Table1_Recruitment of the cardiac conduction system for optimal resynchronization therapy in failing heart.pdf

Heart failure (HF) is a leading health burden around the world. Although pharmacological development has dramatically advanced medication therapy in the field, hemodynamic disorders or mechanical desynchrony deteriorated by intra or interventricular conduction abnormalities remains a critical target beyond the scope of pharmacotherapy. In the past 2 decades, nonpharmacologic treatment for heart failure, such as cardiac resynchronization therapy (CRT) via biventricular pacing (BVP), has been playing an important role in improving the prognosis of heart failure. However, the response rate of BVP-CRT is variable, leaving one-third of patients not benefiting from the therapy as expected. Considering the non-physiological activation pattern of BVP-CRT, more efforts have been made to optimize resynchronization. The most extensively investigated approach is by stimulating the native conduction system, e.g., His-Purkinje conduction system pacing (CSP), including His bundle pacing (HBP) and left bundle branch area pacing (LBBAP). These emerging CRT approaches provide an alternative to traditional BVP-CRT, with multiple proof-of-concept studies indicating the safety and efficacy of its utilization in dyssynchronous heart failure. In this review, we summarize the mechanisms of dyssynchronous HF mediated by conduction disturbance, the rationale and acute effect of CSP for CRT, the recent advancement in clinical research, and possible future directions of CSP.</p

Table1_Identification and verification of IGFBP3 and YTHDC1 as biomarkers associated with immune infiltration and mitophagy in hypertrophic cardiomyopathy.DOCX

Background: Hypertrophic cardiomyopathy (HCM) is the main cause of sudden cardiac death among young adults, yet its pathogenesis remains vague. N6-methyladenosine (m6A) methylation modification was involved in various cardiovascular diseases such as coronary heart disease and heart failure, although its influence on HCM remains unclear. This study aimed to explore the potential role of m6A in the diagnosis and pathogenesis of HCM.Methods: GSE36961 including 106 HCM and 39 controls was used in the study. The HCM-related m6A regulators were selected using support vector machine recursive feature elimination and random forest algorithm. A significant gene signature was then established using least absolute shrinkage and selection operator and then verified by GSE130036. Subgroup classification of HCM was performed based on the expression of m6A biomarkers. Gene set variation analysis was employed to explore the functional difference between distinct subgroups. Weighted gene co-expression network analysis was used to determine the m6A-related hub module. Single-sample gene set enrichment analysis was conducted to assess the immune and mitophagy features between subgroups. Besides, transfection of recombinant plasmids with targeted genes into H9c2 cells was performed to further verify the function of the significant biomarkers.Results: Significant difference existed in m6A landscape between HCM and control patients, among which IGFBP3 and YTHDC1 were identified as the independent biomarkers of HCM. Highly infiltrated immune cells (MDSC, macrophages, etc.), more enriched immune-related pathways (TNFα signaling via NFκB and IL6-JAK-STAT3 signaling) and cardiac remodeling-associated pathways (epithelial mesenchymal transition, angiogenesis, etc.) were identified in the subgroup with higher IGFBP3. Consistently, overexpression of IGFBP3 in H9c2 cells led to upregulation of extracellular-matrix-related genes (COL1A2, COL3A1 and MMP9) and inflammation-related genes (TNFα and IL6). Besides, higher YTHDC1 expression seemed to be consistent with less-activated mitophagy (PINK1-PRKN mediated mitophagy) and energy metabolism. Further experiments demonstrated that overexpression of YTHDC1 resulted in up-regulation of PINK and PRKN in cardiomyocytes, which are essential genes mediating mitophagy.Conclusion: Two m6A readers (IGFBP3 and YTHDC1) well distinguished HCM and may facilitate clinical diagnosis. IGFBP3 may play a role in the immune-microenvironments and remodeling of cardiac tissues, while YTHDC1 may influence mitophagy and energy metabolism in HCM.</p

Alcohol dehydrogenase specific activities at different pHs.

<p>*indicates that the difference is significant (P<0.05).</p><p>Mean ± SD from three independent experiments are shown.</p

Alcohol dehydrogenase specific activities at different temperatures.

<p>*indicates that the difference is significant (P<0.05).</p><p>Mean ± SD from three independent experiments are shown.</p

Cloning strategy.

<p>(A) The construction of integration plasmid pJS700-BmADH. The fragments <i>amyE</i> 5′ and <i>amyE</i> 3′ in plasmid are homologous to the upstream and downstream of the amylase gene in <i>B. subtilis</i> 168 (trp-), respectively; <i>Em</i>^r, erythromycin resistant site; <i>CotC</i>, a <i>B. subtilis</i> spore coat protein encoding gene. (B) The schematic integration of CotC-BmADH to <i>amyE</i> locus. Arrows indicate the positions of primer pairs used in the site-directed PCR for confirmation of the correct integration.</p

Identification of the mutant with CotC-BmADH integration at <i>amyE</i> locus.

<p>(A) Analysis of amylase activity. CotC-BmADH mutant strains and <i>B. subtilis</i> 168 (trp-) wide type grew on the starch-containing LB plate before (1) and after (2) being stained by iodine. The integration of CotC-BmADH might disrupt <i>amyE</i> and made the strain amylase deficient, while the while wide type strain showed a big white halo around colony due the secretion of amylase. (B) Site-directed PCR analysis using different primer pairs. Marker, <i>λ</i> DNA digested by <i>Eco</i>T14I; W: <i>B. subtilis</i> 168 (trp-) wide typ; M: CotC-BmADH mutant; primer pairs used in PCR are labeled below agarose gel.</p

SDS-PAGE analysis of CotC-BmADH and Western blotting.

<p>(A) SDS-PAGE stained by coomassie-blue. (B) CotC-BmADH detected by BmADH specific antibody. Lane 1, <i>B. subtilis</i> 168 (trp-); lane 2, CotC-BmADH strain.</p

Relative remained activity of BmADH and CotC-BmADH after incubation at 37°C for 30 min.

<p>The activity was assayed at pH 9.0, 25°C. *indicates the difference is significant (P<0.05).</p

Mechanical Reinforcement in Thermoplastic Polyurethane Nanocomposite Incorporated with Polydopamine Functionalized Graphene Nanoplatelet

Thermoplastic polyurethane (TPU) nanocomposites incorporated with polydopamine functionalized graphene nanoplatelet (PDA-GNP) were prepared by in situ polymerization. Fourier transform infrared spectroscopy results indicated that the addition of PDA-GNP could promote the formation of hydrogen bonding and microphase separation. The microstructure obtained from small-angle neutron scattering indicated that the addition of PDA-GNP increased the number while significantly it decreased the size of hard microdomains. Scanning electron microscopy demonstrated that PDA-GNP exhibited strong interfacial interactions with TPU matrix. In particular, the tensile strength, strain at break, and toughness of TPU/PDA-GNP with as low as 0.5 wt % PDA-GNP increased by 313, 16, and 279%, respectively. This individualized phenomenon was attributed to the abundant covalent bonding between PDA-GNP and TPU resulting in strong interfacial interactions and good compatibility specifically associated with the changes of TPU microstructure