Biology subjects

Gao, Q.

Publications and source records attributed to Gao, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Innate immune sensing of self-derived double-stranded RNA by RIG-I-MAVS-TNF-α regulates the survival and senescence fate of SARS-2-S syncytia

Patients with pre-existing heart failure are at a particularly high risk of morbidity and mortality resulting from SARS-CoV-2 infection. Direct acute cardiac injury or cytokine storms have been proposed to contribute to depressed cardiac function. However, the pathogenic mechanisms underlying the increased vulnerability to heart failure in SARS-CoV-2 infected patients are still largely unknown. Here, we found that the senescent outcome of SARS-CoV-2 spike protein (SARS-2-S)-induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without denovosynthesis of SARS-2-S. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNF . We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by pseudovirus expressing SARS-2-S (SARS-2-Spp). Signs of senescent multinucleated cells are identified in ascending aorta from SARS-CoV-2 omicron variant-infected patient. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy. Significance StatementIn this paper, we directly linked SARS-2-S-triggered syncytium formation with the ensuing induction of cellular senescence and its pathophysiological contribution to heart failure. We propose that both SARS-2-S expression and SARS-2-S protein internalization were sufficient to induce senescence in nonsenescent ACE2-expressing cells. This is important because of the persistent existence of SARS-2-S or extracellular vesicles containing SARS-2-S during the acute and post-acute stages of SARS-CoV-2 infection in human subjects. In searching for the underlying molecular mechanisms determining syncytial fate, the formation of functional MAVS aggregates dependent on RIG-I was observed at an early stage during fusion and regulated the anti-death to senescence fate of SARS-2-S syncytia through the TNF-TNFR2 axis. We also found impaired cardiac metabolism in SARS-2-S syncytia induced by condensed WNK1. Importantly, SARS-2-Spp-exacerbated heart failure could be largely rescued by WNK1 inhibitor, anti-syncytial drug or senolytic agent. Together, we suggest that rescuing metabolism dysfunction in senescent SARS-2-S syncytia should be taken into consideration in individuals during the acute or post-acute stage of SARS-CoV-2 infection.

cell biology↗

bioRxiv2022

Intranasal delivery of NS1-deleted influenza virus vectored COVID-19 vaccine restrains the SARS-CoV-2 inflammatory response

The emergence of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) variants and "anatomical escape" characteristics threaten the effectiveness of current coronavirus disease (COVID-19) vaccines. There is an urgent need to understand the immunological mechanism of broad-spectrum respiratory tract protection to guide broader vaccines development. In this study, we investigated immune responses induced by an NS1-deleted influenza virus vectored intranasal COVID-19 vaccine (dNS1-RBD) which provides broad-spectrum protection against SARS-CoV-2 variants. Intranasal delivery of dNS1-RBD induced innate immunity, trained immunity and tissue-resident memory T cells covering the upper and lower respiratory tract. It restrained the inflammatory response by suppressing early phase viral load post SARS-CoV-2 challenge and attenuating pro-inflammatory cytokine (IL-6, IL-1B, and IFN-{gamma}) levels, thereby reducing excess immune-induced tissue injury compared with the control group. By inducing local cellular immunity and trained immunity, intranasal delivery of NS1-deleted influenza virus vectored vaccine represents a broad-spectrum COVID-19 vaccine strategy to reduce disease burden.

immunology↗

bioRxiv2022

Single cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia

Measurable residual disease (MRD), defined as the population of cancer cells which persists following therapy, serves as the critical reservoir for disease relapse in acute myeloid leukemia (AML) and other malignancies. Understanding the biology enabling MRD clones to resist therapy is necessary to guide the development of more effective curative treatments. Discriminating between residual leukemic clones, preleukemic clones and normal precursors remains a challenge with current MRD tools. Herein, we developed a single cell (sc) MRD assay by combining flow cytometric enrichment of the targeted precursor/blast population with integrated scDNA sequencing and immunophenotyping. Our scMRD assay shows high sensitivity of approximately 0.01%, deconvolutes clonal architecture and provides clone-specific immunophenotypic data. In summary, our scMRD assay enhances MRD detection and simultaneously illuminates the clonal architecture of clonal hematopoiesis/pre-leukemic and leukemic cells surviving AML therapy. Statement of significanceScMRD assay integrates mutation and immunophenotype at single cell resolution and therefore distinguishes clonal hematopoiesis/preleukemic vs. leukemic clones. This study serves as a framework for identifying high-risk MRD clones and improving our understanding of both the molecular drivers and vulnerabilities of therapy resistant AML clones.

