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Zhao, W.

Publications and source records attributed to Zhao, W..

At least 181 records · Page 10Linked to original sources

E3 ligase ASB3 downregulates antiviral innate immunity by targeting MAVS for ubiquitin-proteasomal degradation

E3 ubiquitin ligases are very important to regulate antiviral immunity during viral infection. Here, we discovered that Ankyrin repeat and SOCS box-containing protein 3 (ASB3), an E3 ligase, are upregulated in the presence of RNA viruses, particularly Influenza A virus (IAV). Notably, overexpression of ASB3 inhibits type I IFN (IFN-I) responses induced by Sendai virus (SeV) and H9N2, and ablation of ASB3 restores SeV and H9N2 infection-mediated transcription of IFN-{beta} and its downstream interferon-stimulated genes (ISGs). Interestingly, animals lacking ASB3 showed a decreased susceptibility to H9N2 and PR8 infections. Mechanistically, ASB3 interacts with MAVS and directly mediates K48-linked polyubiquitination and degradation of MAVS at K297, thereby inhibiting the phosphorylation levels of TBK1 and IRF3, downregulating downstream antiviral signaling. These findings establish ASB3 as a critical negative regulator in controlling the activation of antiviral signaling and describe a novel function of ASB3 that has not been previously reported. IMPORTANCEIAV is a significant zoonotic pathogen that causes infections of the respiratory system. Hosts have evolved multiple strategies to defend against IAV infection. However, not all host proteins play an active defense role. In this study, we found that the E3 ligase ASB3 regulates antiviral immunity by manipulating MAVS stability. Briefly, overexpression of ASB3 degrades MAVS, thereby promoting viral replication. In contrast, ASB3 deletion restores MAVS expression, upregulating IFN-I responses. Additional research revealed that ASB3 mediates the K48-linked polyubiquitination of MAVS at K297, resulting in ASB3 being degraded via the ubiquitin-proteasome pathway. These findings reveal, for the first time, a novel mechanism by which ASB3 negatively regulates antiviral immunity and provides a potential target for anti-IAV drug development.

immunology↗

Consensus scHPF Identifies Cell Type-Specific Drug Responses in Glioma by Integrating Large-Scale scRNA-seq

Single-cell transcriptomic analyses now frequently involve elaborate study designs including samples from multiple individuals, experimental conditions, perturbations, and batches from complex tissues. Dimensionality reduction is required to facilitate integration, interpretation, and statistical analysis. However, these datasets often include subtly different cellular subpopulations or state transitions, which are poorly described by clustering. We previously reported a Bayesian matrix factorization algorithm called single-cell hierarchical Poisson factorization (scHPF) that identifies gene co-expression patterns directly from single-cell RNA-seq (scRNA-seq) count matrices while accounting for transcript drop-out and noise. Here, we describe consensus scHPF, which analyzes scHPF models from multiple random initializations to identify the most robust gene signatures and automatically determine the number of factors for a given dataset. Consensus scHPF facilitates integration of complex datasets with highly multi-modal posterior distributions, resulting in factors that can be uniformly analyzed across individuals and conditions. To demonstrate the utility of consensus scHPF, we performed a meta-analysis of a large-scale scRNA-seq dataset from drug-treated, human glioma slice cultures generated from surgical specimens across three major cell types, 19 patients, 10 drug treatment conditions, and 52 samples. In addition to recapitulating previously reported cell type-specific drug responses from smaller studies, consensus scHPF identified disparate effects of the topoisomerase poisons etoposide and topotecan that are highly consistent with the distinct roles and expression patterns of their respective protein targets.

genomics↗

Multifrequency control of Faraday wave bioassembly for constructing multiscale hPSC-derived neuronal networks

Bioassembly is recently regarded as a critical alternative biofabrication technical route to bioprinting since it can directly manipulate millions of live cells to form multicellular structures with close intercellular proximity, improving contact-dependent cell communication and promoting the emergence of tissue-specific functions. However, acoustic bioassembly techniques are currently limited to generating cytoarchitecture with a single characteristic length which cannot faithfully mimic the multiscale cellular structures in native tissues. To overcome this challenge, herein we report a novel acoustic bioassembly technique that employs multifrequency control of Faraday waves to form multiscale cellular structures. By superimposing multiple sine wave signals with proper amplitude ratios, Faraday waves containing multiple wavelengths can be induced and enabled to generate multiscale structures in few seconds. Using this technique, we construct functional neuronal networks with multiscale connectivity that display spontaneous neuroelectrical activities. We anticipate this technique will find wide applications in tissue engineering and regenerative medicine.

