Biology subjects

Zhao, J.

Publications and source records attributed to Zhao, J..

At least 487 records · Page 27Linked to original sources

bioRxiv2021

An agnostic study of associations between ABO and RhD blood group and phenome-wide disease risk

There are multiple known associations between the ABO and RhD blood groups and disease. However, no systematic population-based studies elucidating associations between a large number of disease states and blood group have been conducted. Using SCANDAT3-S, a comprehensive nationwide blood donation-transfusion database, we modelled outcomes for 1,217 disease categories including 70 million person-years of follow-up, accruing from 5.1 million unique individuals. We discovered 49 and 1 associations between a disease and ABO and RhD blood group, respectively, after adjustment for multiple testing. We identified new associations such as kidney stones and blood group B as compared to O. We also expanded previous knowledge on other associations such as pregnancy-induced hypertension and blood group A and AB as compared to O and RhD positive as compared to negative. Our findings generate strong further support for previously known associations, but also indicate new interesting relations.

physiology↗

bioRxiv2021

Genome recombination-mediated tRNA up-regulation conducts general antibiotic resistance of bacteria at early stage

Bacterial antibiotic resistance sets a great challenge to human health. It seems that the bacteria can spontaneously evolve resistance against any antibiotic within short time without the horizontal transfer of heterologous genes and before accumulating drug-resistant mutations. We have shown that the tRNA-mediated translational regulation counteracts the reactive oxygen species in bacteria. In this study, we demonstrated that isolated and subcultured Escherichia coli elevated its tRNAs under antibiotic stress to rapidly provide antibiotic resistance, especially at the early stage, before upregulating the efflux pump and evolving resistance mutations. The DNA recombination system repaired the antibiotic-induced DNA breakage in the genome, causing numerous structural variations. These structural variations are overrepresented near the tRNA genes, which indicated the cause of tRNA up-regulation. The strains knocking out the recombination system could not up-regulate tRNAs, and coincidently, they could hardly evolve antibiotic resistance in multiple antibiotics, respectively. With these results, we proposed a multi-stage model of bacterial antibiotic resistance in an isolated scenario: the early stage (recombination - tRNA up-regulation - translational regulation); the medium stage (up-regulation of efflux pump); the late stage (resistance mutations). These results also indicated that the bacterial DNA recombination system and tRNA could be targeted to retard the bacterial spontaneous drug resistance.

microbiology↗

bioRxiv2021

Natural variations in the P-type ATPase heavy metal transporter ZmCd1 controlling cadmium accumulation in maize grains

Cadmium (Cd) accumulation in maize grains is detrimental to human health. Developing maize varieties with low-Cd contents via marker-assisted selection is important for ensuring the production of maize grains safe for consumption. However, the key gene controlling maize grain Cd accumulation has not been cloned. In this study, we identified two major loci for maize grain Cd accumulation (qCd1 and qCd2) on chromosome 2 during a genome-wide association study (GWAS). The qCd1 locus was analyzed by bulked segregant RNA-seq and fine mapping with a biparental segregating population of Jing724 (low-Cd line) and Mo17 (high-Cd line). The ZmCd1 candidate gene in the qCd1 locus encodes a vacuolar membrane-localized heavy metal P-type ATPase transporter, ZmHMA3, which is orthologous to the tonoplast Cd transporter OsHMA3. Genomic DNA sequence and transcript analyses suggested that a transposon in intron 1 of ZmCd1 is responsible for the abnormal amino acid sequence in Mo17. An EMS mutant analysis and an allelism test confirmed ZmCd1 influences maize grain Cd accumulation. The natural variations in ZmCd1 were used to develop four PCR-based molecular markers, which revealed five ZmCd1 haplotypes in the GWAS population. The molecular markers were also used to predict the grain Cd contents in commonly cultivated maize germplasms in China. The predicted Cd contents for 36 inbred lines and 13 hybrids were consistent with the measured Cd contents. Furthermore, several low-Cd elite inbred lines and hybrids were identified, including Jing2416, MC01, Jingnonke728, and Jingke968. Therefore, the molecular markers developed in this study are applicable for molecular breeding and developing maize varieties with low grain Cd contents.

