Biology subjects

Dai, Y.

Publications and source records attributed to Dai, Y..

At least 127 records · Page 7Linked to original sources

bioRxiv2022

Tumor landscape of epithelial ovarian cancer highlights that EGR1 drives tumor invasion at single-cell resolution

Identifying underlying molecular mechanisms and biomarkers of epithelial ovarian carcinoma (EOC) proliferation and metastasis remains challenging. Patients of EOC are usually diagnosed at an advanced stage and the availability of invasion-related targets is limited. Herein, we explored the single-cell RNA sequencing (scRNA-seq) dataset of EOC and defined tumor physiological reprograming compared to bulk RNA-seq. The energy metabolism and anti-apoptotic pathway was found as critical contributors to intratumor heterogeneity. Moreover, hypoxia, oxidative phosphorylation (OXPHOS) and glycolysis were positively correlated, which have biologically activity trajectories during epithelial mesenchymal transition (EMT). The HMGH1, EGR1 and RUNX1 were found to be critical inducers of the EMT process in EOC. Experimental validation revealed that suppressed EGR1 decreased the expression of FAS and HSPG2 and associating with EMT progression in EOC. In tumor microenvironment (TME), CAFs were found have significant contribution to tumor immune infiltration and metastasis and accumulation of CAFs was associated with poorer patient survival. In conclusion, physiological features and molecular mechanisms in the TME of EOC were revealed and provided effective targets for the suppression of tumor metastasis.

bioinformatics↗

bioRxiv2022

Using polygenic risk score about complex traits to predict production performance in crossbreeding of yeast

The cultivation of hybrids with favorable complex traits is one of the important goals for animal, plant, and microbial breeding practices. A method that can well predict the production performance of hybrids will be of great significance to the whole research and practice. In our study, polygenic risk scores (PRS) were introduced to estimate the production performance of Saccharomyces Cerevisiae. The genetic variation of 971 published isolates and their growth ratios under 35 medium conditions were analyzed by genome-wide association analysis, and the precise p-value threshold for each phenotype was calculated. Risk markers for the above 35 phenotypes were obtained. By estimating genotype of F1 hybrids according to that of the parents, the PRS of 613 F1 hybrids was predicted. There was a significant linear correlation between YPD40 and PRS in F1 and their parents (R2=0.2582, R2=0.2414, respectively), which indicates that PRS can be used to estimate the production performance of individuals and their hybrids. Our method can provide a reference for strains selection and F1 prediction in yeasts cross-breeding, reduce the workload and improve the work efficiency.

genetics↗

bioRxiv2022

A peculiar evolutionary feature of monkeypox virus

From 1 Jan 2022 to 15 June 2022, more than 2,100 cases of monkeypox have been reported in 42 countries. This unusual outbreak of monkeypox has raised new concerns in academia and the public. To keep abreast of the trend of the monkeypox epidemic, it is extremely urgent and important to surveille the accumulated genomic mutations and the change of the transmission ability of the pathogen, monkeypox virus (MPXV). We report a non-canonical RNA secondary structure, G-quadruplex (RG4), that surprisingly evolved stepwise with various variants. The RG4 motif is located in the coding sequence region of MPXV C9L gene that is functional in inhibiting host innate immune response. The evolution decreases the stability of this RG4 and promotes C9L protein level in living cells. Importantly, all the reported MPXV genomes in 2022 contain the most unstable RG4 variant, which may be the reason of the increasing spread of MPXV. These findings recommend that health authorities and researchers pay attention to the genomic evolution of MPXV.

genetics↗

bioRxiv2022

The immunogenomic landscape of cattle

Here, we report the de novo assembly of a cattle genome using ultra-long-read nanopore sequencing in conjunction with other advanced technologies. The assembled genome contains only 145 contigs (N50 [~] 74.0 Mb). Compare to the current reference cattle genome ARS-UCD1.2, 154 gaps are closed, and 467 scaffolds are further placed in our assembly. Importantly, except two remained gaps in the T-cell receptor /{delta} (TRA/TRD) region, the gene loci of other TRs and immunoglobulins (IGs) are seamlessly assembled and exquisitely annotated. With the characterization of 258 IG genes and 626 TR genes that distributed in seven genomic loci, we illustrate the highest immune gene diversity in mammals to our knowledge. Moreover, the gene structures of major histocompatibility complex (MHC) are integrally depicted with properly phased haplotypes. Thus, our work not only reports a cattle genome with the most continuity and completeness, but also provide a comprehensive view of the complex immune- genome.

