Cardiovascular disease (CVD) remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for its prevention. The ...transcription factor p53 functions as a gatekeeper, regulating a myriad of genes to maintain normal cell functions. It has received a great deal of research attention as a tumor suppressor. In the past three decades, evidence has also shown a regulatory role for p53 in the heart. Basal p53 is essential for embryonic cardiac development; it is also necessary to maintain normal heart architecture and physiological function. In pathological cardiovascular circumstances, p53 expression is elevated in both patient samples and animal models. Elevated p53 plays a regulatory role via anti-angiogenesis, pro-programmed cell death, metabolism regulation, and cell cycle arrest regulation. This largely promotes the development of CVDs, particularly cardiac remodeling in the infarcted heart, hypertrophic cardiomyopathy, dilated cardiomyopathy, and diabetic cardiomyopathy. Roles for p53 have also been found in atherosclerosis and chemotherapy-induced cardiotoxicity. However, it has different roles in cardiomyocytes and non-myocytes, even in the same model. In this review, we describe the different effects of p53 in cardiovascular physiological and pathological conditions, in addition to potential CVD therapies targeting p53.
Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new ex vivo DCM ...model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of Ptgs2 and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy. Inhibition of ferroptosis with ferrostatin-1 and deferoxamine prevented AGE-induced ECT remodeling and dysfunction. Ferroptosis was also evidenced in the heart of type 2 diabetic mice with DCM. Inhibition of ferroptosis by liproxstatin-1 prevented the development of diastolic dysfunction at 3 months after the onset of diabetes. Nuclear factor erythroid 2-related factor 2 (NRF2) activated by sulforaphane inhibited cardiac cell ferroptosis in both AGE-treated ECTs and hearts of DCM mice by upregulating ferritin and SLC7A11 levels. The protective effect of sulforaphane on ferroptosis was AMP-activated protein kinase (AMPK)-dependent. These findings suggest that ferroptosis plays an essential role in the pathogenesis of DCM; sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. This suggests a feasible therapeutic approach with sulforaphane to clinically prevent ferroptosis and DCM.
This study suggests that ferroptosis plays an essential role in the pathogenesis of diabetic cardiomyopathy. Sulforaphane prevents ferroptosis and associated pathogenesis via AMPK-mediated NRF2 activation. Display omitted
Clear cell renal cell carcinomas (ccRCCs) epitomize the most formidable clinical subtype among renal neoplasms. While the impact of tumor-associated fibroblasts on ccRCC progression is duly ...acknowledged, a paucity of literature exists elucidating the intricate mechanisms and signaling pathways operative at the individual cellular level.
Employing single-cell transcriptomic analysis, we meticulously curated UMAP profiles spanning substantial ccRCC populations, delving into the composition and intrinsic signaling pathways of these cohorts. Additionally, Myofibroblasts were fastidiously categorized into discrete subpopulations, with a thorough elucidation of the temporal trajectory relationships between these subpopulations. We further probed the cellular interaction pathways connecting pivotal subpopulations with tumors. Our endeavor also encompassed the identification of prognostic genes associated with these subpopulations through Bulk RNA-seq, subsequently validated through empirical experimentation.
A notable escalation in the nFeature and nCount of Myofibroblasts and EPCs within ccRCCs was observed, notably enriched in oxidation-related pathways. This phenomenon is postulated to be closely associated with the heightened metabolic activities of Myofibroblasts and EPCs. The Myofibroblasts subpopulation, denoted as C3 HMGA1+ Myofibroblasts, emerges as a pivotal subset, displaying low differentiation and positioning itself at the terminal point of the temporal trajectory. Intriguingly, these cells exhibit a high degree of interaction with tumor cells through the MPZ signaling pathway network, suggesting that Myofibroblasts may facilitate tumor progression via this pathway. Prognostic genes associated with C3 were identified, among which TUBB3 is implicated in potential resistance to tumor recurrence. Finally, experimental validation revealed that the knockout of the key gene within the MPZ pathway, MPZL1, can inhibit tumor activity, proliferation, invasion, and migration capabilities.
This investigation delves into the intricate mechanisms and interaction pathways between Myofibroblasts and ccRCCs at the single-cell level. We propose that targeting MPZL1 and the oxidative phosphorylation pathway could serve as potential key targets for treating the progression and recurrence of ccRCC. This discovery paves the way for new directions in the treatment and prognosis diagnosis of ccRCC in the future.
