Biology subjects

Liu, Q.

Publications and source records attributed to Liu, Q..

At least 505 records · Page 28Linked to original sources

bioRxiv2021

Cooperative herbivory between two important pests of rice

Normally, when different species of herbivorous arthropods feed on the same plant this leads to fitness reducing competition. We found this to be uniquely different for two of Asias most destructive rice pests, the brown planthopper and the rice striped stem borer. Both insects directly and indirectly benefit from jointly attacking the same host plant. Double infestation improved plant quality, particularly for the stemborer because the planthopper fully suppresses caterpillar-induced production of proteinase inhibitors. It also drastically reduced the risk of egg parasitism, due to diminished parasitoid attraction. Females of both pests have adapted their oviposition behaviour accordingly. Their strong preference for plants infested by the other species even overrides their avoidance of plants already attacked by conspecifics. This uncovered cooperation between herbivores is telling of the exceptional adaptations resulting from the evolution of plant-insect interactions, and points out mechanistic vulnerabilities that can be targeted to control two major pests.

ecology↗

bioRxiv2021

The landscape of accessible chromatin in quiescent and post-myocardial infarction cardiac fibroblasts

After myocardial infarction, quiescent cardiac fibroblasts are activated and undergo multiple proliferation and differentiation events, which contribute to the extracellular matrix remodeling of the infarcted myocardium. We recently found that cardiac fibroblasts of different differentiation states had distinct expression profiles closely related to their functions. Gene expression is directly regulated by chromatin state. However, the role of chromatin reorganization in the drastic gene expression changes during post-MI differentiation of cardiac fibroblast has not been revealed. In this study, the gene expression profiling and genome-wide mapping of accessible chromatin in mouse cardiac fibroblasts isolated from uninjured hearts and the infarcts at different time points were performed by RNA sequencing (RNA-seq) and the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), respectively. ATAC-seq peaks were highly enriched in the promoter area and distal areas where enhancers might be located. A positive correlation was identified between the transcription level and promoter accessibility for many dynamically expressed genes. In addition, it was found that DNA methylation may contribute to the post-MI chromatin remodeling and gene expression in cardiac fibroblasts. Integrated analysis of ATAC-seq and RNA-seq datasets also identified transcription factors that possibly contributed to the differential gene expression between cardiac fibroblasts of different states.

genomics↗

bioRxiv2021

Therapeutic immunization against Helicobacter pylori infection in BALB/c mice induced by a multi-epitope vaccine based on computer-aided design

BackgroundCombined antibiotic regimens have caused problems such as increasing antimicrobial resistance to H. pylori and intestinal flora disturbance. Vaccination is a great alternative approach, but also faces the limited immune response induced by monovalent vaccines. Therefore, the development of multi-epitope vaccines is promising immunotherapy to control H. pylori infection. ObjectiveTo develop a multi-epitope vaccine and evaluate its therapeutic efficacy against H. pylori infection. Materials and MethodsThe B and T cell epitopes from UreB, FlaA, AlpB, SabA, and HpaA were linked for producing 2 multi-epitope vaccines (CTB-S3 and CTB-S5) by a structural evaluation based on computer-aided design. The abilities to produce antigen-specific antibodies and neutralizing antibodies of CTB-S3 and CTB-S5 were evaluated in BALB/c mice. After that, their therapeutic efficacy was explored in H. pylori-infected mice. ResultsCTB-S3 or CTB-S5 could induce high levels of specific antibodies against UreB, FlaA, AlpB, SabA, HpaA, and neutralizing antibodies against H. pylori urease and adhesion. Also, oral therapeutic immunization with CTB-S3 or CTB-S5 could decrease H. pylori colonization and reduce stomach damage; the protection was correlated with H. pylori-specific IgG, SIgA antibodies, and CD4+ T cell immune response. ConclusionsOur study developed a multi-epitope vaccine based on a computer-aided design. The CTB-S3 and CTB-S5 vaccines may be promising therapeutic candidate vaccines against H. pylori infection and provide a reference for vaccine design of other pathogens.

immunology↗

bioRxiv2021

Structural Basis for SARS-CoV-2 Envelope Protein in Recognition of Human Cell Junction Protein PALS1

