Minor Hydroxylated Triterpenoids Produced in Engineered Yeast by the Enzymes OSC and CYP716s from the Plant Enkianthus chinensis and Their Anti-Inflammatory and Hepatoprotective Activities.

Triterpenoids are a type of specialized metabolites that exhibit a wide range of biological activities. However, the availability of some minor triterpenoids in nature is limited, which has hindered our understanding of their pharmacological potential. To overcome this limitation, heterologous biosynthesis of triterpenoids in yeast has emerged as a promising and time-efficient production platform for obtaining these minor compounds. In this study, we analyzed the transcriptomic data of Enkianthus chinensis to identify one oxidosqualene cyclase (EcOSC) gene and four CYP716s. Through heterologous expression of these genes in yeast, nine natural pentacyclic triterpenoids, including three skeleton products (1-3) produced by one multifunctional OSC and six minor oxidation products (4-9) catalyzed by CYP716s, were obtained. Of note, we discovered that CYP716E60 could oxidize ursane-type and oleanane-type triterpenoids to produce 6ß-OH derivatives, marking the first confirmed C-6ß hydroxylation in an ursuane-type triterpenoid. Compound 9 showed moderate inhibitory activity against NO production and dose-dependently reduced IL-1ß and IL-6 production at the transcriptional and protein levels. Compounds 1, 2, 8, and 9 exhibited moderate hepatoprotective activity with the survival rates of HepG2 cells from 61% to 68% at 10 µM.

High-Efficiency Electrocatalytic Reduction of N2O with Single-Atom Cu Supported on Nitrogen-Doped Carbon.

Nitrous oxide (N2O) is a potent greenhouse gas with a high global warming potential, emphasizing the critical need to develop efficient elimination methods. Electrocatalytic N2O reduction reaction (N2ORR) stands out as a promising approach, offering room temperature conversion of N2O to N2 without the production of NOx byproducts. In this study, we present the synthesis of a copper-based single-atom catalyst featuring atomic Cu on nitrogen-doped carbon black (Cu1-NCB). Attributed to the highly dispersed single-atom Cu sites and the effective suppression of the hydrogen evolution reaction, Cu1-NCB demonstrated an optimal N2 faradaic efficiency (82.1%) and yield rate (3.53 mmol h-1 mgmetal-1) at -0.2 and -0.5 V vs RHE, respectively, outperforming previously reported N2ORR electrocatalysts. Further, a gas diffusion electrode cell was employed to improve mass transfer and achieved a 28.6% conversion rate of 30% N2O with only a 14 s residence time, demonstrating the potential for practical application. Density functional theory calculations identified Cu-N4 as the crucial active site for N2ORR, highlighting the significance of the unsaturated coordination and metal-support electronic structure. O-terminal adsorption of N2O was favored, and the dissociative adsorption (*ON2 → *O + N2) was the rate-determining step. These findings reveal the broad prospects of N2O decomposition via electrocatalysis.

Tailoring Iridium Valence States on ZSM-5 for Enhanced Catalytic Performance in CO Selective Catalytic Reduction of NO under Oxygen-Enriched Environments.

Barium and iridium supported on Zeolite Socony Mobil-5 (ZSM-5) are efficient catalysts for the selective catalytic reduction of nitric oxide by carbon monoxide (CO-SCR), with enhanced cyclic stability. The introduction of Ba hindered the oxidation of metallic Ir active species and enabled Ir to maintain an active metallic state, thereby preventing a decrease in catalytic activity in the CO-SCR reaction. Moreover, the Ba modification increased the NO adsorption of the catalyst, further improving the catalytic activity. Owing to the better anti-oxidation ability of Ir0 in IrBa0.2/ZSM-5(27) than in Ir/ZSM-5(27), IrBa0.2/ZSM-5(27) showed better stability than Ir/ZSM-5(27). Considering that all samples in the present study were tested to simulate actual flue gases (such as sintering flue gas and coke oven flue gas), NH3 was introduced into the reaction system to serve as an extra reductant for NOx. The NOx conversion to N2 (77.1%) was substantially improved using the NH3-CO-SCR system. The proposed catalysts and reaction systems are promising alternatives for treating flue gas, which contains considerable amounts of NOx and CO in oxygen-enriched environments.

