Causal relationship between type 2 diabetes mellitus and aortic dissection: insights from two-sample Mendelian randomization and mediation analysis.

Objective: Some evidence suggests a reduced prevalence of type 2 diabetes mellitus (T2DM) in patients with aortic dissection (AD), a catastrophic cardiovascular illness, compared to general population. However, the conclusions were inconsistent, and the causal relationship between T2DM and AD remains unclear. Methods: In this study, we aimed to explore the causal relationship between T2DM and AD using bidirectional Mendelian randomization (MR) analysis. Mediation MR analysis was conducted to explore and quantify the possible mediation effects of 1400 metabolites in T2DM and AD. Results: The results of 26 datasets showed no causal relationship between T2DM and AD (P>0.05). Only one dataset (ebi-a-GCST90006934) showed that T2DM was a protective factor for AD (I9-AORTDIS) (OR=0.815, 95%CI: 0.692-0.960, P=0.014), and did not show horizontal pleiotropy (P=0.808) and heterogeneity (P=0.525). Vanillic acid glycine plays a mediator in the causal relationship between T2DM and AD. The mediator effect for vanillic acid glycine levels was -0.023 (95%CI: -0.066-0.021). Conclusion: From the perspective of MR analysis, there might not be a causal relationship between T2DM and AD, and T2DM might not be a protective factor for AD. If a causal relationship does exist between T2DM and AD, with T2DM serving as a protective factor, vanillic acid glycine may act as a mediator and enhance such a protective effect.

Effects of the lncRNA MALAT1 gene region rs664589 site mutation on acute myocardial infarction in Chinese Han.

We aimed to study the association between the non-coding region of the lncRNA MALAT1 gene, the non-coding region rs664589 C>G variant, and the risk of acute myocardial infarction (AMI) in the Chinese Han population. 165 NSTEMI and 135 STEMI patients were enrolled in the study. An additional 150 healthy individuals were enrolled as the controls. All subjects were analyzed for the MALAT1 rs664589 locus genotype. The receiver operating curve (ROC) was used to determine the effect of MALAT1 rs664589 single nucleotide polymorphism (SNP) on the diagnosis of AMI by plasma lncRNA MALAT1. The MALAT1 rs664589 site G allele carrier was 1.39 times more likely to have NSTEMI than the C allele carrier (95% CI: 1.16-1.61, P = 0.001) and 1.59 times more likely to have STEMI than the C allele carrier (95% CI: 1.31-1.85, P < 0.001). The MALAT1 rs664589 site C>G mutation resulted in an increase in the area under the ROC curve (AUC) of the plasma lncRNA MALAT1 level for the diagnosis of AMI. The plasma lncRNA MALAT1 levels in AMI patients were negatively correlated with hsa-miR-1972, hsa-miR-194-5p, hsa-miR-4717-5p, hsa-miR-6735-3p, and hsa-miR-3677-5p (r = -0.81, -0.75, -0.66, -0.71, and -0.88). The C>G mutation of MAL6641 rs664589 causes an increased risk of AMI in the Chinese Han population. The SNP at this site affects the value of plasma lncRNA MALAT1 in the diagnosis of AMI. The specific mechanism may indicate that the C>G mutation of the MALAT1 rs664589 changes the regulation of miRNAs expression by lncRNA MALAT1.

High performance of privacy-preserving acute myocardial infarction auxiliary diagnosis based on federated learning: a multicenter retrospective study.

Background: Multicenter medical research is becoming a new trend. However, interagency data privacy security protection has become a major bottleneck of multicenter research. Therefore, to overcome this privacy protection issue, the aim of the present study was to apply a self-developed privacy-preserving machine learning framework for researchers who can build models on medical data from multiple sources, while providing privacy protection for both sensitive data and the learned model. Methods: Based on Arya, a novel privacy computing platform developed by Healink, we constructed a privacy-preserving federated learning (FL) model using the fully connected neural network with datasets from 2-3 individual medical institutions. In the dataset, 80% of records were used for joint modeling on acute myocardial infarction (AMI) diagnosis. Modeling efficacy was evaluated with the remaining 20% of records. As the control, 1,500 medical records from 1 medical institution were used for single-center modeling and efficacy evaluation. During the process, the original data were still kept in individual hospital without moving or transferring out of the hospitial. The diagnostic efficacy (sensitivity, positive predictive value, and accuracy) was evaluated. Results: Our privacy-preserving FL model gives reliable AMI diagnostic efficacy. Three-center modeling (79% sensitivity, 88% positive predictive value, and 82.3% accuracy) and two-center modeling (77.8% or 77.6% sensitivity, 86.7% or 85.30% positive predictive value, and 81% or 79.7% accuracy) achieved relative high diagnostic efficacy; and single-center modeling achieved relative low diagnostic efficacy (76% sensitivity, 84.7% positive predictive value, and 79% accuracy). Conclusions: The Arya privacy computing platform is efficient and practical for the FL model, which could promote multicenter medical research securely without sacrificing diagnostic efficacy.

