Biology subjects

Jia, W.

Publications and source records attributed to Jia, W..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Investigating the antimicrobial and immunomodulatory effects of honeybee venom peptide apamin in the Drosophila genetic platform.

Apamin, an 18-amino acid peptide neurotoxin, constitutes a significant portion of honeybee venom. Although traditionally recognized for its neurotoxic effects, our research demonstrates that apamin exhibits potent antimicrobial properties when genetically expressed in Drosophila. The antimicrobial efficacy of apamin is independent of its disulfide bonds and is enhanced when the peptide is membrane-tethered. This expression selectively targets and inhibits specific harmful bacterial species, such as Pseudomonas aeruginosa, Enterococcus faecalis, and Escherichia coli, while promoting beneficial bacteria like Lactobacillus plantarum thereby improving the gut microbiome. The antimicrobial activity of apamin is localized to the gut and is associated with increased proliferation of intestinal stem cells, acidification of the midgut pH, and activation of enteroendocrine cell calcium signaling. Furthermore, apamins antimicrobial function is dependent on specific peptidoglycan recognition proteins, with PGRP-LA and PGRP-SCs being essential. Apamin expression alone is sufficient to restore the integrity of the gut barrier compromised by stressed conditions. Ultimately, apamin supplementation enhances honeybee gut health, particularly in the presence of ingested bacteria. The expression of other honeybee antimicrobial peptides also significantly reduces bacterial infection in flies. Overall, our study provides a comprehensive understanding of the molecular function and regulation of honeybee venom peptides and antimicrobial peptides, utilizing the Drosophila model system to unravel their mechanisms of action and therapeutic potential.

immunology↗

bioRxiv2024

Spatiotemporal transcriptomic profiling reveals the dynamic immunological landscape of alveolar echinococcosis

Alveolar echinococcosis (AE) is caused by the invasive growth of the metacestodes of Echinococcus multilocularis (E. multilocularis). The early diagnosis, management, and treatment of AE remains challenging. Herein, we integrated bulk RNA-seq, scRNA-seq, and ST technologies to reveal the immune characteristics both spatially and chronologically in E. multilocularis infected mouse liver. An unprecedented high-resolution spatial atlas of the E. multilocularis infection foci was obtained, revealing the pivotal role of neutrophils, Spp1+ monocyte-derived macrophages (MoMFs), and fibroblasts in AE progression. We observed continuous recruitment of neutrophils and macrophages into the infected tissues, indicating prolonged immune stimulation by the growing metacestodes. However, their spatial distribution patterns and functions changed during the infection cause. At the early infection stage, Il1bhi neutrophils aggregated in the lesion displayed the highest pattern-recognition receptor activity and may kill the metacestodes through NETosis, but their death in the infection foci might also trigger immune suppression. Meanwhile, Spp1+ MoMFs attached to the protoscoleces to clear the infection. At the late infection stage, the neutrophils failed to infiltrate into the lesion although their continuous recruitment into the infected liver. Even though the Spp1+ MoMFs enclosing the microcysts of E. multilocularis may retain their pathogen-killing ability, they may also promote fibrosis and angiogenesis through interaction with fibroblasts. The pro- and anti-inflammatory phenotype balance of these immune cells may be associated with the transition of parasite control strategy from "active killing" to "negative segregation" by the host. Our findings identify key molecular traits involved in AE development, which may benefit the treatment of echinococcosis.

