Biology subjects

Zhao, J.

Publications and source records attributed to Zhao, J..

At least 469 records · Page 26Linked to original sources

bioRxiv2021

SARS-CoV-2-Triggered Mast Cell Rapid Degranulation Induces Alveolar Epithelial Inflammation and Lung Injury

SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. Here we showed that SARS-CoV-2-triggeed MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation alterred various signaling pathways in alveolar epithelial cells, particularly, led to the production of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/449680v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@899996org.highwire.dtl.DTLVardef@1c26c0eorg.highwire.dtl.DTLVardef@1442cdcorg.highwire.dtl.DTLVardef@dd4204_HPS_FORMAT_FIGEXP M_FIG C_FIG In BriefSARS-CoV-2 triggers an immediate mast cell (MC) degranulation, which initiates the alveolar epithelial inflammation and disrupts the tight junction. MC stabilizers that block degranulation reduce virus-induced lung inflammation and injury. HighlightsO_LIThe binding of RBD of Spike protein of SARS-CoV-2-to ACE2 receptor protein triggers an immediate MC degranulation C_LIO_LIMC degranulation induces transcriptomic changes include an upregulated inflammatory signaling and a downregulated cell-junction signaling C_LIO_LIMC degranulation leads to alveolar epithelial inflammation and disruption of tight junctions C_LIO_LIMC stabilizer that inhibits degranulation reduces SARS-CoV-2-induced lung inflammation and injury in vivo C_LI

microbiology↗

bioRxiv2021

Telocytes regulate macrophages in periodontal disease

BackgroundTelocytes (TCs) or interstitial cells are characterised in vivo by their long projections that contact other cell types. Although telocytes can be found in many different tissues in luding the heart1, lung2 and intestine3, their tissue-specific roles are poorly understood. Here we identify a cell signalling role for telocytes in the periodontium whereby telocytes regulate macrophage activity. MethodsWe performed scRNA-seq and lineage tracing to identify TCs in mouse periodontium in homeostasis and periodontitis and carried out HGF signalling inhibition experiments using Tivantinib. ResultsWe demonstrated that TCs are quiescent in homeostasis, however, they proliferate and serve as a major source of HGF in periodontitis. Macrophages receive telocyte-derived HGF signals and shift from an M1 to a M1/M2 hybrid state. ConclusionsOur results reveal the source of HGF signals in periodontal tissue and provide new insights into the function of TCs in regulating macrophage behaviour in periodontitis through HGF/c-Met cell signalling, that may provide a novel approach in periodontitis treatment. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/446871v2_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@12e0491org.highwire.dtl.DTLVardef@2de4d0org.highwire.dtl.DTLVardef@10936a8org.highwire.dtl.DTLVardef@1e36089_HPS_FORMAT_FIGEXP M_FIG A population of telocytes (TC) have been identified in the periodontium. They are quiescent in homeostasis, however, in periodontitis, they are activated and send HGF signals to LPS activated iNOS+ (M1) macrophages. Macrophages receive the HGF signals via c-Met, which results in the expression of M2 marker Arg1, representing in an increase of M1/M2 hybrid macrophages. The expression of Arg1 can be inhibited by a HGF/c-Met selective inhibitor Tivantinib. C_FIG

cell biology↗

bioRxiv2021

Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment

Background & AimsPancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma, which contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. MethodsWe used a dual recombinase mouse model to delete Hif1 or Hif2 in -smooth muscle actin (SMA)-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF-Hif2 expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, a HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. ResultsCAF-specific deletion of HIF2, but not HIF1, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = 0.0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. ConclusionsTogether, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.

cancer biology↗

bioRxiv2021

Single-dose AAV-based vaccine induces a high level of neutralizing antibodies and provides long-term protection against SARS-CoV-2 in rhesus macaques

