Biology subjects

Zhao, G.

Publications and source records attributed to Zhao, G..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Simultaneous targeting of AMPK and mTOR is a novel therapeutic strategy against prostate cancer

Metastatic colonization by circulating cancer cells is a highly inefficient process. To colonize distant organs, disseminating cancer cells must overcome many obstacles in foreign microenvironments, and only a small fraction of them survives this process. How these disseminating cancer cells cope with stress and initiate metastatic process is not fully understood. In this study, we report that the metastatic onset of prostate cancer cells is associated with the dynamic conversion of metabolism signaling pathways governed by the energy sensors AMPK and mTOR. While in circulation in blood flow, the disseminating cancer cells display decreased mTOR and increased AMPK activities that protect them from stress-induced death. However, after metastatic onset, the mTOR-AMPK activities are reversed, enabling mTOR-dependent tumor growth. Suppression of this dynamic conversion by co-targeting of AMPK and mTOR signaling significantly suppresses prostate cancer cell and tumor organoid growth in vitro and experimental metastasis in vivo, suggesting that this can be a therapeutic approach against metastasizing prostate cancer.

cancer biology↗

bioRxiv2023

Targeting CD301+ macrophage inhibits endometrial fibrosis and improves pregnancy outcome

Macrophages are a key and heterogeneous cell population involved in endometrial repair and regeneration during the menstrual cycle, but their role in the development of intrauterine adhesion (IUA) and sequential endometrial fibrosis remains unclear. Here, we reported that CD301+ macrophages were significantly increased and showed their most active interaction with profibrotic cells in the endometria of IUA patients compared with the normal endometria by single-cell RNA sequencing, bulk RNA sequencing and experimental verification. Increasing CD301+ macrophages promoted the differentiation of endometrial stromal cells into myofibroblasts and resulted in extracellular matrix accumulation, which destroyed the physiological architecture of endometrial tissue, drove endometrial fibrosis and ultimately led to female infertility or adverse pregnancy outcomes. Mechanistically, CD301+ macrophages secreted GAS6 to activate the AXL/NF-{kappa}B pathway, up-regulating the profibrotic protein synthesis. Targeted deletion of CD301+ macrophages or inhibition of AXL by Bemcentinib blunted the pathology and improved the outcomes of pregnancy in mice, supporting the therapeutic potential of targeting CD301+ macrophages for treating endometrial fibrosis.

immunology↗

bioRxiv2023

Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation

Inflammation upon infectious lung injury is a double-edged sword: while tissue-infiltrating immune cells and cytokines are necessary to control infection, these same factors often aggravate injury. Full appreciation of both the sources and targets of inflammatory mediators is required to facilitate strategies to maintain antimicrobial effects while minimizing off-target epithelial and endothelial damage. Recognizing that the vasculature is centrally involved in tissue responses to injury and infection, we observed that pulmonary capillary endothelial cells (ECs) exhibit dramatic transcriptomic changes upon influenza injury punctuated by profound upregulation of Sparcl1. Endothelial deletion and overexpression of SPARCL1 implicated this secreted matricellular protein in driving key pathophysiologic symptoms of pneumonia, which we demonstrate result from its effects on macrophage polarization. SPARCL1 induces a shift to a pro-inflammatory "M1-like" phenotype (CD86+CD206-), thereby increasing associated cytokine levels. Mechanistically, SPARCL1 acts directly on macrophages in vitro to induce the pro-inflammatory phenotype via activation of TLR4, and TLR4 inhibition in vivo ameliorates inflammatory exacerbations caused by endothelial Sparcl1 overexpression. Finally, we confirmed significant elevation of SPARCL1 in COVID-19 lung ECs in comparison with those from healthy donors. Survival analysis demonstrated that patients with fatal COVID-19 had higher levels of circulating SPARCL1 protein compared to those who recovered, indicating the potential of SPARCL1 as a biomarker for prognosis of pneumonia and suggesting that personalized medicine approaches might be harnessed to block SPARCL1 and improve outcomes in high-expressing patients.

