Biology subjects

Cui, Y.

Publications and source records attributed to Cui, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2021

Breaching the cell-envelope barriers of gram-positive and fungal microbes by a type VI secretion system in Acidovorax citrulli

The type VI secretion system (T6SS) is a double-tubular toxin-injection nanomachine widely found in gram-negative human and plant pathogens. The current model depicts that the T6SS spear-like Hcp tube is powered by the contraction of an outer sheath to drill through the envelope of a neighboring cell, achieving cytosol to cytosol delivery. However, gram-positive bacteria seem to be impenetrable to such T6SS action. Here we report that a plant pathogen Acidovorax citrulli (AC) deploys a highly potent T6SS to kill a range of bacteria including Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Mycobacterium smegmatis as well as fungal species including Candida albicans and Pichia pastoris. Using bioinformatic and biochemical assays, we identified a group of T6SS effectors and characterized one effector RhsB that is critical for interspecies interaction. We report that RhsB contains a conserved YD-repeat domain and a C-terminal nuclease domain. Toxicity of RhsB was neutralized by its downstream immunity proteins through direct interaction. RhsB was cleaved at the C-terminal end and a catalytic mutation within the internal aspartic protease abolished such cleavage. Collectively, the T6SS of AC displays potent activities to penetrate the cell envelope barriers of gram-positive and fungal species, highlighting the greatly expanded capabilities of T6SS in modulating microbiome compositions in complex environments.

microbiology↗

bioRxiv2021

miR-2 contributes to WSSV infection by targeting Caspase 2 in mud crab (Scylla paramamosain)

As we known, Caspase 2 is widely studied for its apoptosis regulatory function in mammals. However, despite the fundamental role of apoptosis during the anti-viral immune response, the relationship between Caspase 2 and virus infection has not been extensively explored in invertebrates, whether miRNAs are involved in this process also remains unclear. To address this issue, the miRNA-mediated regulation of Caspase 2 in mud crab Scylla paramamosain was characterized in this study. The results suggested that Sp-Caspase 2 could suppress white spot syndrome virus (WSSV) infection via apoptosis induction. The further data showed that Caspase 2 was directly targeted by miR-2 in mud crab. Silencing or overexpression of miR-2 could affect apoptosis and WSSV replication through regulating the expression level of Caspase 2. Taken together, all these results demonstrated the crucial role of miR-2-Caspase 2 pathway in the innate immunity of mud crab and revealed a novel mechanism during anti-viral immune response in marine invertebrates.

immunology↗

bioRxiv2021

Assessing the origins of the European Plagues following the Black Death: a synthesis of genomic, historical and ecological information

The Second Plague Pandemic started in Europe with the Black Death in 1346 and lasted until the 19th century. Based on ancient DNA studies, there is a scientific disagreement over whether the bacterium, Yersinia pestis, came into Europe once (Hypothesis 1), or repeatedly over the following four centuries (Hypothesis 2). Here we synthesize the most updated phylogeny together with historical, archeological, evolutionary and ecological information. On the basis of this holistic view, we conclude that Hypothesis 2 is the most plausible. We also suggest that Y. pestis lineages might have developed attenuated virulence during transmission, which can explain the convergent evolutionary signals, including pla-decay, that appeared at the end of the pandemics. Significance StatementOver the last few years there has been a great deal of scientific debate regarding whether the plague bacterium, Yersinia pestis, spread from a Western European reservoir during the Second Plague Pandemic, or if it repeatedly came to Europe from Asia. Here we make a synthesis of the available evidence, including genomes of ancient DNA, historical, archeological and ecological information. We conclude that the bacterium most likely came to Europe from Asia several times during the Second Plague Pandemic.

evolutionary biology↗

bioRxiv2021

Precision Genome and Base Editing by Regulating mRNA Nuclear Export Using Selective Inhibitors of Nuclear Export

CRISPR-based genome engineering tools are associated with off-target effects that constitutively active Cas9 protein may instigate. In the present study, we screened for irreversible small molecule off-switches of CRISPR-Cas9 and discovered that selective inhibitors of nuclear export (SINEs) could inhibit the cellular activity of CRISPR-Cas9 by interfering with the nuclear export of Cas9 mRNA. We subsequently found that SINEs, including an FDA-approved anticancer drug KPT330, could improve the specificities of CRISPR-Cas9-based genome and base editing tools in human cells.

