Biology subjects

Li, S.

Publications and source records attributed to Li, S..

At least 1,153 records · Page 64Linked to original sources

bioRxiv2020

Multiple freeze-thaw cycles lead to a loss of consistency in poly(A)-enriched RNA sequencing

RNA-Seq is ubiquitous, but depending on the study, sub-optimal sample handling may be required, resulting in repeated freeze-thaw cycles. However, little is known about how each cycle impacts downstream analyses, due to a lack of study and known limitations in common RNA quality metrics, e.g., RIN, at quantifying RNA degradation following repeated freeze-thaws. Here we quantify the impact of repeated freeze-thaw on the reliability of downstream RNA-Seq analysis. To do so, we developed a method to estimate the relative noise between technical replicates independently of RIN. Using this approach we inferred the effect of both RIN and the number of freeze-thaw cycles on sample noise. We find that RIN is unable to fully account for the change in sample noise due to freeze-thaw cycles. Additionally, freeze-thaw is detrimental to sample quality and differential expression (DE) reproducibility, approaching zero after three cycles for poly(A)-enriched samples, wherein the inherent 3 bias in read coverage is more exacerbated by freeze-thaw cycles, while ribosome-depleted samples are less affected by freeze-thaws. The use of poly(A)-enrichment for RNA sequencing is pervasive in library preparation of frozen tissue, and thus, it is important during experimental design and data analysis to consider the impact of repeated freeze-thaw cycles on reproducibility. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/020792v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@c2c756org.highwire.dtl.DTLVardef@1ad1c03org.highwire.dtl.DTLVardef@a4136org.highwire.dtl.DTLVardef@13f403f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2020

Revealing the functions of supra-temporal and insular auditory responsive areas in humans

The human auditory sensory area, which includes primary and non-primary auditory cortices, has been considered to locate in the supra-temporal lobe for more than a century. Recently, accumulating evidence shows that the posterior part of insula responses to sounds under non-task states with relevant short latencies. However, whether posterior insula (InsP) contribute to forming auditory sensation remains unclear. Here we addressed this issue by recording and stimulation directly on the supra-temporal and insular areas via intracranial electrodes from 53 epileptic patients. During passive listening to a non-speech sound, the high-{gamma} (60-140 Hz) active rate of InsP (68.8%) was approximate to the non-primary auditory areas (72.4% and 79.0%). Moreover, we could not distinguish InsP from supra-temporal subareas by either activation, latency, temporal pattern or lateral dominance of sound induce high-{gamma}. On the contrary, direct electrical stimulation evoked auditory sensations effectively on supra-temporal subareas (> 65%), while sparsely on InsP (9.49%). The results of cortico-cortical evoked potentials (CCEPs) showed strong bidirectional connectivity within supra-temporal areas, but weak connectivity between supra-temporal areas and InsP. These findings suggest that even the InsP has similar basic auditory response properties to the primary or non-primary cortex, it may not directly participate in the formation of auditory perception.

neuroscience↗

bioRxiv2020

Inhibition of the av integrin-TGF-b axis improves natural killer cell function against glioblastoma stem cells

Glioblastoma, the most aggressive brain cancer, often recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. Here, we show that patient-derived GSCs, but not normal astrocytes, are highly sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. In contrast, single cell analysis of autologous, tissue infiltrating NK cells isolated from surgical samples of high-grade glioblastoma patient tumors using mass cytometry and single cell RNA sequencing revealed an abnormal phenotype associated with impaired lytic function compared with peripheral blood NK cells from GBM patients or healthy donors. This immunosuppression was attributed to an integrin-TGF-{beta} mechanism, activated by direct cell-cell contact between GSCs and NK cells. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-{beta} signaling, or with TGF-{beta} receptor 2 gene-edited NK cells prevented GSC-induced NK cell dysfunction and tumor growth. Collectively, our findings reveal a novel mechanism of NK cell immune evasion by GSCs and implicate the integrin-TGF-{beta} axis as a useful therapeutic target to eliminate GSCs in this devastating tumor.

immunology↗

bioRxiv2020

Vesicular Trafficking Permits Evasion of cGAS/STING Surveillance During Initial Human Papillomavirus Infection

Oncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection. ImportancePersistent infection is the main risk factor for all HPV-associated cancers. However, cellular innate immune pathways exist to detect and limit viral infections. The cGAS/STING pathway senses cytosolic DNA to initiate antiviral IFN responses. Such responses would likely be detrimental towards the establishment of persistent HPV infections. We therefore hypothesize that HPV evades cGAS/STING detection via its unique vesicular trafficking mechanism. Here, we show that indeed HPV is a stealthy virus, capable of infecting keratinocytes with minimal activation of the cGAS/STING pathway. Such evasion is dependent on HPVs vesicular trafficking, as perturbation of vesicular integrity during infection results in sensing of virions.

