Biology subjects

Feng, M.

Publications and source records attributed to Feng, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs and CD8+ T cells

Administration of selective serotonin reuptake inhibitors (SSRIs) is associated with a reduced cancer risk and shows significant anti-tumor effects across multiple tumor types, suggesting the potential for repurposing SSRIs in cancer therapy. Nonetheless, the specific molecular target and mechanism of action of SSRIs remain to be fully elucidated. Here, we reveal that citalopram exerts an immune-dependent anti-tumor effects in hepatocellular carcinoma (HCC). Interestingly, the anti-HCC effects of citalopram are not reliant on its conventional target, the serotonin transporter. Through various drug repurposing approaches, including global reverse gene expression profiling, drug affinity responsive target stability assay, and molecular docking, the complement component 5a receptor 1 (C5aR1) is identified as a new target of citalopram. C5aR1 is predominantly expressed by tumor-associated macrophages (TAMs), and citalopram treatment enhances local macrophage phagocytosis and elicits CD8+ T anti-tumor immunity. C5aR1 deficiency or depletion of CD8+ T cells hinders the anti-HCC effects of citalopram. Collectively, our study reveals the immunomodulatory roles of citalopram in inducing anti-tumor immunity, and provides a basis for considering the repurposing of SSRIs as promising anticancer agents for HCC treatment.

cancer biology↗

bioRxiv2024

Functional and evolutionary characterization of potential auxiliary metabolic genes (AMGs) of the global RNA virome

RNA viruses play an important role in regulating their host and global biogeochemical cycling, and auxiliary metabolic genes (AMGs) are one of the main pathways by which viruses regulate hosts metabolism. However, the AMGs encoded by global RNA viruses are largely unexplored. Here, we annotated RNA viral genomes and identified AMGs from recently published global RNA virome datasets. We found 274 AMGs encoded by 243 RNA viral genomes, which accounts for only 0.008% of all 3,216,257 genomes investigated. These AMGs span 25 functional categories, the most prevalent being translation, energy metabolism, membrane transport, transcription, replication and repair, and signal transduction. Unlike DNA viruses, RNA viruses tend to encode AMGs influencing the genetic and environments information processing of their hosts, with fewer AMGs linked to nutrient cycling, such as carbon and nitrogen metabolism. In addition, RNA viruses encoding these AMGs were taxonomically diverse, spanning five established phyla, the newly proposed phylum "Taraviricota" and fourteen LucaProt supergroups. Host prediction indicated that most of these RNA viruses encoding AMGs infect eukaryotes, while only a few of them, including Leviviricetes and Vidaverviricetes, infect prokaryotes. Interestingly, the potential host phylum for most of these RNA viruses were different from the likely source phylum of their AMGs, suggesting the possibility that these RNA viruses acquired AMGs from organisms outside their predicted host range. This study provides the first comprehensive analysis of AMGs from global RNA virome, which greatly expands our understanding of their function roles, evolutionary history and virus-host interactions.

ecology↗

bioRxiv2024

Nitroxoline evidence Amoebicidal Activity against Acanthamoeba castellanii through DNA damage and the stress response pathways

Acanthamoeba castellanii is a widespread unicellular eukaryote found in diverse environments, including tap water, soil, and swimming pools. It is responsible for severe infections, such as Acanthamoeba keratitis and granulomatous amebic encephalitis, particularly in individuals with immunocompromisation. The ability of protozoans to form dormant cysts complicates treatment, as current therapies are ineffective against cyst stages and suffer from poor specificity and side effects. Nitroxoline, a quinoline derivative with well-established antibacterial, antifungal, and antiviral properties, is a promising therapeutic candidate. This study aimed to elucidate cellular signalling events that counteract the effects of nitroxoline. In this study, nitroxoline significantly reduced the viability of A. castellanii trophozoites in a dose- and time-dependent manner, inducing morphological changes and apoptosis. Transcriptomic analysis revealed substantial alterations in gene expression, including enrichment of metabolic pathways, DNA damage responses, and iron ion binding. Nitroxoline treatment upregulated genes involved in DNA repair and oxidative stress response while regulating genes in the methionine and cysteine cycles. It also decreased the mitochondrial membrane potential, H2S production, and total iron amount in A. castellanii. Bioinformatics analyses and molecular docking studies suggest direct interactions between nitroxoline and A. castellanii proteins. Our research provides a comprehensive molecular map of the response of A. castellanii to nitroxoline, revealing significant changes in gene expression related to the stress response and metabolic pathways. These findings underscore the potential of nitroxoline as a potent anti-Acanthamoeba agent, offering new insights into its mechanism of action and paving the way for effective therapeutic strategies.