Development of Injectable Thermosensitive Nanocomposite Hydrogel for Ratiometric Drug Delivery to Treat Drug Resistant Chondrosarcoma In Vivo.

Chondrosarcoma(CS), a prevalent primary malignant bone tumor, frequently exhibits chemotherapy resistance attributed to upregulated anti-apoptosis pathways such as the Bcl-2 family. In this manuscript, a new strategy is presented to augment chemosensitivity and mitigate systemic toxicity by harnessing a nano-enabled drug delivery hydrogel platform. The platform utilizes "PLGA-PEG-PLGA", an amphiphilic triblock copolymer combining hydrophilic polyethylene glycol (PEG) and hydrophobic polylactide glycolide (PLGA) blocks, renowned for its properties conducive to crafting a biodegradable, temperature-sensitive hydrogel. This platform is tailored to encapsulate a ratiometrically designed dual-loaded liposomes containing a first-line chemo option for CS, Doxorubicin (Dox), plus a calculated amount of small molecule inhibitor for anti-apoptotic Bcl-2 pathway, ABT-737. In vitro and in vivo evaluations demonstrate successful Bcl-2 suppression, resulting in the restoration of Dox sensitivity, evident through impeded tumor growth and amplified necrosis rates at the tumor site. This delivery system showcases remarkable thermal responsiveness, injectability, and biodegradability, all finely aligned with the clinical demands of CS treatment. Collectively, this study introduces a transformative avenue for tackling drug resistance in CS chemotherapy, offering significant clinical potential.

Characterization and Engineering of Two Highly Paralogous Sesquiterpene Synthases Reveal a Regioselective Reprotonation Switch.

Sesquiterpene synthases (STPSs) catalyze carbocation-driven cyclization reactions that can generate structurally diverse hydrocarbons. The deprotonation-reprotonation process is widely used in STPSs to promote structural diversity, largely attributable to the distinct regio/stereoselective reprotonations. However, the molecular basis for reprotonation regioselectivity remains largely understudied. Herein, we analyzed two highly paralogous STPSs, Artabotrys hexapetalus (-)-cyperene synthase (AhCS) and ishwarane synthase (AhIS), which catalyze reactions that are distinct from the regioselective protonation of germacrene A (GA), resulting in distinct skeletons of 5/5/6 tricyclic (-)-cyperene and 6/6/5/3 tetracyclic ishwarane, respectively. Isotopic labeling experiments demonstrated that these protonations occur at C3 and C6 of GA in AhCS and AhIS, respectively. The cryo-electron microscopy-derived AhCS complex structure provided the structural basis for identifying different key active site residues that may govern their functional disparity. The structure-guided mutagenesis of these residues resulted in successful functional interconversion between AhCS and AhIS, thus targeting the three active site residues [L311-S419-C458]/[M311-V419-A458] that may act as a C3/C6 reprotonation switch for GA. These findings facilitate the rational design or directed evolution of STPSs with structurally diverse skeletons.

Tumor markers for lipid metabolism-related genes: Based on small cell lung cancer and bronchial asthma dual analysis.

