Hybrid neural network approaches to predict drug–target binding affinity for drug repurposing: screening for potential leads for Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease that primarily affects elderly individuals. Recent studies have found that sigma-1 receptor (S1R) agonists can maintain endoplasmic reticulum stress homeostasis, reduce neuronal apoptosis, and enhance mitochondrial function and autophagy, making S1R a target for AD therapy. Traditional experimental methods are costly and inefficient, and rapid and accurate prediction methods need to be developed, while drug repurposing provides new ways and options for AD treatment. In this paper, we propose HNNDTA, a hybrid neural network for drug–target affinity (DTA) prediction, to facilitate drug repurposing for AD treatment. The study combines protein–protein interaction (PPI) network analysis, the HNNDTA model, and molecular docking to identify potential leads for AD. The HNNDTA model was constructed using 13 drug encoding networks and 9 target encoding networks with 2506 FDA-approved drugs as the candidate drug library for S1R and related proteins. Seven potential drugs were identified using network pharmacology and DTA prediction results of the HNNDTA model. Molecular docking simulations were further performed using the AutoDock Vina tool to screen haloperidol and bromperidol as lead compounds for AD treatment. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation results indicated that both compounds had good pharmacokinetic properties and were virtually non-toxic. The study proposes a new approach to computer-aided drug design that is faster and more economical, and can improve hit rates for new drug compounds. The results of this study provide new lead compounds for AD treatment, which may be effective due to their multi-target action. HNNDTA is freely available at https://github.com/lizhj39/HNNDTA

miR-21 Overexpression Promotes Esophageal Squamous Cell Carcinoma Invasion and Migration by Repressing Tropomyosin 1

The migration and invasion of esophageal squamous cell carcinoma are associated with clinical outcomes, however, the mechanisms remain poorly understood. Here, we found that miR-21 is significantly overexpressed in ESCC, lung cancer, and bladder cancer compared with the adjacent normal tissue. MiR-21 and TPM1 expressions were analyzed by RT-qPCR and WB in 30 ESCC, 10 lung cancer, and 10 bladder cancer clinical specimens, each with matched adjacent normal tissue. Knockdown and overexpression of miR-21 as well as knockdown of TPM1 in ESCC cell lines were performed using synthetic oligonucleotides. TPM1 3′UTR luciferase reporter constructs were used to investigate targeting of TPM1 by miR-21. ESCC migration and invasion were assessed using transwell migration and invasion assays. Inhibition of miR-21 reduced migration and invasion in two ESCC cell lines, and overexpression of miR-21 promoted migration and invasion in vitro. Interestingly, TPM1 exhibited inverse patterns of expression compared with miR-21 in tissues and cell lines. Luciferase reporter assays demonstrated that TPM1 was directly regulated by miR-21. Moreover, the forced overexpression of miR-21 repressed the TPM1 expression, while silencing of miR-21 restored the TPM1 expression in ESCC cell lines. What is more, simultaneous silencing of miR-21 and TPM1 expressions did not alter the migratory and invasive characteristics demonstrating that the effects of miR-21 were mediated through TPM1. In conclusion, the aberrant overexpression of miR-21 is common in cancer and promotes the migration and invasion of ESCC through inhibiting the TPM1 expression. These results suggest that miR-21 may be a novel predictive marker and therapeutic target for treatment of ESCC

Glutathione Peroxidase 1 Promotes NSCLC Resistance to Cisplatin via ROS-Induced Activation of PI3K/AKT Pathway

