[Cluster Analysis and Ablation Success Rate in Atrial Fibrillation Patients Undergoing Catheter Ablation]. / æˆ¿é¢¤å°„é¢‘æ¶ˆèžæ‚£è€ çš„èšç±»åˆ†æžåŠæ¶ˆèžæˆåŠŸçŽ‡è¯„ä»·.

Objective: Atrial fibrillation (AF) is a disease of high heterogeneity, and the association between AF phenotypes and the outcome of different catheter ablation strategies remains unclear. Conventional classification of AF (e.g. according to duration, atrial size, and thromboembolism risk) fails to provide reference for the optimal stratification of the prognostic risks or to guide individualized treatment plan. In recent years, research on machine learning has found that cluster analysis, an unsupervised data-driven approach, can uncover the intrinsic structure of data and identify clusters of patients with pathophysiological similarity. It has been demonstrated that cluster analysis helps improve the characterization of AF phenotypes and provide valuable prognostic information. In our cohort of AF inpatients undergoing radiofrequency catheter ablation, we used unsupervised cluster analysis to identify patient subgroups, to compare them with previous studies, and to evaluate their association with different suitable ablation patterns and outcomes. Methods: The participants were AF patients undergoing radiofrequency catheter ablation at West China Hospital between October 2015 and December 2017. All participants were aged 18 years or older. They underwent radiofrequency catheter ablation during their hospitalization. They completed the follow-up process under explicit informed consent. Patients with AF of a reversible cause, severe mitral stenosis or prosthetic heart valve, congenital heart disease, new-onset acute coronary syndrome within three months prior to the surgery, or a life expectancy less than 12 months were excluded according to the exclusion criteria. The cohort consisted of 1102 participants with paroxysmal or persistent/long-standing persistent AF. Data on 59 variables representing demographics, AF type, comorbidities, therapeutic history, vital signs, electrocardiographic and echocardiographic findings, and laboratory findings were collected. Overall, data for the variables were rarely missing (<5%), and multiple imputation was used for correction of missing data. Follow-up surveys were conducted through outpatient clinic visits or by telephone. Patients were scheduled for follow-up with 12-lead resting electrocardiography and 24-hours Holter monitoring at 3 months and 6 months after the ablation procedure. Early ablation success was defined as the absence of documented AF, atrial flutter, or atrial tachycardia >30 seconds at 6-month follow-up. Hierarchical clustering was performed on the 59 baseline variables. All characteristic variables were standardized to have a mean of zero and a standard deviation of one. Initially, each patient was regarded as a separate cluster, and the distance between these clusters was calculated. Then, the Ward minimum variance method of clustering was used to merge the pair of clusters with the minimum total variance. This process continued until all patients formed one whole cluster. The "NbClust" package in R software, capable of calculating various statistical indices, including pseudo t2 index, cubic clustering criterion, silhouette index etc, was applied to determine the optimal number of clusters. The most frequently chosen number of clusters by these indices was selected. A heatmap was generated to illustrate the clinical features of clusters, while a tree diagram was used to depict the clustering process and the heterogeneity among clusters. Ablation strategies were compared within each cluster regarding ablation efficacy. Results: Five statistically driven clusters were identified: 1) the younger age cluster (n=404), characterized by the lowest prevalence of cardiovascular and cerebrovascular comorbidities but the highest prevalence of obstructive sleep apnea syndrome (14.4%); 2) a cluster of elderly adults with chronic diseases (n=438), the largest cluster, showing relatively higher rates of hypertension, diabetes, stroke, and chronic obstructive pulmonary disease; 3) a cluster with high prevalence of sinus node dysfunction (n=160), with patients showing the highest prevalence of sick sinus syndrome and pacemaker implantation; 4) the heart failure cluster (n=80), with the highest prevalence of heart failure (58.8%) and persistent/long-standing persistent AF (73.7%); 5) prior coronary artery revascularization cluster (n=20), with patients of the most advanced age (median: 69.0 years old) and predominantly male patients, all of whom had prior myocardial infarction and coronary artery revascularization. Patients in cluster 2 achieved higher early ablation success with pulmonary veins isolation alone compared to extensive ablation strategies (79.6% vs. 66.5%; odds ratio [OR]=1.97, 95% confidence interval [CI]: 1.28-3.03). Although extensive ablation strategies had a slightly higher success rate in the heart failure group, the difference was not statistically significant. Conclusions: This study provided a unique classification of AF patients undergoing catheter ablation by cluster analysis. Age, chronic disease, sinus node dysfunction, heart failure and history of coronary artery revascularization contributed to the formation of the five clinically relevant subtypes. These subtypes showed differences in ablation success rates, highlighting the potential of cluster analysis in guiding individualized risk stratification and treatment decisions for AF patients.