The COVID-19 pandemic caused by the SARS-CoV-2 virus has created a global health and economic emergency. SARS-CoV-2 viruses hijack human proteins to promote their spread and virulence including the interactions involving the viral envelope (E) protein and human proteins. To understand the structural basis for SARS-CoV-2 viral-host recognition, we used cryo-electron microscopy to determine a structure for the human cell junction protein PALS1 and SARS-CoV-2 E protein complex. The structure shows that the E protein C-terminal DLLV motif recognizes a pocket formed exclusively by hydrophobic residues from the PDZ and SH3 domains in PALS1. Our structural analysis provides an explanation for the observation that the viral E protein recruits PALS1 from lung epithelial cell junctions resulting in vascular leakage, lung damage, viral spread, and virulence. In addition, our structure provides novel targets for peptide- and small-molecule inhibitors that could block the PALS1-E interactions to reduce the E-mediated damage to vascular structures.

biochemistry↗

bioRxiv2021

SARS-CoV-2 nucleocapsid protein dually regulates innate immune responses

The recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and a cytokine storm in the late stage of infection, however, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein interacted with the tripartite motif protein 25 (TRIM25), thereby dually regulating the phosphorylation and nuclear translocation of IRF3, STAT1 and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress retinoic acid-inducible gene I (RIG-I) ubiquitination and activation. Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

microbiology↗

bioRxiv2021

Identification and Evaluation of a Panel of Strong Constitutive Promoters in Listeria monocytogenes for Improving the Expression of Foreign Antigens

Attenuated Listeria monocytogenes (L. monocytogenes) could be used as a vaccine vector for immunotherapy of tumors or pathogens. However, the lack of reliable promoters limits its ability to express foreign antigens. In this work, 21 promoters from L. monocytogenes were identified by RNA-seq analysis under two conditions of pH 7.4 and pH 5.5. Based on the constructed fluorescence report system, 7 constitutive promoters showed higher strength than that of Phelp, a previously reported strong promoter. Further, the selected 5 constitutive promoters also showed high activity in the production of UreB, a widely used antigen against Helicobacter pylori (H. pylori). In particular, a well-characterized constitutive promoter P18, which performed best in both fluorescence intensity and UreB production, was proved to be highly active in vitro and in vivo. In summary, we provide a useful promoter library for Listeria species and offer a reference for constitutive promoter mining in other organisms. Key pointsO_LI21 promoters from L. monocytogenes were identified by RNA-seq. C_LIO_LIFluorescent tracer of L. monocytogenes (P18) was performed in vitro and in vivo. C_LIO_LIA well-characterized constitutive promoter P18 could improve the expression level of a foreign antigen UreB in L. monocytogenes C_LI

microbiology↗

bioRxiv2021

Embedding of exogenous B cell epitopes on the surface of UreB structure generates a broadly reactive antibody response against Helicobacter pylori

Since Helicobacter pylori (H. pylori) resistance to antibiotic regimens is increased, vaccination is becoming an increasingly important alternative therapy to control H. pylori infection. UreB, FlaA, AlpB, SabA, and HpaA proteins of H. pylori were previously proved to be used as candidate vaccine antigens. Here, we developed an engineered antigen based on a recombinant chimeric protein containing a structural scaffold from UreB and B cell epitopes from FlaA, AlpB, SabA, and HpaA. The multi-epitope chimeric antigen, named MECU, could generate a broadly reactive antibody response including antigen-specific antibodies and neutralizing antibodies against H. pylori urease and adhesins. Moreover, therapeutic immunization with MECU could reduce H. pylori colonization in the stomach and protect the stomach in BALB/c mice. This study not only provides a promising immunotherapy to control H. pylori infection, but also offers a reference for antigen engineering against other pathogens.

immunology↗

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↗

bioRxiv2021

Outer membrane vesicles derived from Salmonella Typhimurium can deliver Shigella flexneri 2a O-polysaccharide antigen to prevent lethal pulmonary infection in mice

The threat to health from shigellosis has become quite serious in many developing countries, causing severe diarrhea. Shigella flexneri 2a (S. flexneri 2a) is the principal species responsible for this endemic disease. Although there have been multiple attempts to design a vaccine against Shigellosis, one that is effective has not yet been developed. Lipopolysaccharide (LPS) is both an essential virulence factor and a protective antigen against Shigella, due to its outer domain, termed O-polysaccharide antigen. In the present study, S. flexneri 2a O-polysaccharide antigen was innovatively bio-synthesized in Salmonella and attached to core-lipid A by the ligase WaaL, and thus purified outer membrane vesicles (OMVs) were used as a vaccine for subsequent research. Here, we identified the expression of the heterologous polysaccharide antigen and described the isolation, characterization, and immune protection efficiency of the OMV vaccine. The expression of S. flexneri 2a did not affect the formation of Salmonella OMVs or their cytotoxicity. Furthermore, the results of the animal experiments indicated that immunization of the mice both intranasally and intraperitoneally with the OMV vaccine induced significant specific anti-Shigella LPS antibodies in both vaginal secretions and fluid from bronchopulmonary lavage, in addition to within sera. The OMV vaccine immunized by both routes of administration provided significant protection against virulent S. flexneri 2a infection, as judged by a serum bactericidal assay (SBA), opsonization assay, challenge experiment, and pathological analysis. The present study firstly indicates that the proposed vaccination strategy represents a novel and improved approach to control Shigellosis by the combination of bioconjugation of Salmonella glycosyl carrier lipid and OMV. In addition, the strategy of genetic manipulation described here is ideally suited for designs based on other Shigella serotypes, allowing the development of a Shigella vaccine with broad-protection.