Coronavirus disease 2019 (COVID-19), which is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, continues to threaten global public health. Developing a vaccine that only requires single immunization but provides long-term protection for the prevention and control of COVID-19 is important. Here, we developed an adeno-associated virus (AAV)-based vaccine expressing a stable receptor-binding domain (SRBD) protein. The vaccine requires only a single shot but provides effective neutralizing antibodies (NAbs) over 598 days in rhesus macaques (Macaca mulatta). Importantly, our results showed that the NAbs were kept in high level and long lasting against authentic wild-type SARS-CoV-2, Beta, Delta and Omicron variants using plaque reduction neutralization test. Of note, although we detected pre-existing AAV2/9 antibodies before immunization, the vaccine still induced high and effective NAbs against COVID-19 in rhesus macaques. AAV-SRBD immune serum also efficiently inhibited the binding of ACE2 with RBD in the SARS-CoV-2 B.1.1.7 (Alpha), B.1.351 (Beta), P.1/P.2 (Gamma), B.1.617.2 (Delta), B.1.617.1/3(Kappa), and C.37 (Lambda) variants. Thus, these data suggest that the vaccine has great potential to prevent the spread of SARS-CoV-2.

immunology↗

bioRxiv2021

Retro Drug Design: From Target Properties to Molecular Structures

To generate drug molecules of desired properties with computational methods is the holy grail in pharmaceutical research. Here we describe an AI strategy, retro drug design, or RDD, to generate novel small molecule drugs from scratch to meet predefined requirements, including but not limited to biological activity against a drug target, and optimal range of physicochemical and ADMET properties. Traditional predictive models were first trained over experimental data for the target properties, using an atom typing based molecular descriptor system, ATP. Monte Carlo sampling algorithm was then utilized to find the solutions in the ATP space defined by the target properties, and the deep learning model of Seq2Seq was employed to decode molecular structures from the solutions. To test feasibility of the algorithm, we challenged RDD to generate novel drugs that can activate opioid receptor (MOR) and penetrate blood brain barrier (BBB). Starting from vectors of random numbers, RDD generated 180,000 chemical structures, of which 78% were chemically valid. About 42,000 (31%) of the valid structures fell into the property space defined by MOR activity and BBB permeability. Out of the 42,000 structures, only 267 chemicals were commercially available, indicating a high extent of novelty of the AI-generated compounds. We purchased and assayed 96 compounds, and 25 of which were found to be MOR agonists. These compounds also have excellent BBB scores. The results presented in this paper illustrate that RDD has potential to revolutionize the current drug discovery process and create novel structures with multiple desired properties, including biological functions and ADMET properties. Availability of an AI-enabled fast track in drug discovery is essential to cope with emergent public health threat, such as pandemic of COVID-19.

bioinformatics↗

bioRxiv2021

Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used solely for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLN. A low dose of I-R-F induces not only high titer long-lasting neutralizing antibodies but also comprehensive T cell responses than RBD, and even provides comprehensive protection in one dose without adjuvant. This study shows that the I-R-F vaccine provides rapid and complete protection throughout upper and lower respiratory tracts against high dose SARS-CoV-2 challenge in rhesus macaques. Due to its potency and safety, this engineered vaccine may become one of the next-generation vaccine candidates in the global race to defeat COVID-19.

immunology↗

bioRxiv2021

Coil-to-Helix Transition at the Nup358-BicD2 Interface for Dynein Recruitment and Activation

Nup358, a nuclear pore protein, facilitates a nuclear positioning pathway that is essential for many biological processes, including neuromuscular and brain development. Nup358 binds and activates the auto-inhibited dynein adaptor Bicaudal D2 (BicD2), which in turn recruits and activates the dynein machinery to position the nucleus. However, the molecular details of the Nup358/BicD2 interaction remain poorly understood. Here, we show that a minimal Nup358 domain activates dynein/dynactin/BicD2 for processive motility on microtubules. Using nuclear magnetic resonance (NMR) titration and chemical exchange saturation transfer (CEST), a Nup358 helix encompassing residues 2162-2184 was identified, which transitioned from random coil to an -helix upon BicD2-binding and formed the core of the Nup358-BicD2 interface. Mutations in this region of Nup358 decreased the Nup358/BicD2 interaction, resulting in decreased dynein recruitment and impaired motility. BicD2 thus recognizes the cargo adaptor Nup358 though a "cargo recognition -helix", a structural feature that may stabilize BicD2 in its activated state and promote processive dynein motility.