"Honeycomb" Photothermal Lubricated Porous Foam with Low-Temperature, Weak-Light, Anti-Icing/Deicing, and Long-Lasting Lubrication Properties.

The prevalence of icing in nature has become a significant threat to human work and life, prompting the development of more energy-efficient active/passive combination anti-icing/deicing technologies. In order to overcome the disadvantage of the poor durability of superhydrophobic surfaces, lubricated surfaces inspired by nepenthes have been preferred. In this study, a paraffin and silicone oil-infused photothermal foam (PSIPF) with excellent overall performance was prepared using polypyrrole (PPy) as a photothermal conversion material, a mixture of silicone oil and paraffin as a lubricating fluid, and melamine foam (MF) as a carrier. The surface adhesive strength is less than 20 kPa at -20 °C, the melting time is only 1018 s at an irradiance of 200 W/m2 and -20 °C (0.2 sun), and surface droplets do not freeze within 1 h at -10 °C. Furthermore, the surface exhibits excellent mechanical durability and stability, maintaining optimal lubrication properties following repeated cycles of icing/deicing, water rinsing, and immersion for 2 days in acid and alkaline conditions. This photothermal lubricated surface with excellent anti-icing/deicing properties at low temperatures and in weak-light environments provides a wider range of applications for equipment at high latitudes and high altitudes.

Correction: Lonicera japonica Thunb. as a promising antibacterial agent for Bacillus cereus ATCC14579 based on network pharmacology, metabolomics, and in vitro experiments.

[This corrects the article DOI: 10.1039/D3RA00802A.].

Sulfonic Functionalized Polydopamine Coatings with pH-Independent Surface Charge for Optimizing Capillary Electrophoretic Separations.

Enhancing the pH-independence and controlling the magnitude of electroosmotic flow (EOF) are critical for highly efficient and reproducible capillary electrophoresis (CE) separations. Herein, we present a novel capillary modification method utilizing sulfonated periodate-induced polydopamine (SPD) coating to achieve pH-independent and highly reproducible cathodic EOF in CE. The SPD-coated capillaries were obtained through post-sulfonation treatment of periodate-induced PDA (PDA-SP) coatings adhered on the capillary inner surface. The successful immobilization of the SPD coating and the substantial grafting of sulfonic acid groups were confirmed by a series of characterization techniques. The excellent capability of PDA-SP@capillary in masking silanol groups and maintaining a highly robust EOF mobility was verified. Additionally, the parameters of sulfonation affecting the EOF mobilities were thoroughly examined. The obtained optimum SPD-coated column offered the anticipated highly pH-independent and high-strength cathodic EOF, which is essential for enhancing the CE separation performance and improving analysis efficiency. Consequently, the developed SPD-coated capillaries enabled successful high-efficiency separation of aromatic acids and nucleosides and rapid cyclodextrin-based chiral analysis of racemic drugs. Moreover, the SPD-coated columns exhibited a long lifetime and demonstrated good intra-day, inter-day, and column-to-column repeatability.

Nesprin-2 is a novel scaffold protein for telethonin and FHL-2 in the cardiomyocyte sarcomere.

