Biology subjects

Zhou, H.

Publications and source records attributed to Zhou, H..

At least 325 records · Page 18Linked to original sources

bioRxiv2021

Kinetics and mechanisms of catalyzed dual-E (antithetic) controllers

Homeostasis plays a central role in our understanding how cells and organisms are able to oppose environmental disturbances and thereby maintain an internal stability. During the last two decades there has been an increased interest in using control engineering methods, especially integral control, in the analysis and design of homeostatic networks. Several reaction kinetic mechanisms have been discovered which lead to integral control. In two of them integral control is achieved, either by the removal of a single control species E by zero-order kinetics ("single-E controllers"), or by the removal of two control species by second-order kinetics ("antithetic or dual-E control"). In this paper we show results when the control species E1 and E2 in antithetic control are removed enzymatically by ping-pong or ternary-complex mechanisms. Our findings show that enzyme-catalyzed dual-E controllers can work in two control modes. In one mode, one of the two control species is active, but requires zero-order kinetics in its removal. In the other mode, both controller species are active and both are removed enzymatically. Conditions for the two control modes are put forward and biochemical examples with the structure of enzyme-catalyzed dual-E controllers are discussed.

systems biology↗

bioRxiv2021

eIF4A2 targets developmental potency and histone H3.3 transcripts for translational control of stem cell pluripotency

Translational control has emerged as a fundamental regulatory layer of proteome complexity that governs cellular identity and functions. As initiation is the rate-limiting step of translation, we carried out an RNAi screen for key translation initiation factors required to maintain embryonic stem cell (ESC) identity. We identified eIF4A2 and defined its mechanistic action through Rps26-independent and -dependent ribosomes in translation initiation activation of mRNAs encoding pluripotency factors and the histone variant H3.3 with demonstrated roles in maintaining stem cell pluripotency. eIF4A2 also mediates translation initiation activation of Ddx6, which acts together with eIF4A2 to restrict the totipotent 2-cell transcription program in ESCs through Zscan4 mRNA degradation and translation repression. Accordingly, knockdown of eIF4A2 disrupts ESC proteome causing the loss of ESC identity. Collectively, we establish a translational paradigm of the protein synthesis of pluripotency transcription factors and epigenetic regulators imposed on their established roles in controlling pluripotency.

developmental biology↗

bioRxiv2021

Potential inhibitors for blocking the interaction of the coronavirus SARS-CoV-2 spike protein and its host cell receptor ACE2

The outbreak of SARS-CoV-2 continues to pose a serious threat to human health and social and economic stability. In this study, we established an anti-coronavirus drug screening platform based on the Homogeneous Time Resolved Fluorescence (HTRF) technology and the interaction between the coronavirus S protein and its host receptor ACE2. This platform is a rapid, sensitive, specific, and high throughput system. With this platform, we screened two compound libraries of 2,864 molecules and identified three potential anti-coronavirus compounds: tannic acid (TA), TS-1276 (anthraquinone), and TS-984 (9-Methoxycanthin-6-one). Our in vitro validation experiments indicated that TS-984 strongly inhibits the interaction of the coronavirus S-protein and the human cell ACE2 receptor. This data suggests that TS-984 is a potent blocker of the interaction between the S-protein and ACE2, which might have the potential to be developed into an effective anti-coronavirus drug. SIGNIFICANCEThe ongoing pandemic of COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a serious threat to public health worldwide. Given the urgency of the situation, researchers are attempting to repurpose existing drugs for treating COVID-19. In this present study, we screened two compound libraries of 2,864 molecules and identified a potent inhibitor (TS-984) for blocking the coronavirus S-protein and the human cell ACE2 receptor. TS-984 might have the potential to be developed into an effective anti-coronavirus drug for treating COVID-19.

pharmacology and toxicology↗

bioRxiv2021

HBV enveloped particle secretion is positively regulated by GRP78 through direct interaction with preS1