pathology↗

bioRxiv2022

Drug degradation caused by mce3R mutations confers contezolid (MRX-I) resistance in Mycobacterium tuberculosis

Contezolid (MRX-I), a safer antibiotic of the linezolid oxazolidinone class, is a promising new antibiotic with potent activity against Mycobacterium tuberculosis (MTB) both in vitro and in vivo. To identify resistance mechanisms of contezolid in MTB, we isolated several in vitro spontaneous contezolid-resistant MTB mutants, which exhibited 16-fold increase in MICs of contezolid compared with the parent strain but was still unexpectedly susceptible to linezolid. Whole-genome sequencing revealed that most of the contezolid-resistant mutants bore mutations in the mce3R gene which encode a transcriptional repressor. The mutations in mce3R led to markedly increased expression of a monooxygenase encoding gene Rv1936. We then characterized Rv1936 as a putative flavin-dependent monooxygenase that catalyzes the degradation of contezolid into its inactive DHPO ring-opened metabolites, thereby conferring drug resistance. While contezolid is an attractive drug candidate with potent antimycobacterial activity and low toxicity, the occurrence of mutations in Mce3R should be considered when designing combination therapy using contezolid for treating tuberculosis. IMPORTANCETuberculosis (TB) is one of the leading causes of global death and the second deadliest infectious killer after COVID-19. Compared to drug-sensitive TB, the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB is more difficult and less effective due to longer regimens and higher potential for clinical adverse events. Despite the undisputed medical success of linezolid on MDR/XDR-TB therapy, this drug suffers from severe safety limitation. The new NMPA-approved drug contezolid, as an analogue of linezolid, exhibits a superior safety profile and potent antitubercular activity. Since the less-toxic contezolid is a promising drug candidate to optimize the current longer-duration MDR/XDR-TB therapy, it would be of significance to determine the resistance profiles of contezolid in MTB. Here, we present the first exploration of the frequency, mutational targets and molecular mechanisms of contezolid resistance in MTB, which could provide theoretical guidance for its future clinical application.

microbiology↗

bioRxiv2022

Physiology and structure of pathogenic Escherichia coli pOmpT reveal two substrate-binding sites

The pathogenicity of bacteria can be achieved by cleaving antimicrobial peptides (AMPs) through the outer membrane protease family (Omptins) to evade or resist the hosts innate immune response. The OmpT-like proteins in Escherichia coli are members of Omptins, which have highly conserved proteolytic activity. Here, sequence alignment and physiological studies have determined that pOmpT is a virulence factor with atypical proteolytic activity. Comparing pOmpT with cOmpT in terms of structure, proteolytic activity and target substrates, it is found that Asp267 and Ser276 of cOmpT are substrate-binding sites and help its catalytic center to cleave substrates (protamine,synthetic peptide or RNase 7). However, special structural features and the nature of residues Ser267 and Thr276 of pOmpT caused the inability of cleavage protamine, but allows it to specifically cleave the human AMP RNase 7. It is suggested that two sites are related with the substrate specificity. In short, we found that pOmpT presents a new structural basis for the specific recognition of substrates, and providing new clues for the development of antimicrobial drugs.

microbiology↗

bioRxiv2022

Immunological findings in a group of individuals who were non-responders to standard two-dose SARS-CoV-2 vaccines

Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic. The virus has infected more than 505 million people and caused more than 6 million deaths. However, data on non-responders to SARS-CoV-2 vaccines in the general population are limited. The objective of the study is to comprehensively compare the immunological characteristics of non-responders to SARS-CoV-2 vaccines in the 18-59 years with that in the 60 years and older using internationally recognized cutoff values. Participants included 627 individuals who received physical examinations and volunteered to participate in COVID-19 vaccination from the general population. The main outcome was an effective seroconversion characterized by anti-SARS-CoV-2 spike IgG level of at least 4-fold increase from baseline. Profiling of naive immune cells was analyzed prior to vaccination to demonstrate baseline immunity. Outcomes of effective seroconversion in the 18-59 years with that in the 60 years and older were compared. The quantitative level of the anti-spike IgG was significantly lower in the 60 years and older and in men among the 18-59 years. There were 7.5% of non-responders among the 18-59 years and 11.7% of non-responders in the 60 years and older using the 4-fold increase parameter. The effective seroconversion rate was significantly related to the level of certain immune cells before vaccination, such as CD4 cells, CD8 cells and B cells and the age. An individual with a titer of anti-SARS-CoV-2 spike IgG that is below 50 BAU/mL might be considered a non-responder between 14-90 days after the last vaccine dose. Booster vaccination or additional protective measures should be recommended for non-responders as soon as possible to reduce disease severity and mortality.

immunology↗

bioRxiv2022

Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression

Abnormal subchondral bone remodeling featured by over-activated osteoclastogenesis leads to articular cartilage degeneration and osteoarthritis (OA) progression, but the mechanism is still unclear. In this study, we used lymphocyte cytosolic protein 1 (Lcp1) knock-out mice to suppress subchondral osteoclast formation in mice OA model with anterior cruciate ligament transection (ACLT) and Lcp1-/- mice showed decreased bone remodeling and sensory innervation in subchondral bone accompanied by retarded cartilage degeneration. For mechanisms, in wildtype mice with ACLT the activated osteoclasts in subchondral bone induced type-H vessels and elevated oxygen concentration which ubiquitylated hypoxia-inducible factor 1 (HIF-1), vital for maintaining chondrocyte homeostasis in articular chondrocytes and led to cartilage degeneration. Deletion of Lcp1 impeded osteoclast-mediated angiogenesis, which maintained the low levels of oxygen partial pressure (pO2) in subchondral bone as well as the whole joint and delayed the OA progression. Stabilization of HIF-1 delayed cartilage degeneration and knockdown of Hif1a abolished the protective effects of Lcp1 knockout. Notably, we identified a novel subgroup of hypertrophic chondrocytes highly associated with OA by single cell sequencing analysis of human articular chondrocytes. Lastly, we showed that Oroxylin A, an Lcp1-encoded protein L-plastin (LPL) inhibitor, could alleviate OA progression. In conclusion, maintaining hypoxic environment in subchondral bone is an attractive strategy for OA treatment. TeaserInhibiting subchondral osteoclastogenesis alleviates OA progression via maintaining joint hypoxia environment.

biochemistry↗

bioRxiv2021

Mapping pediatric brain tumors to their origins in the developing cerebellum

Understanding the cellular origins of childhood brain tumors is key for discovering novel tumor-specific therapeutic targets. Previous strategies mapping cellular origins typically involved comparing human tumors to murine embryonal tissues1,2, a potentially imperfect approach due to spatio-temporal gene expression differences between species3. Here we use an unprecedented single-nucleus atlas of the developing human cerebellum (Sepp, Leiss, et al) and extensive bulk and single-cell transcriptome tumor data to map their cellular origins with focus on three most common pediatric brain tumors - pilocytic astrocytoma, ependymoma, and medulloblastoma. Using custom bioinformatics approaches, we postulate the astroglial and glial lineages as the origins for posterior fossa ependymomas and radiation-induced gliomas (secondary tumors after medulloblastoma treatment), respectively. Moreover, we confirm that SHH, Group3 and Group4 medulloblastomas stem from granule cell/unipolar brush cell lineages, whereas we propose pilocytic astrocytoma to originate from the oligodendrocyte lineage. We also identify genes shared between the cerebellar lineage of origin and corresponding tumors, and genes that are tumor specific; both gene sets represent promising therapeutic targets. As a common feature among most cerebellar tumors, we observed compositional heterogeneity in terms of similarity to normal cells, suggesting that tumors arise from or differentiate into multiple points along the cerebellar "lineage of origin".

