highly expressed in early-stage bone metastatic cells, associated with poor bone metastasis-free survival, and capable of promoting dormancy reactivation in multiple breast cancer models. Mechanistically, tumor-derived LT{beta} activates NF-{kappa}B2 signaling in osteoblasts to express CCL2/5, facilitating tumor cell seeding and accelerating osteoclastogenesis. Both processes contribute to the reactivation of dormancy and metastatic outgrowth. Blocking LT{beta} signaling with a decoy receptor significantly suppressed bone colonization and metastatic progression, whereas clinical sample analysis revealed significantly higher LT{beta} expression in bone metastases than in primary tumors. Our findings highlight LT{beta} as a bone niche-induced factor that promotes tumor cell seeding and dormancy reactivation, underscoring its potential as a therapeutic target for preventing bone metastatic relapse in patients with breast cancer.

cell biology↗

bioRxiv2023

Osteoclast-Cancer Cell Metabolic Symbiosis Renders PARP Inhibitor Therapy Resistance in Bone Metastasis

Seventy percent of patients with late-stage breast cancer develop distal bone metastases; however, the mechanism by which the metabolic microenvironment affects resistance to therapy remains unknown. We investigated the metabolic bone microenvironment and identified glutathione metabolism as the top pathway in osteoclasts, which provides feedback to tumor cells to help neutralize oxidative stress and generate PARP inhibitor (PARPi) therapy resistance. GPX4, the critical enzyme responsible for glutathione oxidation, was upregulated during PARPi therapy through stress-induced ATF4-dependent transcriptional programming. The increased absorption of glutamine and the upregulation of GPX4 expression work in concert to enhance glutathione metabolism in cancer cells. Human clinical sample analysis of paired primary breast tumor and bone metastasis samples revealed that GPX4 was significantly induced in bone metastases. Combination therapy utilizing PARPi and zoledronate, which blocks osteoclast activity and thereby reduces the microenvironmental glutamine supply, generates a synergistic effect in reducing bone metastasis. Thus, our results identified an essential metabolic symbiosis between bone-resident cells and metastatic cancer cells during PARPi therapy. SIGNIFICANCEOsteoclast-derived glutamine is taken up by tumor cells to synthesize glutathione and neutralize the ROS generated by PARPi. This is the first example of "metabolic symbiosis" in therapeutic resistance of bone metastasis.

cancer biology↗

bioRxiv2023

22kHz Ultrasonic Vocalizations and Body Freezing May Represent Two Systems of Fear in Rodent Fear Conditioning Paradigms

The "two-system" framework of fear proposed by LeDoux and Pine (2016) sparked a discussion on the understanding of fear, prompting a reevaluation of rodent fear conditioning studies. We propose that 22kHz ultrasonic vocalizations (USV) may symbolize the subjective negative emotional states in rats. To evaluate this, we designed a series of fear conditioning experiments with varied parameters, comparing the expression of 22kHz USV and body freezing - a traditional fear index. These expressions were further assessed in fear generalization tests. Our findings suggest a distinct separation between body freezing and 22kHz vocalizations in fear conditioning under different conditions. The results indicate that 22kHz USV may more accurately signify the subjective state of fear, whereas body freezing may denote an automatic defensive response in rats. Consequently, we posit that the two-system fear framework may extend to rodent fear conditioning paradigms. Therefore, researchers should place greater emphasis on 22kHz vocalizations when investigating the subjective state of fear.

animal behavior and cognition↗

bioRxiv2023

Dichotomy of neutralizing antibody, B cell and T cell responses to SARS-CoV-2 vaccination and protection in healthy adults

Heterogeneity in SARS-CoV-2 vaccine responses is not understood. Here, we identify four patterns of live-virus neutralizing antibody responses: individuals with hybrid immunity (with confirmed prior infection); rare individuals with low responses (paucity of S1-binding antibodies); and surprisingly, two further groups with distinct serological repertoires. One group - broad responders - neutralize a range of SARS-CoV-2 variants, whereas the other - narrow responders - neutralize fewer, less divergent variants. This heterogeneity does not correlate with Ancestral S1-binding antibody, rather the quality of the serological response. Furthermore, IgDlowCD27-CD137+ B cells and CCR6+ CD4+ T cells are enriched in broad responders before dose 3. Notably, broad responders have significantly longer infection-free time after their third dose. Understanding the control and persistence of these serological profiles could allow personalized approaches to enhance serological breadth after vaccination.