microbiology↗

bioRxiv2021

Successful spermatogonial stem cells transplantation within Pleuronectiformes: first breakthrough at inter-family level in marine fish

As a promising biotechnology, fish germ cell transplantation shows potentials in conservation germplasm resource, propagation of elite species, and generation of transgenic individuals. In this study, we successfully transplanted the Japanese flounder (P. olivaceus), summer flounder (P. dentatus), and turbot (S. maximus) spermatogonia into triploid Japanese flounder larvae, and achieved high transplantation efficiency of 100%, 75-95% and 33-50% by fluorescence tracking and molecular analysis, respectively. Eventually, donor-derived spermatozoa produced offspring by artificial insemination. We only found male and intersex chimeras in inter-family transplantations, while male and female chimeras in both intra-species and intra-genus transplantations. Moreover, the intersex chimeras could mature and produce turbot functional spermatozoa. We firstly realized inter-family transplantation in marine fish species. These results demonstrated successful spermatogonial stem cells transplantation within Pleuronectiformes, suggesting the germ cells migration, incorporation and maturation within order were conserved across a wide range of teleost species.

developmental biology↗

bioRxiv2021

Hydroxide ions amplified by water entanglement underly the mechanism of general anesthesia

It is believed that inhaled anesthetics occupy hydrophobic pockets within target proteins, but how inhaled anesthetics with diverse shapes and sizes fit into highly structurally selective pockets is unknown. For hydroxide ions are hydrophobic, we determined whether hydroxide ions could bridge inhaled anesthetics and protein pockets. We found that small additional load of cerebral hydroxide ions decreases anesthetic potency. Multiple-water entanglement network, derived from Ising model, has a great ability to amplify ultralow changes in the cerebral hydroxide ion concentration, and consequently, amplified hydroxide ions account for neural excitability. Molecular dynamics simulations showed that inhaled anesthetics produce anesthesia by attenuating the formation of multiple-water entanglement network. This work suggests amplified hydroxide ions underlying a unified mechanism for the anesthetic action of inhaled anesthetics.

animal behavior and cognition↗

bioRxiv2021

Cancer Hallmarks Define a Continuum of Plastic Cell States between Small Cell Lung Cancer Archetypes

Small Cell Lung Cancer (SCLC) tumors are heterogeneous mixtures of transcriptional subtypes. Understanding subtype dynamics could be key to explaining the aggressive properties that make SCLC a recalcitrant cancer. Applying archetype analysis and evolutionary theory to bulk and single-cell transcriptomics, we show that SCLC cells reside within a cell-state continuum rather than in discrete subtype clusters. Gene expression signatures and ontologies indicate each vertex of the continuum corresponds to a functional phenotype optimized for a cancer hallmark task: three neuroendocrine archetypes specialize in proliferation/survival, inflammation and immune evasion, and two non-neuroendocrine archetypes in angiogenesis and metabolic dysregulation. Single cells can trade-off between these defined tasks to increase fitness and survival. SCLC cells can easily transition from specialists that optimize a single task to generalists that fall within the continuum, suggesting that phenotypic plasticity may be a mechanism by which SCLC cells become recalcitrant to treatment and adaptable to diverse microenvironments. We show that plasticity is uncoupled from the phenotype of single cells using a novel RNA-velocity-based metric, suggesting both specialist and generalist cells have the capability of becoming destabilized and transitioning to other phenotypes. We use network simulations to identify transcription factors such as MYC that promote plasticity and resistance to treatment. Our analysis pipeline is suitable to elucidate the role of phenotypic plasticity in any cancer type, and positions SCLC as a prime candidate for treatments that target plasticity.