Nesprins comprise a family of multi-isomeric scaffolding proteins, forming the linker of nucleoskeleton-and-cytoskeleton complex with lamin A/C, emerin and SUN1/2 at the nuclear envelope. Mutations in nesprin-1/-2 are associated with Emery-Dreifuss muscular dystrophy (EDMD) with conduction defects and dilated cardiomyopathy (DCM). We have previously observed sarcomeric staining of nesprin-1/-2 in cardiac and skeletal muscle, but nesprin function in this compartment remains unknown. In this study, we show that specific nesprin-2 isoforms are highly expressed in cardiac muscle and localize to the Z-disc and I band of the sarcomere. Expression of GFP-tagged nesprin-2 giant spectrin repeats 52 to 53, localized to the sarcomere of neonatal rat cardiomyocytes. Yeast two-hybrid screening of a cardiac muscle cDNA library identified telethonin and four-and-half LIM domain (FHL)-2 as potential nesprin-2 binding partners. GST pull-down and immunoprecipitation confirmed the individual interactions between nesprin-2/telethonin and nesprin-2/FHL-2, and showed that nesprin-2 and telethonin binding was dependent on telethonin phosphorylation status. Importantly, the interactions between these binding partners were impaired by mutations in nesprin-2, telethonin, and FHL-2 identified in EDMD with DCM and hypertrophic cardiomyopathy patients. These data suggest that nesprin-2 is a novel sarcomeric scaffold protein that may potentially participate in the maintenance and/or regulation of sarcomeric organization and function.

Institutional gap and enterprise behavior: Evidence from China.

Alternative institutions have played a significant role in the difficult and tenacious development process of private enterprises in recent decades. the paper applied 306 listed companies' data from January 2012 to December 2022 to investigate the relationship between institutional gap and enterprise behavior. Based on the identified, classified, and explained formal and alternative institutions, it proposed the concept of 'institutional gap' to infer the overlapped content of these two states. Concluding from the empirical results, Chinese private enterprises that introduced state-owned equity outperformance in management, financing and entering industries with high barriers. Moreover, the channel of state-owned equity introduction is compared with entrepreneurs' political participation. Although introducing state-owned equity is a crucial approach, the establishment and improvement of relevant legal systems is suggested, such as formal regulations and laws. The government should deepen the reform of the economic system to improve the business environment, so private enterprises consciously rely on market mechanisms to allocate resources efficiently and rationally, instead of actively seeking connections with the government to obtain benefits. The supervisory role of checks and balances shareholders should be exerted to the greatest extent to maintain and increase the value of state-owned assets, rather than allowing the controlling private shareholders to use them as resources acquired political capital.

An augmented diffusion algorithm with bidirectional communication for a distributed active noise control system.

Recent studies on diffusion adaptation for distributed active noise control (DANC) systems have attracted significant research interest due to their balance between computational burden and stability compared to conventional centralized and decentralized adaptation schemes. The conventional multitask diffusion FxLMS algorithm assumes that the converged solutions of all control filters are consistent to each other, which is unrealistic in practice hence results in inferior performance in noise reduction. An augmented diffusion FxLMS algorithm has been proposed to overcome this problem, which adopts a neighborhood-wide adaptation and node-based combination approach to mitigate the bias in the converged solution of the multitask diffusion algorithms. However, the improvement comes at the expense of a higher computational burden and communication cost. All existing DANC systems, including the multitask and augmented diffusion algorithms, assume one-way communication between nodes. By contrast, this paper proposes a bidirectional communication scheme for the augmented diffusion algorithm to further reduce the memory requirement, computational burden, and communication cost. Simulation results in the free field and with measured room impulse responses both demonstrate that the proposed augmented diffusion algorithm with bidirectional communication can achieve a faster convergence speed than that based on one-way communication with a lower memory, computation, and communication burden.

Quantitatively Lighting up the Spatial Organization of CD47/SIRPα Immune Checkpoints on the Cellular Membrane with Single-Molecule Localization Microscopy.

Immunotherapy including immune checkpoint inhibition has reinvigorated the current cancer treatment field. The development of efficient cancer immunotherapies depends on a thorough understanding of the status of immune checkpoints and how they interact. However, the distribution and spatial organization changes of immune checkpoints during their interactions at the single-molecule level remain difficult to directly visualize due to the lack of in situ imaging techniques with appropriate spatial and stoichiometric resolution. Herein, we report the direct visualization and quantification of the spatial distribution and organization of CD47 on the bladder tumor cell membrane and SIRPα on the macrophage membrane by using a single-molecule localization imaging technique called quantitative direct stochastic optical reconstruction microscopy (QdSTORM). Results showed that a portion of CD47 and SIRPα was present on cell membranes as heterogeneous clusters of varying sizes and densities prior to activation. Quantitative analyses of the reconstructed super-resolution images and theoretical simulation revealed that CD47 and SIRPα were reorganized into larger clusters upon binding to each other. Furthermore, we found that blocking the immune checkpoint interaction with small-molecule inhibitors or antibodies significantly impacted the spatial clustering behavior of CD47 on bladder tumor cells, demonstrating the promise of our QdSTORM strategy in elucidating the molecular mechanisms underlying immunotherapy. This work offers a promising strategy to advance our understanding of immune checkpoint state and interactions while also contributing to the fields including signal regulation and cancer therapy.