Hepatitis B virus (HBV) infection is a common cause of liver diseases worldwide. Existing drugs do not effectively eliminate HBV from infected hepatocytes; thus, novel curative therapies are needed. Enveloped-particle secretion is a key but poorly studied aspect of the viral life cycle. Here, we report that GRP78 positively regulates HBV enveloped-particle secretion. GRP78 is the specific target of preS1 binding; HBV can upregulate GRP78 in liver cell lines and sera from chronic hepatitis B patients. GRP78 promoted intact HBV-particle secretion in liver cell lines and an HBV transgenic-mouse model. Some peptides screened from preS1 via phage display could inhibit viral-particle secretion by interacting with GRP78 via hydrogen bonds and hydrophobic interactions, thereby disturbing the interaction with HBV particles. These results provide insight into enveloped-particle secretion in the HBV life cycle. GRP78 might be a potential target for HBV-infection treatment via restricting GRP78-preS1 interactions to block viral-particle secretion. IMPORTANCEHBV is a major human pathogen. The virus More than 250 million n individuals globally are chronically infected with HBV and can result in the infected personsabout 800,000 die for HBV-related disease annually. The mature HBV enveloped particles containing HBs and the relaxed circular (RC) DNA genome could secreted extracellularly as virions. And these enveloped virions serves as the infectious HBV particles for initiating a complete life cycle of the virus. Here, we show the GRP78 is the specific target of preS1 binding, and it could positive regulate HBV enveloped particle secretion in cell and HBV transgenic mice model. Furthermore, several peptides screened from preS1 and Phage screening could inhibit viral particle secretion by interacting with GRP78 and disturbing its interaction with HBV, and then block the life cycle of the virus. This has important implications for our understanding of the mechanisms of antivirals that target intact HBV particles secretion.

microbiology↗

bioRxiv2021

Spatial resolution of an integrated C4+CAM photosynthetic metabolism

C4 and CAM photosynthesis have repeatedly evolved in plants over the past 30 million years. Because both repurpose the same set of enzymes but differ in their spatial and temporal deployment, they have long been considered as distinct and incompatible adaptations. Remarkably, Portulaca contains multiple C4 species that perform CAM when droughted. Spatially explicit analyses of gene expression reveal that C4 and CAM systems are completely integrated in P. oleracea, with CAM and C4 carbon fixation occurring in the same cells and CAM-generated metabolites likely incorporated directly into the C4 cycle. Flux balance analysis corroborates the gene expression and predicts an integrated C4+CAM system under drought. This first spatially explicit description of a C4+CAM photosynthetic metabolism presents a new blueprint for crop improvement.

plant biology↗

bioRxiv2021

Single-cell Transcriptomic Analysis Reveals the Cellular Heterogeneity of Mesenchymal Stem Cells

Ex vivo-expanded mesenchymal stem cells (MSCs) have been demonstrated to be a heterogeneous mixture of cells exhibiting varying proliferative, multipotential, and immunomodulatory capacities. However, the exact characteristics of MSCs remain largely unknown. By single-cell RNA sequencing of 61,296 MSCs derived from bone marrow and Whartons jelly, we revealed five distinct subpopulations. The developmental trajectory of these five MSC subpopulations were mapped, revealing a differentiation path from stem-like active proliferative cells (APCs) to multipotent progenitor cells, followed by the branching into two paths - adipogenesis or osteochondrogenesis - and subsequent differentiation into unipotent prechondrocytes. The stem-like APCs, expressing the perivascular mesodermal progenitor markers CSPG4/MCAM/NES, uniquely exhibited strong proliferation and stemness signatures. Remarkably, the prechondrocyte subpopulation specifically expressed immunomodulatory genes and was able to suppress activated CD3+ T cell proliferation in vitro, supporting the role of this population in immunoregulation. In summary, our analysis mapped the heterogeneous subpopulations of MSCs and identified two subpopulations with potential functions in self-renewal and immunoregulation. Our findings advance the definition of MSCs by identifying the specific functions of its heterogeneous cellular composition, allowing for more specific and effective MSC application through the purification of its functional subpopulations.