bioengineering↗

Cellular COPI components promote geminivirus infections by facilitating the chloroplast localization of viral C4/AC4 proteins

Geminiviruses are a family of viruses that infect numerous crops and cause extensive agricultural losses worldwide. During viral infection, geminiviral C4/AC4 proteins relocate from the plasma membrane (PM) to chloroplasts, where they inhibit chloroplast-mediated host defense, including the biosynthesis of salicylic acid (SA). However, how are C4/AC4 proteins transported to chloroplasts is unknown. We report here that the Coat Protein I (COPI) components play a critical role in redistributing Tomato yellow leaf curl virus (TYLCV) C4 protein to chloroplasts. TYLCV C4 interacts with the {beta} subunit of COPI, and the coexpression of both in Nicotiana benthamiana cells promotes the enrichment of C4 in chloroplasts, which also occurs during TYLCV infection and is blocked by an inhibitor of the COPI pathway. Overexpression of COPI components promotes but knockdown of gene expression inhibits TYLCV infection. The COPI pathway plays similar roles in C4/AC4 transport and infections of other geminiviruses, including Beet curly top virus and East African cassava mosaic virus. Our results identify an unconventional role of the COPI pathway in protein trafficking to chloroplasts during geminiviruses infections in plants, and suggest a broad-spectrum antiviral strategy in controlling geminiviruses by manipulating COPI components.

plant biology↗

Structural insights into the distinct protective mechanisms of human antibodies targeting ZIKV NS1

Zika virus (ZIKV) Non-structural protein 1 (NS1) plays an essential role in viral replication and immune evasion. Our understanding of the differential protective mechanism of NS1-targeting antibodies is limited. Here, we determined the cryoEM structures of ZIKV NS1 in complex with two group antibodies at 2.6-2.9[A]. Group I antibodies (3G2 and 4B8) potently recognize cell surface form of NS1 and multiple oligomeric forms of NS1 by occupy the epitopes on outer surface of dimeric NS1. IgG and Fab from group I antibodies completely abrogate sNS1-mediated endothelial dysfunction in vitro. Group II antibodies (4F10, 2E11, and 14G5) recognize the previously reported epitopes in distal end of the {beta}-ladder domain of monomeric NS1, and their blockade efficiency depends on the affinity with NS1 protein. These findings elucidate the correlation between the epitope recognition and the protective efficacy of anti-NS1 antibodies and highlight the distinct mechanisms of therapeutic potential of 3G2 and 4B8.

microbiology↗

RCoV19: A One-stop Hub for SARS-CoV-2 Genome Data Integration, Variants Monitoring, and Risk Pre-warning

The Resource for Coronavirus 2019 (RCoV19, https://ngdc.cncb.ac.cn/ncov/) is an open-access information resource dedicated to providing valuable data on the genomes, mutations, and variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this updated implementation of RCoV19, we have made significant improvements and advancements over the previous version. Firstly, we have implemented a highly refined genome data curation model. This model now features an automated integration pipeline and optimized curation rules, enabling efficient daily updates of data in RCoV19. Secondly, we have developed a global and regional lineage evolution monitoring platform, alongside an outbreak risk pre-warning system. These additions provide a comprehensive understanding of SARS-CoV-2 evolution and transmission patterns, enabling better preparedness and response strategies. Thirdly, we have developed a powerful interactive mutation spectrum comparison module. This module allows users to compare and analyze mutation patterns, assisting in the detection of potential new lineages. Furthermore, we have incorporated a comprehensive knowledgebase on mutation effects. This knowledgebase serves as a valuable resource for retrieving information on the functional implications of specific mutations. In summary, RCoV19 serves as a vital scientific resource, providing access to valuable data, relevant information, and technical support in the global fight against COVID-19.

bioinformatics↗

Context-aware single-cell multiome approach identified cell-type specific lung cancer susceptibility genes

Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.

genomics↗

Multiplexed CRISPR gene editing in primary human islet cells with Cas9 ribonucleoprotein