Numerous studies have elucidated the intricate relationship between bronchial asthma and small cell lung cancer (SCLC), as well as the role lipid metabolism genes play in transitioning from bronchial asthma to SCLC. Despite this, the predictive power of single gene biomarkers remains insufficient and necessitates the development of more accurate prognostic models. In our study, we downloaded and preprocessed scRNA-seq of SCLC from the GEO database GSE164404 and severe asthma scRNA-seq from GSE145013 using the Seurat package. Using the MSigDB database and geneCard database, we selected lipid metabolism-related genes and performed scRNA-seq data analysis from the gene expression GEO database, aiming to uncover potential links between immune signaling pathways in bronchial asthma and SCLC. Our investigations yielded differentially expressed genes based on the scRNA-seq dataset related to lipid metabolism. We executed differential gene analysis, gene ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. In-depth GSEA pathway activation analysis, crucial target gene predictions via protein-protein interactions, and key cluster gene evaluations for differential and diagnostic ROC values correlation analysis confirmed that key cluster genes are significant predictors for the progression of bronchial asthma to SCLC. To validate our findings, we performed wet laboratory experiments using real-time quantitative PCR to assess the expression of these relevant genes in SCLC cell lines. In conclusion, this research proposes a novel lipid metabolism-related gene marker that can offer comprehensive insights into the pathogenesis of bronchial asthma leading to SCLC. Although this study does not directly focus on senescence-associated molecular alterations, our findings in the lipid metabolism genes associated with inflammation and cancer progression offer valuable insights for further research targeting senescence-related changes in treating inflammatory diseases.

Cadinane sesquiterpenes from the stems and branches of Illicium ternstroemioides.

Three new cadinane sesquiterpenes (1-3) and three known sesquiterpenes were isolated from the stems and branches of Illicium ternstroemioides A. C. Smith. The structures of the new compounds were elucidated by extensive analysis of spectroscopic and HRESIMS data. The structures of illiternins A-C (1-3) were confirmed by single crystal X-ray diffraction, allowing for the determination of their absolute configurations. Compounds 3 and 6 exhibited antiviral activity against Coxsackievirus B3 with IC50 values of 33.3 and 57.7 µM, respectively.

Alleviating effect of Nexrutine on mucosal inflammation in mice with ulcerative colitis: Involvement of the RELA suppression.

BACKGROUND: Nexrutine is an herbal extract derived from Phellodendron amurense, known for its anti-inflammatory, antidiarrheal, and hemostatic properties. However, its effect on ulcerative colitis (UC) remains unclear. METHODS: A mouse model of UC was induced by 3% dextran sulfate sodium, while human colonic epithelial cells NCM-460 were exposed to lipopolysaccharide. Both models were treated with Nexrutine at 300 or 600 mg/kg, with Mesalazine applied as a positive control regimen. The disease activity index (DAI) of mice was calculated, and the pathological injury scores were assessed through hematoxylin and eosin staining. The viability of NCM-460 cells was determined using the CCK-8 method. Inflammatory cytokines were detected using ELISA kits. Expression of mucin 3 (MUC3), Claudin-1, and tight junction protein (ZO-1) was detected to analyze mucosal barrier integrity. Target genes of Nexrutine were predicted using bioinformatics tools. Expression of RELA proto-oncogene (RELA) was analyzed using qPCR and western blot assays. RESULTS: The Nexrutine treatments significantly alleviated DAI of mice, mitigated pathological changes in their colon tissues, decreased the production of pro-inflammatory cytokines, enhanced the barrier integrity-related proteins, and increased NCM-460 cell viability in vitro. RELA, identified as a target gene of Nexrutine, showed elevated levels in UC models but was substantially suppressed by Nexrutine treatment. Adenovirus-mediated RELA upregulation in mice or the overexpression plasmid of RELA in cells counteracted the effects of Nexrutine treatments, exacerbating UC-related symptoms. CONCLUSION: This study demonstrates that Nexrutine alleviates inflammatory mucosal barrier damage in UC by suppressing RELA transcription.

Identification and functional analysis of the female determiner gene in the bean bug, Riptortus pedestris.