microbiology↗

bioRxiv2024

Shape transformation of vesicles induced by orientational arrangement of membrane proteins

Vesicles of lipid bilayer can adopt a variety of shapes due to different coating proteins. The ability of proteins to reshape membrane is typically characterized by inducing spontaneous curvature of the membrane at the coated area. BAR family proteins are known to have a crescent shape and can induce membrane curvature along its concaved body axis but not in the perpendicular direction. We model this type of proteins as a rod-shaped molecule with an orientation and induce normal curvature along its orientation in the tangential plane of the membrane surface. We show how a ring of these proteins reshape an axisymmetric vesicle when the protein curvature or orientation is varied. A discontinuous shape transformation from a protrusion shape without a neck to a one with a neck is found. Increasing the rigidity of the protein ring is able to smooth out the transition. Furthermore, we show that varying the protein orientation is able to induce an hourglass-shaped neck, which is significantly narrower than the reciprocal of the protein curvature. Our results offer a new angle to rationalize the helical structure formed by many proteins that carry out membrane fission functions.

biophysics↗

bioRxiv2024

Diversity and ecological roles of RNA viral communities in the cryosphere of the Tibetan Plateau

RNA viruses play crucial roles in modulating host communities, but their diversity and ecological roles in the cryosphere are poorly understood. We investigated the RNA virome from the cryosphere of the Tibetan Plateau (TPC), the largest area of the cryosphere in the mid-low latitude regions, which includes 79 metatranscriptomes from ecosystems including glaciers, proglacial lake sediments, permafrost wetland and upland soils. We obtained 8,799 RNA-dependent RNA polymerase encoding contigs, which clustered into 5,333 viral species, adding more than 4,900 new RNA viral species to the global RNA virome database. The recovered RNA viruses primarily infect prokaryotes, distinctively different from the dominance of eukaryotic RNA viruses in oceanic ecosystems. In addition to the known taxa such as Leviviricetes, we identified novel clades of putative prokaryotic RNA viruses, which greatly extended our understanding of their diversity. We further expanded the host of RNA virus by 20 additional prokaryotic phylum- or class-level taxonomic groups. Moreover, the TPC RNA viruses encoded dozens of auxiliary metabolic genes that could reprogram the metabolisms of diverse hosts, including photosynthesis in glacier eukaryotic algae and cyanobacteria, which may exert great impacts on glacier dynamics through modulating host adaptation. Furthermore, we identified potential pathogenic RNA viruses in various cryosphere environments, though their overall risks are low. This study provides the first comprehensive view of cryosphere RNA virome, highlighting their high diversity, vital ecological functions, and potential health impacts.

ecology↗

bioRxiv2024

SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1

Although there is growing appreciation for effective repurposing of selective serotonin reuptake inhibitors (SSRIs) for cancer therapy, particularly hepatocellular carcinoma (HCC), efforts are hampered by limited knowledge of their molecular targets and mechanism of action. Global inverse gene-expression profiling method, drug affinity responsive target stability assay, and in silico molecular docking analysis was performed to identify the targets of SSRIs. Murine subcutaneous, orthotopic models, and patient-derived xenograft were employed to explore the therapeutic effects and underlying mechanisms of SSRIs in HCC. The clinical relevance of SSRI use was verified with real world data. SSRIs exhibit significant anti-HCC effects independent of their known target serotonin reuptake transporter. The glucose transporter 1 (GLUT1) is identified as a new target of SSRIs. Citalopram binds to and antagonizes GLUT1, resulting in reduced glycolytic flux and ATP generation. Mutant GLUT1 in the binding site E380 of citalopram compromises the inhibitory effects of citalopram on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth kinetics of GLUT1high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis of health records found that SSRIs use is associated with a lower risk of metastasis among HCC patients. Our study reveals an unprecedented role of SSRIs in cancer metabolism, and establishes a rationale for repurposing SSRIs as potential anticancer drugs for HCC.

cancer biology↗

bioRxiv2024

Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure

Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-like motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, activation of SST neurons in the PLC of male and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos+ and FosB+ neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. Our studies provide a mechanistic rationale for antidepressant efficacy of dendrite-targeting, low-potency GABAA receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.

neuroscience↗

bioRxiv2024

A nanobody-enzyme fusion protein targeting PD-L1 and sialic acid exerts anti-tumor effects by affecting tumor associated macrophages