immunology↗

bioRxiv2024

Targeting GFPT2 to reinvigorate immunotherapy in EGFR-mutated NSCLC

In the evolving field of cancer immunotherapy, EGFR-mutated NSCLC presents a significant challenge, demonstrating marked innate resistance to established treatments. An effective method to counter this resistance remains elusive. Through comprehensive genetic and pharmacological analyses across various models, we have identified glutamine fructose-6-phosphate transaminase 2 (GFPT2) as a key facilitator of immune evasion in EGFR-mutated NSCLC. Mechanistically, under EGFR mutation condition, GFPT2 expression, which is typically low in normal tissues, is highly induced via EGFR/IRE1/Xbp1s signaling axis, leading to a significant increase in intracellular UDP-GlcNAc and consequently, an altered N-glycosylation profile. GFPT2 escalates the expression and glycosylation of PD-L1, PVR and CD276, bolstering their interactions with CD8+T cells, and amplifies CD73 glycosylation, thereby intensifying adenosine-mediated CD8+T cells suppression. These actions collectively reduce tumor cell vulnerability to CD8+T cell-mediated death. Moreover, GFPT2 regulates EGFR glycosylation, which consequentially modulates the EGFR-dependent secretion of CXCL10 and VEGF, thus impeding CD8+T cell infiltration within tumors. We further identified a GFPT2 isoform-specific inhibitor that potentiates PD-1 blockade therapy beyond that of existing strategy, corroborated by results in xenografts and patient-derived organoids. Together, these findings illuminate the promising therapeutic potential of GFPT2 as a metabolic checkpoint, offering an innovative approach to invigorate immunotherapy in NSCLC with EGFR mutations.

cancer biology↗

bioRxiv2024

Selective degradation of multimeric proteins via chemically induced proximity to TRIM21

Targeted protein degradation (TPD) has emerged as an effective strategy to eliminate disease-causing proteins by inducing their interactions with the protein degradation machinery. First-generation TPD agents exploit a limited set of broadly expressed E3 ubiquitin ligases with constitutive activity, forbidding their application to proteins requiring higher levels of targeting selectivity. Here, by phenotype-based screening, we discovered that the antipsychotic drug acepromazine possesses interferon-enhanced cytotoxicity towards cancer cell lines expressing high levels of aldo-keto reductases 1C. These enzymes convert acepromazine into its stereo-selective metabolite (S)-hydroxyl-acepromazine, which recruits the interferon-induced E3 ubiquitin ligase TRIM21 to the vicinity of the nuclear pore complex, resulting in the degradation of nuclear pore proteins. Co-crystal structures of acepromazine and derivatives in complex with the PRYSPRY domain of TRIM21 revealed a ligandable pocket, which was exploited for designing heterobifunctional degraders. The resulting chemicals selectively degrade multimeric proteins-- such as those in biomolecular condensates--without affecting monomeric proteins, consistent with the requirement of substrate-induced clustering for TRIM21 activation. As aberrant protein assemblies have been causally linked to diseases such as neurodegeneration, autoimmunity, and cancer, our findings highlight the potential of TRIM21-based multimer-selective degraders as a strategy to tackle the direct causes of these diseases.

pharmacology and toxicology↗

bioRxiv2024

MXRA8 promotes adipose tissue whitening to drive obesity

Matrix-remodeling associated 8 (MXRA8), also known as Dual immunoglobulin domain cell adhesion molecule (DICAM), is a type 1 transmembrane protein that reportedly binds the V{beta}3 integrin1 and regulates the differentiation of osteoclasts2 and chondrocytes3, tumor growth4, T cell trafficking5, and angiogenesis6. MXRA8 is also an essential entry receptor for chikungunya virus and other related arthritogenic alphaviruses.7-9 We compared MXRA8 expression in 51 tissues in the Human Protein Atlas and found it is most highly expressed in white adipose tissue (WAT), however the function of MXRA8 in WAT is unknown. Here, we found that MXRA8 expression in WAT is increased in people with obesity and that this response is also observed in a mouse model of high fat-diet (HFD)-induced obesity. Single-nucleus RNA sequencing and high-dimensional spectral flow cytometry analyses revealed that MXRA8 is expressed predominantly by adipocyte progenitor (AP) cells and mature adipocytes. MXRA8 mutant primary adipocytes from inguinal (i)WAT exhibited increased expression of Uncoupling protein 1 (UCP1), a thermogenic protein expressed by beige and brown adipocytes that limits obesity pathogenesis.10-12 Indeed, MXRA8 mutant mice fed a HFD had preserved UCP1+ beige and brown adipocytes and were protected from HFD-induced obesity in a UCP1-dependent manner. Collectively, these findings indicate that MXRA8 promotes whitening of beige and brown adipose tissues to drive obesity pathogenesis and identify MXRA8 as a possible therapeutic target to treat obesity and associated metabolic diseases.

physiology↗

bioRxiv2022

Soft and stretchable organic bioelectronics for continuous intra-operative neurophysiological monitoring during microsurgery