BACKGROUND: Homing-based gene drives targeting sex-specific lethal genes have been used for genetic control. Additionally, understanding insect sex determination provides new targets for managing insect pests. While sex determination mechanisms in holometabolous insects have been thoroughly studied and employed in pest control, the study of the sex determination pathway in hemimetabolous insects is limited to only a few species. Riptortus pedestris (Fabricius; Hemiptera: Heteroptera), commonly known as the bean bug, is a significant pest for soybeans. Nonetheless, the mechanism of its sex determination and the target gene for genetic control are not well understood. RESULTS: We identified Rpfmd as the female determiner gene in the sex determination pathway of R. pedestris. Rpfmd encodes a female-specific serine/arginine-rich protein of 436 amino acids and one non-sex-specific short protein of 98 amino acids. Knockdown of Rpfmd in R. pedestris nymphs caused death of molting females with masculinized somatic morphology but did not affect male development. Knockdown of Rpfmd in newly emerged females inhibited ovary development, while maternal-mediated RNA interference (RNAi) knockdown of Rpfmd expression resulted in male-only offspring. Transcriptome sequencing revealed that Rpfmd regulates X chromosome dosage compensation and influences various biological processes in females but has no significant effect on males. Moreover, RNAi mediated knockdown of Rpfmd-C had no influence on the development of R. pedestris, suggesting that Rpfmd regulates sex determination through female-specific splicing isoforms. We also found that Rpfmd pre-mRNA alternative splicing regulation starts at the 24-h embryo stage, indicating the activation of sex differentiation. CONCLUSION: Our study confirms that Rpfmd, particularly its female-specific isoform (Rpfmd-F), is the female determiner gene that regulates sex differentiation in R. pedestris. Knockdown of Rpfmd results in female-specific lethality without affecting males, making it a promising target for genetic control of this soybean pest throughout its development stages. Additionally, our findings improve the understanding of the sex-determination mechanism in hemimetabolous insects. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Simultaneous determination of four phytoecdysteroids by LC-MS/MS: application to a comparative pharmacokinetic study in normal and adjuvant arthritis rats after oral administration of C. officinalis Kuan phytoecdysteroids extract.

C. officinalis Kuan is the dry root of Cyathula officinalis Kuan. Clinically, it is used for fall and flutter injury, rheumatism and arthralgia. Phytoecdysteroids have significant anti-inflammatory effects, and the phytoecdysteroids present in C. officinalis Kuan exhibit potential for treating rheumatoid arthritis.This study first developed a selective, accurate and efficient LC-MS/MS method for 12-day pharmacokinetic studies regarding the simultaneous determination of cyasterone, 25-epi-28-epi-cyasterone, precyasterone and capitasterone from C. officinalis Kuan phytoecdysteroids extract in normal and adjuvant arthritis rats.An Agilent Eclipse Plus C18 RRHD column (1.8 µm, 50mm × 2.1 mm) with a gradient mobile phase consisting of water (A) and acetonitrile (B) was used for analysis. The mass analysis was performed in an Agilent 6430 QQQ-MS mass spectrometer with positive mode multiple reaction monitoring (MRM).The results indicated that the AUC0-t and AUC0-∞ values of the four phytoecdysteroids in adjuvant arthritis rats were different from those in normal rats on the first day, which could provide a helpful reference for pharmacological and toxicological studies, as well as clinical applications of C. officinalis Kuan in the treatment of rheumatoid arthritis.

1. C. officinalis Kuan is the dry root of Cyathula officinalis Kuan which has been used for the treatment of flapping injury, rheumatism arthralgia, foot flaccidity, and tendon contracture thousands of years in China, and has been officially included in the Chinese Pharmacopoeia.2. A highly accurate, stable, and sensitive ultra-performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) method was first established and validated for simultaneously determination four phytoecdysteroids: cyasterone, 25-epi-28-epi-cyasterone, precyasterone and capitasterone in normal and adjuvant arthritis rats plasma samples 12 days of continuous gavage of C. officinalis Kuan phytoecdysteroids extract.3. The phytoecdysteroids is the important component of C. officinalis Kuan, which is difficult to separated. And there is no report for the pharmacokinetic study of phytoecdysteroids from C. officinalis Kuan. And the method provides a good reference for the follow-up studies clinical medication of the phytoecdysteroids from C. officinalis Kuan.