cancer biology↗

bioRxiv2021

Isolation and characterization of fucosylated extracellular vesicles based on a novel GlyExo-Capture technique

Owing to their diagnostic and therapeutic potential, extracellular vesicles (EVs) derived from tumour cells have recently garnered great interest. The presence of different glycosylation sites at the EV surface supports the need for efficient glycosylated EV isolation. Here, we developed a GlyExo-Capture technique for robustly capturing fucosylated EVs from sera and cell supernatants. Lens culinaris lectin (LCA)-immobilized magnetic complexes were found to capture approximately 60% of the total EVs from HepG2 cells. The capture efficiency was reduced to less than 40% in nontumorigenic MIHA cells. Notably, the cellular uptake pattern of highly fucosylated EVs was markedly different from that of EVs with low fucosylation. The unearthing of enriched fucosylated EV miRNA cargos by next-generation deep sequencing (NGS) revealed 75 differentially expressed miRNAs (DEMs) in hepatocellular carcinoma (HCC). Among them, a 4-miRNA panel was chosen and yielded an area under the ROC curve (AUC) of 0.86 and 0.84 for the detection of HCC from non-HCC controls in testing samples and independent validation samples, respectively. The 4-miRNA signature was independent of alpha-fetoprotein (AFP), and a combined model with AFP yielded an increased AUC of 0.92. In conclusion, we developed a high-throughput method for capturing fucosylated EVs efficiently and shed light on the use of fucosylated EVs as potential sources of miRNAs for cancer biomarker detection.

cancer biology↗

bioRxiv2021

Host casein kinase 1-mediated phosphorylation modulates phase separation of a rhabdovirus phosphoprotein and virus infection

Liquid-liquid phase separation (LLPS) plays important roles in forming cellular membraneless organelles. However, how host factors regulate LLPS of viral proteins during negative-sense RNA (NSR) virus infections is largely unknown. Here, we used Barley yellow striate mosaic virus (BYSMV) as a model to demonstrate regulation of host casein kinase 1 in phase separation and infection of NSR viruses. We first found that the BYSMV phosphoprotein (P) formed spherical granules with liquid properties and recruited viral nucleotide (N) and polymerase (L) proteins in vivo. Moreover, the P-formed granules were tethered to the ER/actin network for trafficking and fusion. BYSMV P alone formed droplets and incorporated the N protein and genomic RNA in vitro. Interestingly, phase separation of BYSMV P was inhibited by host casein kinase 1 (CK1)-dependent phosphorylation of an intrinsically disordered P protein region. Genetic assays demonstrated that the unphosphorylated mutant of BYSMV P exhibited condensed phase, which promoted virus replication through concentrating the N, L proteins, and genome RNA into viroplasms. Whereas, the phosphorylation-mimic mutant existed in diffuse phase state leading to enhanced virus transcription. Collectively, our results demonstrate that host CK1 modulates phase separation of viral P protein and virus infection.

microbiology↗

bioRxiv2021

Molecular evolution of classic Hodgkin lymphoma revealed through whole genome sequencing of Hodgkin and Reed Sternberg cells

The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells within a classic Hodgkin lymphoma (cHL) biopsy limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Here we leveraged this method to report the first whole genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events prior to the clinical diagnosis of cHL. We identified alterations in driver genes not previously described in cHL, a high activity of the APOBEC mutational signature, and the presence complex structural variants including chromothripsis. We found that the high ploidy observed in cHL is often acquired through multiple, independent large chromosomal gain events including whole genome duplication. The first of these likely occurs several years prior to the diagnosis of cHL, and the last gains typically occur very close to the time of diagnosis. Evolutionary timing analyses revealed that driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID driven mutagenesis usually preceded large chromosomal gains. The study provides the first temporal reconstruction of cHL pathogenesis and suggests a relatively long time course between the first pathogenic event and the clinical diagnosis.