immunology↗

bioRxiv2023

Ferroptosis induced by phenolic compound-iron complex

Phenolic compounds are the most ubiquitously distributed pollutants, and are highly toxic to living organisms, however the detailed mechanism how phenols exert toxic effects remains elusive. Here,Escherichia coli and phloroglucinol are adapted as proxy to elucidate the molecular mechanism of phenols toxicity. We demonstrated that phloroglucinol complexed with iron and promoted the generation of hydroxyl radicals in Fenton reaction, leading to reducing power depletion and lipid peroxidation, and further leading to ferroptosis-like cell death ofE. coli. This ferroptotic death can be triggered by various phenols in diverse organisms, from bacteria to mammalian cells. Furthermore, we demonstrated that phloroglucinol-induced ferroptosis suppressed tumor growth in mice effectively, indicating phloroglucinol as promising drug for therapy-resistant cancers. Its also discovered that repression of this ferroptosis-like cell death benefited microbial degradation or production of desired phenolic compounds, showing great application potential in biotechnology field.

microbiology↗

bioRxiv2023

Remodeling the central metabolism of Escherichia coli enables a universal chassis

E. coli is the host of choice to produce a wide variety of chemicals and proteins. Overflow metabolism is considered as the widespread and major obstacle in microbial synthesis, and overcoming this common bottleneck may enable a universal chassis. Here, we constructed an E. coli universal chassis (ABKS strain) with significantly suppressed overflow metabolism, presenting similar growth rate, decreased glucose consumption, and increased production of desired chemicals and proteins when compared with wild-type BL21(DE3) strain. Furthermore, we demonstrated that metabolic flux of ABKS strain was reprogrammed from TCA cycle to glyoxylate bypass at isocitrate node via the synergistic effect of multi-layer regulation in gene transcription and protein modification. This metabolic reconfiguration alleviates overflow metabolism, avoids CO2 release in TCA cycle, finally improving the carbon atom economy in bioprocess. Our chassis has widespread and practical use for elevating the production and yield of multiple desired chemicals and proteins from different carbon source. The metabolic reconfiguration also provides theoretical basis for rational design of efficient bioproduction strains.

bioengineering↗

bioRxiv2023

A COVID-19 DNA Vaccine Candidate Elicits Broadly Neutralizing Antibodies Against Multiple SARS-CoV-2 Variants Including the Currently Circulating Omicron BF.5, BF.7, BQ.1 and XBB

Waves of breakthrough infections by SARS-CoV-2 Omicron subvariants pose a global challenge to pandemic control today. We have previously reported a pVAX1-based DNA vaccine candidate, pAD1002, which encodes a receptor-binding domain (RBD) chimera of SARS-CoV-1 and Omicron BA.1. In mouse and rabbit models, pAD1002 plasmid induced cross-neutralizing Abs against heterologous Sarbecoviruses, including SARS-CoV-1 and SARS-CoV-2 prototype, Delta and Omicron variants. However, these antisera failed to block the recent emerging Omicron subvariants BF.7 and BQ.1. To solve this problem, we replaced the BA.1-encoding DNA sequence in pAD1002 with that of BA.4/5. The resulting construct, namely pAD1016, elicited SARS-CoV-1 and SARS-CoV-2 RBD-specific IFN-{gamma}+ cellular responses in BALB/c and C57BL/6 mice. More importantly, pAD1016 vaccination in mice and rabbits generated serum Abs capable of neutralizing pseudoviruses representing multiple SARS-CoV-2 Omicron subvariants including BA.2, BA.4/5, BF.7, BQ.1 and XBB. As a booster vaccine for inactivated SARS-CoV-2 virus preimmunization in C57BL/6 mice, pAD1016 broadened the serum Ab neutralization spectrum to cover the Omicron BA.4/5, BF7 and BQ.1 subvariants. These data highlight the potential benefit of pAD1016 in eliciting neutralizing Abs against broad spectrum Omicron subvariants in individuals previously vaccinated with inactivated prototype SARS-CoV-2 virus and suggests that pAD1016 is worthy further translational study as a COVID-19 vaccine candidate.

