Multi-Omics Investigation into Acute Myocardial Infarction: An Integrative Method Revealing Interconnections amongst the Metabolome, Lipidome, Glycome, and Metallome.

Acute myocardial infarction (AMI) is a leading cause of mortality and morbidity worldwide. This work aims to investigate the translational potential of a multi-omics study (comprising metabolomics, lipidomics, glycomics, and metallomics) in revealing biomechanistic insights into AMI. Following the N-glycomics and metallomics studies performed by our group previously, untargeted metabolomic and lipidomic profiles were generated and analysed in this work via the use of a simultaneous metabolite/lipid extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis workflow. The workflow was applied to blood plasma samples from AMI cases (n = 101) and age-matched healthy controls (n = 66). The annotated metabolomic (number of features, n = 27) and lipidomic (n = 48) profiles, along with the glycomic (n = 37) and metallomic (n = 30) profiles of the same set of AMI and healthy samples were integrated and analysed. The integration method used here works by identifying a linear combination of maximally correlated features across the four omics datasets, via utilising both block-partial least squares-discriminant analysis (block-PLS-DA) based on sparse generalised canonical correlation analysis. Based on the multi-omics mapping of biomolecular interconnections, several postulations were derived. These include the potential roles of glycerophospholipids in N-glycan-modulated immunoregulatory effects, as well as the augmentation of the importance of Ca-ATPases in cardiovascular conditions, while also suggesting contributions of phosphatidylethanolamine in their functions. Moreover, it was shown that combining the four omics datasets synergistically enhanced the classifier performance in discriminating between AMI and healthy subjects. Fresh and intriguing insights into AMI, otherwise undetected via single-omics analysis, were revealed in this multi-omics study. Taken together, we provide evidence that a multi-omics strategy may synergistically reinforce and enhance our understanding of diseases.

Plasma tissue factor coagulation activity in post-acute myocardial infarction patients.

Introduction: Coagulation is involved in fibroproliferative responses following acute myocardial infarction (AMI). Left ventricular (LV) remodeling following AMI is closely associated with progression to heart failure. This study aims to assess the association between plasma tissue factor activity and LV remodeling in post-AMI patients. Methods: We studied 228 patients with AMI and 57 healthy subjects. Patients with AMI were categorized into two age- and sex-matched groups: patients with adverse LV remodeling or reverse LV remodeling, defined by an increase or decrease, respectively, in LV end systolic volume by ≥15% over 6 months. TF activity was measured in plasma collected at baseline (within 72 hours of revascularization), 1 month and 6 months post-AMI. Multiple level longitudinal data analysis with structural equation (ML-SEM) model was used to assess the impact of various clinical variables on TF activity in post-AMI. Results: Plasma TF activity in post-AMI patients at baseline (29.05 ± 10.75 pM) was similar to that in healthy subjects but fell at 1 month (21.78 ± 8.23, p<0.001) with partial recovery by 6 months (25.84 ± 8.80, p<0.001) after AMI. Plasma TF activity at 6 month post-AMI was better restored in patients with reverse LV remodeling than those with adverse LV remodeling (27.35 ± 7.14 vs 24.34 ± 9.99; p=0.009) independent of gender, age and relevant cardiovascular risk factors. Conclusions: Plasma TF activity decreased after AMI but was better restored at 6 months in patients with reverse LV remodeling. The clinical significance of changes in post-AMI plasma TF activity needs further investigation.

Simultaneous Polar Metabolite and N-Glycan Extraction Workflow for Joint-Omics Analysis: A Synergistic Approach for Novel Insights into Diseases.

Bioinformatics and machine learning tools have made it possible to integrate data across different -omics platforms for novel multiomic insights into diseases. To synergistically process -omics data in an integrative manner, analyte extractions for each -omics type need to be done on the same set of clinical samples. Therefore, we introduce a simultaneous dual extraction method for generating both metabolomic (polar metabolites only) and glycomic (protein-derived N-glycans only) profiles from one sample with good extraction efficiency and reproducibility. As proof of the usefulness of the extraction and joint-omics workflow, we applied it on platelet samples obtained from a cohort study comprising 66 coronary heart disease (CHD) patients and 34 matched healthy community-dwelling controls. The metabolomics and N-glycomics data sets were subjected to block partial least-squares-discriminant analysis (block-PLS-DA) based on sparse generalized canonical correlation analysis (CCA) for identifying relevant mechanistic interactions between metabolites and glycans. This joint-omics investigation revealed intermodulative roles that protein-bound carbohydrates or glycoproteins and amino acids have in metabolic pathways and through intermediate protein dysregulations. It also suggested a protective role of the glyco-redox network in CHD, demonstrating proof-of-principle for a joint-omics analysis in providing new insights into disease mechanisms, as enabled by a simultaneous polar metabolite and protein-derived N-glycan extraction workflow.