The pressure difference in buildings under natural state is usually below 10 Pa, and the air change rate at 50 Pa (ACH
50
) is often used to evaluate building airtightness. There is a dearth of ...research on air infiltration predictive model at different pressures in China. Moreover, the airflow coefficient (
C
), a key parameter for air infiltration, is necessary to determine ACH
50
. Based on prior experimental data, several methods including ordinary least squares (OLS), stepwise regression, partial least squares (PLS) and nonlinear fitting with independent variable screening methods, were employed to establish an airflow coefficient model. The determination coefficient (
R
2
) and the variation coefficient of the root-mean-square error (CV(RMSE)) of these models were compared. The simulation results show that
R
2
of the airflow coefficient models for apartments and villas increased by a maximum of 25.9% and 2.3%, respectively, using PLS method. The improvement with nonlinear fitting was weaker. Based on K-P model, a conversion model between ACH
50
and ACH
4
was developed as an air infiltration predictive model under natural state. Blower door and tracer gas tests were conducted to verify the conversion model. The expected error was approximately 10%, which may be caused by measurement errors and shielding from surrounding obstructions. Further studies need to focus on obtaining more experimental data for building airtightness and developing a conversion model for high-rise residential buildings.
The gradual evolution of pharmacogenomics has shed light on the genetic basis for inter-individual drug response variations across diverse populations. This study aimed to identify pharmacogenomic ...variants that differ in Zhuang population compared with other populations and investigate their potential clinical relevance in gene-drug and genotypic-phenotypic associations. A total of 48 variants from 24 genes were genotyped in 200 Zhuang subjects using the Agena MassARRAY platform. The allele frequencies and genotype distribution data of 26 populations were obtained from the 1000 Genomes Project, followed by a comparison and statistical analysis. After Bonferroni correction, significant differences in genotype frequencies were observed of CYP3A5 (rs776746), ACE (rs4291), KCNH2 (rs1805123), and CYP2D6 (rs1065852) between the Zhuang population and the other 26 populations. It was also found that the Chinese Dai in Xishuangbanna, China, Han Chinese in Beijing, China, and Southern Han Chinese, China showed least deviation from the Zhuang population. The Esan in Nigeria, Gambian in Western Division, The Gambia, and Yoruba in Ibadan, Nigeria exhibited the largest differences. This was also proved by structural analysis, Fst analysis and phylogenetic tree. Furthermore, these differential variants may be associated with the pharmacological efficacy and toxicity of Captopril, Amlodipine, Lisinopril, metoclopramide, and alpha-hydroxymetoprolol in the Zhuang population. Our study has filled the gap of pharmacogenomic information in the Zhuang population and has provided a theoretical framework for the secure administration of drugs in the Zhuang population.
The aim of this study was to discover new biomarkers to detect breast cancer (BC), which is an aggressive cancer with a high mortality rate. In this study, bioinformatic analyses (differential ...analysis, weighted gene co-expression network analysis, and machine learning) were performed to identify potential candidate genes for BC to study their molecular mechanisms. Furthermore, Quantitative Real-time PCR and immunohistochemistry assays were used to examine the protein and mRNA expression levels of a particular candidate gene (DLGAP5). And the effects of DLGAP5 on cell proliferation, migration, invasion, and cell cycle were further assessed using the Cell Counting Kit-8 assay, colony formation, Transwell, wound healing, and flow cytometry assays. Moreover, the changes in the JAK2/STAT3 signaling-pathway-related proteins were detected by Western Blot. A total of 44 overlapping genes were obtained by differential analysis and weighted gene co-expression network analysis, of which 25 genes were found in the most tightly connected cluster. Finally, NEK2, CKS2, UHRF1, DLGAP5, and FAM83D were considered as potential biomarkers of BC. Moreover, DLGAP5 was highly expressed in BC. The down-regulation of DLGAP5 may inhibit the proliferation, migration, invasion, and cell cycle of BC cells, and the opposite was true for DLGAP5 overexpression. Correspondingly, silencing or overexpression of the DLGAP5 gene inhibited or activated the JAK2/STAT3 signaling pathway, respectively. DLGAP5, as a potential biomarker of BC, may impact the cell proliferation, migration, invasion, cell cycle, and BC development by modulating the JAK2/STAT3 signaling pathway.