biophysics↗

bioRxiv2021

Mechanistic Insights of High Temperature-Interfered Meiosis in Autotetraploid Arabidopsis thaliana

Environmental temperature has a huge impact on multiple meiosis processes in flowering plants. Polyploid plants derived from whole genome duplication are believed to have an enhanced abiotic stress tolerance. In this study, the impact of high temperatures on male meiosis in autotetraploid Arabidopsis thaliana was investigated. We found that autotetraploid Columbia (Col-0) plants generate a subpopulation of aberrant meiotic products under normal temperature, which is significantly increased under heat stress. Cytological studies revealed that, as the case in diploid Arabidopsis thaliana, assembly of microtubular cytoskeleton network, pairing and segregation of homologous chromosomes, and meiotic recombination in autotetraploid Arabidopsis are compromised under the high temperatures. Immunostaining of {ramshorn}H2A.X and recombinase DMC1 suggested that heat stress inhibits formation of DNA double-strand breaks; additionally, it specifically destabilizes ASY1 and ASY4, but not SYN1 on chromosomes. The loading defects of ASY1 and ASY4 overlap in the syn1 mutant, which supports that the building of lateral element of synaptonemal complex occurs downstream of a SYN1-ASY4-ASY3 stepwise assembly of axis. Remarkably, heat-induced abnormalities of ASY1 and ASY4 co-localize on chromosomes of both diploid and autotetraploid Arabidopsis, suggesting that high temperatures interfere with ASY1-associated SC via an impacted stability of chromosome axis. Furthermore, ZYP1-dependent transverse filament of SC is disrupted by heat stress. Taken together, these findings suggest that polyploidization negatively contributes to instability of chromosome axis and meiotic recombination in Arabidopsis thaliana under heat stress.

plant biology↗

bioRxiv2021

The in vivo RNA structurome of the malaria parasite Plasmodium falciparum, a protozoan with an A/T-rich transcriptome

Plasmodium falciparum, a protozoan parasite and causative agent of human malaria, has one of the most A/T-biased genomes sequenced to date. This may give the genome and the transcriptome unusual structural features. Recent progress in sequencing techniques has made it possible to study the secondary structures of RNA molecules at the transcriptomic level. Thus, in this study we produced the in vivo RNA structurome of a protozoan parasite with a highly A/U-biased transcriptome. We showed that it is possible to probe the secondary structures of P. falciparum RNA molecules in vivo using two different chemical probes, and obtained structures for more than half of all transcripts in the transcriptome. These showed greater stability (lower free energy) than the same structures modelled in silico, and structural features appeared to influence translation efficiency and RNA decay. Finally, we compared the P. falciparum RNA structurome with the predicted RNA structurome of an A/T-balanced species, P. knowlesi, finding a bias towards lower overall transcript stability and more hairpins and multi-stem loops in P. falciparum. This unusual protozoan RNA structurome will provide a basis for similar studies in other protozoans and also in other unusual genomes.

microbiology↗

bioRxiv2021

A chromosome-level genome assembly and annotation of a maize elite breeding line Dan340

BackgroundMaize is not only one of the most important crops grown worldwide for food, forage, and biofuel, but also an important model organism for fundamental research in genetics and genomics. Owing to its importance in crop science, genetics and genomics, several reference genomes of common maize inbred line (genetic material) have been released, but some genomes of important genetic germplasm resources in maize breeding research are still lacking. The maize cultivar Dan340 is an excellent backbone inbred line of the Luda Red Cob Group with several desirable characteristics, such as disease resistance, lodging resistance, high combining ability, and wide adaptability. FindingsIn this study, we constructed a high-quality chromosome-level reference genome for Dan340 by combining PacBio long HiFi sequencing reads, Illumina short reads and chromosomal conformational capture (Hi-C) sequencing reads. The final assembly of the Dan340 genome was 2,348.72 Mb, including 2,738 contigs and 2,315 scaffolds with N50 of 41.49 Mb and 215.35 Mb, respectively. Repeat sequences accounted for 73.40% of the genome size and 39,733 protein-coding genes were annotated. Analysis of genes in the Dan340 genome, together with those from B73, Mo17 and SK, were clustered into 27,654 gene families. There were 1,806 genes from 359 gene families that were specific to Dan340, of which many had functional gene ontology annotations relating to "porphyrin-containing compound metabolic process", "tetrapyrrole biosynthetic process", and "tetrapyrrole metabolic process". ConclusionsThe completeness and continuity of the genome were comparable to those of other important maize inbred lines. The assembly and annotation of this genome not only facilitates our understanding about of intraspecific genome diversity in maize, but also provides a novel resource for maize breeding improvement. Research AreasGenetics and Genomics; Agriculture, Plant Genetics Data Description

