Biology subjects

Zhao, D.

Publications and source records attributed to Zhao, D..

At least 91 records · Page 5Linked to original sources

bioRxiv2023

Visualization and review of reads alignment on the graphical pan-genome with VAG

Recent advances in pangenomics have led to the rapid development of graph-based pangenomes that code genetic variant as nodes and edges preserve the contiguity of the sequence and structural variation between individuals. Data visualization is an essential component of genomic data analysis. However, the further application of the graph-based pangenome is still suffered from lacking bioinformatics tools to visualize graph format pangenomes and understand the reads alignment on graph pangenomes. In this research, we developed a novel bioinformatics platform, VAG (Visualizing read alignments in graph genomes), to overcome these challenges. VAG includes multifunctional modules integrated into a single command line and an online visualization platform supported through a web server. This tool can extract specific sequence regions from a graph pangenome and display read alignments on different paths of a graph pangenome. In addition, VAG provides population-level presence/absence variations frequency analysis and sequence path navigation to identify the population differentiation regions. To demonstrate the usage, we investigated genetic variations using a rice graph pangenome with population-level sequencing data to identify important genes and gene clusters underlying the indica-japonica differentiation with VAG. After investigating read alignments on the graph pangenome, we identified many false-positive alignments due to TE insertions. To reduce the impact of these misleading alignments, we developed a navigation module to determine and filter those false-positive alignments based on the pair-end alignment information. The utilization of mate-pair information in VAG provides a reliable reference for variation identification. Additionally, we developed a VAG web server to provide a user-friendly and interactive platform to visualize the read alignment data. VAG was also applied to SV discovery in the cucumber and soybean graph-based pangenome and details of VAG can be accessed by the following website (https://ricegenomichjx.xiaomy.net/VAG/sequenceextraction.php).

bioinformatics↗

bioRxiv2022

Bioavailability of Schisandrin B and its effect on 5-Fluorouracil metabolism in a xenograft mouse model of colorectal cancer

Schisandrin B (Sch-B) is a predominant bioactive lignan in the fruit of a traditional Chinese medicinal plant Schisandra Chinensis with widely reported anti-cancer properties. Using a xenograft mouse model of colorectal cancer (CRC), we showed potent anti-tumor effects of Sch-B and synergistic effects when co-treated with the chemotherapy drug, fluorouracil (5-FU). To explore the underlying anti-tumor mechanism of Sch-B, we first compared the bioavailability, metabolism and tissue distribution of Sch-B and its metabolites among healthy and tumor-bearing mice. To understand the drug-phytochemical interactions associated with the synergy between Sch-B and 5-FU, we examined their reciprocal influence on drug metabolism, tissue distribution, and multidrug resistance (MDR) gene expression in tumor-bearing mice. Using a targeted metabolomics approach, three Sch-B metabolites and two bioactive 5-FU metabolites were quantified and found to reach tumor tissue. Generally, Sch-B metabolites were present at higher levels in tumor-bearing than healthy mice, whereas 5-FU metabolite accumulation was remarkably higher in the co-treatment than 5-FU alone group. Moreover, MDR genes were significantly downregulated upon co-treatment, demonstrating the capacity of Sch-B to reverse MDR in chemotherapy. This study showed that Sch-B may serve as a promising adjuvant to chemotherapy drugs via favorably modulating drug metabolism and bioavailability, and attenuating MDR.

pharmacology and toxicology↗

bioRxiv2022

Disruption of OsLAT5 is sufficient to endow rice tolerance to dihydropyridine herbicides at commercial application concentrations