Since the steel plate surface defect image often has complicated background and lots of noise, the segmentation accuracy is low when using the single threshold Otsu method. Therefore, this paper ...introduces the whale optimization algorithm (WOA) to optimize the threshold of the dual-threshold image segmentation. To avoid the premature convergence, slow convergence speed and easy fall into the local optimum of the original WOA, an improved WOA is proposed. Firstly, the WOA is discretized by using round function; secondly, the sin mapping generation chaotic sequence is used to replace the randomly generated initial population in the initialization process of the WOA to enhance the multiformity of population; thirdly, the global search and local development capabilities are balanced and improved by nonlinear time-varying factors and inertia weights in the position updating mechanism; finally, the improved WOA is applied to the two-dimensional Otsu (2D-Otsu) algorithm to select the optimal threshold for image segmentation. The simulation results of 8 classic benchmark functions show that the improved WOA can obtain the optimal value of the function 0, − 12,569.5. The improved WOA can raise convergence speed and improve the global search ability and get rid of the local optimum. The experimental results show that the proposed algorithm outperforms the Otsu algorithm and can achieve more accurate segmentation of steel plate surface defect image. Compared with 2D-Otsu algorithm, the proposed algorithm reduces running time by 0.34 s and has the highest segmentation efficiency for rolled-in scale defects.
This experiment investigated the effect of different sensitizing treatment times (2–48 h) at 800 °C on the microstructure and intergranular corrosion of high-nitrogen austenitic stainless steel by ...using scanning electron microscopy, energy-dispersive spectroscopy, double loop electrochemical potentiokinetic reactivation, and an oxalic acid etch test. The results indicate that with increasing sensitizing time, the austenite grains grew significantly and the carbide quantity began to increase at the grain boundary. The lamellar pearlite-like Cr
2
N was precipitated when the specimens were aged at 800 °C for 12 h. DL-EPR testing showed that IGC susceptibility of high-nitrogen austenitic stainless steel is mainly caused by the precipitation of carbide and increases when sensitization time is increased from 2 to 48 h.
Abstract
Genetic algorithm (GA) has been widely used since it was proposed. However, due to the complexity of the algorithm itself, the fact that the actual problems have huge data and scale, and ...that it needs to meet certain real-time requirements, the acceleration of genetic algorithm has become a hot spot in both academia and industry field. Previous work have been done on the acceleration of GA, which primarily focuses on the software aspect, while the existing work in hardware aspect lacks adaptability for different industrial scenarios. Therefore, this paper puts forward a novel architecture based on software/hardware co-design method, in which the software produces random numbers, and the hardware, taking full account of the characteristics of sequential circuit, is implemented in a hierarchical pipeline architecture. This architecture accelerates the algorithm while providing certain flexibility. This paper completes the simulation on MATLAB and Vivado, and the total running time is 987.4.u. Compared with the pure software implementation, the speed is increased by 73.9 times.
Glioma is a highly malignant brain tumor with a grim prognosis. Genetic factors play a role in glioma development. While some susceptibility loci associated with glioma have been identified, the risk ...loci associated with prognosis have received less attention. This study aims to identify risk loci associated with glioma prognosis and establish a prognostic prediction model for glioma patients in the Chinese Han population.
A genome-wide association study (GWAS) was conducted to identify risk loci in 484 adult patients with glioma. Cox regression analysis was performed to assess the association between GWAS-risk loci and overall survival as well as progression-free survival in glioma. The prognostic model was constructed using LASSO Cox regression analysis and multivariate Cox regression analysis. The nomogram model was constructed based on the single nucleotide polymorphism (SNP) classifier and clinical indicators, enabling the prediction of survival rates at 1-year, 2-year, and 3-year intervals. Additionally, the receiver operator characteristic (ROC) curve was employed to evaluate the prediction value of the nomogram. Finally, functional enrichment and tumor-infiltrating immune analyses were conducted to examine the biological functions of the associated genes.
Our study found suggestive evidence that a total of 57 SNPs were correlated with glioma prognosis (
< 5 × 10
). Subsequently, we identified 25 SNPs with the most significant impact on glioma prognosis and developed a prognostic model based on these SNPs. The 25 SNP-based classifier and clinical factors (including age, gender, surgery, and chemotherapy) were identified as independent prognostic risk factors. Subsequently, we constructed a prognostic nomogram based on independent prognostic factors to predict individualized survival. ROC analyses further showed that the prediction accuracy of the nomogram (AUC = 0.956) comprising the 25 SNP-based classifier and clinical factors was significantly superior to that of each individual variable.
We identified a SNP classifier and clinical indicators that can predict the prognosis of glioma patients and established a prognostic prediction model in the Chinese Han population. This study offers valuable insights for clinical practice, enabling improved evaluation of patients' prognosis and informing treatment options.
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