genomics↗

bioRxiv2022

Structure and mechanism of a mitochondrial AAA+ disaggregase CLBP

The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space and functions to promote the solubilization of various mitochondrial proteins. CLPB deficiency by mutations is associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus. The mechanism of CLPB functions as a disaggregase and the role of its ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. CLPB assembles into homo- tetradecamers in apo-state and is remodeled into homo-dodecamers upon binding to substrates. Conserved pore- loops on the ATPase domains form a spiral staircase to grip and translocate the substrate in a step-size of two amino acid residues. The ANK domain is not only responsible for maintaining the higher-order assembly but also essential for the disaggregase activity. Interactome analysis suggests that the ANK domain may directly interact with a variety of mitochondrial substrates. These results reveal unique properties of CLPB as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.

molecular biology↗

bioRxiv2022

Encoding sensing functions into material interface for a rationally engineered integrated electrochemical liquid biopsy

Limited healthcare capacity highlights the needs of integrated and simple sensing systems for personalized health monitoring. However, only a limited set of sensors can be employed for point-of-care applications, emphasizing the lack of a generalizable engineering strategy for sensor construction. Here, we report a de novo rational engineering strategy for the construction of an integrated electrochemical liquid biopsy (ELB) platform capable of direct profiling cancer exosomes from blood. Using a bottom-up approach for sensor design, a series of critical sensing functions is considered and encoded into the material interface by programming the electrode material with different chemical and structure features. We present that the rationally engineered electrochemical liquid biopsy platform is able to achieve one-step sensor fabrication, target isolation, non-fouling and high-sensitivity sensing, direct signal transduction and multiplexed detection. Integrating the multiplexed sensing with principal component analysis, we demonstrate the capability of the programmed sensing system on differentiating cancerous groups from healthy controls by analyzing clinical samples from lung cancer patients.

bioengineering↗

bioRxiv2021

Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/470415v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@14625org.highwire.dtl.DTLVardef@1a43372org.highwire.dtl.DTLVardef@12dc0c8org.highwire.dtl.DTLVardef@cbb835_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Oxalic acid binds to gustatory receptor Gr23a and inhibits feeding in the brown planthopper

Plants produce diverse secondary compounds as natural protection against microbial and insect attack. Most of these compounds, including bitters and acids, are sensed by insect gustatory receptors (Grs). Acids are potentially toxic to insects, but there are few reports on sour compounds as ligands of insect Grs. Here, using two different heterologous expression systems, the insect Sf9 cell line and the mammalian HEK293T cell line, we started from crude extracts of rice (Oryza sativa) and successfully identified oxalic acid (OA) as a ligand of NlGr23a, a Gr in the brown planthopper Nilaparvata lugens. The antifeedant effect of OA on the brown planthopper was dose dependent, and NlGr23a is essential for OAs antifeedant activity in both artificial diets and rice plants. NlGr23a is also indispensable for tarsal OA sensing. To our knowledge, OA is the first identified ligand starting from plant crude extracts and the first known strong acid for insect Grs. These findings on rice-planthopper interactions will be of broad interest for pest control in agriculture and also for better understanding of how insects select host plants. Research organismNilaparvata lugens

ecology↗

bioRxiv2021

A new class of cell wall-recycling L,D-carboxypeptidase determines β-lactam susceptibility and morphogenesis in Acinetobacter baumannii

