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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]

Background: Laminin subunit gamma-1 (LAMC1) is a major extracellular matrix molecule involved in the tumor microenvironment. Knowledge of the biological features and clinical relevance of LAMC1 in cancers remains limited. Methods: We conducted comprehensive bioinformatics analysis of LAMC1 gene expression and clinical relevance in pan-cancer datasets of public databases and validated LAMC1 expression in glioma tissues and cell lines. The association and regulatory mechanism between hypoxia inducible factor-1α (HIF-1α) and LAMC1 expression were explored. Results: LAMC1 expression in most cancers in The Cancer Genome Atlas (TCGA) including glioma was significantly higher than that in normal tissues, which had a poor prognosis and were related to various clinicopathological features. Data from the Chinese Glioma Genome Atlas also showed high expression of LAMC1 in glioma associated with poor prognoses. In clinical glioma tissues, LAMC1 protein was highly expressed and correlated to poor overall survival. LAMC1 knockdown in Hs683 glioma cells attenuated cell proliferation, migration, and invasion, while overexpression of LAMC1 in U251 cells leads to the opposite trend. Most TCGA solid cancers including glioma showed enhancement of HIF-1α expression. High HIF-1α expression leads to adverse prognosis in gliomas, besides, HIF-1α expression was positively related to LAMC1. Mechanistically, HIF-1α directly upregulated LAMC1 promotor activity. Hypoxia (2% O2)-treated Hs683 and U251 cells exhibited upregulated HIF-1α and LAMC1 expression, which was significantly attenuated by HIF-1α inhibitor YC-1 and accompanied by attenuated cell proliferation and invasion. Conclusions: High expression of LAMC1 in some solid tumors including gliomas suggests a poor prognosis. The hypoxic microenvironment in gliomas activates the HIF-1α/LAMC1 signaling, thereby promoting tumor progression. Targeted intervention on the HIF-1α/LAMC1 signaling attenuates cell growth and invasion, suggesting a new strategy for glioma treatment. [ABSTRACT FROM AUTHOR]

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]

Motivated by the pursuit of both encryption efficiency and security, this paper presents a symmetric color image encryption algorithm using a novel cross–plane joint scrambling–diffusion method. To provide high–strength security, the color planes are firstly spliced horizontally and then vertically to be adequately encrypted by the joint scrambling–diffusion method. Therefore, minor changes in any pixel can cross every color plane that significantly influences the final cipher image. To achieve fast encryption speed, all employed chaotic systems have simple structures but robust properties to rapidly generate high–quality pseudorandom sequences. Additionally, the joint scrambling–diffusion method is vectorized to handle pixels in parallel for satisfactory execution efficiency. Security tests demonstrate the outstanding security performance of the proposed algorithm, with correlation coefficients and entropies of cipher images being close to 0 and greater than 7.99, respectively, and results of NPCR and UACI tests being similar to ideal cipher images, which can resist statistical, differential, exhaustive, and even chosen ciphertext/plaintext attacks. Moreover, because of the O(4W + 4H) time complexity of the novel scrambling–diffusion method, even a color image with a size of 1024 × 1024 only costs 0.26 s to be encrypted. Hence, the proposed algorithm can satisfy the efficiency and security requirements of color image encryption. [ABSTRACT FROM AUTHOR]

Objective: To analyze the effect of RhoE gene expression change on protein expression profiles in the cardiac tissue of diabetic rats, and analyse the possible underlying regulatory mechanism. Methods: Six-week-old male RhoE gene knockout (KO) and wild-type (WT) Sprague Dawley rats were injected intraperitoneally with streptozotocin (70 mg/kg) to establish the type 1 diabetes model (T1DM), with injection of the same amount of sodium citrate saline as the control group. A week later, the fasting blood glucose of the rats was measured daily, and blood glucose concentration 16.7 mmol/L was regarded as a successful model. Two additional weeks later, the hearts of the rats in each group were removed and four-dimensional label-free quantitative proteomics technology (4D-LFQ) was used to analyze the changes of protein profiles in the heart tissue. The related functions, enrichment signals, and protein-protein interaction network (PPI) of the differentially expressed proteins were analyzed. Results: T1DM rat models were successfully established. Taking a fold change > 1.5 and P < 0.05 as the threshold, a total of 2 931 quantifiable proteins were identified. In the non-diabetic state, the KO group had 26 and 45 significantly up- and downregulated proteins, respectively, compared with the WT group; in the diabetic state, the KO group had 19 and 28 significantly up- and downregulated proteins, respectively, compared with the WT group. The GO annotation results showed that most of the differentially expressed proteins were located in the extracellular matrix, and their biological functions were mainly concentrated in the immune response and energy metabolism. KEGG analysis showed that the signaling pathways associated with the differentially expressed proteins in cardiac tissue after RhoE knockout were mainly related to ribosomes and fat digestion and absorption. Protein interaction network analysis showed that in the cardiac tissue of the KO group, there were more Col1α1- and Col1α2-interacting proteins among the upregulated proteins, and among the down-regulated proteins, related proteins involved in the ribosomal pathway interact more in the network. Conclusion: RhoE knockout significantly changes the protein expression profiles in diabetic cardiac tissue, affecting multiple signaling pathways closely related to diabetic cardiomyopathy. The results provide insights into the pathogenesis and therapeutic target screening of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

The dynamic changes of RNA N6-methyladenosine (m 6 A) during cancer progression participate in various cellular processes. However, less is known about a possible direct connection between upstream regulator and m 6 A 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 m 6 A contents and significantly suppressed osteosarcoma cell growth, migration and invasion. Further results revealed that NAT10 silence inhibits mRNA stability and translation of m 6 A reader protein YTHDC1, and displayed an increase in glucose uptake, a decrease in lactate production and pyruvate content. YTHDC1 recognizes differential m 6 A 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 m 6 A 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 m 6 A modification can positively regulate the glycolysis of cancer cells and reveals a previously unrecognized signaling axis of NAT10/ac4C-YTHDC1/m 6 A-LDHA/PFKM in osteosarcoma. Video Abstract., (© 2024. The Author(s).)