Metoprolol Improves Myocardial Remodeling and Cardiac Function in Patients with Permanent Pacemaker Implantation.

In China, the incidence of arrhythmia has also increased to approximately 20% of all cardiovascular diseases. The incidence of cardiovascular diseases in China has certain characteristics, which are generally low in the south and high in the north, and they tend to be younger and growing. Permanent pacemaker implantation is currently the most effective means of treating arrhythmia and preventing sudden death. To explore the clinical application value of metoprolol in patients after permanent pacemaker implantation. Ninety patients with permanent dual-chamber pacemaker implantation in our hospital are selected and divided into a metoprolol group and a control group according to whether metoprolol is used one week after the operation and 45 patients in each group. After one postoperative week, the LVEF%, LVEDd, LAD, and E/A of the metoprolol and the control groups had no statistically significant differences (p > 0.05). Twelve months postoperatively, the E/A of the metoprolol group is higher than that of the control group (p < 0.05), and LVEDd and LAD are lower than those of the control group (P < 0.05). The NT-proBNP and hs-CRP levels between the metoprolol and control groups had no significant differences (p > 0.05) in the values recorded immediately postoperatively. The NT-proBNP of the metoprolol group is lower than that of the control group (p < 0.05) at 12 months following pacemaker implantation. At one week after surgery, QTd, Pd, and Tp-Te are not significantly different (P > 0.05) between the metoprolol group and the control group, whereas the QTd and Pd times in the metoprolol group are lower than those in the control group (p < 0.05) at the 12-month follow-up. At one week postoperatively, the SDNN, SDANN, and RMSSD between the metoprolol and control groups did not show any statistically significant differences (p > 0.05). The SDANN of the metoprolol group is higher than that in the control group (p < 0.05) in the 12-month evaluation. One week after the operation, the serum IL-6 and TNF-α levels are not significantly different between the metoprolol and control groups (p > 0.05). At 12 months after surgery, the serum IL-6 and TNF-α levels in the metoprolol group are lower than those in the control group (p < 0.05). The incidence of adverse events in the metoprolol group is 9.30% lower than 26.83% in the control group within 12 months after the operation (p < 0.05). The use of metoprolol in patients with permanent pacemaker implantation after surgery can reduce the expansionary remodeling of the left atrium and have less impact on the QT-dispersion and Pd time.

RRM2 Improves Cardiomyocyte Proliferation after Myocardial Ischemia Reperfusion Injury through the Hippo-YAP Pathway.

OBJECTIVE: Ribonucleotide reductase M2 (RRM2) as an enzyme that catalyzes the deoxyreduction of nucleosides to deoxyribonucleoside triphosphate (dNTP) has been extensively studied, and it plays a crucial role in regulating cell proliferation. However, its role in ischemia-reperfusion injury (I/RI) is still unclear. METHODS: SD rats were used as the research object to detect the expression of RRM2 in the myocardium by constructing an I/RI model. At the same time, primary SD neonatal rat cardiomyocytes were extracted, and hypoxia/reoxygenation (H/R) treatment simulated the I/RI model. Using transfection technology to overexpress RRM2 in cardiomyocytes, quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) was used to detect the expression of RRM2, Cell Counting Kit-8 (CCK-8) assay was used to detect cell viability, and immunofluorescence staining was used to detect Ki67 and EdU-positive cells. Western blot (WB) technology was used to detect YAP and its phosphorylation expression. RESULTS: qRT-PCR results indicated that the expression of RRM2 was inhibited in the model group, and cardiomyocytes overexpressing RRM2 can obviously promote the proliferation of primary cardiomyocytes and improve the damage of cardiac structure and function caused by I/R. At the same time, RRM2 can promote the increase of YAP protein expression and the increase of Cyclin D1 mRNA expression. CONCLUSION: RRM2 expression was downregulated in myocardial tissue with I/R. After overexpression of RRM2, cardiomyocyte proliferation was upregulated and the Hippo-YAP signaling pathway was activated.