genomics↗

bioRxiv2021

Genetic diversity, evolutionary dynamics and pathogenicity of ferret badger rabies virus variants in mainland China, 2008-2018

In contrast to dog associated human rabies cases decline year by year due to the rabies vaccination coverage rates increase in China, ferret badger (FB, Melogale moschata)-associated human rabies cases emerged in the 1990s, and are now an increasingly recognized problem in southeast China. To investigate epidemiology, temporal evolution dynamics, transmission characterization and pathogenicity of FB-associated rabies viruses (RABVs), from 2008 to 2018, we collected 3,622 FB brain samples in Jiangxi and Zhejiang Province, and detected 112 RABV isolates. Four FB-related lineages were identified by phylogenetic analysis (lineages A-D), the estimated Times to Most Recent Common Ancestor were 1941, 1990, 1937 and 1997 for lineages A-D respectively. Furthermore, although no FB-associated human rabies case has been reported there apart from Wuyuan area, FB-RABV isolates are mainly distributed in Jiangxi Province. Pathogenicity of FB-RABVs was assessed using peripheral inoculation in mice and in beagles with masseter muscles, mortality-rates ranging from 20% to 100% in mice and 0 to 20% in beagles in the groups infected with the various isolates. Screening of sera from humans with FB bites and no postexposure prophylaxis to rabies, revealed that 5 of 9 were positive for neutralizing antibodies of RABV. All the results above indicated that FB-RABV variants caused a lesser pathogenicity in mice, beagles and even humans. Vaccination in mice suggests that inactivated vaccine or recombinant subunit vaccine products can be used to control FB- associated rabies, however, oral vaccines for stray dogs and wildlife need to be developed and licensed in China urgently. IMPORTANCEIn recent years FB-associated rabies virus has been identified as a major life-threatening pathogen in some districts in China. To understand the risk to public health and the contemporary dynamics, the present study conducted extensive investigations on FB rabies, distribution, virus isolation, phylogeny analysis, pathogenicity determination of various FB rabies virus strains, besides, serologic epidemiology survey to those whom bit by FB was also collected. The results show that the majority of FBs dwell in southeast China, like Jiangxi and Zhejiang Province, Phylogenetic analysis indicates that all isolated FB RABVs evolved from dogs, and the FB RABV can separate into 4 distinct lineages distributed relatively independent in different areas. The isolate strains differ in pathogenicity, although they have relatively lower pathogenicity compared to dog rabies virus according to our study, the need for further study to licensed oral vaccines and FB RABV pathogenesis is emphasized in order to control rabies.

pathology↗

bioRxiv2021

Plagl1 is part of the mammalian retinal injury response and a critical regulator of Muller glial cell quiescence

Retinal damage triggers reactive gliosis in Muller glia across vertebrate species, but only in regenerative animals, such as teleost fish, do Muller glia initiate repair; proliferating and undergoing neurogenesis to replace lost cells. By mining scRNA-seq and bulk RNA-seq datasets, we found that Plagl1, a maternally imprinted gene, is dynamically regulated in reactive Muller glia post-insult, with transcript levels transiently increasing before stably declining. To study Plagl1 retinal function, we examined Plagl1+/-pat null mutants postnatally, revealing defects in retinal architecture, visual signal processing and a reactive gliotic phenotype. Plagl1+/-pat Muller glia proliferate ectopically and give rise to inner retinal neurons and photoreceptors. Transcriptomic and ATAC-seq profiles revealed similarities between Plagl1+/-pat retinas and neurodegenerative and injury models, including an upregulation of pro-gliogenic and pro-proliferative pathways, such as Notch, not observed in wild-type retinas Plagl1 is thus an essential component of the transcriptional regulatory networks that retain mammalian Muller glia in quiescence.