The hospital-acquired pathogen Acinetobacter baumannii possesses a complex cell envelope that is key to its multidrug resistance and virulence. The bacterium, however, lacks many canonical enzymes that build the envelope in model organisms. Instead, A. baumannii contains a number of poorly annotated proteins that may allow alternative mechanisms of envelope biogenesis. We demonstrated previously that one of these unusual proteins, ElsL, is required for cell elongation and for withstanding antibiotics that attack the septal cell wall. Curiously, ElsL is composed of a leaderless YkuD-family domain usually found in secreted, cell-wall-modifying L,D-transpeptidases (LDTs). Here, we show that, rather than being an LDT, ElsL is actually a new class of cytoplasmic L,D-carboxypeptidase (LDC) that provides a critical step in cell-wall recycling previously thought to be missing from A. baumannii. Absence of ElsL impairs cell wall integrity, elongation, and intrinsic resistance due to buildup of murein tetrapeptide precursors, toxicity of which is bypassed by preventing muropeptide recycling. Multiple pathways in the cell become sites of vulnerability when ElsL is inactivated, including L,D-crosslink formation, cell division, and outer membrane lipid homoeostasis, reflecting its pleiotropic influence on cell envelope physiology. We thus reveal a novel class of cell-wall-recycling LDC critical to growth and homeostasis of A. baumannii and likely many other bacteria. ImportanceTo grow efficiently, resist antibiotics, and control the immune response, bacteria recycle parts of their cell wall. A key step in the typical recycling pathway is the reuse of cell wall peptides by an enzyme known as an LDC. Acinetobacter baumannii, an "urgent-threat" pathogen causing drug-resistant sepsis in hospitals, was previously thought to lack this enzymatic activity due to absence of a known LDC homolog. Here, we show that A. baumannii possesses this activity in the form of an enzyme class not previously associated with cell wall recycling. Absence of this protein intoxicates and weakens the A. baumannii cell envelope in multiple ways due to the accumulation of dead-end intermediates. Several other organisms of importance to health and disease encode homologs of the A. baumannii enzyme. This work thus reveals an unappreciated mechanism of cell wall recycling, manipulation of which may contribute to enhanced treatments targeting the bacterial envelope.

microbiology↗

bioRxiv2021

deCS: A tool for systematic cell type annotations of single-cell RNA sequencing data among human tissues

Single-cell RNA sequencing (scRNA-seq) is revolutionizing the study of complex and dynamic cellular mechanisms. However, cell-type annotation remains a main challenge as it largely relies on a priori knowledge and manual curation, which is cumbersome and less accurate. The increasing number of scRNA-seq data sets, as well as numerous published genetic studies, motivated us to build a comprehensive human cell type reference atlas. Here, we present deCS (decoding Cell type-Specificity), an automatic cell type annotation method augmented by a comprehensive collection of human cell type expression profiles and marker genes. We used deCS to annotate scRNA-seq data from various tissue types and systematically evaluated the annotation accuracy under different conditions, including reference panels, sequencing depth and feature selection strategies. Our results demonstrated that expanding the references is critical for improving annotation accuracy. Compared to many existing state-of-the-art annotation tools, deCS significantly reduced computation time and increased accuracy. deCS can be integrated into the standard scRNA-seq analytical pipeline to enhance cell type annotation. Finally, we demonstrated the broad utility of deCS to identify trait-cell type associations in 51 human complex traits, providing deeper insights into the cellular mechanisms of disease pathogenesis. All documents, including source code, user manual, demo data, and tutorials, are freely available at https://github.com/bsml320/deCS.

bioinformatics↗

bioRxiv2021

Gestational insulin resistance is mediated by the gut microbiome-indoleamine 2,3-dioxygenase axis

Background and aimsNormal gestation involves reprogramming of maternal gut microbiome (GM) that may contribute to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of GM - maternal metabolism interaction. MethodsThe GM and plasma metabolome of CD1, NIH-Swiss and C57BL/6J mice were analyzed using 16S rRNA sequencing and untargeted LC-MS throughout gestation and postpartum. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM in the process was studied using fecal microbial transplants (FMT). ResultsSignificant variation in gut microbial alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time-point specific, with species enriched at gestation day 15/19 (G15/19), a point of heightened IR, distinct from those enriched pre- or post- pregnancy. Untargeted and targeted metabolomics revealed elevated plasma kynurenine at G15/19 in all three mouse strains. IDO1, the rate limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine levels effects on IR derive from the GM in both mouse and human pregnancy. ConclusionsGM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1.