Temporal Changes in Extracellular Vesicle Hemostatic Protein Composition Predict Favourable Left Ventricular Remodeling after Acute Myocardial Infarction.

The subset of plasma extracellular vesicles (EVs) that coprecipitate with low-density lipoprotein (LDL-EVs) carry coagulation and fibrinolysis pathway proteins as cargo. We investigated the association between LDL-EV hemostatic/fibrinolysis protein ratios and post-acute myocardial infarction (post-AMI) left ventricular (LV) remodeling which precedes heart failure. Protein concentrations of von Willebrand factor (VWF), SerpinC1 and plasminogen were determined in LDL-EVs extracted from plasma samples obtained at baseline (within 72 h post-AMI), 1 month and 6 months post-AMI from 198 patients. Patients were categorized as exhibiting adverse (n = 98) or reverse (n = 100) LV remodeling based on changes in LV end-systolic volume (increased or decreased ≥15) over a 6-month period. Multiple level longitudinal data analysis with structural equation (ML-SEM) model was used to assess predictive value for LV remodeling independent of baseline differences. At baseline, protein levels of VWF, SerpinC1 and plasminogen in LDL-EVs did not differ between patients with adverse versus reverse LV remodeling. At 1 month post-AMI, protein levels of VWF and SerpinC1 decreased whilst plasminogen increased in patients with adverse LV remodeling. In contrast, VWF and plasminogen decreased whilst SerpinC1 remained unchanged in patients with reverse LV remodeling. Overall, compared with patients with adverse LV remodeling, higher levels of SerpinC1 and VWF but lower levels of plasminogen resulted in higher ratios of VWF:Plasminogen and SerpinC1:Plasminogen at both 1 month and 6 months post-AMI in patients with reverse LV remodeling. More importantly, ratios VWF:Plasminogen (AUC = 0.674) and SerpinC1:Plasminogen (AUC = 0.712) displayed markedly better prognostic power than NT-proBNP (AUC = 0.384), troponin-I (AUC = 0.467) or troponin-T (AUC = 0.389) (p < 0.001) to predict reverse LV remodeling post-AMI. Temporal changes in the ratios of coagulation to fibrinolysis pathway proteins in LDL-EVs outperform current standard plasma biomarkers in predicting post-AMI reverse LV remodeling. Our findings may provide clinical cues to uncover the cellular mechanisms underpinning post-AMI reverse LV remodeling.

Variability of the Plasma Lipidome and Subclinical Coronary Atherosclerosis.

OBJECTIVE: While the risk of acute coronary events has been associated with biological variability of circulating cholesterol, the association with variability of other atherogenic lipids remains less understood. We evaluated the longitudinal variability of 284 lipids and investigated their association with asymptomatic coronary atherosclerosis. Approach and Results: Circulating lipids were extracted from fasting blood samples of 83 community-sampled symptom-free participants (age 41-75 years), collected longitudinally over 6 months. Three types of coronary plaque volume (calcified, lipid-rich, and fibrotic) were quantified using computed tomography coronary angiogram. We first deconvoluted between-subject (CVg) and within-subject (CVw) lipid variabilities. We then tested whether the mean lipid abundance was different across groups categorized by Framingham risk score and plaques phenotypes (lipid-rich, fibrotic, and calcified). Finally, we investigated whether visit-to-visit variability of each lipid was associated with plaque burden. Most lipids (72.5%) exhibited higher CVg than CVw. Among the lipids (n=145) with 1.2-fold higher CVg than CVw, 26 species including glycerides and ceramides were significantly associated with Framingham risk score and the 3 plaque phenotypes (false discovery rate <0.05). In an exploratory analysis of person-specific visit-to-visit variability without multiple testing correction, high variability of 3 lysophospholipids (lysophosphatidylethanolamines 16:0, 18:0, and lysophosphatidylcholine O-18:1) was associated with lipid-rich and fibrotic (noncalcified) plaque volume while high variability of diacylglycerol 18:1_20:0, triacylglycerols 52:2, 52:3, and 52:4, ceramide d18:0/20:0, dihexosylceramide d18:1/16:0, and sphingomyelin 36:3 was associated with calcified plaque volume. CONCLUSIONS: High person-specific longitudinal variation of specific nonsterol lipids is associated with the burden of subclinical coronary atherosclerosis. Larger studies are needed to confirm these exploratory findings.