biochemistry↗

bioRxiv2021

Enhancing Drug-Drug Interaction Prediction Using Deep Attention Neural Networks

Drug-drug interactions are one of the main concerns in drug discovery. Accurate prediction of drug-drug interactions plays a key role in increasing the efficiency of drug research and safety when multiple drugs are c o-prescribed. With various data sources that describe the relationships and properties between drugs, the comprehensive approach that integrates multiple data sources would be considerably effective in making high-accuracy prediction. In this paper, we propose a Deep Attention Neural Network based Drug-Drug Interaction prediction framework, abbreviated as DANN-DDI, to predict unobserved drug-drug interactions. First, we construct multiple drug feature networks and learn drug representations from these networks using the graph embedding method; then, we concatenate the learned drug embeddings and design an attention neural network to learn representations of drug-drug pairs; finally, we adopt a deep neural network to accurately predict drug-drug interactions. The experimental results demonstrate that our model DANN-DDI has improved prediction performance compared with state-of-the-art methods. Moreover, the proposed model can predict novel drug-drug interactions and drug-drug interaction-associated events.

bioinformatics↗

bioRxiv2021

Multiple nucleotide polymorphism DNA markers for the accurate evaluation of genetic variations

DNA markers are an essential tool for the detection and evaluation of genetic variations, a central theme in genetics and biology. Effective markers must be highly reproducible, polymorphic, accurate and efficient to profile. We developed multiple dispersed nucleotide polymorphism (MNP) DNA marker and an efficient MNP genotyping method called MNP-Seq. The MNP marker was 17.48% more polymorphic than the highly polymorphic marker of microsatellites on a collection of hybrid rice plants. When applied to genotype more than 80,000 individual MNP markers of diploid rice and polyploidy hybrid cotton varieties which were notoriously difficult to genotype accurately, MNP-Seq finished in two days and achieved accuracies of 99.999% and 99.988%, respectively. We adopted MNP-Seq to reveal the ubiquitous, albeit subtle and neglected, genetic heterogeneities in homonyms of Nipponbare rice, a popular model organism for plant biology. This result raised a question on the consistency of the published results using the model plant. We also used MNP-Seq to accurately and efficiently determine the identities of plant varieties, a key but difficult problem for the protection of plant intellectual property rights. While being applied to plants in the current study, the MNP marker and MNP-Seq are general and readily applicable to similar problems in animals and micro-organisms.

molecular biology↗

bioRxiv2021

Exploring the dynamic mechanisms of steady-state visual evoked potentials at the whole-brain level: evidence from a computational study

Periodic visual stimulation can induce stable steady-state visual evoked potentials (SSVEPs) distributed in multiple brain regions and has potential applications in both neural engineering and cognitive neuroscience. However, the underlying dynamic mechanisms of SSVEPs at the whole-brain level are still not completely understood. Here, we addressed this issue by simulating the rich dynamics of SSVEPs with a large-scale brain model designed with constraints of neuroimaging data acquired from the human brain. By eliciting activity of the occipital areas using an external periodic stimulus, our model was capable of replicating both the spatial distributions and response features of SSVEPs that were observed in experiments. In particular, we confirmed that alpha-band (8-12 Hz) stimulation could evoke stronger SSVEP responses; this frequency sensitivity was due to nonlinear entrainment and resonance, and could be modulated by endogenous factors in the brain. Interestingly, the stimulus-evoked brain networks also exhibited significant superiority in topological properties near this frequency-sensitivity range, and stronger SSVEP responses were demonstrated to be supported by more efficient functional connectivity at the neural activity level. These findings not only provide insights into the mechanistic understanding of SSVEPs at the whole-brain level but also indicate a bright future for large-scale brain modeling in characterizing the complicated dynamics and functions of the brain.

neuroscience↗

bioRxiv2021

Compensating complete loss of signal recognition particle during co-translational protein targeting by the translation speed and accuracy

Signal recognition particle (SRP) is critical for delivering co-translational proteins to the bacterial inner membrane. Previously, we identified SRP suppressors in Escherichia coli that inhibit translation initiation and elongation, which provided insights into the mechanism of bypassing the requirement of SRP. Suppressor mutations tended to be located in regions that govern protein translation under evolutionary pressure. To test this hypothesis, we re-executed the suppressor screening of SRP. Here we isolated a novel SRP suppressor mutation located in the Shine-Dalgarno sequence of the S10 operon, which partially offset the targeting defects of SRP-dependent proteins. We found that the suppressor mutation decreased the protein translation rate, which extended the time window of protein targeting. This increased the possibility of the correct localization of inner membrane proteins. Furthermore, the fidelity of translation was decreased in suppressor cells, suggesting that the quality control of translation was inactivated to provide an advantage in tolerating toxicity caused by the loss of SRP. Our results demonstrated that the inefficient protein targeting due to SRP deletion can be rescued through modulating translational speed and accuracy.