cell biology↗

bioRxiv2021

Visual Attention in The Fovea and The Periphery during Visual Search

Active vision requires coordinated attentional processing across both foveal and peripheral receptive fields (RFs), yet the underlying neural dynamics and computational mechanisms remain poorly understood. Previous research has predominantly focused on attention in the visual periphery, leaving the role of foveal processing in naturalistic tasks largely unexplored. Here, we recorded neural activity from both foveal and peripheral RFs in areas V4 and IT of monkeys during free-gaze visual search among complex stimuli. We found robust feature-based attentional enhancements in foveal units, challenging the prevailing view that such modulation is predominantly peripheral. By integrating data from foveal and peripheral recordings, we revealed a non-uniform, dynamically distributed pattern of feature attention across the visual field. Behaviorally, foveal attentional enhancements promoted sustained or repeated fixations on targets, while peripheral attentional signals facilitated target detection and guidance of future saccades. These findings suggest that foveal and peripheral attention operate in a complementary fashion, and highlight the critical role of foveal feature attention in shaping global attention allocation and fixation behavior during active vision. This work advances our understanding of the neural computations that support complex visual search and underscores the need to account for foveal processing in models of attention.

neuroscience↗

bioRxiv2021

A large-scale genome and transcriptome sequencing analysis reveals the mutation landscapes induced by high-activity adenine base editors in plants

BackgroundThe high-activity adenine base editors (ABEs), engineered with the recently-developed tRNA adenosine deaminases (TadA8e and TadA9), show robust base editing activity but raise concerns about off-target effects. ResultsIn this study, we performed a comprehensive evaluation of ABE8e- and ABE9-induced DNA and RNA mutations in Oryza sativa. Whole-genome sequencing analysis of plants transformed with four ABEs, including SpCas9n-TadA8e, SpCas9n-TadA9, SpCas9n-NG-TadA8e, and SpCas9n-NG-TadA9, revealed that ABEs harboring TadA9 lead to a higher number of off-target A-to-G (A>G) single-nucleotide variants (SNVs), and that those harboring the CRISPR/SpCas9n-NG lead to a higher total number of off-target SNVs in the rice genome. An analysis of the T-DNAs carrying the ABEs indicated that the on-target mutations could be introduced before and/or after T-DNA integration into plant genomes, with more off-target A>G SNVs forming after the ABEs had integrated into the plant genome. Furthermore, we detected off-target A>G RNA mutations in plants with high expression of ABEs but not in plants with low expression of ABEs. The off-target A>G RNA mutations tended to cluster, while off-target A>G DNA mutations rarely clustered. ConclusionOur findings that Cas proteins, TadA variants, temporal expression of ABEs, and expression levels of ABEs contribute to ABE specificity in rice provide insight into the specificity of ABEs and suggest alternative ways to increase ABE specificity besides engineering TadA variants.

plant biology↗

bioRxiv2021

A framework for detecting noncoding rare variant associations of large-scale whole-genome sequencing studies

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare variants (RVs) associations with complex human traits. Variant set analysis is a powerful approach to study RV association, and a key component of it is constructing RV sets for analysis. However, existing methods have limited ability to define analysis units in the noncoding genome. Furthermore, there is a lack of robust pipelines for comprehensive and scalable noncoding RV association analysis. Here we propose a computationally-efficient noncoding RV association-detection framework that uses STAAR (variant-set test for association using annotation information) to group noncoding variants in gene-centric analysis based on functional categories. We also propose SCANG (scan the genome)-STAAR, which uses dynamic window sizes and incorporates multiple functional annotations, in a non-gene-centric analysis. We furthermore develop STAARpipeline to perform flexible noncoding RV association analysis, including gene-centric analysis as well as fixed-window-based and dynamic-window-based non-gene-centric analysis. We apply STAARpipeline to identify noncoding RV sets associated with four quantitative lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several noncoding RV associations in an additional 9,123 TOPMed samples.

genetics↗

bioRxiv2021

A trimeric NTD and RBD SARS-CoV-2 subunit vaccine induced protective immunity in CAG-hACE2 transgenic mice and rhesus macaques