physiology↗

bioRxiv2021

Quercetin ameliorates mitochondrial dysfunction and mitigates methamphetamine-induced anxiety-like behavior

Methamphetamine (MA) abuse results in neurotoxic outcomes, including increased anxiety and depression, during both MA use and withdrawal. Although numerous studies have reported an association between MA exposure and anxiety, the underlying mechanism remains elusive. In this study, escalating dose of MA was used to establish an MA-treated mouse model presenting anxiety behavior. RNA seq was then performed to profile the gene expression patterns in the hippocampus (HIPP). Differentially expressed genes (DEGs) were identified and function enrichment analysis was conducted to explore the underlying mechanisms. Quercetin as an mitochondria protector was used in vivo and in vitro. The C57BL/6J mice were co-treated with 50 mg/kg Quercetin and escalating MA. Anxiety behavior was evaluated by utilizing the elevated plus maze and the open field test. Transmission electron microscopy and immunohistochemistry were conducted to study the pathology of MA-inducced anxiety. The effects of MA and Quercetin on astrocytes were investigated by fluorescence staining, transmission electron microscopy, flow cytometry, and oxygen consumption rate. Western blot and qPCR were performed to analyze altered protein and gene levels of HIPP in mice and astrtocytes. The results demonstrated that forteen upregulated differentially expressed genes were identified and significantly enriched in signaling pathways related to psychiatric disorders and mitochondrial function. Interestingly, we found that quercetin was able to alleviate MA-induced anxiety-like behavior by improving neuron number and mitochondria injury. Mechanistically, quercetin can mitigate aberrant mitochondrial morphology and mitochondrial dysfunction not only by decreasing the levels of total cytoplasmic reactive oxygen species (ROS), mitochondria-derived ROS (mtROS), and mitochondrial membrane potential (MMP), but also increasing the oxygen consumption rate (OCR) and mitochondrial ATP production in vitro, indicating Quercetin ameliorated MA-induced anxiety-like behavior by modifying mitochondrial morphology and function. Furthermore, quercetin reversed OPA1 and DRP1 expression in astrocytes, and mitigated astrocyte activation and the release of inflammatory factors, which can trigger neuronal apoptosis and synaptic loss. Taken together, we provided evidence showing that MA can induce anxiety-like behavior via the induction of oxidative stress and mitochondrial dysfunction. Quercetin exerted antipsychotic activity through mitochondrial modulation, suggesting its potential for further therapeutic development in MA-induced anxiety.

neuroscience↗

bioRxiv2021

Double-stranded RNA drives SARS-CoV-2 nucleocapsid protein to undergo phase separation at specific temperatures

Betacoronavirus SARS-CoV-2 infections caused the global Covid-19 pandemic. The nucleocapsid protein (N-protein) is required for multiple steps in the betacoronavirus replication cycle. SARS-CoV-2-N-protein is known to undergo liquid-liquid phase separation (LLPS) with specific RNAs at particular temperatures to form condensates. We show that N-protein recognizes at least two separate and distinct RNA motifs, both of which require double-stranded RNA (dsRNA) for LLPS. These motifs are separately recognized by N-proteins two RNA binding domains (RBDs). Addition of dsRNA accelerates and modifies N-protein LLPS in vitro and in cells and controls the temperature condensates form. The abundance of dsRNA tunes N-protein-mediated translational repression and may confer a switch from translation to genome packaging. Thus, N-proteins two RBDs interact with separate dsRNA motifs, and these interactions impart distinct droplet properties that can support multiple viral functions. These experiments demonstrate a paradigm of how RNA structure can control the properties of biomolecular condensates.

molecular biology↗

bioRxiv2021

A novel and accurate full-length HTT mouse model for Huntington's disease

Here we report the generation and characterization of a novel Huntingtons disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with [~]226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like mood and cognitive phenotypes at 2 months. From 3-4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibit neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers and testing gene-targeting therapeutic approaches for HD.

neuroscience↗

bioRxiv2021

A studyforrest extension, MEG recordings while watching the audio-visual movie "Forrest Gump"