Successful genome editing in primary human islets could reveal features of the genetic regulatory landscape underlying {beta} cell function and diabetes risk. Here, we describe a CRISPR-based strategy to interrogate functions of predicted regulatory DNA elements using electroporation of a complex of Cas9 ribonucleoprotein (Cas9 RNP) and guide RNAs into primary human islet cells. We successfully targeted coding regions including the PDX1 exon 1, and non-coding DNA linked to diabetes susceptibility. CRISPR/Cas9 RNP approaches revealed genetic targets of regulation by DNA elements containing candidate diabetes risk SNPs, including an in vivo enhancer of the MPHOSPH9 gene. CRISPR/Cas9 RNP multiplexed targeting of two cis-regulatory elements linked to diabetes risk in PCSK1, which encodes an endoprotease crucial for insulin processing, also demonstrated efficient simultaneous editing of PCSK1 regulatory elements, resulting in impaired {beta} cell PCSK1 regulation and insulin secretion. Multiplex CRISPR/Cas9 RNP provides powerful approaches to investigate and elucidate human islet cell gene regulation in health and diabetes.

cell biology↗

OBIA: An Open Biomedical Imaging Archive

With the development of artificial intelligence (AI) technologies, biomedical imaging data play an important role in scientific research and clinical application, but the available resources are limited. Here we present Open Biomedical Imaging Archive (OBIA), a repository for archiving biomedical imaging and related clinical data. OBIA adopts five data objects (Collection, Individual, Study, Series, and Image) for data organization, accepts the submission of biomedical images of multiple modalities, organs, and diseases. In order to protect personal privacy, OBIA has formulated a unified de-identification and quality control process. In addition, OBIA provides friendly and intuitive web interface for data submission, browsing and retrieval, as well as image retrieval. As of September 2023, OBIA has housed data for a total of 937 individuals, 4136 studies, 24,701 series, and 1,938,309 images covering 9 modalities and 30 anatomical sites. Collectively, OBIA provides a reliable platform for biomedical imaging data management and offers free open access to all publicly available data to support research activities throughout the world. OBIA can be accessed at https://ngdc.cncb.ac.cn/obia.

bioinformatics↗

Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma

Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target because of its dual roles in proliferation and invasion. The clinical utility of KIF11 inhibitors has been limited by drug resistance, which has mainly been studied in animal models. We used multiplexed lineage tracing barcodes and scRNA-seq to analyze drug resistance time courses for patient-derived GBM neurospheres treated with ispinesib, a potent KIF11 inhibitor. Similar to GBM progression in patients, untreated cells lost their neural lineage identity and transitioned to a mesenchymal phenotype, which is associated with poor prognosis. In contrast, cells subjected to long-term ispinesib treatment exhibited a proneural phenotype. We generated patient-derived xenografts to show that ispinesib-resistant cells form less aggressive tumors in vivo, even in the absence of drug. Finally, we used lineage barcodes to nominate drug combination targets by retrospective analysis of ispinesib-resistant clones in the drug-naive setting and identified drugs that are synergistic with ispinesib.

cancer biology↗

Parental dietary vitamin B12 causes intergenerational growth acceleration and protects offspring from pathogenic microsporidia and bacteria

The parental environment of C. elegans can have lasting effects on progeny development and immunity. Vitamin B12 exposure in C. elegans has been shown to accelerate development and to reduce killing caused by pathogenic Pseudomonas aeruginosa. Vitamin B12 is also maternally transferred to offspring, suggesting a potential role in progeny development. However, the intergenerational effects of vitamin B12 in C. elegans remain uncharacterized. Here, we show that parental exposure to dietary vitamin B12 or vitamin B12-producing bacteria results in offspring with accelerated growth. We find that this inherited acceleration phenotype is vitamin B12 dose-dependent and persists for a single generation. Progeny from vitamin B12 treated parents display reduced levels of the acdh-1 dietary sensor in the earliest larval stages, with expression of this protein recovering into adulthood. During infection with Nematocida parisii, a natural microsporidian pathogen, the offspring of worms fed vitamin B12 diets have better reproductive fitness. However, vitamin B12 diet does not affect offspring infection levels, suggesting that accelerated development provides tolerance to microsporidian infection. Offspring from parents exposed to vitamin B12 are also protected from killing by pathogenic Pseudomonas vranovensis. Vitamin B12-induced intergenerational growth acceleration and N. parisii tolerance is dependent upon the methionine biosynthesis pathway. However, protection from P. vranovensis killing is mediated through both the methionine biosynthesis and the propionyl-CoA breakdown pathways. Our results show how parental microbial diet impacts progeny development through the transfer of vitamin B12 which results in accelerated growth and pathogen tolerance.

