To delineate the metabolomic differences in plasma samples between patients with coronary artery disease (CAD) and those with concomitant CAD and type 2 diabetes mellitus (T2DM), and to pinpoint ...distinctive metabolites indicative of T2DM risk.
Plasma samples from CAD and CAD-T2DM patients across three centers underwent comprehensive metabolomic and lipidomic analyses. Multivariate logistic regression was employed to discern the relationship between the identified metabolites and T2DM risk. Characteristic metabolites' metabolic impacts were further probed through hepatocyte cellular experiments. Subsequent transcriptomic analyses elucidated the potential target sites explaining the metabolic actions of these metabolites.
Metabolomic analysis revealed 192 and 95 significantly altered profiles in the discovery (FDR < 0.05) and validation (P < 0.05) cohorts, respectively, that were associated with T2DM risk in univariate logistic regression. Further multivariate regression analyses identified 22 characteristic metabolites consistently associated with T2DM risk in both cohorts. Notably, pipecolinic acid and L-pipecolic acid, lysine derivatives, exhibited negative association with CAD-T2DM and influenced cellular glucose metabolism in hepatocytes. Transcriptomic insights shed light on potential metabolic action sites of these metabolites.
This research underscores the metabolic disparities between CAD and CAD-T2DM patients, spotlighting the protective attributes of pipecolinic acid and L-pipecolic acid. The comprehensive metabolomic and transcriptomic findings provide novel insights into the mechanism research, prophylaxis and treatment of comorbidity of CAD and T2DM.
Photosynthetic bacteria are beneficial to plants, but knowledge of photosynthetic bacterial community dynamics in field crops during different growth stages is scarce. The factors controlling the ...changes in the photosynthetic bacterial community during plant growth require further investigation. In this study, 35 microbial community samples were collected from the seedling, flowering, and mature stages of tomato, cucumber, and soybean plants. 35 microbial community samples were assessed using Illumina sequencing of the photosynthetic reaction center subunit M (pufM) gene. The results revealed significant alpha diversity and community structure differences among the three crops at the different growth stages. Proteobacteria was the dominant bacterial phylum, and Methylobacterium, Roseateles, and Thiorhodococcus were the dominant genera at all growth stages. PCoA revealed clear differences in the structure of the microbial populations isolated from leaf samples collected from different crops at different growth stages. In addition, a dissimilarity test revealed significant differences in the photosynthetic bacterial community among crops and growth stages (P<0.05). The photosynthetic bacterial communities changed during crop growth. OTUs assigned to Methylobacterium were present in varying abundances among different sample types, which we speculated was related to the function of different Methylobacterium species in promoting plant growth development and enhancing plant photosynthetic efficiency. In conclusion, the dynamics observed in this study provide new research ideas for the detailed assessments of the relationship between photosynthetic bacteria and different growth stages of plants.
Previous studies on investment decisions with endogenous contracts typically adopt differences among discount rates to describe decision makers’ impatience. Yet evidences from behavioral economics ...and neuroeconomics suggest that decision makers are impatient with short-term choices, but patient with long-term choices. Using quasi-hyperbolic discounting and real options agency framework, we investigate the effect of this time-vary impatience, i.e., time-inconsistent preference, on compensation contracts and investment triggers. We reveals that time inconsistency does not affect the dominance of restricted stock, but intensifies agency conflicts between the manager and shareholders. Our study provides a new perspective for understanding underinvestment and high equity incentives.
•Incorporate time inconsistency into investment decisions with endogenous contracts.•Model time-varying impatience using the quasi-hyperbolic discounting.•Time inconsistency does not affect the dominance of restricted stock on compensation contracts.•Time inconsistency intensifies the agency conflicts between the manager and shareholders.
Households consume a large amount of indirect energy through the consumption of goods and services. This fact makes the quantitative analysis of indirect household energy consumption the foundation ...of energy policy design. This paper improves the compilation method of energy input–output tables, and establishes a sequence of energy input–output tables for China. Based on these tables, the indirect energy consumption of both rural and urban households is calculated. Then, with economic data for the year of 2005, the adjusted input–output price model is applied to evaluate how the alternative energy policies impact production prices, consumption prices, and real income of rural and urban households through the mechanism of indirect energy consumption by using electricity as an example. This research has practical implications for Chinese economy. The integration of energy-efficiency improvements and energy prices increase serves as a means to achieve both economic and energy conservation goals, and may also have a positive effect on residents’ real income and a minimal effect on production prices.