microbiology↗

bioRxiv2020

De novo macrocyclic peptides for inhibiting, stabilising and probing the function of the Retromer endosomal trafficking complex

The Retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signalling. Mutations in Retromer cause late-onset Parkinsons disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function we have created a novel series of macrocyclic peptides that bind Retromer with high affinity and specificity. Crystal structures show the majority of cyclic peptides bind to Vps29 via a Pro-Leu-containing sequence, structurally mimicking known interactors such as TBC1D5, and blocking their interaction with Retromer in vitro and in cells. By contrast, macrocyclic peptide RT-L4 binds Retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting Retromer. Finally, tagged peptides can be used to probe the cellular localisation of Retromer and its functional interactions in cells, providing novel tools for studying Retromer function.

biochemistry↗

bioRxiv2020

Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2

The ongoing SARS-CoV-2 pandemic has brought an urgent need for animal models to study the pathogenicity of the virus. Herein, we generated and characterized a novel mouse-adapted SARS-CoV-2 strain, named MASCp36, that causes severe acute respiratory symptoms and mortality in standard laboratory mice. Particularly, this model exhibits age and gender related skewed distribution of mortality akin to severe COVID-19, and the 50% lethal dose (LD50) of MASCp36 was 58 PFU in 9-month-old, male BALB/c mice. Deep sequencing identified three amino acid substitutions, N501Y, Q493H, and K417N, subsequently emerged at the receptor binding domain (RBD) of MASCp36, during in vivo passaging. All three mutations in RBD significantly enhanced the binding affinity to its endogenous receptor, mouse ACE2 (mACE2). Cryo-electron microscopy (cryo-EM) analysis of human ACE2 (hACE2) or mACE2 in complex with the RBD of MASCp36 at 3.1 to 3.7 angstrom resolution elucidates molecular basis for the receptor-binding switch driven by specific amino acid substitutions. Interestingly, N501Y and Q493H enhanced the binding affinity to human ACE2 (hACE2); while triple mutations N501Y/Q493H/K417N decreased affinity to hACE2, thus led to the reduced infectivity of MASCp36 to human cells. Our study not only provides a robust platform for studying the pathogenesis of severe COVID-19 and rapid evaluation of coutermeasures against SARS-CoV-2, but also unveils the molecular mechanism for the rapid adaption and evolution of SARS-CoV-2 in human and animals. One sentence summaryA mouse adapted SARS-CoV-2 strain that harbored specific amino acid substitutions in the RBD of S protein showed 100% mortality in aged, male BALB/c mice.

microbiology↗

bioRxiv2020

The genomic formation of First American ancestors in East and Northeast Asia

Upward Sun River 1, an individual from a unique burial of the Denali tradition in Alaska (11500 calBP), is considered a type representative of Ancient Beringians who split from other First Americans 22000-18000 calBP in Beringia. Using a new admixture graph model-comparison approach resistant to overfitting, we show that Ancient Beringians do not form the deepest American lineage, but instead harbor ancestry from a lineage more closely related to northern North Americans than to southern North Americans. Ancient Beringians also harbor substantial admixture from a lineage that did not contribute to other Native Americans: Amur River Basin populations represented by a newly reported site in northeastern China. Relying on these results, we propose a new model for the genomic formation of First American ancestors in Asia. One Sentence SummaryAncient Beringians do not form the deepest American lineage, but harbor admixture from Amur River Basin populations.

genetics↗

bioRxiv2020

CancerMIRNome: a web server for interactive analysis and visualization of cancer miRNome data