immunology↗

bioRxiv2023

Changes in physicochemical properties and microbial community succession during leaf stacking fermentation

Leaf stacking fermentation involves enzymatic actions of many microorganisms and is an efficient and environmentally benign process for degrading macromolecular organic compounds. We investigated the dynamics of metabolite profiles, bacterial and fungal communities and their interactions during fermentation using cigar leaves from three geographic regions. The results showed that the contents of total sugar, reducing sugar, starch, cellulose, lignin, pectin, polyphenol and protein in cigar tobacco leaves was significantly decreased during fermentation. Notably, the furfural, neophytadiene, pyridine, benzyl alcohol, geranyl acetone, 2-butanone, 3-hydroxy-, N-hexanal, isoamylalcohol and 2,3-pentanedione were important features volatile aroma compounds during fermentation. The -diversity of fungi and bacteria initially increased and then decreased during fermentation. The microbial diversity was influenced by fermentation stages and growing locations, in which the fermentation stages had greater impacts on the microbial diversity than locations. Microbiome profiling had identified several core bacteria including Sphingomonas, Bacillus, Staphylococcus, Pseudomonas, Ralstonia, Massilia and Fibrobacter. Fungal biomarkers included Aspergillus, Penicillium, Fusarium, Cladosporium and Trichomonascus. Interestingly, the molecular ecological networks showed that the core taxa had significant correlations with metabolic enzymes and physicochemical properties; bacteria and fungi jointly participated in the carbohydrate and nitrogen compound degrading and volatile aroma compound chemosynthesis processes during fermentation. These studies provide insights into the coupling of material conversion and microbial community succession during leaf fermentation. IMPORTANCECigar tobacco leaves are still crude after air curing. Fermentation can eliminate the pungent and bitter taste of the leaves and promote the accumulations of aromatic compounds. Hitherto, there has been no systematic study on the material conversion, metabolic enzymes and microbial community changes and their interactions in fermented leaves. The significance of our research is in identifying the potential metabolic cooperation related to microbial community, which will greatly enhance our understanding of microorganism to convert macromolecular organic to small molecules during the leaf stacking fermentation process.

microbiology↗

bioRxiv2023

Label-free quantitative proteomics analyses of mouse astrocytes provides insight into the host response mechanism at different developmental stages of Toxoplasma gondii

Toxoplasma gondii (T. gondii) is an opportunistic parasite that can infect the central nervous system (CNS), causing severe toxoplasmosis and behavioral cognitive impairment. Mortality is high in immunocompromised individuals with toxoplasmosis, most commonly due to reactivation of infection in the CNS. There are still no effective vaccines and drugs for the prevention and treatment of toxoplasmosis. There are five developmental stages for T. gondii to complete life cycle, of which the tachyzoite and bradyzoite stages are the key to the acute and chronic infection. In this study, to better understanding of how T. gondii interacts with the host CNS at different stages of infection, we constructed acute and chronic infection models of T. gondii in astrocytes, and used label-free proteomics to detect the proteome changes before and after infection, respectively. A total of 4676 proteins were identified, among which 163 differentially expressed proteins (DEPs) (fold change[≥]1.5 or [≤]0.67 and p-value[≤]0.05) including 109 up-regulated proteins and 54 down-regulated proteins in C8-TA vs C8 group, and 719 DEPs including 495 up-regulated proteins and 224 down-regulated proteins in C8-BR vs C8-TA group. After T. gondii tachyzoites infected astrocytes, DEPs were enriched in immune-related biological processes to promote the formation of bradyzoites and maintain the balance of T. gondii, CNS and brain. After T. gondii bradyzoites infected astrocytes, the DEPs up-regulated the hosts glucose metabolism, and some up-regulated DEPs were closely related to neurodegenerative diseases. These findings not only provide new insights into the psychiatric pathogenesis of T. gondii, but also provide potential targets for the treatment of acute and chronic Toxoplasmosis.