microbiology↗

bioRxiv2020

Molecular architecture of the luminal ring of the Xenopus laevis nuclear pore complex

Nuclear pore complex (NPC) mediates the flow of substances between the nucleus and cytoplasm in eukaryotic cells. Here we report the cryo-electron tomography (cryo-ET) structure of the luminal ring (LR) of the NPC from Xenopus laevis oocyte. The observed key structural features of the LR are independently confirmed by single-particle cryo-electron microscopy (cryo-EM) analysis. The LR comprises eight butterfly-shaped subunits, each containing two symmetric wings. Each wing consists of four elongated, tubular protomers. Within the LR subunit, the eight protomers form a Finger domain, which directly contacts the fusion between the inner and outer nuclear membranes, and a Grid domain, which serves as a rigid base for the Finger domain. Two neighbouring LR subunits interact with each other through the lateral edges of their wings to constitute a Bumper domain, which displays two major conformations and appears to cushion neighbouring NPCs. Our study reveals previously unknown features of the LR and potentially explains the elastic property of the NPC.

biophysics↗

bioRxiv2020

Organized cannabinoid receptor distribution in neurons revealed by super-resolution fluorescence imaging

G-protein-coupled receptors (GPCRs) play important roles in cellular functions. However, their intracellular organization is largely unknown. Through investigation of the cannabinoid receptor 1 (CB1), we discovered periodically repeating clusters of CB1 hotspots within the axons of neurons. We observed these CB1 hotspots interact with the membrane-associated periodic skeleton (MPS) forming a complex crucial in the regulation of CB1 signaling. Furthermore, we found that CB1 hotspot periodicity increased upon CB1 agonist application, and these activated CB1 displayed less dynamic movement compared to non-activated CB1. Our results suggest that CB1 forms periodic hotspots organized by the MPS as a mechanism to increase signaling efficacy when being activated.

neuroscience↗

bioRxiv2020

Screening for functional circular RNAs using the CRISPR-Cas13 system

Circular RNAs (circRNAs) produced from back-spliced exons are widely expressed, but individual circRNA functions remain poorly understood due to inadequate methods, such as RNAi and genome engineering, in distinguishing overlapped exons in circRNAs from those in linear cognate mRNAs1,2. Here we report that the programable RNA-guided, RNA-targeting CRISPR-Cas13, RfxCas13d, effectively and specifically discriminates circRNAs from mRNAs, using guide (g)RNAs targeting sequences spanning the back-splicing junction (BSJ) sites featured in RNA circles. Using a lentiviral library that targets sequences across BSJ sites of highly expressed human circRNAs, we show that a group of circRNAs are important for cell growth mostly in a cell-type specific manner and that a common oncogenic circRNA, circFAM120A, promotes cell proliferation in vitro and in vivo by preventing FAM120A mRNA from binding the translation inhibitor IGF2BP2 for efficient translation. Application of RfxCas13d/BSJ-gRNA screening has also uncovered circMan1a2 with regulatory potential in mouse embryo preimplantation development. Together, these results establish CRISPR-RfxCas13d as a useful tool for the discovery and functional study of circRNAs at both individual and large-scale levels.

molecular biology↗

bioRxiv2020

Delineating the relationship between immune system aging and myogenesis in muscle repair

How aging affects the communication between immune cells and myoblasts during myogenesis is unclear. We therefore investigated how aging impacts the cellular synchronization of these two processes after muscle injury. Muscles of old mice (20 months) had chronic inflammation and fewer satellite cells compared to young mice (3 months). After injury, young mice developed a robust, but transient inflammatory response and a stepwise myogenic gene expression program. These responses were impaired with age. Replacement of old bone marrow (BM) via heterochronic bone marrow transplantation (BMT) increased muscle mass and performance on locomotive and behavioural tests. After injury, Y-O BMT restored the immune cell and cytokine profiles to a young phenotype and enhanced satellite cell activity while O-O BMT amplified a late-onset proinflammatory response. In vitro, conditioned media from young or old macrophages had no effect or impaired myoblast proliferation, respectively. Thus, BM age negatively affects myogenesis by inhibiting myoblast proliferation.

immunology↗

bioRxiv2020

Iatrogenic Iron Promotes Neurodegeneration and Activates Self-protection of Neural Cells against Exogenous Iron Attacks