Breeding non-selective herbicide-resistant crops is important constituent of weed management system in modern rice production. Non-selective dihydropyridine herbicide shares transporters with polyamine (PA), making construction of a dihydropyridine herbicide-resistant rice line possible by inactivating the PA transporter function via gene editing. Success depends on understanding substrate selection for homologues in the PA transporter family and amino acid sites that play critical roles. Here, OsLAT1 was mainly responsible for root uptake and root-to-shoot transport; whereas, OsLAT5 was more responsible for intracellular transport to chloroplasts. The oslat5 disruption line tolerated relevant concentrations, while oslat1 did not. Compared to GY11 wild type, plant height, 1000-grain weight, and spermidine, spermine, and putrescine content changes occurred in GY11-oslat5 lines, implying involvement of OsLAT5 in yield and quality regulation. OsLAT5P44F, P44Y and P44R showed declined dihydropyridine herbicide uptake but no spermidine and putrescine transport competence disruption in yeast, providing a candidate site for precisely editing in breeding a dihydropyridine herbicide-resistant rice cultivar without impairing rice yield and grain quality.

plant biology↗

bioRxiv2022

The generation of the first chromosome-level de-novo genome assembly and the development and validation of a 50K SNP array for North American Atlantic salmon

Given the genetic and genomic differences between Atlantic salmon of European origin and North American (N.A.) origin, it is crucial to develop unique genomic resources for each lineage. Here we describe the resources that we recently developed for genomic and genetic research in N.A. Atlantic salmon. Firstly, a new single nucleotide polymorphism (SNP) database for N.A. Atlantic salmon consisting of 3.1 million putative SNPs was generated using data from whole genome resequencing of 80 N.A. Atlantic salmon individuals; Secondly, a high density 50K SNP array enriched for the genic regions of the genome and containing three sex determination and 61 continent of origin markers was developed and validated; Thirdly, a genetic map composed of 27 linkage groups with 36K SNP markers, was generated from 2,512 individuals in 141 full-sib families; Finally, a chromosome level de-novo assembly of a male N.A. Atlantic salmon genome was generated using PacBio long-reads. Information from Hi-C proximity ligation sequences and Bionano optical mapping was used to concatenate the contigs into scaffolds. The assembly contains 1,755 scaffolds and only 1,253 gaps, with a total length of 2.83 Gb and N50 of 17.2 Mb. A BUSCO analysis detected 96.2% of conserved Actinopterygii genes in the assembly and the genetic linkage information was used to guide the formation of 27 chromosome sequences. In contrast, the karyotype of the European Atlantic salmon lineage is composed of 29 chromosomes. Comparative analysis with the reference genome assembly of the European Atlantic salmon confirmed that the karyotype differences between the two linages are caused by a fission in chromosome Ssa01 and three chromosome fusions including the p arm of chromosome Ssa01 with Ssa23, Ssa08 with Ssa29 and Ssa26 with Ssa28. The genomic resources we have generated for Atlantic salmon provide a crucial boost for genetic research and for management of farmed and wild populations in this highly valued species.

genomics↗

bioRxiv2022

Mechanistic insights into zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches

Zearalenone (ZEA), a secondary metabolite of Fusarium fungi found in cereal-based foods, promotes the growth of colon, breast, and prostate cancer cells in vitro. However, the lack of animal studies hinders a deeper mechanistic understanding of the cancer-promoting effects of ZEA. This study aimed to determine the effect of ZEA on colon cancer progression and its underlying mechanisms. Through integrative analyses of transcriptomics, metabolomics, metagenomics, and host phenotypes, we investigated the impact of a 4-week ZEA intervention on colorectal cancer in xenograft mice. Our results showed a twofold increase in tumor weight with the 4-week ZEA intervention. ZEA exposure significantly increased the mRNA and protein levels of BEST4, DGKB, and Ki67 and the phosphorylation levels of ERK1/2 and AKT. Serum metabolomic analysis revealed that the levels of amino acids, including histidine, arginine, citrulline, and glycine, decreased significantly in the ZEA group. Furthermore, ZEA lowered the alpha diversity of the gut microbiota and reduced the abundance of nine genera, including Tuzzerella and Rikenella. Further association analysis indicated that Tuzzerella was negatively associated with the expression of BEST4 and DGKB genes, serum uric acid levels, and tumor weight. Additionally, circulatory hippuric acid levels positively correlated with tumor weight and the expression of oncogenic genes, including ROBO3, JAK3, and BEST4. Altogether, our results indicated that ZEA promotes colon cancer progression by enhancing the BEST4/AKT/ERK1/2 pathway, lowering circulatory amino acid concentrations, altering gut microbiota composition, and suppressing short chain fatty acids production.