plant biology↗

bioRxiv2020

Structural insights into the recognition of histone H3Q5 serotonylation by WDR5

Serotonylation of histone H3Q5 (H3Q5ser) is a recently identified posttranslational modification of histones that apparently acts as a permissive marker for gene activation in synergy with H3K4me3 during neuronal cell differentiation. However, any proteins which specifically recognize H3Q5ser remain unknown. Here, we discovered that WDR5 interacts with the N-terminal tail of histone H3 and functions as a reader for H3Q5ser. Crystal structures of WDR5 in complex with H3Q5ser and H3K4me3Q5ser peptides revealed that the serotonyl group is accommodated in a shallow surface pocket of WDR5. Experiments in neuroblastoma cells demonstrate that WDR5 colocalizes with H3Q5ser in the promoter regions of cancer-promoting genes, where it promotes gene transcription to induce cell proliferation. Thus, beyond revealing a previously unknown mechanism through which WDR5 reads H3Q5ser to activate transcription, our study suggests that this WDR5-H3Q5ser mediated epigenetic regulation apparently promotes tumorigenesis.

biochemistry↗

bioRxiv2020

Precise Regulation and Site-specifically Covalent Labeling of NSUN2 Enable by Genetic Encoding Expansion

RNA plays a critical role in gene expression regulation, cell migration, differentiation, cell death in living organism. 5-Methylcytosine is a post transcriptional RNA modification identified across wide ranges of RNA species including message RNAs. It is reported the addition of m5C to RNA cytosines is enabled by use of NSUN family enzyme, NSUN2 is identified as a critical RNA methyltransferase for adding m5C to mRNA. We demonstrated here that natural lysines modified with special groups were synthesized via chemical synthesis. Through two rounds of positive screening and one round of negative screening, MbPylRS-tRNAcua unnatural lysine substitution system which can specifically recognize lysine with defined group was evaluated and identified. Non-natural lysine substitution at C271 of NSUN2 active site and subsequently fluorescent labeling was realized via so-called click reaction. The function of NSUN2 mutant and its upregulated CDK1 gene and its effect on cell proliferation were also evaluated.

molecular biology↗

bioRxiv2020

Recombinant Fc-fusion vaccine of RBD induced protection against SARS-CoV-2 in non-human primate and mice

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to infect people globally. The increased COVID-19 cases and no licensed vaccines highlight the need to develop safe and effective vaccines against SARS-CoV-2 infection. Multiple vaccines candidates are under pre-clinical or clinical trails with different strengths and weaknesses. Here we developed a pilot scale production of a recombinant subunit vaccine (RBD-Fc Vacc) with the Receptor Binding Domain of SARS-CoV-2 S protein fused with the Fc domain of human IgG1. RBD-Fc Vacc induced SARS-CoV-2 specific neutralizing antibodies in non-human primates and human ACE2 transgenic mice. The antibodies induced in macaca fascicularis neutralized three divergent SARS-CoV2 strains, suggesting a broader neutralizing ability. Three times immunizations protected Macaca fascicularis (20ug or 40ug per dose) and mice (10ug or 20ug per dose) from SARS-CoV-2 infection respectively. These data support clinical development of SARS-CoV-2 vaccines for humans. RBD-Fc Vacc is currently being assessed in randomized controlled phase 1/II human clinical trails. SummaryThis study confirms protective efficacy of a SARS-CoV-2 RBD-Fc subunit vaccine.

immunology↗

bioRxiv2020

First demonstration of the FLASH effect with ultrahigh dose-rate high energy X-rays

Ultrahigh dose-rate (FLASH) radiotherapy has attracted immense attention because of its tumor control efficiency and healthy tissue protection during preclinical experiments with electrons, kilo-voltage X-rays, and protons. Using high-energy X-rays (HEXs) in FLASH is advantageous owing to its deep penetration, small divergence, and cost-effectiveness. This is the first report on the implementation of HEXs with FLASH (HEX-FLASH) and its corresponding application in vivo. With a high-current and high-energy superconducting linear accelerator, FLASH with a good dose rate and high penetration was achieved. Breast cancers artificially induced in BAL b/c mice were efficiently controlled, and normal tissues surrounding the thorax/abdomen in C57BL/6 mice were protected from radiation with HEX-FLASH. Theoretical analyses of cellular responses following HEX-FLASH irradiation were performed to interpret the experimental results and design further experiments. Thus, this study highlights the generation of HEX-FLASH for the first time and its potential in future clinical applications.