Protease inhibitor ASP enhances freezing tolerance by inhibiting protein degradation in kumquat.

Cold acclimation is a complex biological process leading to the development of freezing tolerance in plants. In this study, we demonstrated that cold-induced expression of protease inhibitor FmASP in a Citrus-relative species kumquat [Fortunella margarita (Lour.) Swingle] contributes to its freezing tolerance by minimizing protein degradation. Firstly, we found that only cold-acclimated kumquat plants, despite extensive leaf cellular damage during freezing, were able to resume their normal growth upon stress relief. To dissect the impact of cold acclimation on this anti-freezing performance, we conducted protein abundance assays and quantitative proteomic analysis of kumquat leaves subjected to cold acclimation (4°C), freezing treatment (-10°C) and post-freezing recovery (25°C). FmASP (Against Serine Protease) and several non-specific proteases were identified as differentially expressed proteins induced by cold acclimation and associated with stable protein abundance throughout the course of low-temperature treatment. FmASP was further characterized as a robust inhibitor of multiple proteases. In addition, heterogeneous expression of FmASP in Arabidopsis confirmed its positive role in freezing tolerance. Finally, we proposed a working model of FmASP and illustrated how this extracellular-localized protease inhibitor protects proteins from degradation, thereby maintaining essential cellular function for post-freezing recovery. These findings revealed the important role of protease inhibition in freezing response and provide insights on how this role may help develop new strategies to enhance plant freezing tolerance.

Assessment of mitral valve geometry in nonvalvular atrial fibrillation patients with or without ventricular dysfunction: insights from high volume rate three-dimensional transesophageal echocardiography.

Meticulous understanding of the mechanisms underpinning mitral regurgitation in atrial fibrillation (AF) patients is crucial to optimize therapeutic strategies. The morphologic characteristics of mitral valves in atrial functional mitral regurgitation (FMR) patients with and without left ventricular (LV) dysfunction were evaluated by high volume rate (HVR) three-dimensional transesophageal echocardiography (3D-TEE). In our study, 68 of 265 AF patients who underwent 3D-TEE were selected, including 36 patients with AF, FMR, and preserved LV function (AFMR group) and 32 patients with AF, FMR, and LV dysfunction (VFMR group). In addition, 36 fever patients without heart disease were included in the control group. Group comparisons were performed by one-way analysis of variance for continuous variables. The left atrium (LA) was enlarged in the AFMR and VFMR groups compared with the control group. The mitral annulus (MA) in the AFMR group was enlarged and flattened compared with the control group and was smaller than in the VFMR group. The annulus area fraction was significantly diminished in the AFMR and VFMR groups, indicative of reduced MA contractility. The posterior mitral leaflet (PML) angle was smallest in the AFMR group and largest in the control group, whereas the distal anterior mitral leaflet angle did not significantly differ among the three groups. LA remodeling causes expansion of the MA and reduced MA contractility, disruption of the annular saddle shape, and atriogenic PML tethering. Comparison of atrial FMR patients with and without LV dysfunction indicates that atriogenic PML tethering is an important factor that aggravates FMR. HVR 3D-TEE improves the 3D temporal resolution greatly.

DOX_BDW: Incorporating Solvation and Desolvation Effects of Cavity Water into Nonfitting Protein-Ligand Binding Affinity Prediction.