microbiology↗

bioRxiv2023

Neutrophil extracellular trap stabilization by platelet factor 4 reduces thrombogenicity and endothelial cell injury

Neutrophil extracellular traps (NETs) are abundant in sepsis, and proposed NET-directed therapies in sepsis prevent their formation or accelerate degradation. Yet NETs are important for microbial entrapment, as NET digestion liberates pathogens and NET degradation products (NDPs) that deleteriously promote thrombosis and endothelial cell injury. We proposed an alternative strategy of NET-stabilization with the chemokine, platelet factor 4 (PF4, CXCL4), which we have shown enhances NET-mediated microbial entrapment. We now show that NET compaction by PF4 reduces their thrombogenicity. In vitro, we quantified plasma thrombin and fibrin generation by intact or degraded NETs and cell-free (cf) DNA fragments, and found that digested NETs and short DNA fragments were more thrombogenic than intact NETs and high molecular weight genomic DNA, respectively. PF4 reduced the thrombogenicity of digested NETs and DNA by interfering, in part, with contact pathway activation. In endothelial cell culture studies, short DNA fragments promoted von Willebrand factor release and tissue factor expression via a toll-like receptor 9-dependent mechanism. PF4 blocked these effects. Cxcl4-/- mice infused with cfDNA exhibited higher plasma thrombin anti-thrombin (TAT) levels compared to wild-type controls. Following challenge with bacterial lipopolysaccharide, Cxcl4-/- mice had similar elevations in plasma TAT and cfDNA, effects prevented by PF4 infusion. Thus, NET-stabilization by PF4 prevents the release of short fragments of cfDNA, limiting the activation of the contact coagulation pathway and reducing endothelial injury. These results support our hypothesis that NET-stabilization reduces pathologic sequelae in sepsis, an observation of potential clinical benefit. HIGHLIGHTSO_LIIn contrast to intact NETs, degraded NETs and cfDNA are prothrombotic and injure the endothelium. C_LIO_LIPF4 reduces the ability of degraded NETs and cfDNA to promote thrombosis and injure the endothelium. C_LI

cell biology↗

bioRxiv2022

A dedicated hypothalamic oxytocin circuit controls aversive social learning

To survive and thrive in a complex social group, it is essential to not only know who to approach but more importantly who to avoid. After a single defeat, mice learn to stay away from the winning aggressor for weeks. Here, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin receptor expressing cells in the anterior subdivision of ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance learning. After defeat, aVMHvlOXTR cells drastically increase their responses to aggressor cues. This response change is functionally important as optogenetic activation of aVMHvlOXTR cells elicits time-locked social avoidance towards a benign social target whereas inactivating the cells suppresses defeat-induced social avoidance. Furthermore, OXTR in the aVMHvl is itself essential for the behavior change. Knocking out OXTR in the aVMHvl or antagonizing the receptor during defeat, but not during post-defeat social interaction, impairs defeat-induced social avoidance. aVMHvlOXTR receives its private source of oxytocin from SOROXT cells, which are highly activated by the noxious somatosensory inputs associated with defeat. Oxytocin released from SOROXT depolarizes aVMHvlOXTR cells and facilitates their synaptic potentiation, and hence, increases aVMHvlOXTR cell responses to aggressor cues. Ablating SOROXT cells impairs defeat-induced social avoidance learning whereas activating the cells promotes social avoidance after a subthreshold defeat experience. Altogether, our study reveals an essential role of SOROXT-aVMHvlOXTR circuit in defeat-induced social learning and highlights the importance of brain oxytocin system in social plasticity.