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to significant public health, economic and social problems. Development of effective vaccines is still a priority to contain the virus and end the global pandemic. In this study, we reported that ReCOV, a recombinant trimeric NTD and RBD two-component SARS-CoV-2 subunit vaccine adjuvanted with BFA03 (an AS03-like squalene adjuvant), induced high levels of neutralizing antibodies against SARS-CoV-2 and the circulating variants in mice, rabbits and rhesus macaques. Notably, two-dose immunizations of ReCOV provided complete protection against challenge with SARS-CoV-2 in hACE2 transgenic mice and rhesus macaques, without observable antibody-dependent enhancement of infection. These results support further clinical development of ReCOV and the vaccine is currently being evaluated in a phase I clinical trial in New Zealand (NCT04818801).

immunology↗

bioRxiv2021

Multi-site phosphorylation of yeast Mif2/CENP-C promotes inner kinetochore assembly

Kinetochores control eukaryotic chromosome segregation by connecting chromosomal centromeres to spindle microtubules. Duplication of centromeric DNA necessitates kinetochore disassembly and subsequent reassembly on the nascent sisters. To search for a regulatory mechanism that controls the earliest steps of kinetochore assembly, we studied Mif2/CENP-C, an essential basal component. We found that Polo-like kinase (Cdc5) and Dbf4-dependent kinase (DDK) phosphorylate the conserved PEST region of Mif2/CENP-C and that this phosphorylation directs inner kinetochore assembly. Mif2 phosphorylation promotes kinetochore assembly in a reconstituted biochemical system, and it strengthens Mif2 localization at centromeres in cells. Disrupting one or more phosphorylation sites in the Mif2-PEST region progressively impairs cellular fitness and sensitizes cells to microtubule poisons. The most severe Mif2-PEST mutations are lethal in cells lacking otherwise non-essential Ctf19 complex factors. These data suggest that multi-site phosphorylation of Mif2/CENP-C is a robust switch that controls inner kinetochore assembly, ensuring accurate chromosome segregation.

cell biology↗

bioRxiv2021

DeePVP: Identification and classification of phage virion protein using deep learning

The poor annotation of phage virion protein (PVP) is the bottleneck of many areas of viral research, such as viral phylogenetic analysis, viral host identification and antibacterial drug design. Because of the high diversity of the PVP sequences, the PVP annotation remains a great challenging bioinformatic task. Based on deep learning, we present DeePVP that contains a main module and an extended module. The main module aims to identify the PVPs from non-PVP over a phage genome, while the extended module can further classify the predicted PVP into one of the ten major classes of PVP. Compared with the state-of-the-art tools that can distinguish PVP from non-PVP, DeePVPs main module performs much better, with an F1-score 9.05% higher in the PVP identification task. Compared with PhANNs, a tool that can further classify the predicted PVP into a specific class, the overall accuracy of DeePVPs extended module is approximately 3.72% higher in the PVP classification task. Two application cases on the genome of mycobacteriophage PDRPxv and Escherichia phage HP3 show that the predictions of DeePVP are much more reliable and can better reveal the compact PVP-enriched region, which may be conserved during the viral evolution process, over the phage genome.

bioinformatics↗

bioRxiv2021

Neutralization of Mu and C.1.2 SARS-CoV-2 Variants by Vaccine-elicited Antibodies in Individuals With and Without Previous History of Infection