cancer biology↗

bioRxiv2020

3D Adaptive Optical Nanoscopy for Thick Specimen Imaging at sub-50 nm Resolution

Understanding cellular organization demands the best possible spatial resolution in all three dimensions (3D). In fluorescence microscopy, this is achieved by 4Pi nanoscopy methods that combine the concepts of using two opposing objectives for optimal diffraction-limited 3D resolution with switching fluorescent molecules between bright and dark states to break the diffraction limit. However, optical aberrations have limited these nanoscopes to thin samples and prevented their application in thick specimens. Here, we have developed a nanoscope that, by utilizing an advanced adaptive optics strategy, achieves sub-50 nm isotropic resolution of structures such as neuronal synapses and ring canals previously inaccessible in tissue.

biophysics↗

bioRxiv2020

Sucrose represses the expression of the strigolactone signalling gene D3/RMS4/MAX2 to promote tillering

- Shoot branching, a major component of shoot architecture, is regulated by multiple signals. Previous studies have indicated that sucrose may promote branching through suppressing the inhibitory effect of the hormone strigolactone (SL). However, the molecular mechanisms underlying this effect are unknown. - Here we used molecular and genetic tools to identify the molecular targets underlying the antagonistic interaction between sucrose and SL. - We showed that sucrose antagonises the suppressive action of SL on tillering in rice and on the degradation of D53, a major target of SL signalling. Sucrose inhibits the expression of D3, the orthologue of the arabidopsis F-box protein MAX2 required for SL signalling. Over-expression of D3 prevents sucrose from inhibiting D53 degradation and enabled the SL inhibition of tillering under high sucrose. Sucrose also prevents SL-induced degradation of D14, the SL receptor involved in D53 degradation. Interestingly, D14 over-expression enhances D53 protein levels and sucrose-induced tillering. - Our results show that sucrose inhibits SL perception by targeting key components of SL signalling and, together with previous studies reporting the inhibition of SL synthesis by nitrate and phosphate, demonstrate the central role played by strigolactones in the regulation of plant architecture by nutrients.

plant biology↗

bioRxiv2020

CD127 imprints functional heterogeneity to diversify monocyte responses in human inflammatory diseases

Studies on human monocytes historically focused on characterization of bulk responses, whereas functional heterogeneity is largely unknown. Here, we identified an inducible population of CD127-expressing human monocytes under inflammatory conditions and named the subset M127. M127 is nearly absent in healthy individuals yet abundantly present in patients with infectious and inflammatory conditions such as COVID-19 and rheumatoid arthritis. Multiple genomic and functional approaches revealed unique gene signatures of M127 and unified anti-inflammatory properties imposed by the CD127-STAT5 axis. M127 expansion correlated with mild COVID-19 disease outcomes. Thereby, we phenotypically and molecularly characterized a human monocyte subset marked by CD127 that retained anti-inflammatory properties within the pro-inflammatory environments, uncovering remarkable functional diversity among monocytes and signifying M127 as a potential therapeutic target for human inflammatory disorders.