Cancer cells employ various mechanisms to evade immune surveillance. Their surface features, including a protective "sugar coat" and immune checkpoints like PD-L1 (programmed death ligand 1), can impede immune cell recognition. Sialic acids, which carry negative charges, may hinder cell contact through electrostatic repulsion, while PD-L1 transmits immunosuppressive signals to T cells. Furthermore, cancer cells manipulate macrophages within the tumor microenvironment to facilitate immune escape. Prior research has demonstrated the effectiveness of separately blocking the PD-L1 and sialic acid pathways in eliciting anti-tumor effects. In this study, we investigated the relationship between PD-L1 expression and genes associated with sialic acid in clinical databases. Subsequently, we developed a novel nanobody enzyme fusion protein termed Nb16-Sia to simultaneously target both PD-L1 and sialic acid pathways. In vivo experiments confirmed the anti-tumor activity of Nb16-Sia and highlighted its dependence on macrophages. Further investigations revealed that Nb16-Sia could polarize macrophages towards the M1 phenotype through the C-type lectin pathway in vitro and eliminate tumor-associated macrophages in vivo. In conclusion, our findings demonstrate that the fusion of PD-L1 nanobody with sialidase effectively targets tumor-associated macrophages, resulting in significant anti-tumor effects. This approach holds promise for drug development aimed at enhancing immune responses against cancer.

pharmacology and toxicology↗

bioRxiv2024

Decoding Missense Variants by Incorporating Phase Separation via Machine Learning

Computational models have made significant progress in predicting the effect of protein variants. However, deciphering numerous variants of unknown significance (VUS) located within intrinsically disordered regions (IDRs) remains challenging. To address this issue, we introduced phase separation (PS), which is tightly linked to IDRs, into the investigation of missense variants. Phase separation is vital for multiple physiological processes. By leveraging missense variants that alter phase separation propensity, we developed a machine learning approach named PSMutPred to predict the impact of missense mutations on phase separation. PSMutPred demonstrated robust performance in predicting missense variants that affect natural phase separation. In vitro experimental findings further underscore its validity. By applying PSMutPred on over 522,000 ClinVar missense variants, it significantly contributes to decoding the pathogenesis of disease variants, especially those in IDRs. Our work provides unique insights into the understanding of a vast number of VUSs in IDRs, thereby expediting clinical interpretation and diagnosis of disease variants.

bioinformatics↗

bioRxiv2024

Optogenetics-integrated gut organ culture system connects enteric neurons dynamics and gut homeostasis

The enteric nervous system (ENS) senses microbiota-derived signals and orchestrates mucosal immunity and epithelial barrier functions, in health and disease. However, mechanistic dissections of intestinal neuro-immune-microbiota communications remain challenging and existing research methods limit experimental controllability and throughput. Here, we present a novel optogenetics-integrated gut organ culture system that enables real-time, whole-tissue stimulation of specific ENS lineages, allowing for detailed analysis of their functional impact. We demonstrate that optogenetic activation of enteric cholinergic neurons rapidly modulates intestinal physiology. Interestingly, distinct neuronal firing patterns differentially modulate neuro-immunological gene expression and epithelial barrier integrity. Furthermore, diverse enteric neuronal lineages exert distinct regulatory roles. While cholinergic activation promotes gene-sets associated with type-2 immunity, tachykininergic enteric neurons differentially control mucosal defense programs. Remarkably, luminal introduction of the immunomodulatory bacterium C. ramosum significantly remodeled cholinergic-induced neuro-immunological transcription. These findings suggest that complex combinatorial signals delivered by gut microbes and enteric neurons are locally integrated to fine-tune intestinal immunity and barrier defense. Collectively, we provide a powerful platform for systematic discovery and mechanistic exploration of functional neuroimmune connections, and their potential modulation by drugs, microbes, or metabolites. Short abstractThe enteric nervous system senses microbiota-derived signals and orchestrates mucosal immunity and epithelial barrier functions. Mechanistic dissections of intestinal neuro-immune-microbiota communications remain challenging. We developed an optogenetics-integrated gut organ culture system for real-time neuronal stimulation and analysis. We revealed neuronal-specific activity patterns, which differentially regulate intestinal transcription and epithelial barrier integrity. Collectively, we provide a powerful platform to test neuroimmune connections and their potential modulation by drugs, microbes, or metabolites.