Purpose. Reactive oxygen species (ROS)-induced cytotoxicity is an important mechanism by which cisplatin kills tumor cells. Glutathione peroxidase family (GPXs) is an important member of antioxidant system which metabolizes intracellular ROS and maintains homeostasis of cells. Altered expressions of GPXs enzymes, especially GPX1, have been described in a variety of human cancers. However, their functional roles in cisplatin-based chemoresistance in human malignancies including non-small cell lung cancer have never been explored. Methods. A panel of NSCLC cell lines were selected for this study. GPX1 expression was detected using quantitative RT-PCR and Western blot. Cisplatin-induced cell killing was analyzed by CCK8 assay. Intracellular ROS levels were detected by fluorescence-based flow cytometry analysis. In vitro overexpression and knockdown of GPX1 expression were performed using GPX1 expression vector and siRNA approaches. Protein levels of PTEN, NF-κB, BCL2, Bax, and phosphorylated AKT were detected with western blot analysis using specific antibodies. Results. GPX1 expression was upregulated in a subset of NSCLC cell lines resistant to cisplatin treatment. Expression vector-mediated forced overexpression of GPX1 significantly increased cisplatin resistance in NSCLC cell lines, whereas RNA inference-mediated downregulation of GPX1 could restore sensitivity to cisplatin. Overexpression of GPX1 significantly suppressed elevation of intracellular ROS and activation of AKT pathway when NSCLC cell lines were exposed to different concentrations of cisplatin. Activation of the AKT pathway inhibited proapoptotic cascade and subsequently led to cisplatin resistance in NSCLC cells. Inhibition of NF-κB by its chemical inhibitor BAY can significantly downregulate GPX1 expression and restore the cisplatin sensitivity of the cell lines resistant to cisplatin. Conclusions. Our findings suggested that overexpression of GPX1 is a novel molecular mechanism for cisplatin-based chemoresistance in NSCLC. GPX1 overexpression blocks cisplatin-induced ROS intracellular accumulation, activates PI3K-AKT pathway by increased AKT phosphorylation, and further leads to cisplatin resistance in NSCLC cells. Inhibition of NF-κB signaling may be an alternative approach for restoring cisplatin sensitivity for NSCLC cells resistant to cisplatin-based chemotherapy

Relational model of accidents and vessel traffic using AIS Data and GIS: A case study of the Western port of Shenzhen City

Following the growth in global trade activities, vessel traffic has increased dramatically in some busy waterways and ports. However, such increments have made it more complex to manage the regional vessel traffic, which can increase the risk of an accident in the area. To model and analyze the relationship between vessel traffic and maritime traffic, this paper proposes a gridded geography information system (GIS)-based relation analysis model using the historical automatic identification system (AIS) data and accident records over a 10-year-span. Firstly, the extent of the hazards posed by a maritime accident in terms of hull loss, fatality, and direct economic loss is quantified using set pair analysis. Consequently, the hazardous degree posed by an accident is obtained. The relative consequence of the regional hazard (RCORH) is then estimated by summing up all the relative hazardous degrees of accidents that have occurred in a certain gridded area. Secondly, the vessel traffic in the gridded areas is analyzed using characteristics such as speed, heading variance, and traffic volume as indicators. Based on the analysis of both the maritime traffic accidents and the vessel traffic, the spatial relationships are analyzed with an overlay between the RCORH and vessel traffic data of each grid, as well as a regression analysis. In a case study of the Western port of Shenzhen City, China, the methodology proves to be effective for vessel traffic management and traffic engineering design.Safety and Security Scienc

Applicable Value of AMSS-PCR in Lung Cancer Gene Mutation Detection

Background and objective The detection of driver oncogenes of lung cancer is of great importance. There are various gene detection techniques nowadays which are different from each other. We carried out this study to investigate the specificity and sensitivity of assay panels based on an Amplification Refractory Mutation System-polymerase chain reaction (ARMS-PCR) technique of Amplification Mutation Specific System (AMSS) in detection of lung cancer gene mutation. To estimate the applicable value of assay panels in clinical settings. Methods We collected cancer tissue specimens or fluid specimens from 309 patients. Mutation results were presented for those samples previously detected by ARMS-PCR. In comparison, we carried out AMSS-PCR using (epidermal growth factor receptor, EGFR) assay panel and Six-Alliance assay panel as well as Sanger sequencing. Software SPSS 22.0 (SPSS IBM) was used for statistical analysis. Results The rates of consistency between the results by assay panels and Sanger sequencing or ARMS-PCR were 97.41% and 97.73%, respectively. Besides, EGFR assay panel had higher consistency rates with other detection methods than Six-Alliance assay panel. As for consistency test, the Kappa values of assay panels with Sanger sequencing, assay panels with ARMS-PCR, and ARMS-PCR with Sanger sequencing were 0.946, 0.953, and 0.913, respectively. The receiver operating characteristic curve (ROC) area under curve (AUC) of assay panels was 0.976 referring to Sanger sequencing, and 0.975 as ARMS-PCR was referred to. Conclusion AMSS-PCR can make an optimal cancer gene mutation detection method for clinical settings

Human skeletal muscle aging atlas.

Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment. We found that distinct subsets of muscle stem cells exhibit decreased ribosome biogenesis genes and increased CCL2 expression, causing different aging phenotypes. Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction. Overall, we present a comprehensive human skeletal muscle aging resource ( https://www.muscleageingcellatlas.org/ ) together with an in-house mouse muscle atlas to study common features of muscle aging across species