neuroscience↗

bioRxiv2022

Discovery and remodeling of Vibrio natriegens as a microbial platform for efficient formic acid biorefinery

Formic acid (FA), an organic one-carbon source that is easily produced from CO2, has emerged as a promising CO2-equivalent feedstock for one-carbon biorefinery. However, developing efficient formatotrophs for an economically competitive FA utilization system remains a grand challenge. Here, we discovered that the gram-negative bacterium Vibrio natriegens has exceptional FA tolerance and metabolic capacity natively. This strain was then remodeled by rewiring the serine cycle and the TCA cycle which resulted in a non-native closed loop (S-TCA) for enhancing FA assimilation. The rational design generated a powerful metabolic sink that enabled rapid emergence of the evolved strains with further significantly improved performance in using FA as the major or sole carbon source. Furthermore, the introduction of a foreign indigoidine-forming pathway into the best-performing V. natriegens strain (S-TCA-2.0) led to production of 29.0 g{middle dot}L-1 indigoidine and consumption of 233.7 g{middle dot}L-1 formate within 72 h, achieving an order of magnitude higher formate consumption rate (3.2 g{middle dot}L-1{middle dot}h-1) than the reported highest level in microorganisms. This work represents a significant step towards the development of industrially viable microorganisms for FA biorefinery.

microbiology↗

bioRxiv2022

Potent Immunogenicity and Broad-Spectrum Protection Potential of Microneedle Array Patch-Based COVID-19 DNA Vaccine Candidates Encoding Dimeric RBD Chimera of SARS-CoV and SARS-CoV-2 Variants

Breakthrough infections by SARS-CoV-2 variants pose a global challenge to pandemic control, and the development of more effective vaccines of broadspectrum protection is needed. In this study, we constructed pVAX1-based plasmids encoding heterodimeric receptor-binding domain (RBD) chimera of SARS-CoV and SARS-CoV-2 Omicron BA.1 (RBDSARS/BA1), SARS-CoV and SARS-CoV-2 Beta (RBDSARS/Beta), or Omicron BA.1 and Beta (RBDBA1/Beta) in secreted form. When i.m. injected in mice, RBDSARS/BA1 and RBDSARS/Beta encoding plasmids (pAD1002 and pAD131, respectively) were by far more immunogenic than RBDBA1/Beta plasmid (pAD1003). Dissolvable microneedle array patches (MAP) laden with these DNA plasmids were fabricated. All 3 resulting MAP-based vaccine candidates, namely MAP-1002, MAP1003 and MAP-131, were comparable to i.m. inoculated plasmids with electroporation assistance in eliciting strong and durable IgG responses in BALB/c and C57BL/6 mice as well as rabbits, while MAP-1002 was comparatively the most immunogenic. More importantly, MAP-1002 significantly outperformed inactivated SARS-CoV-2 virus vaccine in inducing RBD-specific IFN-{gamma}+ T cells. Moreover, MAP-1002 antisera effectively neutralized pseudoviruses displaying spike proteins of SARS-CoV, prototype SARS-CoV-2 or Beta, Delta, Omicron BA1, BA2 and BA4/5 variants. Collectively, MAP-based DNA constructs encoding chimeric RBDs of SARS-CoV and SARS-CoV-2 variants, as represented by MAP-1002, are potential COVID-19 vaccine candidates worthy further translational study.

immunology↗

bioRxiv2022

Revealing the structure of somatic cell membranes by in situ cryo-electron tomography