neuroscience↗

bioRxiv2023

Bacterial vitamin B6 required for post-embryonic development in C. elegans

Nutritional intake influences animal growth, reproductive capacity, and survival of animals. Under nutrition deficiency, animal developmental arrest occurs as an adaptive strategy to survive. However, the nutritional basis and the underlying nutrient sensing mechanism essential for initiating animal regrowth after developmental arrest remain to be explored. In Caenorhabditis elegans, larvae undergo early developmental arrest are stress resistant, and they require certain nutrients to initiate postembryonic development. Here, we investigated the developmental arrest in C. elegans feeding on Lactobacillus plantarum, and the rescue of the diapause state with trace supplementation of Escherichia coli. We performed a genome-wide screen using 3983 individual gene deletion E. coli mutants and identified E. coli genes that are indispensable for C. elegans larval growth on original not nutritionally sufficient bacteria L. plantarum. Among these crucial genes, we confirmed E. coli pdxH, and the downstream metabolite pyridoxal 5-P (PLP, Vitamin B6) as essential nutritional factors initiating C. elegans postembryonic development. Transcriptome results suggest that bacterial pdxH affects host development by coordinating host metabolic processes and PLP binding. Additionally, bacterial PLP may act as a cofactor for host tyrosine aminotransferase, thereby promoting the translocation of daf-16 to nucleus. Altogether, these results highlight the role of microbial metabolite PLP as a crucial micronutrient to recover postembryonic development in C. elegans.

developmental biology↗

bioRxiv2023

Integrated characterization of cell types, states and molecular programs in disseminated appendiceal neoplasms

Appendiceal neoplasms include a heterogeneous group of epithelial and non-epithelial tumors with varying malignant potential. Despite the rise in incidence of appendiceal neoplasms in recent years, limited progress has been made in the understanding, management and therapeutic treatment. To comprehensively characterize the cell types and molecular mechanisms driving cellular remodeling in epithelial appendiceal neoplasms, we performed an integrated scRNA-seq study. We analyzed 126,998 cells from 16 appendix samples (11 peritoneal metastases samples, 5 healthy controls) and identified 33 distinct cell types/cell states with seven being cancer-specific. Highlights of our study include the characterization of tumor cells across the histologic spectrum, the identification of a novel cancer-associated-fibroblast (CAF) subtypes (fiCAFs) and the identification of pathologic-specific cellular crosstalk between tumor cells and the tumor microenvironment (TME). Together, our study provides a high-resolution insight into the complexity and heterogeneity of epithelial appendiceal neoplasms and a valuable resource for therapeutic strategies.

genomics↗

bioRxiv2023

Bacterial purine metabolism modulates C. elegans development and stress tolerance via DAF-16 translocation

Purine homeostasis is crucial for cellular function and is a conserved metabolic network from prokaryotes to humans. While extensively studied in microorganisms like yeast and bacteria, the impact of perturbed dietary purine levels on animal development and balanced growth remains poorly understood. To investigate the mechanisms underlying this deficiency, we utilized Caenorhabditis elegans as the metazoan model. Through a high-throughput screening of an E. coli mutant library Keio collection, we identified 34 E. coli mutants that delay C. elegans development. Among these mutants, we found that E. coli purE gene is an essential genetic component that promotes host development in a dose-dependent manner. Additionally, we observed increased nuclear accumulation of the FoxO transcription factor DAF-16 when fed E. coli purE- mutants, suggesting the role of DAF-16 in response to nutrient, especially purine deficiency. RNA-seq analysis and phenotype assays revealed that worms fed the E. coli purE mutant exhibited elevated lifespan, thermotolerance, and pathogen resistance. These findings collectively suggest that perturbations in bacterial purine metabolism likely serve as a cue to promote development and activate the defense response in the nematode C. elegans through DAF-16 nuclear translocation.

developmental biology↗

bioRxiv2023

A conserved graft formation process in Picea abies and Arabidopsis thaliana identifies the PAT gene family as central regulators of wound healing

The widespread use of plant grafting has enabled eudicots and gymnosperms to join with closely related species and grow as one. Gymnosperms have dominated forests for over 200 million years and despite their economic and ecological relevance, we know little about how they graft. Here, we developed a micrografting method in conifers using young tissues that allowed efficient grafting between closely related species and distantly related genera. Conifer graft junctions rapidly connected vasculature and differentially expressed thousands of genes including auxin and cell wall-related genes. By comparing these genes to those induced during Arabidopsis thaliana graft formation, we found a common activation of cambium, cell division, phloem and xylem-related genes. A gene regulatory network analysis in Picea abies (Norway spruce) predicted that PHYTOCHROME A SIGNAL TRANSDUCTION 1 (PAT1) acted as a core regulator of graft healing. This gene was strongly upregulation during both P. abies and Arabidopsis grafting, and Arabidopsis mutants lacking PAT-genes failed to attach tissues or successfully graft. Complementing Arabidopsis PAT mutants with the P. abies PAT1 homolog rescued tissue attachment and enhance callus formation. Together, our data demonstrate an ability for young tissues to facilitate grafting with distantly related species and identifies the PAT gene family as conserved regulators of graft healing and tissue regeneration.