Continuous intra-operative neurophysiological monitoring (CINM) that provides precise mapping of neural anatomy through the entire microsurgery process is essential to preserve the structural and functional integrity of the nerve. However, bulky and rigid electrodes used currently in clinics are usually unable to reliably maintain continuous and stable contacts with the vulnerable and complex nerve networks, thus often resulting in detrimental post-operative complications, such as hemiplegia and sensory disturbances. Here, we describe a biomechanically compatible, suture-free, and individually reconfigurable CINM based on soft and stretchable organic electronic materials. Due to both low impedance and modulus of our conducting polymer electrodes, we achieved for the first time continuous recording of near-field action potential with high signal-to-noise ratio and minimal invasiveness during microsurgeries. Utilizing this unprecedented CINM modality, in conjunction with localized neurostimulation, we further demonstrated our approach in enabling optimal post-operative prognosis in preclinical animal models by preserving normal neural functions after a variety of tumor resection surgeries.

bioengineering↗

bioRxiv2022

Quantification of adulterated fox-derived components in meat Products by Drop Digital Polymerase Chain Reaction

There are still large research gaps in the testing standards for non-edible meat-derived components at present. Here we report a novel approach to quantification of adulterated fox-derived components in meat products by drop digital polymerase chain reaction(ddPCR). It was better to identify the adulteration that has been added either inadvertently or deliberately during the process by designing single primers on housekeeping genes. In this paper, the fox meat was used as the experimental materials and the relationship between sample quality and copy number was established by extracting DNA and using DNA concentration as an intermediary. The results of ddPCR showed that both the relationships between meat weight and DNA concentration and between DNA concentration and DNA copy number (C) were nearly linear within the dynamic range. The DNA concentration was utilized as an intermediate value to establish the formulae about the relationship between the original meat weight and DNA copy number: Mfox=0.05C+2.7. The methods feasibility was validated using artificial adulteration of different proportions The establishment of this method provides technical support for relevant regulatory authorities to monitor the adulteration of fox meat.

molecular biology↗

bioRxiv2022

Novel mRNA vaccines encoding Monkeypox virus M1R and A35R protect mice from a lethal virus challenge

The outbreak of Monkeypox virus infection urgently need effective vaccines. However, the vaccines so far approved are all based on whole-virus, which raises safety concerns. MRNA vaccines has demonstrated its high efficacy and safety against SARS-Cov-2 infection. Here, we developed three mRNA vaccines encoding Monkeypox proteins M1R and A35R, including A35R-M1R fusions (VGPox1 and VGPox 2) and a combination of encapsulated full-length mRNAs for A35R and M1R (VGPox 3). All three vaccines induced anti-A35R total IgGs as early as day 7 following a single vaccination. However, only VGPox 1 and 2 produced anti-M1R total IgGs at early dates following vaccination while VGPox 3 did not show significant anti-M1R antibody till day 35. Similar results were also found in neutralizing antibodies and T cell immune response. However, all mRNA vaccine groups completely protected mice from a lethal dose virus challenge and effectively cleared virus in lungs. Collectively, our results indicate that the novel mRNA vaccines coding for a fusion protein of A35R and M1R had a better anti-virus immunity than co-expression of the two individual proteins. The mRNA vaccines are highly effective and can be an alternative to the current whole-virus vaccines to defend Monkeypox virus infection.

immunology↗

bioRxiv2022

Axon guidance pathways modulate neurotoxicity of ALS-associated UBQLN2

Mutations in the ubiquitin (Ub) chaperone Ubiquilin 2 (UBQLN2) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage of Unc-5 or its coreceptor Dcc/frazzled diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2ALS alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALS knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALS alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.

neuroscience↗

bioRxiv2022

Single-cell Landscape Analysis of the Circulating Human B Cell Pool under Selective Pressure of Allogeneic Stem Cell Transplantation

Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT) chronic graft-versus-host disease (cGVHD), a B cell-mediated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B Cell Receptor (BCR)-activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells under selective pressure of alloantigens, we performed scRNA-Seq analysis on high numbers of purified B cells from allo-HCT patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation and memory. We found striking transcriptional differences in the memory B cell compartment after allo-HCT compared to healthy or infected individuals. To identify intrinsic properties when B-cell tolerance is lost after allo-HCT, we then assessed clusters for differentially expressed genes (DEGs) between patients with vs. without autoimmune-like manifestations (Active cGVHD vs. No cGVHD, respectively). DEGs were found in Active cGVHD in both naive and BCR-activated clusters, suggesting functional diversity. Some DEGs were also differentially expressed across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides new understanding of B-cell memory in the face of chronic alloantigen stimulation. One Sentence SummaryOur scRNA-Seq study of purified B cells after allo-HCT clarifies molecular differences in human B cell subsets when immune tolerance is lost or maintained. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/512162v4_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@5c452eorg.highwire.dtl.DTLVardef@1c1d34borg.highwire.dtl.DTLVardef@171310org.highwire.dtl.DTLVardef@e4bf15_HPS_FORMAT_FIGEXP M_FIG C_FIG The circulating human B cell compartment under the selective pressure of allogeneic hematopoietic stem cell transplantation (Allo-HCT) has an intrinsically altered memory B cell pool. In allo-HCT, genetically disparate donor stem and progenitor cells engraft, regenerating a new peripheral B cell compartment in the host. During ongoing B lymphopoiesis and diversification, selective pressure from alloantigens and other extrinsic factors, including B Cell Activating Factor (BAFF), result in either B cell maturation and immune tolerance (No Chronic GVHD) or altered B cell homeostasis and autoimmune manifestations (Active Chronic GVHD). B cells within defined subsets in patients with Active GVHD have distinct intrinsic programs delineated by differentially expressed genes (DEGs). Some DEGs occur across nearly all B cell subsets ( Differentially Expressed Broadly), while other DEGs are more restricted within only one or a few B cell subsets ( Naive, BCR-activated, or Memory). We affirm altered trajectories for diversification (blue arrow) and enrichment of an atypical memory B cell (ABC) pool, with intrinsic differences when chronic GVHD occurs.

immunology↗

bioRxiv2022

Heterologous boost with mRNA vaccines against SARS-CoV-2 Delta/Omicron variants following an inactivated whole-virus vaccine

The coronavirus SARS-CoV-2 has mutated quickly and caused significant global damage. This study characterizes two mRNA vaccines ZSVG-02 (Delta) and ZSVG-02-O (Omicron BA.1), and associating heterologous prime-boost strategy following the prime of a most widely administrated inactivated whole-virus vaccine (BBIBP-CorV). The ZSVG-02-O induces neutralizing antibodies that effectively cross-react with Omicron subvariants following an order of BA.1>BA.2>BA.4/5. In naive animals, ZSVG-02 or ZSVG-02-O induce humoral responses skewed to the vaccines targeting strains, but cellular immune responses cross-react to all variants of concern (VOCs) tested. Following heterologous prime-boost regimes, animals present comparable neutralizing antibody levels and superior protection across all VOCs. Single-boost only generated ancestral and omicron dual-responsive antibodies, probably by "recall" and "reshape" the prime immunity. New Omicron-specific antibody populations, however, appeared only following the second boost with ZSVG-02-O. Overall, our results support a heterologous boost with ZSVG-02-O, providing the best protection against current VOCs in inactivated virus vaccine- primed populations.

molecular biology↗

bioRxiv2022

FOXP2 confers oncogenic effects in prostate cancer through activating MET signalling

Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found that FOXP2 is overexpressed in human prostate cancer cells and prostate tumors, but its expression is absent in normal prostate epithelial cells and low in benign prostatic hyperplasia. To date, little is known regarding the link of FOXP2 to prostate cancer. We observed that high FOXP2 expression and frequent amplification are significantly associated with high Gleason score. Ectopic expression of FOXP2 induces malignant transformation of mouse NIH3T3 fibroblasts and human prostate epithelial cell RWPE-1. Conversely, FOXP2 knockdown suppresses the proliferation of prostate cancer cells. Transgenic overexpression of FOXP2 in the mouse prostate causes prostatic intraepithelial neoplasia. Overexpression of FOXP2 aberrantly activates oncogenic MET signalling and inhibitors targeting MET signalling effectively reverts the FOXP2-induced oncogenic phenotype. Additionally, the novel recurrent FOXP2-CPED1 fusion identified in prostate tumors results in high expression of truncated FOXP2, which exhibit a similar capacity for malignant transformation. Together, our data demonstrate for the first time that FOXP2 is an oncogene involved in tumorigenicity of prostate.