Anti-inflammatory and Anti-thrombotic Efficacy of Targeted Ultrasound Microbubbles on LPS-induced HUVEC Cells.

BACKGROUND/AIM: The early stage of atherosclerosis (AS) demonstrates a lipid-driven inflammatory cytokine increase. In the present study, we aimed to use ultrasound-targeted microbubble delivery (UTMD) therapy with the Endostar-loaded target microbubbles (MBs) to reduce AS-related inflammatory response. MATERIALS AND METHODS: Normal and lipopolysaccharide (LPS) induced human umbilical vein endothelial cells (HUVECs) were placed in a parallel-plate flow chamber. MBs were perfused through the parallel-plate flow chamber to mimic physiological blood flow. Five groups were set up: G1: Negative control (normal HUVECs); G2: LPS control (LPS induced HUVECs); G3: ICAM-1-loaded-MBs (MBi); G4: Endostar-loaded-MBs (MBe) and G5: Endostar-ICAM-1-loaded-MBs (MBei). mRNA expression of inflammatory factors and release of inflammatory cytokines were detected by RT-PCR and ELISA, respectively. RESULTS: After treatment with MBei, the mRNA expression of cell adhesion molecule-1 (CD31) (p=0.004), endothelin-1 (ET-1) (p=0.010), von willebrand factor (vWF) (p=0.018), extracellular regulated protein kinases (ERK) (p=0.046) and nuclear factor kappa B (NF-κB) (p=0.003) were significantly reduced compared to LPS-induced HUVECs. Release of inflammatory cytokines including tissue factor (TF) (p=0.033), tissue factor pathway inhibitor (TF-PI) (p=0.019), ET-1 (p=0.014), vWF (p=0.030) and blood-coagulation factor VIIα (FVIIα) (p=0.000) were also significantly reduced compared to LPS-induced HUVECs. CONCLUSION: UTMD therapy can inhibit the inflammatory response by reducing atherosclerotic-related inflammatory factors, suggesting a potential treatment at the early-stage of AS.

Static Softening Behavior and Modified Kinetics of Al 2219 Alloy Based on a Double-Pass Hot Compression Test.

In this paper, the static softening mechanism of a 2219 aluminum alloy was studied based on a double-pass isothermal compression test. For the experiment, different temperatures (623 K, 723 K, and 773 K), strain rates (0.1/s, 1/s, and 10/s), deformation ratios (20%, 30%, and 40%), and insulation periods (5 s, 30 s, and 60 s) were used. Based on the double-pass flow stress curves obtained from the experiment, the step rate expressed by the equivalent dynamic recrystallization fraction is dependent on the deformation parameters, which increases with the increase in strain rate and insulation time, while it decreases with the increase in temperature and strain. Based on the microstructure observed using electron backscattered diffraction (EBSD), the static softening mechanism of the Al 2219 alloy is mainly static recovery and incomplete static recrystallization. A new expression for the static recrystallization fraction is proposed using the reduction rate of the sub-grain boundary. The dependent rule on the deformation parameters is consistent with the step rate, but it is of physical significance. In addition, the modified static recrystallization kinetics established by the new SRX fraction method was proven to have a good modeling and prediction performance under given deformation conditions.

Association of Gene Polymorphisms in the Human MicroRNA-126 Gene with Plasma-Circulating MicroRNA-126 Levels and Acute Myocardial Infarction.

Objective: Our objective was to study the association of the human microRNA-126 (miR-126) gene rs4636297 and rs1140713 polymorphisms and the plasma-circulating miR-126 level in acute myocardial infarction (AMI). Methods: The genotypes of the miR-126 gene rs4636297 and rs1140713 loci were characterized by the direct sequencing method in 350 AMI patients and 350 healthy controls. The level of plasma-circulating miR-126 was measured by reverse transcription real-time polymerase chain reaction. Results: Plasma-free miR-126 levels and Gensini scores (r = -0.684, p < 0.001), serum brain natriuretic peptide (BNP) levels (r = -0.808, p < 0.001), low-density lipoprotein cholesterol (LDL-C) levels (r = -0.769, p < 0.001), and cardiac troponin I (cTnI) levels (r = -0.754, p < 0.001) were negatively correlated. The risk of AMI for rs4636297 locus A allele carriers was significantly lower than G allele carriers (adjusted odds ratio = 0.79, 95% confidence interval (CI) = 0.65-0.93, p = 0.004). The rs1140713 locus T allele carriers were 1.56 times more likely to develop AMI than the C allele carriers (95% CI = 1.35-1.73, p < 0.001). The single nucleotide polymorphisms (SNPs) rs4636297 and rs1140713 of the miR-126 gene were correlated with the Gensini score, serum BNP, LDL-C, cTnI, and serum vascular endothelial growth factor levels in patients with AMI (p < 0.05). Conclusion: The miR-126 gene SNPs rs4636297 and rs1140713 are associated with AMI, possibly by influencing the expression levels of the miR-126 gene.