MicroRNAs (miRNAs), which play critical roles in gene regulatory networks, have emerged as promising diagnostic and prognostic biomarkers for human cancer. In particular, circulating miRNAs that are secreted into circulation exist in remarkably stable forms, and have enormous potential to be leveraged as non-invasive biomarkers for early cancer detection. Novel and user-friendly tools are desperately needed to facilitate data mining of the vast amount of miRNA expression data from The Cancer Genome Atlas (TCGA) and large-scale circulating miRNA profiling studies. To fill this void, we developed CancerMIRNome, a comprehensive database for the interactive analysis and visualization of miRNA expression profiles based on 10,998 samples from 33 TCGA projects and 21,993 samples from 40 public circulating miRNome datasets. A series of cutting-edge bioinformatics tools and machine learning algorithms have been packaged in CancerMIRNome, allowing for the pan-cancer analysis of a miRNA of interest across multiple cancer types and the comprehensive analysis of miRNome profiles to identify dysregulated miRNAs and develop diagnostic or prognostic signatures. The data analysis and visualization modules will greatly facilitate the exploit of the valuable resources and promote translational application of miRNA biomarkers in cancer. The CancerMIRNome database is publicly available at http://bioinfo.jialab-ucr.org/CancerMIRNome.

bioinformatics↗

bioRxiv2020

Myogenic Vasoconstriction Requires Canonical Gq/11 Signaling of Angiotensin II Type 1a Receptor in Murine Vasculature

BackgroundThe myogenic response is an inherent vasoconstrictive property of resistance arteries to keep blood flow constant in response to increases in intravascular pressure. Angiotensin II (Ang II) type 1 receptors (AT1R) are broadly distributed, mechanoactivated receptors, which have been proposed to transduce myogenic vasoconstriction. However, the AT1R subtype(s) involved and their downstream G protein- and {beta}-arrestin-mediated signaling pathways are still elusive. ObjectiveTo characterize the function of AT1aR and AT1bR in the regulation of the myogenic response of resistance size arteries and possible downstream signaling cascades mediated by Gq/11 and/or {beta}-arrestins. MethodsWe used Agtr1a-/-, Agtr1b-/- and tamoxifen-inducible smooth muscle-specific AT1aR knockout mice (SM-Agtr1a mice). FR900359, [Sar1, Ile4, Ile8] Ang II (SII) and TRV120055 were used as selective Gq/11 protein inhibitor and biased agonists to activate non-canonical {beta}-arrestin and canonical Gq/11 signaling of the AT1R, respectively. ResultsMyogenic and Ang II-induced vasoconstrictions were diminished in the perfused renal vasculature of Agtr1a-/- and SM-Agtr1a mice. Similar results were observed in isolated pressurized mesenteric and cerebral arteries. Myogenic tone and Ang II-induced vasoconstrictions were normal in arteries from Agtr1b-/- mice. The Gq/11 blocker FR900359 decreased myogenic tone and Ang II vasoconstrictions while selective biased targeting of AT1R {beta}-arrestin signaling pathways had no effects. ConclusionThe present study demonstrates that myogenic arterial constriction requires Gq/11-dependent signaling pathways of mechanoactivated AT1aR but not G protein-independent, noncanonical alternative signaling pathways in the murine mesenteric, cerebral and renal circulation.

physiology↗

bioRxiv2020

Efficient cooperation of chloroplasts and mitochondria enhances ATP and sucrose production

Efficient photosynthesis requires a balance of ATP and NADPH production/consumption in chloroplasts and the exportation of reducing equivalents from chloroplasts is important for balancing stromal ATP/NADPH ratio. Here we showed that the overexpression of purple acid phosphatase 2 on the outer membranes of chloroplasts and mitochondria can streamline the production and consumption of reducing equivalents in these two organelles, respectively. A higher capacity of consumption of reducing equivalents in mitochondria can indirectly help chloroplasts to balance the ATP/NADPH ratio in stroma and recycle NADP+, the electron acceptors of the linear electron flow. A higher rate of ATP and NADPH production from the linear electron flow, a higher capacity of carbon fixation by the Calvin-Benson-Bassham cycle and a greater consumption of NADH in mitochondria, enhance photosynthesis in the chloroplasts, ATP production in the mitochondria, sucrose synthesis in the cytosol, and eventually boosting plant growth and seed yields in the overexpression lines.

plant biology↗

bioRxiv2020

Capture of mouse and human stem cells with features of formative pluripotency

Pluripotent cells emerge via a naive founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse embryonic stem (ES) cells and epiblast stem cells (EpiSCs) represent the initial naive and final primed phases of pluripotency, respectively. Here we investigate the intermediate formative stage. Using minimal exposure to specification cues, we expand stem cells from formative mouse epiblast. Unlike ES cells or EpiSCs, formative stem (FS) cells respond directly to germ cell induction. They colonise chimaeras including the germline. Transcriptome analyses show retained pre-gastrulation epiblast identity. Gain of signal responsiveness and chromatin accessibility relative to ES cells reflect lineage capacitation. FS cells show distinct transcription factor dependencies from EpiSCs, relying critically on Otx2. Finally, FS cell culture conditions applied to human naive cells or embryos support expansion of similar stem cells, consistent with a conserved attractor state on the trajectory of mammalian pluripotency.

developmental biology↗

bioRxiv2020

Azetidines kill Mycobacterium tuberculosis without detectable resistance by blocking mycolate assembly.