Alkali metal doped crystalline g-C3N4 with an enriched cyano group for visible-light photocatalytic degradation of methylamine.

In this study, alkali-metal-doped crystalline g-C3N4 with an enriched cyano group was synthesized using the molten salt method and used for the visible-light photocatalytic degradation of methylamine (MA), a common organic amine compound with a low odor threshold. Different types and proportions of melting salts (Li, K, and Na) were added during secondary calcination to regulate the morphology, crystallinity, and surface defects of graphitic carbon nitride (g-C3N4). With molten salt treatment matched the melting point of the binary salt system, a cyano group and alkali metal co-doped crystalline g-C3N4 with a high surface area and good crystallinity were prepared. Co-decorating the alkali metal and cyano groups on crystalline g-C3N4 facilitated the adsorption of MA, realized an excellent photo-charge transfer efficiency, and generated more superoxide radicals. Compared with pristine g-C3N4 (PCN), the apparent rate constant of LiK15 : 5-CCN for the degradation of MA increased by 10.2 times and the degradation efficiency of 1000 ppm MA gas was 93.1% after 90 min of irradiation with visible light, whereas the degradation efficiency of PCN was 19.2%.

The Roles of transformer-2 (tra-2) in the Sex Determination and Fertility of Riptortus pedestris, a Hemimetabolous Agricultural Pest.

In most holometabolous insects, transformer-2 (tra-2) is an auxiliary gene required for sex determination, exerting a crucial role in regulating sexual differentiation; however, the study of tra-2 in hemimetabolous insects remains very sparse and limited to just a few species. In this study, we investigated the sequence and expression profile of the tra-2 gene in the bean bug, Riptortus pedestris, an agricultural pest belonging to the Heteroptera order. Three non-sex-specific splicing isoforms of Rptra-2 were found, Rptra-2293, Rptra-2284, and Rptra-2299, which shared most exons and exhibited similar expression throughout all stages of development, with particularly elevated levels in the embryo, ovary, and testis. RNAi knockdown experiments revealed that the suppression of Rptra-2 in nymphs led to abnormal females, characterized the formation of male-specific external genital, and also caused longer nymph duration. Knockdown of the expression of the Rptra-2 gene in newly emergent virgin females would cause ovarian arrest, and injecting the 8th-day virgin females with dsRptra-2 also caused a noticeable decline in the offspring numbers. Conversely, in dsRptra-2-treated males, the testes maintained normal morphology but experienced impaired reproductive capacity, attributed to diminished sperm viability. These findings highlight the crucial role of Rptra-2 in the sex determination and fertility of R. pedestris, providing valuable insights into the sex determination mechanisms of hemimetabolous insects.

IgG4-related digestive diseases: diagnosis and treatment.

IgG4-related digestive diseases encompass a group of chronic inflammatory disorders characterized by autoimmune reactions and fibrosis affecting multiple digestive organs. These diseases are identified by elevated serum levels of IgG4 and the presence of IgG4-positive plasma cell infiltration in the affected sites, along with storiform fibrosis, obliterative phlebitis, and eosinophilic infiltration. Although extensive research has been conducted, a comprehensive understanding of these conditions remains elusive. Current clinical diagnosis often relies on the application of integrated diagnostic criteria for IgG4-related diseases, combined with specific organ involvement criteria. Distinguishing them from malignancies poses considerable challenges. Moreover, further investigations are required to elucidate the underlying pathogenic mechanisms and explore potential therapeutic interventions. This review provides a systematic classification of IgG4-related digestive diseases while discussing their diagnostic strategies, clinical presentations, and treatment modalities. The comprehensive insights shared herein aim to guide clinicians in their practice and contribute to the advancement of knowledge in this field.

Prenylated C6-C3 derivatives from the root of Illicium ternstroemioides with antiviral activity.