genetics↗

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has a remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signaling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

immunology↗

OBMeta: a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases

Gut dysbiosis is closely associated with obesity and related metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). The gut microbial features and biomarkers have been increasingly investigated in recent studies, which require further validation due to the limited sample size and various confounding factors that may affect microbial compositions. So far, it lacks a comprehensive bioinformatics pipeline providing automated statistical analysis and integrating independent studies for cross validation simultaneously. OBMeta aims to streamline the standard metagenomics data analysis from diversity analysis, comparative analysis, functional analysis, to co-abundance network analysis. In addition, a curated database has been established with a total of 88 public research projects, covering three different phenotypes (Obesity, T2D, and NAFLD) and more than five different intervention strategies (exercise, diet, probiotics, medication, and surgery). With OBMeta, users can not only analyze their own research projects, but also search and match public datasets of interest for cross-project validation. Moreover, OBMeta provides cross-phenotype and cross-intervention-based advanced validation that maximally supports preliminary findings from an individual study. To summarize, OBMeta is a comprehensive web server to analyze and validate gut microbial features and biomarkers for obesity-associated metabolic diseases. OBMeta is freely available at: http://obmeta.met-bioinformatics.cn/. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/552363v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1b58a9borg.highwire.dtl.DTLVardef@19efa47org.highwire.dtl.DTLVardef@418597org.highwire.dtl.DTLVardef@1a9bc3c_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

Muscle-restricted Nox4 knockout partially corrects muscle contractility following spinal cord injury in mice

Spinal cord injury (SCI) results in severe atrophy of skeletal muscle in paralyzed regions, and a decrease in the force generated by muscle per unit of cross-sectional area. Oxidation of skeletal muscle ryanodine 1 receptors (RyR1) reduces contractile force due to reduced binding of calstabin 1 to RyR1 together with altered gating of RyR1. One cause of RyR1 oxidation is NADPH oxidase 4 (Nox4). We have previously shown that in rats, RyR1 was oxidized and bound less calstabin 1 at 56 days after spinal cord injury (SCI) by transection. Here, we used a conditional knock-out mouse model of Nox4 in muscle to investigate the role of Nox4 in reduced muscle specific force after SCI. Peak twitch force in control mice after SCI was reduced by 42% compared to sham-operated controls but was increased by approximately 43% in SCI Nox4 conditional KO mice compared to SCI controls although it remained less than that for sham-operated controls. Unlike what observed in rats, after SCI the expression of Nox4 was not increased in gastrocnemius muscle and binding of calstabin 1 to RyR1 was not reduced in this muscle. The results suggest a link between Nox4 expression in muscle tissue and reduction in muscle twitch force, however further studies are needed to understand the mechanistic basis for this linkage.

physiology↗

ASB3 expression aggravates inflammatory bowel disease by targeting TRAF6 protein stability and affecting the intestinal microbiota

E3 ubiquitin ligase (E3) plays a vital role in regulating inflammatory responses by mediating ubiquitination. Previous studies have shown that ankyrin repeat and SOCS box-containing protein 3 (ASB3) is involved in immunomodulatory functions associated with cancer. However, the impact of ASB3 on the dynamic interplay of microbiota and inflammatory responses in inflammatory bowel disease (IBD) is unclear. Here we systematically identify the E3 ligase ASB3 as a facilitative regulator in the development and progression of IBD. ASB3-/- mice are resistant to DSS-induced colitis. I{kappa}B phosphorylation levels and production of proinflammatory factors IL-1{beta}, IL-6, and TNF- were reduced in colonic tissues of ASB3-/- mice compared to WT mice. This colitis-resistant phenotype was suppressed after coprophagic microbial transfer and reversed after combined antibiotic clearance of the microbiota. Mechanistically, ASB3 specifically catalyzes K48-linked polyubiquitination of TRAF6 in IECs. In contrast, in ASB3-deficient organoids, the integrity of the TRAF6 protein is shielded, consequently decelerating the onset of intestinal inflammation. Taken together, Our findings demonstrates that ASB3 is associated with dysregulation of the colitis microbiota and promotes proinflammatory factors production by disrupting the TRAF6 stability. Strategies to limit the protein level of ASB3 in intestinal epithelial cells may help in the treatment of colitis.

immunology↗

A large sensory and multi-omics evaluation unraveled chemical and genetic basis of orange flavor