Purpose
This nested case–control study aimed to evaluate the association of candidate genetic variants with statin-induced myotoxicity in Chinese patients with coronary artery disease (CAD).
Methods
...One hundred forty-eight Chinese patients experiencing statin-induced myotoxicity were included in our study, and 255 patients without muscular side effects served as controls. Five SNPs in CYP3A5, SLCO1B1, and APOE were genotyped. The effect of genetic variants on statin-induced myotoxicity was assessed.
Results
Patients who carried at least one SLCO1B1 521C allele had a higher risk for myotoxicity (OR = 1.69, 95%CI = 1.07–2.67,
P
= 0.024). Significant association was found between SLCO1B1 521C mutant allele mutation and risk of myotoxicity in individuals that received rosuvastatin (OR = 3.67, 95%CI = 1.42–9.47,
P
= 0.007). However, non-significant association was observed between 521C mutant allele and risk of myotoxicity (
P
> 0.5) in patients that received atorvastatin and simvastatin. The other four single nucleotide polymorphisms (SNPs), namely rs776746, rs2306283, rs7412, and rs429358, showed no significant association with any statin induced myotoxicity (
P
> 0.5).
Conclusions
SLCO1B1 (rs4149056, 521T > C) is associated with statin-induced myotoxicity in Chinese patients with coronary artery disease. In addition, SLCO1B1 521C mutant allele increased the risk of rosuvastatin-associated myotoxicity.
It is widely accepted that genetic polymorphisms impact atorvastatin (ATV) metabolism, clinical efficacy, and adverse events. The objectives of this study were to identify novel genetic variants ...influencing ATV metabolism and outcomes in Chinese patients with coronary artery disease (CAD). A total of 1079 CAD patients were enrolled and followed for 5 years. DNA from the blood and human liver tissue samples were genotyped using either Global Screening Array-24 v1.0 BeadChip or HumanOmniZhongHua-8 BeadChip. Concentrations of ATV and its metabolites in plasma and liver samples were determined using a verified ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) method. The patients carrying A allele for the rs4148323 polymorphism (
) showed an increase in 2-hydroxy ATV/ATV ratio (
= 1.69E-07, false discovery rate FDR = 8.66E-03) relative to the value in individuals without the variant allele. The result was further validated by an independent cohort comprising an additional 222 CAD patients (
= 1.08E-07). Moreover, the rs4148323 A allele was associated with an increased risk of death (hazard ratio HR 1.774; 95% confidence interval CI, 1.031-3.052;
= 0.0198). In conclusion, our results suggested that the
rs4148323 A allele was associated with increased 2-hydroxy ATV formation and was a significant death risk factor in Chinese patients with CAD.
SWEETs （sugars will eventually be exported transporters） are a novel class of recently identified sugar transporters that play important roles in diverse physiological processes. However, only a few ...species of the plant SWEETgene family have been functionally identified. Up till now, there has been no systematic analysis of the SWEETgene family in Cucurbitaceae crops. Here, a genome-wide characterization of this family was conducted in cucumber（Cucumis sativus L.）. A total of 17 CsSWEETgenes were identified, which are not evenly distributed over the seven cucumber chromosomes. Cucumber SWEET protein sequences possess seven conserved domains and two putative serine phosphorylation sites. The phylo- genetic tree of the SWEET genes in cucumber, Arabidopsis thaliana, and Oryza sativa was constructed, and all the SWEET genes were divided into four clades. In addition, a number of putative cis-elements were identified in the promoter regions of these CsSWEET genes： nine types involved in phytohormone responses and eight types involved in stress responses. Moreover, the transcript levels of CsSWEETgenes were analyzed in various tissues using quantitative real-time polymerase chain reaction. A majority （70.58%） of the CsSWEET genes were confined to reproductive tissue development. Finally, 18 putative watermelon ClaSWEETgenes and 18 melon CmSWEETgenes were identified that showed a high degree of similarity with CsSWEETgenes. The results from this study provided a basic understanding of the CsSWEETgenes and may also facilitate future research to elucidate the function of SWEET genes in cucumber and other Cucurbitaceae crops.