immunology↗

bioRxiv2023

An Empirical Study on the Motivation of Helping Behavior in Rats

Using rodent models to explore the motivation of helping behaviors has become a new trend in recent years. Empathy, the alleviation of personal distress, and desire for social contact have been considered motivations for rodents to engage in helping behaviors. We used 108 Sprague-Dawley rats as subjects and modified the two-chambered helping behavior experimental setup in Carvalheiro and colleagues study to explore the main motivations of helping behavior in rodents through three experiments. The findings suggest that (1) the desire for social contact and pursuit of an interesting environment are the primary motivations for helping behavior, regardless of the presence of a dark chamber, and (2) the alleviation of personal distress and prior experience of social contact rather than distress experience contribute to the onset and persistence of helping behavior.

animal behavior and cognition↗

bioRxiv2023

Chromosome-level genomes of multicellular algal sisters to land plants illuminate signaling network evolution

The filamentous and unicellular algae of the class Zygnematophyceae are the closest algal relatives of land plants. Inferring the properties of the last common ancestor shared by these algae and land plants allows us to identify decisive traits that enabled the conquest of land by plants. We sequenced four genomes of filamentous Zygnematophyceae (three strains of Zygnema circumcarinatum and one strain of Z. cylindricum) and generated chromosome-scale assemblies for all strains of the emerging model system Z. circumcarinatum. Comparative genomic analyses reveal expanded genes for signaling cascades, environmental response, and intracellular trafficking that we associate with multicellularity. Gene family analyses suggest that Zygnematophyceae share all the major enzymes with land plants for cell wall polysaccharide synthesis, degradation, and modifications; most of the enzymes for cell wall innovations, especially for polysaccharide backbone synthesis, were gained more than 700 million years ago. In Zygnematophyceae, these enzyme families expanded, forming co-expressed modules. Transcriptomic profiling of over 19 growth conditions combined with co-expression network analyses uncover cohorts of genes that unite environmental signaling with multicellular developmental programs. Our data shed light on a molecular chassis that balances environmental response and growth modulation across more than 600 million years of streptophyte evolution. HIGHLIGHTSO_LIGenomes of four filamentous algae (Zygnema) sisters to land plants C_LIO_LIZygnema are rich in genes for multicellular growth and environmental acclimation: signaling, lipid modification, and transport C_LIO_LICell wall innovations: diversification of hexameric rosette cellulose synthase in Zygnematophyceae C_LIO_LICo-expression networks reveal conserved modules for balancing growth and acclimation C_LI

evolutionary biology↗

bioRxiv2022

A tRNA Modification-based strategy for Identifying amiNo acid Overproducers (AMINO)

Amino acids have a multi-billion-dollar market with rising demand, prompting the development of high-performance microbial factories. However, a general screening strategy applicable to all proteinogenic and non-proteinogenic amino acids is still lacking. Modification of the critical structure of tRNA could decrease the aminoacylation level of tRNA catalyzed by aminoacyl-tRNA synthetases. Involved in a two-substrate sequential reaction, amino acids with increased concentration could elevate the reduced aminoacylation rate caused by specific tRNA modification. Here, we developed a selection system for overproducers of specific amino acids using corresponding engineered tRNAs and reporter genes. As a proof-of-concept, overproducers of five amino acids such as L-tryptophan were screened out by growth-based and/or fluorescence-activated cell sorting (FACS)-based screening from random mutation libraries of Escherichia coli and Corynebacterium glutamicum, respectively. This study provided a universal strategy that could be applied to screen overproducers of proteinogenic and non-proteinogenic amino acids in amber-stop-codon-recoded or non-recoded hosts.

synthetic biology↗