cancer biology↗

bioRxiv2021

Reference genomes of 545 silkworms enable high-throughput exploring genotype-phenotype relationships

The silkworm Bombyx mori is a domestic insect for silk production and a lepidopteran model. The currently available genomes limit a full understanding of its genetic and phenotypic diversity. Here we assembled long-read genomes of 545 domestic and wild silkworms and constructed a high-resolution pan-genome dataset. We found that the silkworm population harbors extremely variable genomes containing 7,308 new gene families, 4,260 (22%) core gene families, and 3,432,266 non-redundant SVs. We deciphered a series of causal genes and variants associated with domestication, breeding, and ecological adaptation traits, and experimentally validated two of those genes using CRISPR-Cas9 or RNA interference. This unprecedented large-scale genomic resource allows for high-throughput screening of interesting traits for functional genomic research and breeding improvement of silkworms and may serve as a guideline for traits decoding in other species.

genomics↗

bioRxiv2021

Unraveling three-dimensional chromatin structural dynamics during spermatogonial differentiation

Spermatogonial stem cells (SSCs) are able to undergo self-renewal and differentiation. Unlike the self-renewal that replenishes the SSC and progenitor pool, the differentiation is an irreversible process committed to meiosis. While the preparations for meiotic events in differentiating spermatogonia (Di-SG) are likely to be accompanied by alterations in chromatin structure, the three-dimensional (3D) chromatin architectural difference between SSCs and Di-SG, and the higher-order chromatin dynamics during spermatogonial differentiation, have not been systematically investigated. Here, we performed in situ high-throughput chromosome conformation capture (Hi-C), RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses on porcine undifferentiated spermatogonia (Un-SG, which consist of SSCs and progenitors) and Di-SG. By integrating and analyzing these data, we identified that Di-SG exhibited increased disorder but weakened compartmentalization and topologically associating domains (TADs) in comparison with Un-SG, suggesting that diminished higher-order chromatin architecture in meiotic cells, as shown by recent reports, is preprogramed in Di-SG. Our data also revealed that A/B compartments and TADs were related to dynamic gene expression during spermatogonial differentiation. We further unraveled the contribution of promoter-enhancer interactions (PEIs) to pre-meiotic transcriptional regulation, which has not been accomplished in previous studies due to limited cell input and resolution. Together, our study uncovered the 3D chromatin structure of SSCs/progenitors and Di-SG, as well as the interplay between higher-order chromatin architecture and dynamic gene expression during spermatogonial differentiation, providing novel insights into the mechanisms for SSC self-renewal and differentiation and having implications for diagnosis and treatment of male sub-/infertility.

developmental biology↗

bioRxiv2021

Genetic loci of the R. anatipestifer serotype discovered by Pan-GWAS and its application for the development of a multiplex PCR serotyping method

The disease caused by Riemerella anatipestifer (R. anatipestifer) causes large economic losses to the global duck industry every year. Serotype-related genomic variation (such as in O-antigen and capsular polysaccharide gene clusters) has been widely used for the serotyping in many gram-negative bacteria. To date, there have been few studies focused on genetic basis of serotypes in R. anatipestifer. Here, we used pan-genome-wide association studies (Pan-GWAS) to identify the serotype-specific genetic loci of 38 R. anatipestifers strain. Analyses of the loci of 11 serotypes showed that the loci could be well mapped with the serotypes of the corresponding strains. We constructed the knockout strain for the wzy gene at the locus, and the results showed that the mutant lost the agglutination characteristics to positive antisera. Based on the of Pan-GWAS results, we developed a multiple PCR method to identify serotypes 1, 2, and 11 of R. anatipestifer. Our study provides a precedent for systematically analysing the genetic basis of the R anatipestifer serotypes and establishing a complete serotyping system in the future. HighlightsO_LIR. anatipestifer serotype-specific locus was identified by Pan-GWAS for the first time. C_LIO_LIMolecular serotyping multiplex PCR was developed based on O-antigen biosynthesis gene clusters C_LI

genomics↗

bioRxiv2021

How alginate lyase produces quasi-monodisperse oligosaccharides: a normal mode analysis-based docking and molecular dynamics simulation study