Naturalistic stimuli, such as movies, are being increasingly used to map brain function because of their high ecological validity. The pioneering studyforrest and other naturalistic neuroimaging projects have provided free access to multiple movie-watching functional magnetic resonance imaging (fMRI) datasets to prompt the community for naturalistic experimental paradigms. However, sluggish blood-oxygenation-level-dependent fMRI signals are incapable of resolving neuronal activity with the temporal resolution at which it unfolds. Instead, magnetoencephalography (MEG) measures changes in the magnetic field produced by neuronal activity and is able to capture rich dynamics of the brain at the millisecond level while watching naturalistic movies. Herein, we present the first public prolonged MEG dataset collected from 11 participants while watching the 2 h long audio-visual movie "Forrest Gump". Minimally preprocessed data was also provided to facilitate the use of the dataset. As a studyforrest extension, we envision that this dataset, together with fMRI data from the studyforrest project, will serve as a foundation for exploring the neural dynamics of various cognitive functions in real-world contexts.

neuroscience↗

bioRxiv2021

Temporal and spatial topography of cell proliferation in cancer

Proliferation is a fundamental trait of cancer cells but is poorly characterized in tumors by classical histologic methods. We use multiplexed tissue imaging to quantify the abundance of multiple cell cycle regulating proteins at single-cell level and develop robust multivariate proliferation metrics. Across cancers, the proliferative architecture is organized at two distinct spatial scales: large domains, and local niches enriched for specific immune lineages. A subset of tumor cells express cell cycle regulators in canonical patterns consistent with unrestrained proliferation, a phenomenon we refer to as "cell cycle coherence". By contrast, the cell cycles of other tumor cell populations are skewed toward a specific phase or characterized by non-canonical (incoherent) marker combinations. Coherence varies across space, with changes in oncogene activity, and with therapeutic intervention, and is associated with aggressive behavior. Multivariate measures capture clinically significant features of cancer proliferation, a fundamental step in enabling more precise use of anti-cancer therapies.

systems biology↗

bioRxiv2021

Identification of organ-specific transcriptomic shifts in the vasculature during systemic inflammation using TrendCatcher

Studying temporal gene expression shifts during disease progression provides important insights into the biological mechanisms that distinguish adaptive and maladaptive responses. Existing tools for the analysis of time course transcriptomic data are not designed to optimally identify distinct temporal patterns when analyzing dynamic differentially expressed genes (DDEGs). Moreover, there is a lack of methods to assess and visualize the temporal progression of biological pathways mapped from time course transcriptomic datasets. In this study, we developed an open-source R package TrendCatcher (https://github.com/jaleesr/TrendCatcher), which applies the smoothing spline ANOVA model and break point searching strategy to identify and visualize distinct dynamic transcriptional gene signatures and biological processes from longitudinal datasets. We used TrendCatcher to perform a systematic temporal analysis of COVID-19 peripheral blood transcriptomes, including bulk RNA-seq and scRNA-seq time course data. TrendCatcher uncovered the early and persistent activation of neutrophils and coagulation pathways as well as impaired type I interferon (IFN-I) signaling in circulating cells as a hallmark of patients who progressed to severe COVID-19, whereas no such patterns were identified in individuals receiving SARS- CoV-2 vaccinations or patients with mild COVID-19. These results underscore the importance of systematic temporal analysis to identify early biomarkers and possible pathogenic therapeutic targets.

cell biology↗

bioRxiv2021

Detection of Junctional Ectopic Tachycardia by Central Venous Pressure

Central venous pressure (CVP) is the blood pressure in the venae cavae, near the right atrium of the heart. This signal waveform is commonly collected in clinical settings, and yet there has been limited discussion of using this data for detecting arrhythmia and other cardiac events. In this paper, we develop a signal processing and feature engineering pipeline for CVP waveform analysis. Through a case study on pediatric junctional ectopic tachycardia (JET), we show that our extracted CVP features reliably detect JET with comparable results to the more commonly used electrocardiogram (ECG) features. This machine learning pipeline can thus improve the clinical diagnosis and ICU monitoring of arrhythmia. It also corroborates and complements the ECG-based diagnosis, especially when the ECG measurements are unavailable or corrupted.

bioinformatics↗