immunology↗

bioRxiv2020

Genomic Insights into the Demographic History of Southern Chinese

Southern China is the birthplace of rice-cultivating agriculture, different language families, and human migrations that facilitated these cultural diffusions. The fine-scale demographic history in situ, however, remains unclear. To comprehensively cover the genetic diversity in East and Southeast Asia, we generated genome-wide SNP data from 211 present-day Southern Chinese and co-analyzed them with more than 1,200 ancient and modern genomes. We discover that the previously described Southern East Asian or Yangtze River Farmer lineage is monophyletic but not homogeneous, comprising four regionally differentiated sub-ancestries. These ancestries are respectively responsible for the transmission of Austronesian, Kra-Dai, Hmong-Mien, and Austroasiatic languages and their original homelands successively distributed from East to West in Southern China. Multiple phylogenetic analyses support that the earliest living branching among East Asian-related populations is First Americans ([~]27,700 BP), followed by the pre-LGM differentiation between Northern and Southern East Asians ([~]23,400 BP) and the pre-Neolithic split between Coastal and Inland Southern East Asians ([~]16,400 BP). In North China, distinct coastal and inland routes of south-to-north gene flow had established by the Holocene, and further migration and admixture formed the genetic profile of Sinitic speakers by [~]4,000 BP. Four subsequent massive migrations finalized the complete genetic structure of present-day Southern Chinese. First, a southward Sinitic migration and the admixture with Kra-Dai speakers formed the Sinitic Cline. Second, a bi-directional admixture between Hmong-Mien and Kra-Dai speakers gave rise to the Hmong-Mien Cline in the interior of South China between [~]2,000 and [~]1,000 BP. Third, a southwestward migration of Kra-Dai speakers in recent [~]2,000 years impacted the genetic profile for the majority of Mainland Southeast Asians. Finally, an admixture between Tibeto-Burman incomers and indigenous Austroasiatic speakers formed the Tibeto-Burman speakers in Southeast Asia by [~]2,000 BP.

genomics↗

bioRxiv2020

Resuscitation of soil microbiota after > 70-years of desiccation

The abundance and diversity of bacteria in 24 historical soil samples under air-dried storage conditions for more than 70 years were assessed by quantification and high-throughput sequencing analysis of 16S rRNA genes. All soils contained a measurable abundance of bacteria varying from 103 to 108 per gram of soil and contrasting community compositions were observed in different background soils, suggesting that the bacteria detected were indigenous to the soil. Following a 4-week soil rewetting event, the bacterial abundance significantly increased in soils, indicating strong adaptation of soil bacteria to extreme osmotic change and high resuscitation potential of some bacteria over long periods of desiccation. Paenibacillus, Cohnella and two unclassified Bacillales genera within the phylum Firmicutes represented the most ubiquitously active taxa, which showed growth in the highest number of soils ([≥]12 soils), while genera Tumebacillus, Alicyclobacillus and Brevibacillus in the phylum Firmicutes displayed the highest growth rates in soils (with >1000-fold average increase) following rewetting. Additionally, some Actinobacteria and Proteobacteria genera showed relatively high activity following rewetting, suggesting that the resilience to long-term desiccation and rewetting is a common trait across phylogenetically divergent microbes. The present study thus demonstrated that diversified groups of microbes are present and potentially active in historically desiccated soils, which might be of importance in the context of microbial ecology.

microbiology↗

bioRxiv2020

Large-scale single-cell analysis reveals critical immune characteristics of COVID-19 patients

Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19. HIGHLIGHTSO_LILarge-scale scRNA-seq analysis depicts the immune landscape of COVID-19 C_LIO_LILymphopenia and active T and B cell responses coexist and are shaped by age and sex C_LIO_LISARS-CoV-2 infects diverse epithelial and immune cells, inducing distinct responses C_LIO_LICytokine storms with systemic S100A8/A9 are associated with COVID-19 severity C_LI

genomics↗

bioRxiv2020

Remdesivir Metabolite GS-441524 Efficiently Inhibits SARS-CoV-2 Infection in Mouse Model

The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.

pharmacology and toxicology↗

bioRxiv2020

Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens

Immunomodulatory agents dexamethasone and colchicine, antiviral drugs remdesivir, favipiravir and ribavirin, as well as antimalarial drugs chloroquine phosphate and hydroxychloroquine are currently used in the combat against COVID-191-16. However, whether some of these drugs have clinical efficacy for COVID-19 is under debate. Moreover, these drugs are applied in COVID-19 patients with little knowledge of genetic biomarkers, which will hurt patient outcome. To answer these questions, we designed a screen approach that could employ genome-wide sgRNA libraries to systematically uncover genes crucial for these drugs action. Here we present our findings, including genes crucial for the import, export, metabolic activation and inactivation of remdesivir, as well as genes that regulate colchicine and dexamethasones immunosuppressive effects. Our findings provide preliminary information for developing urgently needed genetic biomarkers for these drugs. Such biomarkers will help better interpret COVID-19 clinical trial data and point to how to stratify COVID-19 patients for proper treatment with these drugs.

