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Background: Nonischemic cardiomyopathy (NISCM) is a clinical challenge with limited therapeutic targets. This study aims to identify promising drug targets for NISCM. Methods: We utilized cis-pQTLs from the deCODE study, which includes data from 35,559 Icelanders, and SNPs from the FinnGen study, which includes data from 1,754 NISCM cases and 340,815 controls of Finnish ancestry. Mendelian randomization (MR) analysis was performed to estimate the causal relationship between circulating plasma protein levels and NISCM risk. Proteins with significant associations underwent false discovery rate (FDR) correction, followed by Bayesian colocalization analysis. The expression of top two proteins, LILRA5 and NELL1, was further analyzed using various NISCM datasets. Descriptions from the Human Protein Atlas (HPA) validated protein expression. The impact of environmental exposures on LILRA5 was assessed using the Comparative Toxicogenomics Database (CTD), and molecular docking identified the potential small molecule interactions. Results: MR analysis identified 255 circulating plasma proteins associated with NISCM, with 16 remaining significant after FDR correction. Bayesian colocalization analysis identified LILRA5 and NELL1 as significant, with PP.H4 > 0.8. LILRA5 has a protective effect (OR = 0.758, 95% CI, 0.670–0.857) while NELL1 displays the risk effect (OR = 1.290, 95% CI, 1.199–1.387) in NISCM. Decreased LILRA5 expression was found in NISCM such as diabetic, hypertrophic, dilated, and inflammatory cardiomyopathy, while NELL1 expression increased in hypertrophic cardiomyopathy. HPA data indicated high LILRA5 expression in neutrophils, macrophages and endothelial cells within normal heart and limited NELL1 expression. Immune infiltration analysis revealed decreased neutrophil in diabetic cardiomyopathy. CTD analysis identified several small molecules that affect LILRA5 mRNA expression. Among these, Estradiol, Estradiol-3-benzoate, Gadodiamide, Topotecan, and Testosterone were found to stably bind to the LILRA5 protein at the conserved VAL-15 or THR-133 residues in the Ig-like C2 domain. Conclusion: Based on European Ancestry Cohort, this study reveals that LILRA5 and NELL1 are potential therapeutic targets for NISCM, with LILRA5 showing particularly promising prospects in diabetic cardiomyopathy. Several small molecules interact with LILRA5, implying potential clinical implication. [ABSTRACT FROM AUTHOR]

Nanoscale vacuum semiconductor devices utilize vacuum as an electron transport medium, offering the advantages of rapid response and immunity to extreme environments. In this study, we present a nanoscale vertical channel vacuum triode with a side-gate structure. The device employs vacuum as the gate insulating medium, which enhances its reliability compared to conventional vertical structure vacuum triodes. Furthermore, the side-gate design reduces the gate input capacitance to approximately 10−18 F, making it more suitable for high-frequency operations. We systematically investigate the impact of structural dimensions on device performance. Simulation results demonstrate that when the dielectric layer thickness is around 35 nm, the maximum transconductance of the device reaches 1.23 μS. Increasing the gate dielectric layer thickness leads to an increase in cut-off frequency but decreases channel current. Smaller gap widths between the cathode and gate result in higher transconductance and cut-off frequencies. However, when the gap width is less than 40 nm, noticeable gate leakage currents occur. Introducing negative offset of alignment between the anode and channel edge enhances transconductance and cut-off frequency but may introduce stability issues. These research findings provide valuable insights for developing high-frequency vacuum triode devices. [ABSTRACT FROM AUTHOR]

[Objectives] Both the mechanical impedance of the foundation and the homogenization of foundation impedance among loading points can affect the radiation noise of underwater structures.[Methods] The mechanical impedance of a typical long underwater foundation was studied. A mathematical topology model in which the density of web plate was set to be the design variable was established to improve the homogenization of foundation impedance. An effective form of web perforation was put forward according to the result of topology optimization. On this basis,a multi-objective size optimization mathematical model based on tolerance ranking method was proposed. The thicknesses of plates constituting the foundation were used as design variables while the objective was to maximize the mechanical impedance and impedance uniformity simultaneously. Finally an optimum proposal of thicknesses of face plates,webs and knee plates was found.[Results] The result of topology optimization indicates that hole formed on foundation webs are not the same,and the centers of holes do not coincide with web centers. The size optimization result shows that the maximum dispersion of foundation impedance can be reduced by 9.37% with 33.31% weight saving,while the minimum mechanical impedance remains nearly unchanged by redistributing the material in plates of the foundation by matching thicknesses of face plates,webs and knee plates.[Conclusions] In order to improve the impedance homogenization among loading points, forms of perforations on foundation webs should not be the same. And foundation components in different areas can be different in order to take into account both the mechanical impedance and impedance homogenization. The study in this paper can provide reference for the optimal design of underwater structure foundation.

The dynamic changes of RNA N6-methyladenosine (m6A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m6A modification, and therefore affects oncogenic progression. Here, we have identified that a key enzyme in N4-acetylcytidine (ac4C) acetylation NAT10 is highly expressed in human osteosarcoma tissues, and its knockdown enhanced m6A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m6A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m6A sites on key enzymes of glycolysis phosphofructokinase (PFKM) and lactate dehydrogenase A (LDHA) mRNAs, which suppress glycolysis pathway by increasing mRNA stability of them in an m6A methylation-dependent manner. YTHDC1 partially abrogated the inhibitory effect caused by NAT10 knockdown in tumor models in vivo, lentiviral overexpression of YTHDC1 partially restored the reduced stability of YTHDC1 caused by lentiviral depleting NAT10 at the cellular level. Altogether, we found ac4C driven RNA m6A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m6A-LDHA/PFKM in osteosarcoma. 6WoSibQBSZGZLQEcMB75Lw Video Abstract [ABSTRACT FROM AUTHOR]