Growth and properties of spinel structure Zn1.8Co0.2TiO4 single crystals by the optical floating zone method.

The spinel structure Zn1.8Co0.2TiO4 single crystals with 5 mm diameter and 30 mm length were successfully grown by an optical floating zone method. The as-grown crystals were characterized by X-ray diffraction (XRD), Raman and X-ray photoelectron spectroscopy (XPS). Some Zn2+ ions at tetrahedral and octahedral sites should be replaced by doped transition metal Co2+ ions. The temperature-dependent Raman spectra of spinel Zn1.8Co0.2TiO4 crystals were also described. The optical phonon behaviors of Zn1.8Co0.2TiO4 are stable within the temperature range. The magnetic properties of Zn1.8Co0.2TiO4 were investigated by using Physical Property Measurement System.

Ultrasound Microbubble Delivery Targeting Intraplaque Neovascularization Inhibits Atherosclerotic Plaque in an APOE-deficient Mouse Model.

BACKGROUND/AIM: Intraplaque neovascularization is often associated with plaque formation, development and instability, and clinical symptoms in atherosclerosis. The aim of the present study was to investigate a new strategy for treating athrosclerosis by ultrasound-targeted microbubble delivery (UTMD) targeting intraplaque neovascularization in an APOE-deficient mouse model of atherosclerosis. MATERIALS AND METHODS: A mouse model of atherosclerosis was induced by feeding Apoe-/- mice a hypercholesterolemic diet and was verified with hematoxylin and eosin staining and intercellular adhesion molecule 1 (ICAM-1) expression. Targeted microbubbles (MB) were prepared by conjugating microbubbles with biotinylated antibody to ICAM1 (MBi) or with both biotinylated anti-ICAM1 and the angiogenesis inhibitor Endostar (MBie). The targeted microbubbles were analyzed with epifluorescence microscopy and flow cytometry. The animals with induced atherosclerotic plaques received MBi or MBie followed by UTMD treatment. Endostar treatment alone was given to other animals for comparison. Morphological assessment of atherosclerotic plaques was performed after treatment. The expression of angiogenesis marker CD31 was detected by immunohistochemical analysis. RESULTS: Atherosclerotic plaques developed in the entire aorta with significant intraplaque ICAM-1 expression in the APOE-deficient mice following a 30-week hypercholesterolemic diet. Microbubbles were successfully conjugated with anti-ICAM-1 and Endostar, with a conjugation rate of 98.3% and 63.5%, respectively. UTMD with MBie significantly reduced the area of atherosclerotic plaque as compared to the model control (p<0.05). Treatment with Endostar and UTMD with MBie significantly reduced CD31 expression compared with the model control group (p<0.01). Greater significant inhibitory effect on CD31 expression was found in the group treated with UTMD and MBie compared to the Endostar- and UTMD with MBi groups (p<0.01). CONCLUSION: UTMD targeting intraplaque neovascularization was found to inhibit atherosclerotic plaque in a mouse model of atherosclerosis, suggesting the potential of microbubble-mediated ultrasound technology in aiding drug delivery for atherosclerosis treatment.

Effect of pressure and solvent on Raman spectra of all-trans-beta-carotene.

The ground state Raman spectra of all-trans-beta-carotene in n-hexane and CS2 solutions are measured by simultaneously changing the solvent environment and molecular structure under high hydrostatic pressure. The diverse pressure dependencies of several representative Raman bands are explained using a competitive mechanism involving bond length changes and vibronic coupling. It is therefore concluded that (a) the in-phase C=C stretching mode plays an essential role in the conversion of energy from S1 to S0 states in carotenoids, (b) internal conversion and intramolecular vibrational redistribution can be accelerated by high pressure, and (c) the environmental effect, but not the structural distortion or pi-electron delocalization, is responsible for the spectral properties of a given carotenoid species. These findings revealed the potential of high pressure in exploring the nature of the biological functions of carotenoids.