pharmacology and toxicology↗

bioRxiv2020

TIGIT-Fc Promotes Antitumour Immunity

T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a checkpoint receptor that mediates both T cell and natural killer (NK) cell exhaustion in tumours. An Fc-TIGIT fusion protein was shown to induce an immune-tolerance effect in a previous report, but the relevance of the TIGIT-Fc protein to tumour immunity is unknown. Here, we unexpectedly found that TIGIT-Fc promotes rather than suppresses tumour immunity. TIGIT-Fc treatment promoted the effector function of CD8+ T and NK cells in several tumour-bearing mouse models. Additionally, TIGIT-Fc treatment resulted in potent T cell and NK-cell-mediated tumour reactivity, sustained memory-induced immunity in tumour re-challenge models, enhanced therapeutic effects via an antibody against PD-L1, and induction of Th1 development in CD4+ T cells. TIGIT-Fc showed a potent antibody-dependent cell-mediated cytotoxicity (ADCC) effect but no intrinsic effect on tumour cell development. Our findings elucidate the unexpected role of TIGIT-Fc in tumour immune reprogramming, suggesting that TIGIT-Fc treatment alone or in combination with other checkpoint receptor blockers is a promising anticancer therapeutic strategy.

bioengineering↗

bioRxiv2020

Structural basis of SARS-CoV-2 polymerase inhibition by Favipiravir

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into an unprecedented global pandemic. Nucleoside analogues, such as Remdesivir and Favipiravir, can serve as the first-line broad-spectrum antiviral drugs against the newly emerging viral diseases. Recent clinical trials of these two drugs for SARS-CoV-2 treatment revealed antiviral efficacies as well as side effects with different extents1-4. As a pyrazine derivative, Favipiravir could be incorporated into the viral RNA products by mimicking both adenine and guanine nucleotides, which may further lead to mutations in progeny RNA copies due to the non-conserved base-pairing capacity5. Here, we determined the cryo-EM structure of Favipiravir bound to the replicating polymerase complex of SARS-CoV-2 in the pre-catalytic state. This structure provides a missing snapshot for visualizing the catalysis dynamics of coronavirus polymerase, and reveals an unexpected base-pairing pattern between Favipiravir and pyrimidine residues which may explain its capacity for mimicking both adenine and guanine nucleotides. These findings shed lights on the mechanism of coronavirus polymerase catalysis and provide a rational basis for developing antiviral drugs to combat the SARS-CoV-2 pandemic.

microbiology↗

bioRxiv2020

Duple extinguishment of COVID-19: single compound synergized inhibition of SARS-CoV-2 replication and direct suppression of inflammatory cytokines in vitro/vivo

We firstly disclose single compound yields better therapeutic outcome than Remdesivir in COVID-19 hamster treatments as it is armed with direct inhibition viral replication and intrinsic suppression inflammatory cytokines expression. Crystal data reveals that Au (I), released from Au22Glutathione18 (GA), covalently binds thiolate of Cys145 of SARS-CoV-2 Mpro. GA directly decreases SARS-CoV-2 viral replication (EC50: ~0.24 M) and intrinsically down-regulates NF{kappa}B pathway therefore significantly inhibiting expression of inflammatory cytokines in cells. The lung viral load and inflammatory cytokines in GA-treated COVID-19 transgenic mice are found to be significantly lower than that of control mice. When COVID-19 golden hamsters are treated by GA, the lung inflammatory cytokines levels are significantly lower than that of Remdesivir while their lung viral load are decreased to same level. The pathological results show that GA treatment significantly reduce lung inflammatory injuries when compared to that of Remdesivir-treated COVID-19 golden hamsters. One Sentence SummaryWe found that gold cluster molecule directly inhibits SARS-CoV-2 replication and intrinsically suppresses inflammatory cytokines expression in COVID-19 transgenic mouse and golden hamster model, gold cluster providing a better lung injury protection than Remdesivir in COVID-19 golden hamsters via intranasally dropping administration.

microbiology↗