Recently identified SARS-CoV-2 variants Mu and C.1.2 have mutations in the receptor binding domain and N- and C-terminal domains that might confer resistance to natural and vaccine-elicited antibody. Analysis with pseudotyped lentiviruses showed that viruses with the Mu and C.1.2 spike proteins were partially resistant to neutralization by antibodies in convalescent sera and those elicited by mRNA and adenoviral vector-based vaccine-elicited antibodies. Virus with the C.1.2 variant spike, which is heavily mutated, was more neutralization-resistant than that of any of variants of concern. The resistance of the C.1.2 spike was caused by a combination of the RBD mutations N501Y, Y449H and E484K and the NTD mutations. Although Mu and C.1.2 were partially resistant to neutralizing antibody, neutralizing titers elicited by mRNA vaccination remained above what is found in convalescent sera and thus are likely to remain protective against severe disease. The neutralizing titers of sera from infection-experienced BNT162b2-vaccinated individuals, those with a history of previous SARS-CoV-2 infection, were as much as 15-fold higher than those of vaccinated individuals without previous infection and effectively neutralized all of the variants. The findings demonstrate that individuals can raise a broadly neutralizing humoral response by generating a polyclonal response to multiple spike protein epitopes that should protect against current and future variants.

immunology↗

bioRxiv2021

Nuclear PHGDH promotes neutrophil recruitment to drive liver cancer progression

Metabolic dysregulation and the communications between cancer and immune cells are emerging as two essential features of malignant tumors. In this study, we observed that nuclear localization of phosphoglycerate dehydrogenase (PHGDH) associates with poor prognosis of liver cancer patients, and Phgdh is required for liver cancer progression in a mouse model. Unexpectedly, the impairment of Phgdh enzyme activity exerts a slight effect on liver cancer model, indicating PHGDH contributes to liver cancer progression mainly depending on its non-metabolic roles with nuclear location. PHGDH uses its ACT domain to bind cMyc in nuclear and forms a transactivation axis "PHGDH/p300/cMyc/AF9" which drives CXCL1/8 gene expression. Chemokines CXCL1/8 promotes neutrophils recruitment and then supports tumor associated macrophages (TAMs) filtration in liver, thereby urging liver cancer into advanced stages. Forced cytosolic location of PHGDH or destruction of the PHGDH/cMyc interaction abolishes the oncogenic function of nuclear PHGDH. Collectively, this study reveals a non-metabolic role of PHGDH with altered cellular location in liver cancer, and suggests a promising drug target for liver cancer therapy by targeting the interaction between PHGDH and "undruggable" cMyc.

cancer biology↗

bioRxiv2021

CAR modulates plasma membrane nano-organization and immune signaling downstream of RALF1-FERONIA ligand-receptor signaling system

O_LIThe receptor-like kinase (RLK) FERONIA (FER) senses peptide ligands in the plasma membrane (PM), modulates plant growth and development, and integrates biotic and abiotic stress signaling for downstream adaptive response. However, the molecular interplay of these diverse processes is largely unknown. C_LIO_LIHere, we show that FER, the receptor of Rapid Alkalinization Factor 1 (RALF1), physically interacts with C2 domain ABA-related (CAR) proteins to control the nano-organization of the PM in Arabidopsis. C_LIO_LIDuring this process, the RALF1-FER pathway upregulates CAR protein translation, and then more CAR proteins are recruited to PM. This acts as a rapid feedforward loop to stabilize PM liquid-ordered phase. FER interacts with and phosphorylates CARs, and reducing their lipid-binding ability, which breaks the feedback regulation CAR activity at latter time point. C_LIO_LISimilar to FER mutant, pentuple car14569 mutants inhibit flg22-induced FLS2-BAK1 immune complex formation, which depends on the integrity of nanodomains. O_LITogether, we propose that the FER-CAR module controls the formation of the PM nano-organization during RALF signaling through a self-contained amplifying loop including both positive and negative feedbacks. C_LI C_LI