cancer biology↗

bioRxiv2022

Bioinformatics analysis of immune-related prognostic genes and immunotherapy in renal clear cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor and investigating the immunorelated genes is of great significance. To investigate the immunoprognostic genes of ccRCC, we analyzed the data assimilated from a public database (The Cancer Genome Atlas (TCGA) database and the gene expression omnibus (GEO) database) using bioinformatics. Then, a immunoprognosis model was constructed to identify 4 hub genes with moderate predictive values for the prognosis of ccRCC patients. Interestingly, these 4 genes were associated with the prognosis of ccRCC patients based on Oncomine and Gena Expression Profiling Interactive Analysis (GEPIA) databases. The correlation analysis between the immune infiltrate, immune checkpoints, and immunotherapy and this immunoprognosis model showed that immune infiltrate and could predict the immunotherapy effects. We also conducted a quantitative real-time polymerase chain reaction analysis and found that the expressions of 3 hub genes were associated with tumor progression (P<0.1). In conclusion, 4 genes that may serve as potential biomarkers in ccRCC were identified with respect to prognosis.

cancer biology↗

bioRxiv2022

CARD8 negatively regulates NLRP1 inflammasome activation level by interaction with NLRP1

NLRP1 inflammasome functions as canonical cytosolic sensor in response to intracellular infections and is implicated in auto-inflammatory diseases. But the regulation and signal transduction mechanisms of NLRP1 are incompletely understood. Here, we show that the T60 variant of CARD8, but not the canonical T48 isoform, negatively regulates NLRP1 inflammasome activation by directly interacting with the receptor molecule NLRP1 and inhibiting inflammasome assembly. Furthermore, our results suggest that the different ASC preference in three types of inflammasomes, namely ASC-indispensable NLRP1 inflammasome, ASC-dispensable mNLRP1b inflammasome and ASC-independent CARD8 inflammasome, is mainly caused by the CARD domain, not the UPA subdomain. Based on the systematic site-directed mutagenesis and structural analysis, we find that the signal transduction of NLRP1 inflammasome relies on multiple interaction surfaces on its death domain superfamily member CARD domain. Finally, our results partly explain the mechanism of the NLRP1 mutation-derived auto-inflammatory diseases caused by the overactivation of the NLRP1 inflammasome. In conclusion, our study not only reveals how CARD8 downregulates NLRP1 inflammasome activation, but also provides insights into the mechanisms of CARD-containing inflammasome assembly.

immunology↗

bioRxiv2022

The GC box at the proximal enhancer of the Hdc gene is critical for Hdc gene transcription and histamine-mediated anaphylaxis

Background: Histamine is a critical mediator of anaphylaxis, a neurotransmitter, and a regulator of gastric acid secretion. Histidine decarboxylase is a rate-limiting enzyme for histamine synthesis. However, in vivo regulation of Hdc, the gene that encodes histidine decarboxylase is poorly understood. Objective: We sought to investigate how enhancers regulate Hdc gene transcription and histamine synthesis in resting conditions and in a mouse model of anaphylaxis. Methods: H3K27 acetylation histone modification and chromatin accessibility were used to identify candidate enhancers; The enhancer activity of candidate enhancers was measured in a reporter gene assay; and the function enhancers were validated using CRISPR deletion. Results: Deletion of the GC box, which binds to zinc finger transcription factors, in the proximal Hdc enhancer, reduced Hdc gene transcription and histamine synthesis in the mouse and human mast cell lines. Mast cells, basophils, brain cells, and stomach cells from GC box-deficient mice transcribed the Hdc gene much less than similar cells from wild-type mice and Hdc GC box-deficient mice failed to develop anaphylaxis. Conclusion: Our results demonstrate that the HDC GC box within the proximal enhancer in the mouse and human HDC gene is essential for Hdc gene transcription, histamine synthesis, and histamine-mediated anaphylaxis in vitro and in vivo. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/495950v3_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@106f99org.highwire.dtl.DTLVardef@10ec8b8org.highwire.dtl.DTLVardef@19bb1ceorg.highwire.dtl.DTLVardef@b663cd_HPS_FORMAT_FIGEXP M_FIG C_FIG Key messages: O_LIThe HDC GC box within the proximal enhancer of the mouse and human HDC gene is essential for Hdc gene transcription and histamine synthesis in mouse and human mast cells. C_LIO_LIThe mouse Hdc GC box is required for histamine-mediated anaphylaxis in vivo. C_LI Capsule summary Our results demonstrate that the Hdc GC box within the proximal enhancer of the mouse and human HDC gene is essential for Hdc gene transcription and histamine synthesis in mast cells. The mouse Hdc GC box is required for histamine-mediated anaphylaxis in the mouse model of anaphylaxis.