neuroscience↗

bioRxiv2021

Sex- and context-dependent effects of acute isolation on vocal and non-vocal social behaviors in mice

Humans are extraordinarily social, and social isolation has profound effects on our behavior, ranging from increased social motivation following short periods of social isolation to increased anti-social behaviors following long-term social isolation. Mice are frequently used as a model to understand how social isolation impacts the brain and behavior. While the effects of chronic social isolation on mouse social behavior have been well studied, much less is known about how acute isolation impacts mouse social behavior and whether these effects vary according to the sex of the mouse and the behavioral context of the social encounter. To address these questions, we characterized the effects of acute (3-day) social isolation on the vocal and non-vocal social behaviors of male and female mice during same-sex and opposite-sex social interactions. Our experiments uncovered pronounced effects of acute isolation on social interactions between female mice, while revealing more subtle effects on the social behaviors of male mice during same-sex and opposite-sex interactions. Our findings advance the study of same-sex interactions between female mice as an attractive paradigm to investigate neural mechanisms through which acute isolation enhances social motivation and promotes social behavior.

animal behavior and cognition↗

bioRxiv2021

Community Evaluation of Glycoproteomics Informatics Solutions Reveals High-Performance Search Strategies of Glycopeptide Data

Glycoproteome profiling (glycoproteomics) is a powerful yet analytically challenging research tool. The complex tandem mass spectra generated from glycopeptide mixtures require sophisticated analysis pipelines for structural determination. Diverse software aiding the process have appeared, but their relative performance remains untested. Conducted through the HUPO Human Proteome Project - Human Glycoproteomics Initiative, this community study, comprising both developers and users of glycoproteomics software, evaluates the performance of informatics solutions for system-wide glycopeptide analysis. Mass spectrometry-based glycoproteomics datasets from human serum were shared with all teams. The relative team performance for N- and O-glycopeptide data analysis was comprehensively established and validated through orthogonal performance tests. Excitingly, several high-performance glycoproteomics informatics solutions were identified. While the study illustrated that significant informatics challenges remain, as indicated by a high discordance between annotated glycopeptides, lists of high-confidence (consensus) glycopeptides were compiled from the standardised team reports. Deep analysis of the performance data revealed key performance-associated search variables and led to recommendations for improved "high coverage" and "high accuracy" glycoproteomics search strategies. This study concludes that diverse software for comprehensive glycopeptide data analysis exist, points to several high-performance search strategies, and specifies key variables that may guide future software developments and assist informatics decision-making in glycoproteomics.

biochemistry↗

bioRxiv2021

MR-APSS: a unified approach to Mendelian Randomization accounting for pleiotropy and sample structure using genome-wide summary statistics

Mendelian Randomization (MR) is a valuable tool for inferring causal relationships among a wide range of traits using summary statistics from genome-wide association studies (GWASs). Existing summary-level MR methods often rely on strong assumptions, resulting in many false positive findings. To relax MR assumptions, ongoing research has been primarily focused on accounting for confounding due to pleiotropy. Here we show that sample structure is another major confounding factor, including population stratification, cryptic relatedness, and sample overlap. We propose a unified MR approach, MR-APSS, which (i) accounts for pleiotropy and sample structure simultaneously by leveraging genome-wide information; and (ii) allows to include more genetic variants with moderate effects as instrument variables (IVs) to improve statistical power without inflating type I errors. We first evaluated MR-APSS using comprehensive simulations and negative controls, and then applied MR-APSS to study the causal relationships among a collection of diverse complex traits. The results suggest that MR-APSS can better identify plausible causal relationships with high reliability. In particular, MR-APSS can perform well for highly polygenic traits, where the IV strengths tend to be relatively weak and existing summary-level MR methods for causal inference are vulnerable to confounding effects.