To investigate the influence of DNA methylation on ticagrelor major metabolite M8 elimination and platelet function recovery after ticagrelor discontinuation.
Among healthy Chinese subjects, a causal ...inference test was conducted to identify CpG sites located on absorption, distribution, metabolism and excretion genes that mediate genetic variants on M8 elimination. Colocalization analysis was used to identify the CpG sites that shared causal variants with platelet function recovery.
cg05300248 (
), cg05640674 (
) and cg00846580 (
) mediated genetic variants on the M8 elimination. cg06338150 (
) and cg17456097 (
) were demonstrated to have strong evidence of colocalization with platelet function recovery.
The results provide new biological insights into the impact of DNA methylation on M8 elimination and platelet function recovery after ticagrelor discontinuation.
Clinical trial registration:
, identifier:
To evaluate the independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and atorvastatin metabolism, the relationships among three levels of factors, namely (1) ...clinical characteristics, CYP3A4/5 genotypes, and miRNAs, (2) CYP3A4 and CYP3A5 mRNAs, and (3) CYP3A activity, as well as their individual impacts on atorvastatin metabolism, were assessed in 55 human liver tissues. MiR-27b, miR-206, and CYP3A4 mRNA respectively accounted for 20.0%, 5.8%, and 9.5% of the interindividual variations in CYP3A activity. MiR-142 was an independent contributor to the expressions of CYP3A4 mRNA (partial R(2) = 0.12, P = 0.002) and CYP3A5 mRNA (partial R(2) = 0.09, P = 0.005) but not CYP3A activity or atorvastatin metabolism. CYP3A activity was a unique independent predictor of variability of atorvastatin metabolism, explaining the majority of the variance in reduction of atorvastatin (60.0%) and formation of ortho-hydroxy atorvastatin (78.8%) and para-hydroxy atorvastatin (83.9%). MiR-27b and miR-206 were found to repress CYP3A4 gene expression and CYP3A activity by directly binding to CYP3A4 3'-UTR, while miR-142 was found to indirectly repress CYP3A activity. Our study indicates that miRNAs play significant roles in bridging the gap between epigenetic effects and missing heritability in CYP3A functionality.
Background
The relationship between the combined hematological parameters and echocardiography and long‐term prognosis in patients with coronary artery disease (CAD) remains unclear.
Methods
We ...examined the ability of hematological parameters to predict all‐cause death and major adverse cardiovascular events (MACE) based on Lasso Cox regression analysis. The significant predictors of hematological parameters from the Lasso Cox model were analyzed via multivariate Cox regression analysis and by adjusting for echocardiographic data. We calculated the continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI) of the hematological parameters to assess the improvement in prediction.
Results
A low hemoglobin and lymphocyte ratio and high hematocrit, red blood cell distribution width‐coefficient of variation, and monocyte ratio significantly increased the risk of MACE and death in CAD patients. Neutrophil‐to‐lymphocyte ratio was associated with MACE but not death in CAD patients. After adjustment for echocardiographic parameters, hemoglobin, hematocrit, and lymphocyte ratio remained independently related to death and MACE. The addition of hematological and echocardiographic parameters to the Framingham risk score model significantly improved the area under the curve of mortality (0.794 vs. 0.713, p = 0.0007) and reclassification with cNRI of 30.6% (p = 0.002) and IDI of 0.055 (p < 0.001). Mendelian randomization analyses identified that fibrinogen and neutrophil‐to‐lymphocyte ratio were associated with increased brain natriuretic peptide and decreased left ventricular ejection fraction.
Conclusions
These findings suggest that the blood immune inflammatory indicators fibrinogen and neutrophil‐to‐lymphocyte ratio were causally associated with the risk of heart failure after CAD. The combination of hematological biomarkers and echocardiography parameters as predictor variables is a useful predictive tool for all‐cause mortality in patients with CAD.
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