immunology↗

bioRxiv2022

A distal enhancer is required for TNF gene transcription in human macrophages in response to TLR3 stimulation

Macrophages play a critical role in inflammatory responses during infections. These cells are activated by infections through stimulation of TLRs expressed on their cell surface and produce pro-inflammatory cytokines, including TNF. However, distal enhancers that regulate TNF gene transcription in human macrophages have not been investigated. This study used an unbiased genomic approach to identify six candidate enhancers in human primary alveolar macrophages within a 131 kb region from the transcription start site (TSS) of the TNF gene, covering 13 genes. Of these candidate enhancers, five showed enhancer activity, with three targeting the TNF gene and two targeting neighboring genes. Deletion of the distal TNF E-16 enhancer led to a 73% reduction in TNF gene transcription in response to poly (I:C) stimulation in the THP-1 human leukemia monocytic cell line. Additionally, deletion of the E-7.1/hHS-8 enhancer resulted in a 41% reduction in TNF mRNA, while deletion of the PE enhancer had a lesser effect, resulting in a 52% reduction in TNF gene transcription. Massively parallel reporter assays (MPRA) indicated that the transcription factor AP-1 and EGR1-binding sites at the distal TNF E-16 enhancer were crucial in mediating enhancer activity. This study shows that both distal and proximal enhancers work together to fully transcribe the TNF gene in human macrophages in response to TLR ligand poly (I:C) stimulation.

immunology↗

bioRxiv2022

Comparative genomic insights into the evolution of Halobacteria-associated "Candidatus Nanohaloarchaeota"

The phylum "Candidatus Nanohaloarchaeota" is a representative halophilic lineage within DPANN superphylum. They are characterized by their nanosized cells and symbiotic lifestyle with Halobacteria. However, the development of the symbiosis remains unclear for the lack of genomes located at the transition stage. Here, we performed a comparative genomic analysis of "Ca. Nanohaloarchaeota". We propose a novel family "Candidatus Nanoanaerosalinaceae" represented by five de-replicated metagenome-assembled genomes obtained from hypersaline sediments and the enrichment cultures of soda-saline lakes. Phylogeny analysis reveals that the novel family are placed at the root of the family "Candidatus Nanosalinaceae" including the well-researched taxa. Most members of "Ca. Nanoanaerosalinaceae" contain lower proportion of putative horizontal gene transfers from Halobacteria than "Ca. Nanosalinaceae", while they maintain moderately acidic proteomes for hypersaline adaptation of "salt-in" strategy, suggesting that "Ca. Nanoanaerosalinaceae" have not established an intimate association with Halobacteria, and may descend from an intermediate stage. Functional prediction discloses that they exhibit divergent potentials in carbohydrate and organic acids metabolism, and environmental responses. Historical events reconstruction illustrates that the involved genes acquired at the putative ancestors possibly drive the evolutionary and symbiotic divergences. Globally, this research on the new family "Ca. Nanoanaerosalinaceae" enriches the taxonomic and functional diversity of "Ca. Nanohaloarchaeota", and provides insights into the evolutionary process of "Ca. Nanohaloarchaeota" and their Halobacteria-associated symbiosis. ImportanceDPANN superphylum is a group of archaea widely distributing in various habitats. They generally have small cells, and perform a symbiotic lifestyle with other archaea. The archaeal symbiotic interaction is important to understand microbial community. However, the formation and evolution of the symbiosis between the DPANN lineages and other diverse archaea remain unclear. Based on phylogeny, hypersaline adaptation, functional potentials, and historical events of "Ca. Nanohaloarchaeota", a representative phylum within the DPANN superphylum, we report a novel family descending from an intermediate stage, and we illustrate the evolutionary process of "Ca. Nanohaloarchaeota" and their Halobacteria-associated symbiosis. Furthermore, we find the acquired genes involved in carbohydrate and organic acids metabolism and environmental responses possibly drive the evolutionary and symbiotic divergences. Altogether, this research helps in understanding the evolution of the archaeal symbiosis, and provides a model for the evolution of the other DPANN lineages.