Anticancer Drug Release System Based on Hollow Silica Nanocarriers Triggered by Tumor Cellular Microenvironments.

Targeted release of anticancer drugs to tumor sites has a pivotal role in clinical oncology. pH-responsive drug delivery systems, with an intelligent and targeted release of anticancer drugs in a controllable manner based on sensitivities to the weakly acidic environments of tumor cellular microenvironments, are desirable. Herein, the design of such a pH-responsive drug delivery system is detailed using in situ amino-functionalized hollow mesoporous silica nanoparticles as carriers. The drug release behavior of the pH-responsive delivery system was evaluated under an in vitro simulation of tumor cellular microenvironments. The drug delivery system has efficient drug loadings and targeted release. Zorubicin hydrochloride releasing percentage is almost up to 100% at a buffer pH of 5.0. The drug release systems described demonstrating great potential in anticancer therapy.

Bagasse as a carbon structure with high sulfur content for lithium-sulfur batteries.

A bagasse-based 3D carbon matrix (BC) with high specific surface area and high conductivity was obtained by carbonization and pore-forming processes with bagasse as the carbon precursor and K2FeO4 as the pore-former. The microporous structure and nitrogenous functional groups were determined in the prepared carbon matrix, which could allow high sulfur loading and improve the polysulfide absorption capacity during cycling. After sulfur infusion, the S/BC composite with 68.8% sulfur content was obtained. The lithium-sulfur (Li-S) battery with the S/BC cathode shows high specific capacity and good cycling performance. It delivers a specific capacity of 1360 mA h g-1 at 0.2C and remains at 790 mA h g-1 after 200 cycles. At 1C, the Li-S with this composite cathode exhibits 601 mA h g-1 after 150 cycles. This work offers a new kind of green material and a new method for Li-S batteries.

Sources of variability in quantifying circulating thymosin beta-4: literature review and recommendations.

INTRODUCTION: Thymosin beta-4 (TB4) is an endogenous peptide with protective and regenerative effects in models of cellular and organ injury. TB4 is increasingly measured as a potential plasma or serum biomarker in human cardiovascular, liver, infectious, and autoimmune disease. AREAS COVERED: The focus of this review is the quantification of TB4 in clinical cohort studies and whether reported TB4 concentrations differ with respect to method of sample preparation. We survey current literature for studies measuring TB4 in human serum or plasma and compare reported concentrations in healthy controls. EXPERT OPINION: We find substantial intra- and inter- study variability in healthy controls, and a lack of protocol standardization. We further highlight three factors that may confound TB4 clinical measurements and should be considered in future study design: 1) residual platelets remaining in suspension after centrifugation, 2) TB4 release following ex vivo platelet activation, and 3) specificity of assays towards posttranslational modifications. Accordingly, we put forth our recommendations to minimize residual and activated platelets during sample collection, and to cross-validate TB4 measurements using both antibody-based and mass spectrometry-based methods.

Adamantyl- and Furanyl-Protected Nanoscale Silver Sulfide Clusters.

The silver salts of 1-adamantanethiol (AdSH) and furan-2-ylmethanethiol (FurCH2 SH) were successfully applied as building blocks for ligand-protected Ag2 S nanoclusters. The reaction of the silver thiolates [AgSAd]x and [AgSCH2 Fur]x with S(SiMe3 )2 and 1,5-bis(diphenylphosphino)pentane (dpppt) afforded three different clusters with 58, 94 and, 190 silver atoms. The intensely colored compounds [Ag58 S13 (SAd)32 ] (1), [Ag94 S34 (SAd)26 (dpppt)6 ] (2), and [Ag190 S58 (SCH2 Fur)74 (dpppt)8 ] (3) were structurally characterized by single-crystal X-ray diffraction and exhibit different cluster core geometries and ligand shells. The diameters of the well-defined sphere-shaped nanoclusters range from 2.2 nm to 3.5 nm.

Red-luminescent biphosphine stabilized 'Cu12S6' cluster molecules.

The synthesis, molecular structures and luminescence properties of two 'Cu12S6' cluster molecules with stabilizing bidentate phosphine ligands are described. Both display in the solid state at ambient temperature high photoluminescence quantum yields (≥48%) and good stability towards oxygen.