Metal implants are used worldwide, with millions of metal nails, plates and fixtures grafted during orthopaedic surgeries. Iron is the most common element of these metal implants. As time passes metal elements can be corroded and iron can be released from the implants in the form of ferric (Fe3+) or ferrous (Fe2+). These iron ions can permeate the surrounding tissues and enter circulation; importantly both Fe3+ and Fe2+ freely pass blood brain barrier (BBB). Can iron from implants represent a risk factor for neurological diseases? This remains an unanswered question. In this study, we discovered that the probability of metal implants delivered through orthopaedic surgeries was higher in patients of Parkinsons diseases (PD) or ischemic stroke than in healthy subjects. This finding instigated subsequent study of iron effects on neuronal cells. In experiments in vivo, we found that iron selectively decreased presence of divalent metal transporter 1 (DMT1) in neurones through increasing the expression of Ndfip1, which degrades DMT1 and rarely exists in glial cells. At the same time iron accumulation increased expression of DMT1 in astrocytes and microglial cells and triggered reactive astrogliosis and microglial activation. Facing the attack of excess iron, glial cells act as neuroprotectors to uptake more extracellular iron by up-regulating DMT1, whereas neurones limit iron uptake through decreasing DMT1 operation. Cerebral accumulation of iron was associated with impaired cognition, locomotion and mood. Excess iron thus affects neural cells and could increase the risk of neurodegeneration.

neuroscience↗

bioRxiv2020

Impact of library preparation-induced low GC sequencing bias on Salmonella serotype prediction using SeqSero2

A recent study by Uezle et al. reported a lack of O antigen prediction by SeqSero2. We found that Nextera XT-prepared genomes in the study were abnormally challenging for O antigen prediction because of unusually high sequencing bias against low GC regions that was not seen in similarly prepared genomes from other laboratories. We recommend that SeqSero2 users be mindful of the GC-related sequencing bias when analyzing Nextera XT-prepared genomes. Although it is unusual for such biases to compromise serotype prediction by SeqSero2 per our knowledge and analysis, it is unknown whether they could affect subtyping and characterization of other low-GC regions, such as Salmonella pathogenicity islands, when genome assembly is affected by such biases.

genomics↗

bioRxiv2020

Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles

Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype (SASP) and implicated in age-related pathologies including cancer. Here we report that senescent cells actively synthesize and release small extracellular vesicles (sEVs) with a distinctive size distribution. Mechanistically, SIRT1 loss supports accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly alter the expression profile of recipient cancer cells and enhance their aggressiveness, specifically drug resistance mediated by expression of ATP binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with an agonist SRT2104 prevents development of cancer resistance through restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients are readily detectable by routine biotechniques, presenting a novel biomarker to monitor therapeutic efficacy and to predict long term outcome. Together, our study identifies a distinct mechanism supporting pathological activities of senescent cells, and provides a novel avenue to circumvent advanced human malignancies by co-targeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells.

cell biology↗

bioRxiv2020

DNA methylation is indispensable for leukemia inhibitory factor dependent embryonic stem cells reprogramming

Naive pluripotency can be maintained by the 2i/LIF supplements (CHIR99021, PD0325901 and LIF), which primarily affect canonical WNT, FGF/ERK, and JAK/STAT3 signaling. However, whether one of these tripartite supplements alone is sufficient to maintain naive self-renewal remain unclear. Here we show that LIF alone is sufficient to induce reprogramming of 2i/LIF cultured ESCs (2i/L-ESCs) to ESCs with hypermethylated state (L-ESCs). In vitro, upon withdrawal of 2i, 2i/L-ESCs overcome the epigenetic barrier and DNA hypermethylated, which accompanies transcriptional changes and subsequent establishment of epigenetic memory. Global transcriptome features also show that L-ESCs are close to 2i/L-ESCs and in a stable state between naive and primed pluripotency. Notably, our results demonstrate that DNA methylation was indispensable for LIF-dependent mouse ESCs reprogramming and self-renew. LIF-dependent ESCs reprogramming efficiency is significantly increased in serum treatment and reduced in Dnmt3a or Dnmt3l knockout ESCs. Importantly, unlike epiblast and EpiSCs, L-ESCs contribute to somatic tissues and germ cells in chimaeras. Such simple culture system of ESCs is more conducive to clarify the molecular mechanism of ESCs in vitro culture. SignificanceEmbryonic stem cell (ESCs) exhibit naive pluripotency which reflects their ability to contribute to all embryonic lineages upon injection into blastocyst. ESCs were originally derived by co-culture with feeder cells and fetal calf serum. In this manuscript, we took a detailed approach to dissect the roles of LIF alone in ESC reprogramming of 2i/LIF cultured ESCs (2i/L-ESCs). Here, for the first time, we derived stable hypermethylated pluripotent ESCs under culture of LIF alone (L-ESCs). We further assessed L-ESCs properties both in vitro and in vivo, and provide molecular insights to the mechanism which allows LIF alone to maintain pluripotency and a hypermethylated state. We believe these findings are novel and valuable for future ESCs study.