cancer biology↗

bioRxiv2022

Epsin2, a novel target for multiple system atrophy therapy via regulating α-synuclein propagation associated with FABP7

Multiple system atrophy (MSA) is a neurodegenerative disease showing accumulation of misfolded -synuclein and myelin disruption. However, the mechanism how -synuclein (-syn) accumulate in MSA brain remains unclear. Here, we identify the protein epsin-2 as a novel target for MSA therapy via controlling -synuclein accumulation. In MSA mouse model, PLP-hSyn transgenic mice and FABP7/-syn hetero-aggregates injected mice, we firstly found that fatty acid-binding protein 7 (FABP7) related to MSA development and formed hetero-aggregates with -syn, which exhibited stronger toxicity than -syn aggregates. Furthermore, injected FABP7/-syn hetero-aggregates in mice selectively accumulated in oligodendrocytes and Purkinje neurons and cause cerebellar dysfunction. By bioinformatic analyses, the protein epsin-2 expresses in both oligodendrocyte and Purkinje cells was found as a potential target to regulate FABP7/-syn hetero-aggregates propagation via clathrin-dependent endocytosis. The AAV5-dependent epsin-2 knock-down mice exhibited decreased levels of aggregates accumulation in Purkinje neurons and oligodendrocytes as well as performed improved myelin levels and Purkinje neurons in cerebellum and motor functions. Thus, we propose epsin-2 as a novel and therapeutic candidate for MSA.

pathology↗

bioRxiv2022

Gut microbiome-linked metabolites in the pathobiology of depression and anxiety - a role for bile acids

BackgroundThe gut microbiome may play a role in the pathogenesis of neuropsychiatric diseases including major depressive disorder (MDD). Bile acids (BAs) are steroid acids that are synthesized in the liver from cholesterol and further processed by gut-bacterial enzymes, thus requiring both human and gut microbiome enzymatic processes in their metabolism. BAs participate in a range of important host functions such as lipid transport and metabolism, cellular signaling and regulation of energy homeostasis. BAs have recently been implicated in the pathophysiology of Alzheimers and several other neuropsychiatric diseases, but the biochemical underpinnings of these gut microbiome-linked metabolites in the pathophysiology of depression and anxiety remains largely unknown. MethodUsing targeted metabolomics, we profiled primary and secondary BAs in the baseline serum samples of 208 untreated outpatients with MDD. We assessed the relationship of BA concentrations and the severity of depressive and anxiety symptoms as defined by the 17-item Hamilton Depression Rating Scale (HRSD17) and the 14-item Hamilton Anxiety Rating Scale (HRSA-Total), respectively. We also evaluated whether the baseline metabolic profile of BA informs about treatment outcomes. ResultsThe concentration of the primary BA chenodeoxycholic acid (CDCA) was significantly lower at baseline in both severely depressed (log2 fold difference (LFD)= -0.48; p=0.021) and highly anxious (LFD= -0.43; p=0.021) participants compared to participants with less severe symptoms. The gut bacteria-derived secondary BAs produced from CDCA such as lithocholic acid (LCA) and several of its metabolites, and their ratios to primary BAs, were significantly higher in the more anxious participants (LFDs range=[0.23,1.36]; ps range=[6.85E-6,1.86E-2]). The interaction analysis of HRSD17 and HRSA-Total suggested that the BA concentration differences were more strongly correlated to the symptoms of anxiety than depression. Significant differences in baseline CDCA (LFD= -0.87, p=0.0009), isoLCA (LFD= -1.08, p=0.016) and several BA ratios (LFDs range [0.46, 1.66], ps range [0.0003, 0.049]) differentiated treatment failures from remitters. ConclusionIn patients with MDD, BA profiles representing changes in gut microbiome compositions are associated with higher levels of anxiety and increased probability of first-line treatment failure. If confirmed, these findings suggest the possibility of developing gut microbiome-directed therapies for MDD characterized by gut dysbiosis.