Sweet orange (Citrus sinensis) exhibits limited genetic diversity and high susceptibility to Huanglongbing (HLB). New HLB-tolerant orange-like hybrids are promising alternatives. However, the genetic control of key flavor compounds in oranges remains unknown. Evaluating 179 juice samples, including oranges, mandarins, Poncirus trifoliata and hybrids, distinct volatile compositions were found. A random forest model predicted untrained samples with 78% accuracy and identified 26 compounds crucial for orange flavor. Notably, seven esters--methyl hexanoate, ethyl hexanoate, ethyl 3-hydroxyhexanoate, ethyl octanoate, methyl butanoate, ethyl butanoate, and ethyl 2-methylbutanoate--differentiated orange from mandarin. Cluster analysis showed six esters with shared genetic control. Differential gene expression analysis identified CsAAT1, an alcohol acyltransferase responsible for ester production in orange. Its activity was validated through overexpression assays. A SNP-based DNA marker in the CDS region accurately predicted phenotypes. This study enhances our understanding of orange flavor compounds, their biosynthetic pathways, and expands breeding options for orange-like cultivars.

genetics↗

Pan-genome and Haplotype Map of Cultivars and Their Wild Ancestors Provides Insights into Adaptive Evolution of Cassava (Manihot esculenta Crantz)

Cassava is the most important starch sources, a tropical model crop. We constructed nearly T2T genomes of cultivar AM560, wild ancestors FLA4047 and W14, pan-genome of 24 representatives and a clarified evolutionary tree with 486 accessions. Comparison of SVs and SNVs between the ancestors and cultivated cassavas revealed predominant expansion, contraction of genes and gene families. Significantly selective sweeping occurred in the cassava genomes in 122 footprints with 1,519 candidate domestication genes. We identified selective mutations in MeCSK and MeFNR3 promoting photoreaction associated with MeNADP-ME of C4 assimilation in modern cassava. Co-evolved retardation of floral primordia and initiation of storage roots arose from MeCOL5 mutants with altered bindings to MeFT1, MeFT2 and MeTFL2. MebHLHs evolved to regulate the biosynthesis, transport and endogenous remobilization of cyanogenic glucosides, with new functionalities of MeMATE1, MeGTR in selected sweet cassava. These findings enhanced comprehensive knowledge and database on the evolution and breeding of cassava. HIGHLIGHTSO_LIThree nearly T2T cassava genomes of cultivar AM560 and its wild ancestors FLA4047 and W14. C_LIO_LIA species-level cassava panSV haplotype map across 346,322 structural variations over 31,362 gene families and 96,032,008 SNPs and InDels variations globally and a clarified evolutionary tree with 486 accessions. C_LIO_LISelective mutations in MeCSK and MeFNR3 promoted photoreaction associated with MeNADP-ME of C4 assimilation shaped the C3-C4 intermediate photosynthesis of modern cassava. C_LIO_LICoevolution of floral primordia contrary to initiated storage root is pivotal for the domestication of cassava, and arose from MeCOL5 mutants altered the binding with MeFT1, MeFT2 (SP6A), and MeTFL2. C_LI

systems biology↗

Polygenic basis of strong and rapid flowering time response to environment perturbations in wild Arabidopsis thaliana population

Despite the importance in understanding the impact of climate change, the genetics of rapid response to changing environments and its role in adaptive evolution remains elusive. Here, we studied flowering time response to environment changes using 514 Arabidopsis thaliana worldwide accessions with re-sequencing genomes and flowering time measurements from ten unique environments with variable temperature, drought, daylight and competition stresses. We revealed a polygenic basis of flowering time mean and plasticity, underpinned by 52 mean and plasticity QTL. Widespread interaction between mean QTL, polygenic background and surrounding environments considerably altered the amount of additive genetic variance and allelic effects of detected QTL. This caused variability in phenotype plasticity and across environment variation in genetic variance, resulting in rapid flowering time response to environment perturbations. In addition, the plastic alleles showed a higher correlation with the environment factors than that from randomly sampled alleles, suggesting a potential role in climate adaptation. We therefore proposed a polygenic interaction model, whereby large effect QTL and polygenic background simultaneously interacted with the surrounding environment, underlying rapid response to changing environments. Results from our study thus provided deeper insights into the genetics of plasticity, with potential benefit in genomic selection of crops in heterogeneous environments and predicting changes in species distribution and the evolutionary trajectory of wild populations.

genetics↗