Six previously undescribed prenylated C6-C3 derivatives (1-6) were isolated from the root of Illicium ternstroemioides A. C. Smith. Their structures were elucidated based on extensive spectroscopic analyses (UV, IR, 1D and 2D NMR, and HRESIMS). The absolute configurations of 1-3 were determined using electronic circular dichroism (ECD), and Mo2(OAc)4 induced circular dichroism (ICD). Compound 3 exhibited weak activity against Coxsackievirus B3 with an IC50 value of 33.3 µM, and compound 5 exhibited more potent activity against Coxsackievirus B3 with an IC50 value of 6.4 µM.

Advances in genetic variation in metabolism-related fatty liver disease.

Metabolism-related fatty liver disease (MAFLD) is the most common form of chronic liver disease in the world. Its pathogenesis is influenced by both environmental and genetic factors. With the upgrading of gene screening methods and the development of human genome project, whole genome scanning has been widely used to screen genes related to MAFLD, and more and more genetic variation factors related to MAFLD susceptibility have been discovered. There are genetic variants that are highly correlated with the occurrence and development of MAFLD, and there are genetic variants that are protective of MAFLD. These genetic variants affect the development of MAFLD by influencing lipid metabolism and insulin resistance. Therefore, in-depth analysis of different mechanisms of genetic variation and targeting of specific genetic variation genes may provide a new idea for the early prediction and diagnosis of diseases and individualized precision therapy, which may be a promising strategy for the treatment of MAFLD.

Diverse prenylated C6-C3 derivatives from the stems and branches of Illicium ternstroemioides A. C. Smith with anti-inflammatory and antiviral activities.

Fifteen unreported prenylated C6-C3 derivatives (1-15) were isolated from the stems and branches of Illicium ternstroemioides A. C. Smith, including one bis-prenylated C6-C3 derivative (1), three prenylated C6-C3 derivative-shikimic acid ester hybrids (2-4) and 11 prenylated C6-C3 monomers (5-15). The structures of compounds 1-15 were elucidated by spectroscopic analysis (UV, IR, 1D and 2D NMR, and HRESIMS). The absolute configurations of the compounds were determined using electronic circular dichroism (ECD), induced circular dichroism (ICD), and the modified Mosher's method. Among the isolates, compounds 11, 12, and 15 exhibited significant anti-inflammatory activities by inhibiting the nitric oxide with IC50 values ranging from 1.89 to 24.83 µM in lipopolysaccharide-stimulated murine RAW 264.7 macrophages and murine BV2 microglial cells; compounds 2, 3, and 7 exhibited antiviral activitives against Coxsackievirus B3 with an IC50 value of 33.3, 25.9, and 27.8 µM, respectively.

The regulatory role of bile acid microbiota in the progression of liver cirrhosis.

Bile acids (BAs) are synthesized in liver tissue from cholesterol and are an important endocrine regulator and signaling molecule in the liver and intestine. It maintains BAs homeostasis, and the integrity of intestinal barrier function, and regulates enterohepatic circulation in vivo by modulating farnesoid X receptors (FXR) and membrane receptors. Cirrhosis and its associated complications can lead to changes in the composition of intestinal micro-ecosystem, resulting in dysbiosis of the intestinal microbiota. These changes may be related to the altered composition of BAs. The BAs transported to the intestinal cavity through the enterohepatic circulation are hydrolyzed and oxidized by intestinal microorganisms, resulting in changes in their physicochemical properties, which can also lead to dysbiosis of intestinal microbiota and overgrowth of pathogenic bacteria, induction of inflammation, and damage to the intestinal barrier, thus aggravating the progression of cirrhosis. In this paper, we review the discussion of BAs synthesis pathway and signal transduction, the bidirectional regulation of bile acids and intestinal microbiota, and further explore the role of reduced total bile acid concentration and dysregulated intestinal microbiota ratio in the development of cirrhosis, in order to provide a new theoretical basis for the clinical treatment of cirrhosis and its complications.

Insight into the Mechanism of Selective Catalytic Reduction of NO by CO over a Bimetallic IrRu/ZSM-5 Catalyst in the Absence/Presence of O2 by Isotopic C13O Tracing Methods.