neuroscience↗

bioRxiv2022

Gut microbiota-derived tryptamine impairs insulin sensitivity

Gut-microbiota plays a pivotal role in development of type 2 diabetes (T2D), yet the molecular mechanism remains elusive. Here, we show that tryptamine, a microbial metabolite of tryptophan, impairs glucose tolerance and insulin sensitivity. Tryptamine presents a higher level in monkeys with spontaneous diabetes and human with T2D and positively correlated with the glucose tolerance. In parallel, tryptamine level was suppressed by dietary fibers intervention in T2D subjects and negatively correlated with improvement of glucose tolerance. The inhibitory effect of tryptamine on insulin signaling as shown was dependent on a trace amine-associated receptor 1 (TAAR1)-extracellular signal-regulated kinase (ERK) signaling axis. Monoassociation of T2D-associated tryptamine-producing bacteria Ruminococcus gnavus impairs insulin sensitivity in pseudo germ-free mice. Our findings indicate gut microbiota-derived tryptamine contributes to the development of insulin resistance in T2D and may serve as a new target for intervention. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

microbiology↗

bioRxiv2022

Topological supramolecular network enabled highly conductive and stretchable organic bioelectronics

Intrinsically stretchable bioelectronic devices based on soft and conducting organic materials have been regarded as the ideal interface for seamless and biocompatible integration with the human body. However, the grand challenge remains for the conducting polymer to possess both high mechanical ductility and good electrical conduction at cellular level feature sizes. This longstanding material limitation in organic bioelectronics has impeded the full exploitation of its unique benefits. Here, we introduce a new molecular engineering strategy based on rationally designed topological supramolecular networks, which allows effective decoupling of competing effects from multiple molecular building blocks to meet complex requirements. We achieve two orders of magnitude improvement in the conductivity under 100% strain in physiological environment, along with the capability for direct photopatterning down to 2 m. These unprecedented capabilities allow us to realize previously inaccessible bioelectronic applications including high-resolution monitoring of soft and malleable creatures, e.g., octopus, and localized neuromodulation down to single nucleus precision for controlling organ-specific activities through delicate tissues, e.g., brainstem.

bioengineering↗

bioRxiv2021

NRF2-dependent epigenetic regulation can promote the hybrid epithelial/mesenchymal phenotype

The epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.

systems biology↗

bioRxiv2021

Both Simulation and Sequencing Data Reveal Multiple SARS-CoV-2 Variants Coinfection in COVID-19 Pandemic

SARS-CoV-2 is a single-stranded RNA betacoronavirus with a high mutation rate. The rapidly emerged SARS-CoV-2 variants could increase the transmissibility, aggravate the severity, and even fade the vaccine protection. Although the coinfections of SARS-CoV-2 with other respiratory pathogens have been reported, whether multiple SARS-CoV-2 variants coinfection exists remains controversial. This study collected 12,986 and 4,113 SARS-CoV-2 genomes from the GISAID database on May 11, 2020 (GISAID20May11) and April 1, 2021 (GISAID21Apr1), respectively. With the single-nucleotide variants (SNV) and network clique analysis, we constructed the single-nucleotide polymorphism (SNP) coexistence networks and noted the SNP number of the maximal clique as the coinfection index. The coinfection indices of GISAID20May11 and GISAID21Apr1 datasets were 16 and 34, respectively. Simulating the transmission routes and the mutation accumulations, we discovered the linear relationship between the coinfection index and the coinfected variant number. Based on the linear relationship, we deduced that the COVID-19 cases in the GISAID20May11 and GISAID21Apr1 datasets were coinfected with 2.20 and 3.42 SARS-CoV-2 variants on average. Additionally, we performed Nanopore sequencing on 42 COVID-19 patients to explore the virus mutational characteristics. We found the heterozygous SNPs in 41 COVID-19 cases, which support the coinfection of SARS-CoV-2 variants and challenge the accuracy of phylogenetic analysis. In conclusion, our findings reported the coinfection of SARS-CoV-2 variants in COVID-19 patients, demonstrated the increased coinfected variants number in the epidemic, and provided clues for the prolonged viral shedding and severe symptoms in some cases.

bioinformatics↗