Accurate prediction of the protein-ligand binding affinity (PLBA) with an affordable cost is one of the ultimate goals in the field of structure-based drug design (SBDD), as well as a great challenge in the computational and theoretical chemistry. Herein, we have systematically addressed the complicated solvation and desolvation effects on the PLBA brought by the difference of the explicit water in the protein cavity before and after ligands bind to the protein-binding site. Based on the new solvation model, a nonfitting method at the first-principles level for the PLBA prediction was developed by taking the bridging and displaced water (BDW) molecules into account simultaneously. The newly developed method, DOX_BDW, was validated against a total of 765 noncovalent and covalent protein-ligand binding pairs, including the CASF2016 core set, Cov_2022 covalent binding testing set, and six testing sets for the hit and lead compound optimization (HLO) simulation. In all of the testing sets, the DOX_BDW method was able to produce PLBA predictions that were strongly correlated with the corresponding experimental data (R = 0.66-0.85). The overall performance of DOX_BDW is better than the current empirical scoring functions that are heavily parameterized. DOX_BDW is particularly outstanding for the covalent binding situation, implying the need for considering an electronic structure in covalent drug design. Furthermore, the method is especially recommended to be used in the HLO scenario of SBDD, where hundreds of similar derivatives need to be screened and refined. The computational cost of DOX_BDW is affordable, and its accuracy is remarkable.

Ultrasound enhanced destruction of tetracycline hydrochloride with peroxydisulfate oxidation over FeS/NBC catalyst: Governing factors, strengthening mechanism and degradation pathway.

In this study, FeS/N-doped biochar (NBC) derived from the co-pyrolysis of birch sawdust and Mohr's salt was applied to evaluate the efficiency of catalyzed peroxydisulfate (PDS) oxidation for tetracycline (TC) degradation. It is found that the combination of ultrasonic irradiation can distinctly enhance the removal of TC. This study investigated the effects of control factors such as PDS dose, solution pH, ultrasonic power, and frequency on TC degradation. Within the applied ultrasound intensity range, TC degradation increases with increasing frequency and power. However, excessive power can lead to a reduced efficiency. Under the optimized experimental conditions, the observed reaction kinetic constant of TC degradation increased from 0.0251 to 0.0474 min-1, with an increase of 89%. The removal ratio of TC also increased from ∼85% to ∼99% and the mineralization level from 45% to 64% within 90 min. Through the decomposition testing of PDS, reaction stoichiometric efficiency calculation, and electron paramagnetic resonance experiments, it is shown that the increase in TC degradation of the ultrasound-assisted FeS/NBC-PDS system was attributed to the increase in PDS decomposition and utilization, as well as the increase in SO4•- concentration. The radical quenching experiments showed that SO4•-, •OH, and O2•- radicals were the dominant active species in TC degradation. TC degradation pathways were speculated according to intermediates from HPLC-MS analysis. The test of simulated actual samples showed that dissolved organic matter, metal ions, and anions in waters can undercut the TC degradation in FeS/NBC-PDS system, but ultrasound can significantly reduce the negative impact of these factors.

Columbianadin attenuates doxorubicin-induced cardiac injury, oxidative stress, and apoptosis via Sirt1/FOXO1 signaling pathway.

PURPOSE: Oxidative stress and apoptosis contribute to the pathological basis of doxorubicin (DOX)-induced cardiotoxicity. Columbianadin (CBN) is one of the main bioactive constituents isolated from the root of Angelica pubescens. Herein, we intended to explore the potential role and molecular basis of CBN in DOX-induced cardiotoxicity. METHODS: C57BL/6 mice were subjected to DOX (15 mg/kg/day, i.p.) to generate DOX-induced cardiotoxicity. CBN (10 mg/kg/day, i.p.) was administered for four week following DOX injection. RESULTS: DOX administered markedly dampened cardiac function, increased cardiac injury, excessive reactive oxygen species (ROS) production, and cardiomyocyte loss. These alterations induced by DOX significantly alleviated by CBN treatment. Mechanistically, our results demonstrated that the CBN exerts cardioprotection role against DOX by up-regulating silent information regulator 1 (Sirt1) and decreasing acetylation of forkhead box O1 (FOXO1). Moreover, Sirt1 inhibition with Ex-527 significantly blunt the beneficial effect of CBN on DOX-induced cardiotoxicity, including cardiac dysfunction, ROS, and apoptosis. CONCLUSION: Collectively, CBN attenuated oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity through maintaining Sirt1/FOXO1 signaling pathway. Our results demonstrated that CBN might be used to treat DOX-related cardiotoxicity.

Coordination Stoichiometry Effects on the Binding Hierarchy of Histamine and Imidazole-M2+ Complexes.