microbiology↗

bioRxiv2022

BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility over BA.21. The new variants receptor binding and immune evasion capability require immediate investigation. Here, coupled with Spike structural comparisons, we show that BA.2.12.1 and BA.4/BA.5 exhibit comparable ACE2-binding affinities to BA.2. Importantly, BA.2.12.1 and BA.4/BA.5 display stronger neutralization evasion than BA.2 against the plasma from 3-dose vaccination and, most strikingly, from post-vaccination BA.1 infections. To delineate the underlying antibody evasion mechanism, we determined the escaping mutation profiles2, epitope distribution3 and Omicron neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype-induced humoral memory. The resulting elicited antibodies could neutralize both wildtype and BA.1 and are enriched on non-ACE2-competing epitopes. However, most of these cross-reactive NAbs are heavily escaped by L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1; nevertheless, these NAbs are largely escaped by BA.2/BA.4/BA.5 due to D405N and F486V, and react weakly to pre-Omicron variants, exhibiting poor neutralization breadths. As for therapeutic NAbs, Bebtelovimab4 and Cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

immunology↗

bioRxiv2022

Quality Control Framework of TCM Preparations based on Multi-type Fingerprints using a Source Proportion Estimation Model

Traditional Chinese Medicine (TCM) preparations have been widely used in clinical practice for the treatment of various diseases. The quality of TCM preparations is related to clinical efficacy and safety and is highly valued by researchers. The authenticity of TCM preparation can be guaranteed objectively by accurate quality control according to the composition. Here, we proposed a quality control framework of TCM preparations, which is based on multi-type fingerprints using the source proportion estimation model (SPEM). The high-performance liquid chromatography (HPLC) analysis and the high-throughput sequencing analysis are employed to acquire the chemical and taxonomic fingerprints of samples, respectively. The quality of TCM preparations among different manufacturers or batches is evaluated by using SPEM, which is an unsupervised method for source identification of TCM samples. Results showed the good performance of the quality control framework, for example, SPEM achieved a mean accuracy of 0.778 based on the ITS2 taxonomic fingerprint when differentiating manufacturer of BazhenYimu Wan pill. Applications of the quality control framework revealed the batch effect in TCM samples, and environmental factors, such as geography have a profound impact on the consistency of TCM preparations. In summary, this study is an exploration in the field of digital development of TCM preparations and provide a new insight to quantify the batch effect among different batches of TCM samples.

pharmacology and toxicology↗

bioRxiv2022

A high potent synthetic nanobody with broad-spectrum activity neutralizes SARS-Cov-2 virus and Omicron variant through a unique binding mode