The development of efficient catalysts for the selective catalytic reduction of NO by CO (CO-SCR) in the presence of O2 is highly desirable for controlling the emission of toxic gases from tailpipes. Here, a bimetallic IrRu/ZSM-5 catalyst was prepared for the selective catalytic reduction of NO by CO in the presence of O2 (5%) for the low-temperature treatment of exhaust gas. IrRu/ZSM-5 afforded 90% NOx conversion in the range of 225-250 °C and maintained 90% NOx conversion after 12 h of reaction. Ru addition inhibited agglomeration of the Ir particles during the reduction process and provided more active sites for NO adsorption. Isotopic C13O tracing and in situ diffuse reflectance infrared Fourier-transform spectroscopy experiments were used to elucidate the CO-SCR mechanism in the absence or presence of O2. NCO could easily form on the surface of catalysts in the absence of O2, whereas NCO formation has been inhibited owing to the quick consumption of CO in the presence of O2. Moreover, some byproducts such as N2O and NO2 are generated in the presence of O2. Finally, a possible mechanism for CO-SCR under different conditions was proposed based on in situ experiments and physicochemical analyses.

Heterogeneity of tumor immune microenvironment in malignant and metastatic change in LUAD is revealed by single-cell RNA sequencing.

Lung adenocarcinoma (LUAD) is the most common type of non-small cell lung cancer and accounts for approximately 40% of all lung cancer cases. Multiple distant metastases are the major cause of mortality in lung cancer. In this study, single-cell sequencing datasets of LUAD were utilized to depict the transcriptome characteristic of LUAD based on the bioinformatic method. Firstly, the transcriptome landscape of heterogeneous cell types in LUAD was analyzed and memory T cells, NK cells, and helper T cells were revealed to be the common immune cells in tumor, normal, and metastasis tissue, respectively. Then, marker genes were calculated and 709 genes were identified to play a vital role in the microenvironment of LUAD. While macrophages were reported to act as one of the cells in LUAD, enrichment analysis of macrophage marker genes revealed the important role of macrophages in the activation of neutrophils. Next, the results of cell-cell communication analysis suggested that pericytes interact with broad immune cells via MDK-NCL pathways in metastasis samples, MIF-(CD74+CXCR4) and MIF-(CD74+CC44) interaction especially occurred between different cell types in tumor and normal samples. Finally, bulk RNA-seq was integrated to validate the prognosis effect of the marker gene and the maker gene of M2 macrophage, CCL20, showed the most related to LUAD prognosis. Besides, ZNF90 (Helper T cells), FKBP4 (memory T, helper T, Cytotoxic T, and B cells), CD79A (B cells), TPI1 (pericyte), and HOPX (epithelial cells, pericytes) were also pivotal in the pathology of LUAD, helping researchers understand the molecular insight of microenvironment in LUAD.

Medical-Knowledge-Based Graph Neural Network for Medication Combination Prediction.

Medication combination prediction (MCP) can provide assistance for experts in the more thorough comprehension of complex mechanisms behind health and disease. Many recent studies focus on the patient representation from the historical medical records, but neglect the value of the medical knowledge, such as the prior knowledge and the medication knowledge. This article develops a medical-knowledge-based graph neural network (MK-GNN) model which incorporates the representation of patients and the medical knowledge into the neural network. More specifically, the features of patients are extracted from their medical records in different feature subspaces. Then these features are concatenated to obtain the feature representation of patients. The prior knowledge, which is calculated according to the mapping relationship between medications and diagnoses, provides heuristic medication features according to the diagnosis results. Such medication features can help the MK-GNN model learn optimal parameters. Moreover, the medication relationship in prescriptions is formulated as a drug network to integrate the medication knowledge into medication representation vectors. The results reveal the superior performance of the MK-GNN model compared with the state-of-the-art baselines on different evaluation metrics. The case study manifests the application potential of the MK-GNN model.