plant biology↗

bioRxiv2023

Auxin signaling in the cambium promotes tissue attachment and vascular development during Arabidopsis thaliana graft formation

The remarkable ability of plants to regenerate wounds is exemplified during the process of plant grafting when two plants are cut and joined together to grow as one. During graft healing, damaged tissues attach, cells proliferate and the vasculatures connect to form a graft union. The plant hormone auxin plays a central role and mutants perturbed in auxin response fail to successfully graft. Here, we investigated the role of individual cell types and their response to auxin during Arabidopsis thaliana graft formation. By employing an inducible misexpression system, we blocked auxin response in individual cell types using the bodenlos mutation. We found that auxin signaling in procambial tissues was critical for both successful tissue attachment and also for vascular differentiation. In addition, we found that auxin signaling was required for cell divisions of the procambial cells during graft formation. Loss of function mutants in cambial pathways also perturbed attachment and phloem reconnection. We propose that cambium and procambium are key tissues that allow both tissue attachment and vascular differentiation during successful grafting. Our study thus refines our knowledge of graft development and furthers our understanding of regeneration biology and the function of cambium.

plant biology↗

bioRxiv2023

Structural basis of CMKLR1 signaling induced by chemerin9

Chemokine-like receptor 1 (CMKLR1), also known as chemerin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, including macrophages and neutrophils. The signaling pathways of CMKLR1 can lead to both pro- and anti-inflammatory effects depending on the ligands and physiological contexts. To understand the molecular mechanisms of CMKLR1 signaling, we determined a high-resolution cryo-electron microscopy (cryo-EM) structure of the CMKLR1-Gi signaling complex with chemerin9, a nanopeptide agonist derived from chemerin, which induced complex phenotypic changes of macrophages in our assays. The cryo-EM structure, together with molecular dynamics simulations and mutagenesis studies, revealed the molecular basis of CMKLR1 signaling by elucidating the interactions at the ligand-binding pocket and the agonist-induced conformational changes. Our results are expected to facilitate the development of small molecule CMKLR1 agonists that mimic the action of chemerin9 to promote the resolution of inflammation.

biophysics↗

bioRxiv2023

PME-mediated pectin modifications promote haustoria initiation and xylem bridge development in the parasitic plant Phtheirospermum japonicum

O_LIParasitic plants produce cell wall modifying enzymes that are thought to be important for efficient host infection. Here, we investigated the role of pectin methylesterases (PMEs) and their inhibitors (PMEIs) during haustorium development in the facultative parasitic plant Phtheirospermum japonicum infecting Arabidopsis thaliana. C_LIO_LIWe employed immunohistochemistry to characterise tissue-specific changes in pectin methylesterification during haustorium development. We found putative PME and PMEI genes in P. japonicum and used genetic and transcriptomic approaches to identify those involved in haustorium development. C_LIO_LIOur results show tissue-specific changes in pectin methylesterification during haustorium development. De-methylesterified pectin correlated with haustorial intrusive cells whereas highly methylated pectin correlated with vascular tissues. We also found that inhibition of PME activity delayed haustoria development and xylem connectivity. Several PjPME and PjPMEI genes increased expression specifically during haustorium development but such increases did not occur when haustorium initiation or xylem connections were blocked by chemical treatment. C_LIO_LIThis study describes the importance of pectin modifications in parasitic plants during host infection. Our results suggest a dynamic regulation of PMEs and PMEIs contributes to haustoria initiation and to the establishment of xylem connections between parasite and host. C_LI

plant biology↗

bioRxiv2023

Emergence of distributed working memory in a human brain network model

Working memory is a fundamental cognitive function which allows to transiently store and manipulate relevant information in memory. While it has been traditionally linked to activity in specific prefrontal cortical areas, recent electrophysiological and imaging evidence has shown co-occurrent activities in different brain regions during working memory. To dissect the mechanisms behind the emergence of such distributed working memory activity in the human brain, we built and analyzed a detailed, data-constrained model of the human brain combining multiple sources of large-scale brain data. The model reveals the emergence of distributed working memory patterns which rely on long-range synaptic projections, differing from classical models where working memory emerges due to local recurrent connectivity. When compared to existing evidence regarding areas linked to working memory, our model explains almost 80% of the observed variability across brain areas. Our results predict important differences between the distributed working memory in human and non-human primates, and propose a potential solution for the debate regarding the role of early visual areas in working memory encoding. This work provides a novel approach to simulate the human brain which combines the richness of large-scale brain dynamics with the insight of mechanistic models of cognitive functions.

neuroscience↗