Tuberculosis (TB) is the leading cause of global morbidity and mortality resulting from infectious disease, with over 10 million new cases and 1.5 million deaths in 2019. This global emergency is exacerbated by the emergence of multi-drug-resistant MDR-TB and extensively-drug-resistant XDR-TB, therefore new drugs and new drug targets are urgently required. From a whole-cell phenotypic screen a series of azetidines derivatives termed BGAz, that elicit potent bactericidal activity with MIC99 values <10 M against drug-sensitive Mycobacterium tuberculosis and MDR-TB were identified. These compounds demonstrate no detectable drug resistance. Mode of action and target deconvolution studies suggest that these compounds inhibit mycobacterial growth by interfering with cell envelope biogenesis, specifically late-stage mycolic acid biosynthesis. Transcriptomic analysis demonstrates that the BGAz compounds tested display a mode of action distinct from existing mycobacterial cell-wall inhibitors. In addition, the compounds tested exhibit toxicological and PK/PD profiles that pave the way for their development as anti-tubercular chemotherapies.

microbiology↗

bioRxiv2020

Heterogeneity of midgut cells and their differential responses to blood meal ingestion by the mosquito, Aedes aegypti

Mosquitoes are the most notorious hematophagous insects and due to their blood feeding behavior and genetic compatibility, numerous mosquito species are highly efficient vectors for certain human pathogenic parasites and viruses. The mosquito midgut is the principal organ of blood meal digestion and nutrient absorption. It is also the initial site of infection with blood meal acquired parasites and viruses. We conducted an analysis based on single-nucleus RNA sequencing (snRNA-Seq) to assess the cellular diversity of the midgut and how individual cells respond to blood meal ingestion to facilitate its digestion. Our study revealed the presence of 20 distinguishable cell-type clusters in the female midgut of Aedes aegypti. The identified cell types included intestinal stem cell (ISC), enteroblasts (EB), differentiating EB (dEB), enteroendocrine cells (EE), enterocytes (EC), EC-like cells, cardia cells, and visceral muscle (VM) cells. Blood meal ingestion dramatically changed the overall midgut cell type composition, profoundly increasing the proportions of ISC and three EC/EC like clusters. In addition, transcriptional profiles of all cell types were strongly affected while genes involved in various metabolic processes were significantly upregulated. Our study provides a basis for further physiological and molecular studies on blood digestion, nutrient absorption, and cellular homeostasis in the mosquito midgut.

genomics↗

bioRxiv2020

The global landscape of SARS-CoV-2 genomes, variants, and haplotypes in 2019nCoVR

On 22 January 2020, the National Genomics Data Center (NGDC), part of the China National Center for Bioinformation (CNCB), created the 2019 Novel Coronavirus Resource (2019nCoVR), an open-access SARS-CoV-2 information resource. 2019nCoVR features a comprehensive integration of sequence and clinical information for all publicly available SARS-CoV-2 isolates, which are manually curated with value-added annotations and quality evaluated by our in-house automated pipeline. Of particular note, 2019nCoVR performs systematic analyses to generate a dynamic landscape of SARS-CoV-2 genomic variations at a global scale. It provides all identified variants and detailed statistics for each virus isolate, and congregates the quality score, functional annotation, and population frequency for each variant. It also generates visualization of the spatiotemporal change for each variant and yields historical viral haplotype network maps for the course of the outbreak from all complete and high-quality genomes. Moreover, 2019nCoVR provides a full collection of SARS-CoV-2 relevant literature on COVID-19 (Coronavirus Disease 2019), including published papers from PubMed as well as preprints from services such as bioRxiv and medRxiv through Europe PMC. Furthermore, by linking with relevant databases in CNCB-NGDC, 2019nCoVR offers data submission services for raw sequence reads and assembled genomes, and data sharing with National Center for Biotechnology Information. Collectively, all SARS-CoV-2 genome sequences, variants, haplotypes and literature are updated daily to provide timely information, making 2019nCoVR a valuable resource for the global research community. 2019nCoVR is accessible at https://bigd.big.ac.cn/ncov/.

genomics↗