plant biology↗

bioRxiv2021

Flagellin FLiC Enhances Resistance of Upland Cotton to Verticillium dahliae

The mechanism by which flagellin induces an immune response in plants is still unclear. The purpose of this study is to reveal the effect and mechanism of flagellin in inducing plants to produce an immune response to increase the resistance to Verticillium dahliae (VD). The full-length flagellin gene C (FliC) was cloned from an endophytic bacteria (Pseudomonas) in the root of upland cotton cultivar Zhongmiansuo 41. The FliC protein purified in vitro has 47.50% and 32.42% biocontrol effects on resistant and susceptible cotton cultivars, respectively. FLiC can induce allergic reactions in tobacco leaf cells and immune responses in cotton plants. Smearing FLiC to cotton and performing RNA-seq analysis, it is significantly enriched in the activity of positive ion transporters such as potassium ions and calcium ions (Ca2+), diterpenoid biosynthesis, phenylpropane biosynthesis and other disease-resistant metabolic pathways. FLiC inhibits the expression of calcium antiporter activity gene (GhCAA) to accelerate intracellular Ca2+ influx and stimulate the increase of intracellular hydrogen peroxide (H2O2) and nitric oxide (NO) content. The coordinated regulation of Ca2+, H2O2 and NO enhances disease resistance. The resistance of transgenic FLiC gene Arabidopsis to VD was significantly improved. The FLiC gene can be used as an anti-VD gene and as a regulator to improve resistance to VD.

pathology↗

bioRxiv2021

Beneficial Effects of Celastrol on Immune Balance by Modulating Gut Microbiota in Dextran Sodium Sulfate-Induced Ulcerative Colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by multi-factors including colonic inflammation and microbiota dysbiosis. Previous studies have indicated that Celastrol (CSR) has strong anti-inflammatory and immune-inhibitory effects. Here, we investigated the effects of CSR on colonic inflammation and the mucosal immunity in an experimental colitis model, and addressed the mechanism by which CSR preforms the protective effect. We characterized the therapeutic effects and the potential mechanism of CSR in treating UC using histological staining, intestinal permeability assay, cytokine assay, flow cytometry, fecal microbiota transplantation (FMT), 16S rRNA sequencing, untargeted metabolomics, and cell differentiation approaches. CSR administration significantly ameliorated DSS-induced colitis, as evidenced by the recovery of body weight and colon length, decreased disease activity index (DAI) score, as well as decreased intestinal permeability. CSR down-regulated the secretion of proinflammatory cytokines, upregulated the anti-inflammatory mediators, and improved the balances of Treg/Th1 and Treg/Th17 to maintain colonic immune homeostasis. However, the protective effects of CSR disappeared when the antibiotic cocktail was applied to deplete the gut microbiota, and the gut microbiota-mediated effect was confirmed by FMT. Furthermore, CSR treatment increased the gut microbiota diversity and composition, and raised the metabolic productions of pyruvate and adenosine, which probably involve in gut microbiota mediated protective effect. In conclusion, CSR ameliorates colonic inflammation in a gut microbiota-dependent manner. The underlying protective mechanism is associated with the rectified Treg/Th1 and Treg/Th17 balance, and increased pyruvate and adenosine production. The study provided the solid evidence that CSR might be a promising therapeutic drug for UC.

microbiology↗

bioRxiv2021

Mitochondrial UPR negatively regulates wounding-induced innate immune response in C. elegans epidermis

Tissue damage elicits a rapid innate immune response that is essential for efficient wound healing and survival of metazoans. It is well known that p38 MAPK kinase, TGF-{beta}, and hemidesmosome signaling pathways have been involved in wounding-induced innate immunity in C. elegans. Here, we find that loss of function of ATFS-1 increased innate immune response while an elevated level of mitochondrial unfolded protein response (mitoUPR) inhibits the innate immune response upon epidermal wounding. Epidermal wounding triggers the nucleus export of ATFS-1 and inhibits themitoUPR in C. elegans epidermis. Moreover, genetic analysis suggests that ATFS-1 functions upstream of the p38 MAP kinase, TGF-{beta} and DAF-16 signaling pathways in regulating AMPs induction. Thus, our results suggest that the mitoUPR function as an intracellular signal required to fine-tune innate immune response after tissue damage. Highlights-- ATFS-1 inhibits the wounding-induced innate immune response in C. elegans -- mitoUPR inhibits wounding-induced innate immune response -- Epidermal wounding induces downregulation of ATFS-1 in the epidermis -- mitoUPR acts upstream of p38MAPK and TGF-{beta} pathways to regulate innate immunity

cell biology↗