The major challenge to control COVID pandemic is the rapid mutation rate of the SARS-Cov-2 virus, leading to the escape of the protection of vaccines and most of the neutralizing antibodies to date. Thus, it is essential to develop neutralizing antibodies with broad-spectrum activity targeting multiple SARS-Cov-2 variants. Here, we reported a synthetic nanobody (named C5G2) obtianed by phage display and subsequent antibody engineering. C5G2 has a single digit nanomolar binding affinity to RBD domain and inhibits its binding to ACE2 with an IC50 of 3.7 nM. Pseudovirus assay indicated that the monovalent C5G2 could protect the cells from the infection of SARS-Cov-2 wild type virus and most of the virus of concern, i.e. Alpha, Beta, Gamma and Omicron variants. Strikingly, C5G2 has the highest potency against Omicron among all the variants with the IC50 of 4.9ng/mL. The Cryo-EM structure of C5G2 in complex with the Spike trimer showed that C5G2 bind to RBD mainly through its CDR3 at a conserved region that not overlapping with the ACE2 binding surface. Additionally, C5G2 bind simultaneously to the neighboring NTD domain of spike trimer through the same CDR3 loop, which may further increase its potency against the virus infection. Third, the steric hindrance caused by FR2 of C5G2 could inhibit the binding of ACE2 to RBD as well. Thus, this triple-function nanobody may be served as an effective drug for the prophylaxis and therapy against Omicron as well as future variants.

biochemistry↗

bioRxiv2022

Cas9-Mediated Knockout of Ndrg2 Enhances the Regenerative Potential of Dendritic Cells for Wound Healing

Chronic wounds impose a significant healthcare burden to a broad patient population. Cell based therapies, while having shown benefits for the treatment of chronic wounds, have not achieved widespread adoption into clinical practice. Here, we developed a novel CRISPR/Cas9 approach to precisely edit dendritic cells (DCs) to enhance their therapeutic potential for healing chronic wounds. Using single-cell RNA sequencing (scRNA-seq) of tolerogenic DCs, we discover N-myc downregulated gene 2 (Ndrg2), which marks a specific population of DC progenitors, as a promising target for CRISPR knockout (KO). Ndrg2-KO alters the transcriptomic profile of DCs and preserves an immature cell state with a strong, pro-angiogenic and regenerative capacity. We then incorporated our CRISPR-based cell engineering within a hydrogel technology for in vivo cell delivery and developed a highly effective translational approach for DC based immunotherapy that accelerated healing of full-thickness wounds in both non-diabetic and diabetic mouse models. These findings could open the door to future clinical trials using safe gene editing in DCs for treating various types of chronic wounds.

cell biology↗

bioRxiv2022

Estrogen suppresses DMRT1 expression during ovarian development in the chicken

Primary sex determination is the choice between two different developmental fates, a testis or an ovary. This selection is thought to require the action of a master regulator gene that triggers expression of a gene cascade in the bipotential gonad precursor in one sex. The selection of a particular developmental pathway is also thought to suppress the alternative developmental pathway. In birds, where the male is the homogametic sex (ZZ) and females the heterogametic sex (ZW), the Z-linked transcription factor DMRT1 is considered the master regulator and has been shown to be essential for testis development, and to also inhibit the ovarian pathway. Here, we characterise in detail, DMRT1 transcription and protein levels during gonadal development in the chick. Our analysis suggests that DMRT1 protein levels are equivalent in male and female gonads during the bipotential phase of development, and that DMRT1 protein levels are reduced in the developing ovary during the differentiation phase. The reduction in DMRT1 protein levels in the somatic cells of the female medulla, coincides with the induction of aromatase expression and the initiation of estrogen synthesis. Analysis of sex-reversed gonads and mixed-sex chimeric gonads, suggests that the reduction in DMRT1 protein is due to inhibition of DMRT1 expression by estrogen. Our data suggests that estrogen signalling is involved in primary sex determination by regulation of DMRT1 protein expression.