Polysaccharide degradation products are widely used in medicine, health food, textile and other industries. The preparation of monosaccharides by enzymatic degradation is a key technology in bio industrial production. Unfortunately, most of the known digested products are complex oligosaccharide mixtures, which limit their industrial processing and application. In this study, we explored a docking technique based on normal mode analysis to examine the possible cleavage mechanism of an alginate lyase (AlyB) from Birio Splendidus, which contains the catalytic domain of polysaccharide lyase family 7 (PL7) and a CBM32 sugar binding module, and was observed to produce trisaccharide products with quasi-monosaccharide distribution. We compared the molecular interactions of the enzyme with the natural alginates, the polyMG whose products has the quasi-monodisperse distribution of tri-saccharide and two synthetic polysaccharides, the polyM and polyG whose products has a wider distribution of oligosaccharides. Our calculations quantitatively show that there are a series of deterministic conformational changes in the catalytic pocket, which control the specificity of the substrate; at the same time, it determines the uniformity of the final product together with the spatial position of the key catalytic sites. The dynamic simulations revealed that CBM domain plays a key role in assisting the release of tri-saccharides. Our data highlights the important role of enzyme flexibility in determining product uniformity, which may provide new insight into design of enzymes for the production of high-value mono-distributed oligosaccharides.

biochemistry↗

bioRxiv2021

A high-continuity and annotated tomato reference genome

Genetic and functional genomics studies require a high-quality genome assembly. Tomato (Solanum lycopersicum), an important horticultural crop, is an ideal model species for the study of fruit development. Here, we assembled an updated reference genome of S. lycopersicum cv. Heinz 1706 that was 799.09 Mb in length, containing 34,384 predicted protein-coding genes and 65.66% repetitive sequences. By comparing the genomes of S. lycopersicum and S. pimpinellifolium LA2093, we found a large number of genomic fragments probably associated with human selection, which may have had crucial roles in the domestication of tomato. Our results offer opportunities for understanding the evolution of the tomato genome and will facilitate the study of genetic mechanisms in tomato biology. Information for the assembled genome SLT1.0 was deposited both into the Genome Warehouse (GWH) database (https://bigd.big.ac.cn/gwh/) in the BIG Data Center under Accession Number GWHBAUD00000000.

genomics↗

bioRxiv2021

Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

immunology↗

bioRxiv2021

Gallic Acid, a Methyl 3,4-Dihydroxybenzoate Derivative, Induces Neural Stem Cells to Differentiate and Proliferate

Differentiation and proliferation of neural stem cells (NSCs) are both important biological processes in cerebral neural network. However, these two capacities of NSCs are limited. Thus, the induction of differentiation and/or proliferation via administration of small molecules derived from natural plants can be considered as a potential approach to repair damaged neural networks. This paper reports that gallic acid, a catechol compound selected from derivatives of methyl 3,4-dihydroxybenzoate (MDHB), selectively induces NSCs to differentiate into immature neurons and promotes proliferation by activating phosphorylation of key proteins in the MAPK-ERK pathway. In addition, we found that 3,4-dihydroxybenzoic acid was the main active structure which could show neurotrophic activity. The substitution of carboxyl group on the benzene ring into ester group may promote differentiation on the basis of the structure of 3,4-dihydroxybenzoic acid. Meanwhile, the introduction of 5-hydroxyl group may promote proliferation. Generally, this study identified a natural catechol compound that promotes differentiation and proliferation of NSCs in vitro.

neuroscience↗