The cell membrane, which separates the cell from the environment, plays a key role in signal transduction, energy conversion and substance transport. Although previous membrane models have successfully interpreted some functions of the cell membrane, no consensus has been reached for the lack of direct and in situ evidence. Here, we characterized the high-resolution 3D structure of 293T cell membranes in situ for the first time by cryo-electron tomography. Due to the excellent thickness of our cryo-samples, we could clearly observe membrane proteins with an average molecular weight of 100 kD. By analysing tomograms, we found that the total thickness of a 293T plasma membrane is approximately 20 nm and that there is a 4-nm lipid bilayer structure within the membrane. We observed that membrane proteins and protein complexes with a similar height (7-11 nm) are densely embedded in the ectoplasmic side of 293T plasma membranes, whereas membrane proteins aggregate to form islands with heights reaching dozens of nanometres on the cytoplasmic side. Additionally, we measured the average sizes of membrane proteins on the cytoplasmic side of 293T plasma membranes and found them to be approximately 7 nm in length and 4 nm in width. Moreover, if more precise structural information is obtained in future studies, we will identify the molecular interactions and detailed structures of membrane protein clusters that can be easily distinguished on a 293T cell membrane. Our work represents the first in situ structural characterization of a native somatic cell membrane with cryo-electron tomography and advances cell membrane structural studies from the model prediction stage to the real structure observation stage.

cell biology↗

bioRxiv2022

Respiratory mucosal vaccination of peptide-poloxamine-DNA nanoparticles provides complete protection against lethal SARS-CoV-2 challenge

The ongoing SARS-CoV-2 pandemic represents a brutal reminder of the continual threat of mucosal infectious diseases. Mucosal immunity may provide robust protection at the predominant sites of SARS-CoV-2 infection. However, it remains unclear whether respiratory mucosal administration of DNA vaccines could confer protective immune responses against SARS-CoV-2 challenge due to the insurmountable barriers posed by the airway. Here, we applied self-assembled peptide-poloxamine nanoparticles with mucus-penetrating properties for pulmonary inoculation of a COVID-19 DNA vaccine (pSpike/PP-sNp). Not only displays the pSpike/PP-sNp superior gene-transfection and favorable biocompatibility in the mouse airway, but pSpike/PP-sNp promotes a tripartite immunity consisting of systemic, cellular and mucosal immune responses that are characterized by mucosal IgA secretion, high levels of neutralizing antibodies, and resident memory phenotype T-cell responses in the lungs of mice. Most importantly, pSpike/PP-sNp completely eliminates SARS-CoV-2 infection in both upper and lower respiratory tracts and enables 100% survival rate of mice following lethal SARS-CoV-2 challenge. Our findings indicate PP-sNp might be a promising platform in mediating DNA vaccines to elicit all-around mucosal immunity against SARS-CoV-2.

immunology↗

bioRxiv2022

The Balance between Saturated and Unsaturated Fatty Acids Regulates Ovarian Cancer Cell Fate

Fatty acids are an important source of energy and a key component of phospholipids in membranes and organelles. Saturated (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an enzyme highly active in cancer. Here we studied how the balance between SFAs and UFAs maintained by SCD impacts cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman spectroscopy (SRS). Further, the loss of equilibrium between UFAs and SFAs resulting from SCD knock down triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1/XBP1 and PERK/eIF2/ATF4 axes. Stiff and disorganized ER membrane was visualized by electron microscopy and SRS imaging in cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and apoptosis could be readily rescued by supplementation with UFAs and re-equilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro, translated into suppression of intraperitoneal tumor growth in xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA enriched diet, initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the cancer cell fate under metabolic stress and point to new treatment strategies targeting the lipid balance. Significance StatementWe show that the balance between saturated and unsaturated fatty acids tightly regulated by the desaturase SCD impacts the survival of cancer cells; increased levels of unsaturation being protective against ER stress induced apoptosis. Decreasing fatty acid unsaturation, either through SCD depletion or through SCD inhibition coupled with a dietary intervention blocks tumor progression in vivo. Our findings support the concept of targeting the lipid balance as a new target in cancer.

cancer biology↗

bioRxiv2022

Identification of key molecules and biological processes in TCF21 treated tumor pericytes