cell biology↗

bioRxiv2020

Characterization of the SARS-CoV-2 Spike in an Early Prefusion Conformation

Pandemic coronavirus disease 2019 (COVID-19) is caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which there are no efficacious vaccines or therapeutics that are urgently needed. We expressed three versions of spike (S) proteins--receptor binding domain (RBD), S1 subunit and S ectodomain--in insect cells. RBD appears monomer in solutions, whereas S1 and S associate into homotrimer with substantial glycosylation. The three proteins confer excellent antigenicity with six convalescent COVID-19 patient sera. Cryo-electron microscopy (cryo-EM) analyses indicate that the SARS-CoV-2 S trimer dominate in a unique conformation distinguished from the classic prefusion conformation of coronaviruses by the upper S1 region at lower position ~15 [A] proximal to viral membrane. Such conformation is proposed as an early prefusion state for the SARS-CoV-2 spike that may broaden the knowledge of coronavirus and facilitate vaccine development.

molecular biology↗

bioRxiv2020

Temporal coordination of collective migration and lumen formation by antagonism between two nuclear receptors

During development, cells often undergo multiple, distinct morphogenetic processes to form a tissue or organ, but how their temporal order and time interval are determined remain poorly understood. Here we show that the nuclear receptors E75 and DHR3 regulate the temporal order and time interval between the collective migration and lumen formation of a coherent group of about 8 cells called border cells during Drosophila oogenesis. In wild type egg chambers, border cells need to first collectively migrate to the anterior border of oocyte before undergoing lumen formation to form micropyle, the structure that is essential for sperm entry into the oocyte. We show that E75 is required for border cell migration and it antagonizes the activity of DHR3, which is necessary and sufficient for the subsequent lumen formation during micropyle formation. Furthermore, E75s loss of function or DHR3 overexpression each leads to precocious lumen formation before collective migration, an incorrect temporal order for the two morphogenetic processes. Interestingly, both E75 and DHR3s levels are simultaneously elevated in response to signaling from the EcR, a steroid hormone receptor that initiates border cell migration. Subsequently, the decrease of E75 levels in response to decreased EcR signaling leads to the de-repression of DHR3s activity and hence switch-on of lumen formation, contributing to the regulation of time interval between collective migration and micropyle formation.

developmental biology↗

bioRxiv2020

MMS2plot: an R package for visualizing multiple MS/MS spectra for groups of modified and non-modified peptides

A large number of post-translational modifications (PTMs) in proteins are buried in the unassigned mass spectrometric (MS) spectra in shot-gun proteomics datasets. Because the modified peptide fragments are low in abundance relative to the corresponding non-modified versions, it is critical to develop tools that allow facile evaluation of assignment of PTMs based on the MS/MS spectra. Such tools would preferably have the ability to allow comparison of fragment ion spectra and retention time between the modified and unmodified peptide pairs or group. Herein, we describe MMS2plot, an R package for visualizing peptide-spectrum matches (PSMs) for multiple peptides. MMS2plot features a batch mode and generates the output images in vector graphics file format that facilitate evaluation and publication of the PSM assignment. We expect MMS2plot to play an important role in PTM discovery from large-scale proteomics datasets generated by LC (liquid chromatography)-MS/MS. The MMS2plot package is freely available at https://github.com/lileir/MMS2plot under the GPL-3 license.

bioinformatics↗

bioRxiv2020

Targeted genome editing in Nicotiana tabacum using inducible CRISPR/Cas9 system

Targeted genome editing has been achieved in multiple plant species using the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) system, in which the Cas9 gene is usually driven by constitutive promoters. However, constitutive expression of Cas9 is not necessary and can be harmful to plant development. In this study, we developed an estrogen-inducible CRISPR/Cas9 system by taking advantage of the chimeric transcription activator XVE and tested the efficacy of this inducible system in Nicotiana tabacum by targeting the phytoene desaturase (NtPDS) gene, whose mutation resulted in albino phenotypes. Treatment of four independent transgenic lines with exogenous estradiol successfully induced targeted mutagenesis in NtPDS. Sanger sequencing assay uncovered the presence of indel mutations (nucleotides insertions or deletions) at the target site as expected, and at least two types of mutations were identified for each line. Transgenic plants with mutated NtPDS gene after estradiol treatment exhibited pale green or incomplete albino leaves. Moreover, the expression of Cas9 in transgenic plants was strongly induced by estradiol treatment. Our results demonstrate the efficacy of XVE-based CRISPR/Cas9 system in N. tabacum, and the system reported here promises to be a useful approach for conditional genome editing, which would facilitate the study of genes of interest, especially those developmentally important genes.

plant biology↗

bioRxiv2020

Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.

microbiology↗

bioRxiv2020

A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.

systems biology↗