developmental biology↗

bioRxiv2022

Comprehensive Epitope Mapping of Broad Sarbecovirus Neutralizing Antibodies

Omicron sub-lineage BA.2 has rapidly surged globally, accounting for over 60% of recent SARS-CoV-2 infections. Newly acquired RBD mutations and high transmission advantage over BA.1 urge the investigation of BA.2s immune evasion capability. Here, we show that BA.2 causes strong neutralization resistance, comparable to BA.1, in vaccinated individuals plasma. However, BA.2 displays more severe antibody evasion in BA.1 convalescents, and most prominently, in vaccinated SARS convalescents plasma, suggesting a substantial antigenicity difference between BA.2 and BA.1. To specify, we determined the escaping mutation profiles1,2 of 714 SARS-CoV-2 RBD neutralizing antibodies, including 241 broad sarbecovirus neutralizing antibodies isolated from SARS convalescents, and measured their neutralization efficacy against BA.1, BA.1.1, BA.2. Importantly, BA.2 specifically induces large-scale escape of BA.1/BA.1.1-effective broad sarbecovirus neutralizing antibodies via novel mutations T376A, D405N, and R408S. These sites were highly conserved across sarbecoviruses, suggesting that Omicron BA.2 arose from immune pressure selection instead of zoonotic spillover. Moreover, BA.2 reduces the efficacy of S309 (Sotrovimab)3,4 and broad sarbecovirus neutralizing antibodies targeting the similar epitope region, including BD55-5840. Structural comparisons of BD55-5840 in complexes with BA.1 and BA.2 spike suggest that BA.2 could hinder antibody binding through S371F-induced N343-glycan displacement. Intriguingly, the absence of G446S mutation in BA.2 enabled a proportion of 440-449 linear epitope targeting antibodies to retain neutralizing efficacy, including COV2-2130 (Cilgavimab)5. Together, we showed that BA.2 exhibits distinct antigenicity compared to BA.1 and provided a comprehensive profile of SARS-CoV-2 antibody escaping mutations. Our study offers critical insights into the humoral immune evading mechanism of current and future variants.

immunology↗

bioRxiv2021

Inhibition of Kallikrein-related peptidases 7 restrains pancreatic tumor growth through induction of ferroptosis

Pancreatic cancer is one of the most aggressive and lethal malignancies with extremely poor prognosis, and KLK7 was considered as a potential therapeutic target. In this study, we analyzed the expression of KLK7 in TCGA and GTEx databases and found that KLK7 had a negative correlation to long-term survival rate (>1.5 years) of pancreatic cancer patients. Compound 42 is a coumarinic derivative, a suicide substrate inhibitor of KLK7, which has been proved to inhibit the proliferation of PANC-1 cells in vitro effectively in our previous study. In this study, we further investigated the inhibition ability of Compound 42 in tumor formation and development in CDX and PDX tumor models of pancreatic cancer subsequently. Besides, we studied the inhibitory mechanism of Compound 42 and the result showed that Compound 42 arrested the pancreatic cancer cell cycle in G0/G1 phase and induced ferroptosis through down-regulation of GPX4 protein level and accumulation of iron ion. Thus, these experiments demonstrate that Compound 42, suppressing pancreatic cancer in vivo, is expected to become a novel drug for pancreatic cancer treatment.

molecular biology↗

bioRxiv2021

Machine learning enables accurate and rapid prediction of active molecules against breast cancer cells

SummaryBreast cancer (BC) has surpassed lung cancer as the most frequently occurring cancer, and it is the leading cause of cancer-related death in women. Therefore, there is an urgent need to discover or design new drug candidates for BC treatment. In this study, we first collected a series of structurally diverse datasets consisting of 33,757 active and 21,152 inactive compounds for 13 breast cancer cell lines and one normal breast cell line commonly used in in vitro antiproliferative assays. Predictive models were then developed using five conventional machine learning algorithms, including naive Bayesian, support vector machine, k-Nearest Neighbors, random forest, and extreme gradient boosting, as well as five deep learning algorithms, including deep neural networks, graph convolutional networks, graph attention network, message passing neural networks, and Attentive FP. A total of 476 single models and 112 fusion models were constructed based on three types of molecular representations including molecular descriptors, fingerprints, and graphs. The evaluation results demonstrate that the best model for each BC cell subtype can achieve high predictive accuracy for the test sets with AUC values of 0.689-0.993. Moreover, important structural fragments related to BC cell inhibition were identified and interpreted. To facilitate the use of the model, an online webserver called ChemBC and its local version software were developed to predict potential anti-BC agents. AvailabilityChemBC webserver is available at http://chembc.idruglab.cn/ and its local version Python software is maintained at a GitHub repository (https://github.com/idruglab/ChemBC). Contactzjqgmc@163.com or lingwang@scut.edu.cn Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