systems biology↗

bioRxiv2021

New insights on folliculogenesis and follicular placentation in marine viviparous fish black rockfish (Sebastes schlegelii)

In viviparous fish, a considerable degree of variation in placental structures have been described. However, no distinct structures are reported in Scorpaenidae. In this study, we demonstrate a new type of folliculogenesis and follicular placentation in Sebastes schlegelii. Before copulation, the germinal epithelium gradually surrounds the oocytes and develops to individually follicles with a stalk-like structure hanging on the ovigerous lamella, which ensures each follicle have access to spermatozoa after copulation. From stage V to early gestation, the cyp17-I highly expressed accompanied by cyp19a1a signals disappearance, and 11-ketotestosterone level keeps rising and peaks at blastula stage, while 17{beta}-estradiol declines to the bottom. Meanwhile, the theca cells rapidly proliferate and invade outwards forming a highly hypertrophied and folded microvillous placenta. This unbalance of hormone might be an important factor driving the theca cells proliferation and invasion. Additionally, some conserved genes related to mammalian placentation are significantly high expression in follicular placenta suggesting the high convergence in vertebrate placenta evolution.

evolutionary biology↗

bioRxiv2021

Human colorectal pre-cancer atlas identifies distinct molecular programs underlying two major subclasses of pre-malignant tumors

Most colorectal cancers (CRCs) develop from either adenomas (ADs) or sessile serrated lesions (SSLs). The origins and molecular landscapes of these histologically distinct pre-cancerous polyps remain incompletely understood. Here, we present an atlas at single-cell resolution of sporadic conventional tubular/tubulovillous ADs, SSLs, hyperplastic polyps (HPs), microsatellite stable (MSS) and unstable (MSI-H) CRC, and normal colonic mucosa. Using single-cell transcriptomics and multiplex imaging, we studied 69 datasets from 33 participants. We also examined separate sets of 66 and 274 polyps for RNA and targeted gene sequencing, respectively. We performed multiplex imaging on a tissue microarray of 14 ADs and 15 CRCs, and we integrated pre-cancer polyp data with published single-cell and The Cancer Genome Atlas (TCGA) bulk CRC data to establish potential polyp-cancer relationships. Striking differences were observed between ADs and SSLs that extended to MSS and MSI-H CRCs, respectively, reflecting their distinct origins and trajectories. ADs arose from WNT pathway dysregulation in stem cells, which aberrantly expanded and expressed a Hippo and ASCL2 regenerative program. In marked contrast, SSLs were depleted of stem cell-like populations and instead exhibited a program of gastric metaplasia in the setting of elevated cytotoxic inflammation. Using subtype-specific gene regulatory networks and shared genetic variant analysis, we implicated serrated polyps, including some HPs conventionally considered benign, as arising from a metaplastic program in committed absorptive cells. ADs and SSLs displayed distinct patterns of immune cell infiltration that may influence their natural history. Our multi-omic atlas provides novel insights into the malignant potential of colorectal polyps and serves as a framework for precision surveillance and prevention of sporadic CRC.

cancer biology↗

bioRxiv2021

High-throughput tandem-microwell assay for ammonia repositions FDA-Approved drugs to Helicobacter pylori infection

To date, little attempt has been made to develop new treatments for Helicobacter pylori (H. pylori), although the community is aware of the shortage of treatments for H. pylori. In this study, we developed a 192-tandem-microwell-based high-throughput-assay for ammonia that is a known virulence factor of H. pylori and a product of urease. We could identify few drugs, i.e. panobinostat, dacinostat, ebselen, captan and disulfiram, to potently inhibit the activity of ureases from bacterial or plant species. These inhibitors suppress the activity of urease via substrate-competitive or covalent-allosteric mechanism, but all except captan prevent the antibiotic-resistant H. pylori strain from infecting human gastric cells, with a more pronounced effect than acetohydroxamic acid, a well-known urease inhibitor and clinically used drug for the treatment of bacterial infection. This study offers several bases for the development of new treatments for urease-containing pathogens and to study the mechanism responsible for the regulation of urease activity.

biochemistry↗

bioRxiv2020

X-MOL: large-scale pre-training for molecular understanding and diverse molecular analysis