genetics↗

bioRxiv2021

Exploration of polyyne biosynthetic gene cluster diversity in bacteria leads to the discovery of the Pseudomonas polyyne protegencin

Natural products that possess alkyne or polyyne moieties have been isolated from a variety of biological sources. In bacteria their biosynthesis has been defined, however, the distribution of polyyne biosynthetic gene clusters (BGCs), and their evolutionary relationship to alkyne biosynthesis, have not been addressed. We explored the distribution of alkyne biosynthesis gene cassettes throughout bacteria, revealing evidence of multiple horizontal gene transfer events. Investigating the evolutionary connection between alkyne and polyyne biosynthesis identified a monophyletic clade possessing a conserved seven-gene cassette for polyyne biosynthesis. Mapping the diversity of these conserved genes revealed a phylogenetic clade representing a polyyne BGC in Pseudomonas, pgn, and subsequent pathway mutagenesis and analytical chemistry characterised the associated metabolite, protegencin. In addition to unifying and expanding our knowledge of polyyne diversity, our results show that alkyne and polyyne biosynthetic gene clusters are promiscuous within bacteria. Systematic mapping of conserved biosynthetic genes across bacterial genomic diversity has proven to be a successful method for discovering natural products.

microbiology↗

bioRxiv2021

Methylomic alteration in peripheral blood lymphocytes of prodromal stage and first-episode Chinese Han schizophrenia patients

BackgroundAlthough epigenetic dysregulation has long been proposed to promote the onset of schizophrenia, the landscape of the methylomic changes across the whole genome is yet established. MethodsUsing Infinium Human Methylation 850 BeadChip Array and MethylTarget sequencing method, we investigated the genome-wide methylation profiles and further validated methylation profiles of target genes in peripheral blood lymphocytes between individuals with psychosis risk syndrome (PRS), patients with first-episode schizophrenia (FES) and healthy controls (HC) in Chinese Han population. ResultsWe detected 372 sites between psychosis risk syndrome (PRS) and healthy controls (HC), which increased to 460 sites in first-episode schizophrenia (FES) with 207 sites shared. Both PRS and FES featured profound hypomethylation within gene body. Gene ontology and network annotation merged on loci enriched in disease associated signaling pathways (MAPK(Mitogen Activated Protein Kinases), Glutamatergic, GABAergic etc.). ConclusionsOur study implicated characteristic hypomethylation in both the discovery and validation cohorts in SYNGAP1, one of the frequently studied genes in neurodevelopmental disorders. This is the first methylome-wide association study between PRS and FES in Chinese Han population. Our findings provide potential biomarkers that can be used for future development of disease therapy and management.

genetics↗

bioRxiv2021

Targeting CTP Synthetase 1 to Restore Interferon Induction and Impede Nucleotide Synthesis in SARS-CoV-2 Infection

The newly emerged SARS-CoV-2 caused a global pandemic with astonishing mortality and morbidity. The mechanisms underpinning its highly infectious nature remain poorly understood. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. Screening a SARS-CoV-2 expression library identified ORF7b and ORF8 that suppressed IFN induction via inducing the deamidation of interferon regulatory factor 3 (IRF3). Deamidated IRF3 fails to bind the promoters of classic IRF3-responsible genes, thus muting IFN induction. Conversely, a shRNA-mediated screen focused on cellular glutamine amidotransferases corroborated that CTPS1 deamidates IRF3 to inhibit IFN induction. Functionally, ORF7b and ORF8 activate CTPS1 to promote de novo CTP synthesis while shutting down IFN induction. De novo synthesis of small-molecule inhibitors of CTPS1 enabled CTP depletion and IFN induction in SARS-CoV-2 infection, thus impeding SARS-CoV-2 replication. Our work uncovers a strategy that a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means for developing antiviral therapy that would be resistant to SARS-CoV-2 mutation.

microbiology↗