Histidine-M2+ coordination bonds are a recognized bond motif in biogenic materials with high hardness and extensibility, which has led to growing interest in their use in soft materials for mechanical function. However, the effect of different metal ions on the stability of the coordination complex remains poorly understood, complicating their implementation in metal-coordinated polymer materials. Herein, rheology experiments and density functional theory calculations are used to characterize the stability of coordination complexes and establish the binding hierarchy of histamine and imidazole with Ni2+ , Cu2+ , and Zn2+ . It is found that the binding hierarchy is driven by the specific affinity of the metal ions to different coordination states, which can be macroscopically tuned by changing the metal-to-ligand stoichiometry of the metal-coordinated network. These findings facilitate the rational selection of metal ions for optimizing the mechanical properties of metal-coordinated materials.

Lonicera japonica Thunb. as a promising antibacterial agent for Bacillus cereus ATCC14579 based on network pharmacology, metabolomics, and in vitro experiments.

Lonicera japonica Thunb. has attracted much attention for its treatment of bacterial and viral infectious diseases, while its active ingredients and potential mechanisms of action have not been fully elucidated. Here, we combined metabolomics, and network pharmacology to explore the molecular mechanism of Bacillus cereus ATCC14579 inhibition by Lonicera japonica Thunb. In vitro inhibition experiments showed that the Lonicera japonica Thunb.'s water extracts, ethanolic extract, luteolin, quercetin, and kaempferol strongly inhibited Bacillus cereus ATCC14579. In contrast, chlorogenic acid and macranthoidin B had no inhibitory effect on Bacillus cereus ATCC14579. Meanwhile, the minimum inhibitory concentrations of luteolin, quercetin, and kaempferol against Bacillus cereus ATCC14579 were 15.625 µg mL-1, 31.25 µg mL-1, and 15.625 µg mL-1. Based on the previous experimental basis, the metabolomic analysis showed the presence of 16 active ingredients in Lonicera japonica Thunb.'s water extracts and ethanol extracts, with differences in the luteolin, quercetin, and kaempferol contents between the water extracts and ethanol extracts. Network pharmacology studies indicated that fabZ, tig, glmU, secA, deoD, nagB, pgi, rpmB, recA, and upp were potential key targets. Active ingredients of Lonicera japonica Thunb. may exert their inhibitory effects by inhibiting ribosome assembly, the peptidoglycan biosynthesis process, and the phospholipid biosynthesis process of Bacillus cereus ATCC14579. An alkaline phosphatase activity assay, peptidoglycan concentration assay, and protein concentration assay showed that luteolin, quercetin, and kaempferol disrupted the Bacillus cereus ATCC14579 cell wall and cell membrane integrity. Transmission electron microscopy results showed significant changes in the morphology and ultrastructure of the cell wall and cell membrane of Bacillus cereus ATCC14579, further confirming the disruption of the cell wall and cell membrane integrity of Bacillus cereus ATCC14579 by luteolin, quercetin, and kaempferol. In conclusion, Lonicera japonica Thunb. can be used as a potential antibacterial agent for Bacillus cereus ATCC14579, which may exert its antibacterial activity by destroying the integrity of the cell wall and membrane.

Nonnegative matrix factorization analysis and multiple machine learning methods identified IL17C and ACOXL as novel diagnostic biomarkers for atherosclerosis.

BACKGROUND: Atherosclerosis is the common pathological basis for many cardiovascular and cerebrovascular diseases. The purpose of this study is to identify the diagnostic biomarkers related to atherosclerosis through machine learning algorithm. METHODS: Clinicopathological parameters and transcriptomics data were obtained from 4 datasets (GSE21545, GSE20129, GSE43292, GSE100927). A nonnegative matrix factorization algorithm was used to classify arteriosclerosis patients in GSE21545 dataset. Then, we identified prognosis-related differentially expressed genes (DEGs) between the subtypes. Multiple machine learning methods to detect pivotal markers. Discrimination, calibration and clinical usefulness of the predicting model were assessed using area under curve, calibration plot and decision curve analysis respectively. The expression level of the feature genes was validated in GSE20129, GSE43292, GSE100927. RESULTS: 2 molecular subtypes of atherosclerosis was identified, and 223 prognosis-related DEGs between the 2 subtypes were identified. These genes are not only related to epithelial cell proliferation, mitochondrial dysfunction, but also to immune related pathways. Least absolute shrinkage and selection operator, random forest, support vector machine- recursive feature elimination show that IL17C and ACOXL were identified as diagnostic markers of atherosclerosis. The prediction model displayed good discrimination and good calibration. Decision curve analysis showed that this model was clinically useful. Moreover, IL17C and ACOXL were verified in other 3 GEO datasets, and also have good predictive performance. CONCLUSION: IL17C and ACOXL were diagnostic genes of atherosclerosis and associated with higher incidence of ischemic events.