In silico modelling and analysis of small molecules substantially accelerates the process of drug development. Representing and understanding molecules is the fundamental step for various in silico molecular analysis tasks. Traditionally, these molecular analysis tasks have been investigated individually and separately. In this study, we presented X-MOL, which applies large-scale pre-training technology on 1.1 billion molecules for molecular understanding and representation, and then, carefully designed fine-tuning was performed to accommodate diverse downstream molecular analysis tasks, including molecular property prediction, chemical reaction analysis, drug-drug interaction prediction, de novo generation of molecules and molecule optimization. As a result, X-MOL was proven to achieve state-of-the-art results on all these molecular analysis tasks with good model interpretation ability. Collectively, taking advantage of super large-scale pre-training data and super-computing power, our study practically demonstrated the utility of the idea of "mass makes miracles" in molecular representation learning and downstream in silico molecular analysis, indicating the great potential of using large-scale unlabelled data with carefully designed pre-training and fine-tuning strategies to unify existing molecular analysis tasks and substantially enhance the performance of each task.

bioinformatics↗

bioRxiv2020

Phospholipid Metabolism Is Associated with HIV Rebound Upon Treatment Interruption

Lipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that phospholipids and their derivatives, lysophospholipids, can reactivate latent (dormant) tumor cells, causing cancer recurrence. However, the potential link between lipids and HIV latency, persistence, and viral rebound after cessation of antiretroviral therapy (ART) has never been investigated. We explored the links between plasma lipids and the burden of HIV during ART. We profiled the circulating lipidome from the plasma of 24 chronically HIV-infected individuals on suppressive ART who subsequently underwent an analytic treatment interruption (ATI) without concurrent immunotherapies. The pre-ATI viral burden was estimated as time-to-viral-rebound and viral load setpoints post-ATI. We found that higher pre-ATI levels of lysophospholipids, including the pro-inflammatory lysophosphatidylcholine, were associated with faster time-to-viral-rebound and higher viral setpoints upon ART cessation. Furthermore, higher pre-ATI levels of the pro-inflammatory byproduct of intestinal lysophosphatidylcholine metabolism, trimethylamine-N-oxide (TMAO), were also linked to faster viral rebound post-ART. Finally, pre-ATI levels of several phosphatidylcholine species (lysophosphatidylcholine precursors) correlated strongly with higher pre-ATI levels of HIV DNA in peripheral CD4+ T cells. Our proof-of-concept data point to phospholipids and lysophospholipids as plausible pro-inflammatory contributors to HIV persistence and rapid post-ART HIV rebound. The potential interplay between phospholipid metabolism and both the establishment and maintenance of HIV latent reservoirs during- and post-ART warrants further investigation. IMPORTANCEThe likelihood of HIV rebound after stopping antiretroviral therapy (ART) is a function of the interplay between the size of HIV reservoirs that persist despite ART and the host immunological and inflammatory factors that modulate these reservoirs. There is a need to comprehensively understand these host factors to develop a strategy to cure HIV infection and prevent viral rebound post-ART. Lipids are important biologically active molecules that are known to mediate several cellular functions, including reactivating latent tumor cells; however, their role in HIV latency, persistence, and post-ART rebound has never been investigated. We observed significant links between higher levels of the pro-inflammatory lysophosphatidylcholine and its intestinal metabolic byproduct, trimethylamine-N-oxide, and both faster time-to-viral rebound and higher viral load setpoint post ART. These data highlight the need for further studies to understand the potential contribution of phosphatidylcholine and lysophosphatidylcholine metabolism in shaping host immunological and inflammatory milieu during- and post-ART.

microbiology↗

bioRxiv2020

Data-informed discovery of hydrolytic nanozymes

Nanozyme is a collection of nanomaterials with enzyme-like activity but exhibits higher environmental tolerance and long-term stability than their natural counterparts. Improving the catalytic activity and expanding the category of nanozymes are prerequisites to complement or even supersede natural enzymes. Specifically, a powerful hydrolytic nanozyme is demanded to degrade the unsustainable substance which natural enzymes hardly achieve. However, the development of hydrolytic nanozymes is still hindered by diverse hydrolytic substrates and following complicated mechanisms. Here, we apply two strategies which are informed by data to screen and predict catalytic active sites of MOF (metal-organic framework) based hydrolytic nanozymes. One is to increase the intrinsic activity by finely tuned Lewis acidity of the metal clusters. The other is to adjust the volume density of the active sites by shortening the length of ligands. Finally, we construct a Ce-FMA-MOF-based hydrolytic nanozyme with robust cleavage ability towards phosphate bonds, amide bonds, glycosidic bonds whose energy ascend in order; and even their mixture, biofilms. This work provides a rational methodology to design hydrolytic nanozyme, enriches the diversity of nanozymes, and potentially sheds a light on the evolution of enzyme engineering in the future.

biophysics↗