Colorectal cancer has become a major public health problem in the US. Transcription factor 21 (TCF21) is reported to be silenced in colorectal cancer tissues. However, the mechanism of TCF21 in tumor pericytes is still unclear. In our study, we aim to identify the key biological processes and signaling pathways by analyzing the RNA-seq data. The GSE200064 was produced by the Illumina NovaSeq 6000 (Homo sapiens). The KEGG and GO analyses showed that MAPK signaling pathway and complement/coagulation cascades are the major changed signaling pathways in the progression of tumor pericytes with overexpression of TCF21. Moreover, we identified several interactive molecules including VEGFA, MMP2, CCL2, COL3A1, COL1A2, CXCL12, ELN, PDGFRB, VWF, and APOE. These findings may benefit the study of colorectal cancer treatment.

bioinformatics↗

bioRxiv2022

DTSyn: a dual-transformer-based neural network to predict synergistic drug combinations

Drug combination therapies are superior to monotherapy for cancer treatment in many ways when addressing tumor heterogeneity issue. For wet-lab experiment, screening out novel synergistic drug pairs is challenging due to the enormous searching space of possible drug pairs. Thus, computational methods have been developed to predict drug pairs with potential synergistic function. Notwithstanding the success of current models, the power of generalization to other datasets as wells as understanding of mechanism for chemical-chemical interaction or chemical-sample interaction are lack of study, hindering current algorithms from real application. In this paper, we proposed a deep neural model termed DTSyn (Dual Transformer model for drug pair Synergy prediction) based on multi-head attention mechanism to identify novel drug combinations. We designed a fine-granularity transformer for capturing chemical substructure-gene and gene-gene associations and a coarse-granularity transformer for extracting chemical-chemical and chemical-cell line interactions. DTSyn achieves highest Receiver operating characteristic area under curve (ROC AUC) of 0.73, 0.78. 0.82 and 0.81 on four different cross validation tasks, outperforming all competing methods. Further, DTSyn achieved best True Positive Rate (TPR) over five independent datasets. The ablation study showed that both transformer blocks contributed to the performance of DTSyn. In addition, DTSyn can extract interactions among chemicals and cell lines, which may represent the mechanisms of drug action. Thus, we envision our model a valuable tool to prioritize synergistic drug pairs by utilizing chemicals and transcriptome data.

bioinformatics↗

bioRxiv2022

Metabolome and transcriptome analysis reveal components regulating soapberry triterpenoid saponin biosynthesis

Soapberry (Sapindus mukorossi Gaertn.) pericarps are rich in valuable bioactive triterpenoid saponins. However, the saponin content dynamics and the molecular regulatory network of saponin biosynthesis in soapberry pericarps remain largely unclear. Here, we performed combined metabolite profiling and transcriptome analysis to identify saponin accumulation kinetic patterns, investigate gene networks, and characterize key candidate genes and transcription factors involved in saponin biosynthesis in soapberry pericarps. A total of 54 saponins were tentatively identified, including 25 that were differentially accumulated. Furthermore, 49 genes putatively involved in sapogenin backbone biosynthesis and some candidate genes assumed to be responsible for the backbone modification, including 41 cytochrome P450s and 45 glycosyltransferases, were identified. Saponin-specific clusters/modules were identified by Mfuzz clustering and weighted gene co-expression network analysis, and one TF-gene regulatory network underlying saponin biosynthesis was proposed. The results of yeast one-hybrid assay and electrophoretic mobility shift assay suggested that SmbHLH2, SmTCP4, and SmWRKY27 may play important roles in the triterpenoid saponin biosynthesis by directly regulating the transcription of SmCYP71D-3 in soapberry pericarp. Overall, these findings provide valuable information for understanding the molecular regulatory mechanism of saponin biosynthesis, enriching the gene resources, and guiding further research on triterpenoid saponin accumulation in soapberry pericarps. One-sentence summaryCombining metabolome and transcriptome analysis to identify saponin kinetic patterns, gene networks, and key candidate genes and transcription factors involved in saponin biosynthesis of soapberry.

molecular biology↗