Reshaping the Diversity of Oxidized Polyquinane Sesquiterpenoids by Cytochrome P450s.

Polyquinane sesquiterpenoids (PQSTs) are complex compounds with two or three fused cabocyclopentane ring systems, and the biocatalysts for direct C-H bond oxidation on these scaffolds have rarely been discovered. In this study, we discovered two versatile fungal CYP450s capable of performing diverse oxidations on seven PQST scaffolds, resulting in the generation of 20 unique products. Our findings significantly expand the diversity of oxidized PQST scaffolds and provide important biocatalysts for the selective oxidation of inert carbons of terpenoids in future research.

Geranylated or prenylated flavonoids from Cajanus volubilis.

Five new flavonoid derivatives, cajavolubones A-E (1-5), along with six known analogues (6-11) were isolated from Cajanus volubilis, and their structures were elucidated by spectroscopic analysis and quantum chemical calculations. Cajavolubones A and B (1 and 2) were identified as two geranylated chalcones. Cajavolubone C (3) was a prenylated flavone, while cajavolubones D and E (4 and 5) were two prenylated isoflavanones. Compounds 3, 8, 9 and 11 displayed cytotoxicity against HCT-116 cancer cell line.

Structural insight into the substrate-binding mode and catalytic mechanism for MlrC enzyme of Sphingomonas sp. ACM-3962 in linearized microcystin biodegradation.

Removing microcystins (MCs) safely and effectively has become an urgent global problem because of their extremely hazardous to the environment and public health. Microcystinases derived from indigenous microorganisms have received widespread attention due to their specific MC biodegradation function. However, linearized MCs are also very toxic and need to be removed from the water environment. How MlrC binds to linearized MCs and how it catalyzes the degradation process based on the actual three-dimensional structure have not been determined. In this study, the binding mode of MlrC with linearized MCs was explored using a combination of molecular docking and site-directed mutagenesis methods. A series of key substrate binding residues, including E70, W59, F67, F96, S392 and so on, were identified. Sodium dodecane sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to analyze samples of these variants. The activity of MlrC variants were measured using high performance liquid chromatography (HPLC). We used fluorescence spectroscopy experiments to research the relationship between MlrC enzyme (E), zinc ion (M), and substrate (S). The results showed that MlrC enzyme, zinc ion and substrate formed E-M-S intermediates during the catalytic process. The substrate-binding cavity was made up of N and C-terminal domains and the substrate-binding site mainly included N41, E70, D341, S392, Q468, S485, R492, W59, F67, and F96. The E70 residue involved in both substrate catalysis and substrate binding. In conclusion, a possible catalytic mechanism of the MlrC enzyme was further proposed based on the experimental results and a literature survey. These findings provided new insights into the molecular mechanisms of the MlrC enzyme to degrade linearized MCs, and laid a theoretical foundation for further biodegradation studies of MCs.

Dearomatization-Rearomatization Reaction of Metal-Polarized Aza-ortho-Quinone Methides.

Metal-polarized aza-ortho-quinone methides (aza-o-QMs) are a unique and efficient handle for azaheterocycle synthesis. Despite great achievements, the potential of these reactive intermediates has not yet been fully exploited, especially the new reaction modes. Herein, we disclosed an unprecedented dearomatization process of metal-polarized aza-o-QMs, affording transient dearomatized spiroaziridine intermediates. Based on this serendipity, we accomplished three sequential dearomatization-rearomatization reactions of benzimidazolines with aza-sulfur ylides, enabling the divergent synthesis of bis-nitrogen heterocycles with high efficiency and flexibility. Moreover, experimental and theoretical studies were performed to explain the proposed mechanisms and observed selectivity. Further cellular evaluation of the dibenzodiazepine products identified a hit compound for new antitumor drugs.