Inhibiting MDM2-p53 interaction is considered an efficient mode of cancer treatment. In our current study, Gaussian-accelerated molecular dynamics (GaMD), deep learning (DL), and binding free energy ...calculations were combined together to probe the binding mechanism of non-peptide inhibitors K23 and 0Y7 and peptide ones PDI6W and PDI to MDM2. The GaMD trajectory-based DL approach successfully identified significant functional domains, predominantly located at the helixes α2 and α2’, as well as the β-strands and loops between α2 and α2’. The post-processing analysis of the GaMD simulations indicated that inhibitor binding highly influences the structural flexibility and collective motions of MDM2. Calculations of molecular mechanics–generalized Born surface area (MM-GBSA) and solvated interaction energy (SIE) not only suggest that the ranking of the calculated binding free energies is in agreement with that of the experimental results, but also verify that van der Walls interactions are the primary forces responsible for inhibitor–MDM2 binding. Our findings also indicate that peptide inhibitors yield more interaction contacts with MDM2 compared to non-peptide inhibitors. Principal component analysis (PCA) and free energy landscape (FEL) analysis indicated that the piperidinone inhibitor 0Y7 shows the most pronounced impact on the free energy profiles of MDM2, with the piperidinone inhibitor demonstrating higher fluctuation amplitudes along primary eigenvectors. The hot spots of MDM2 revealed by residue-based free energy estimation provide target sites for drug design toward MDM2. This study is expected to provide useful theoretical aid for the development of selective inhibitors of MDM2 family members.
Bromodomain 4 and 9 (BRD4 and BRD9) have been regarded as important targets of drug designs in regard to the treatment of multiple diseases. In our current study, molecular dynamics (MD) simulations, ...deep learning (DL) and binding free energy calculations are integrated to probe the binding modes of three inhibitors (H1B, JQ1 and TVU) to BRD4 and BRD9. The MD trajectory-based DL successfully identify significant functional function domains, such as BC-loop and ZA-loop. The information from the post-processing analysis of MD simulations indicates that inhibitor binding highly influences the structural flexibility and dynamic behavior of BRD4 and BRD9. The results of the MM-GBSA calculations not only suggest that the binding ability of H1B, JQ1 and TVU to BRD9 are stronger than to BRD4, but they also verify that van der Walls interactions are the primary forces responsible for inhibitor binding. The hot spots of BRD4 and BRD9 revealed by residue-based free energy estimation provide target sites of drug design in regard to BRD4 and BRD9. This work is anticipated to provide useful theoretical aids for the development of selective inhibitors over BRD family members.
The differential expression of circular RNAs (circRNAs) in individuals with very severe chronic obstructive pulmonary disease (COPD) and healthy individuals was screened using microarray technology. ...The related functions and mechanisms were analyzed using bioinformatic methods to explore the potential of target circRNAs as biomarkers of COPD and provide insights for future pathogenesis.
Thirty patients with very severe COPD and thirty healthy controls were diagnosed at The Second People's Hospital of Hefei from September 2021 to September 2022. The differential expression of circRNAs was compared and analyzed using a gene microarray and verified using quantitative real-time polymerase chain reaction (qRT-PCR) technology.
A total of 90 upregulated and 29 downregulated circRNAs were screened in patients with very severe COPD and compared with those in healthy controls. qRT-PCR analysis showed that hsa_circ_0062683 of patients with very severe COPD was significantly upregulated, and hsa_circ_0089763 and hsa_circ_0008882 were significantly downregulated. By constructing the circRNA-miRNA interaction network, it was found that hsa-miR-612, hsa-miR-593-5p, hsa-miR-765, and hsa-miR-103a-2-5p are the miRNAs regulated by more differentially expressed circRNAs (DEcircRNAs). DEcircRNAs may participate in the development of COPD through hypoxia or regulation of various immune cells.
Plasma circRNAs may play a helpful role in the diagnosis and assessment of COPD and be valuable disease biomarkers.
Conducting load pattern analysis is an important task in obtaining typical load profiles (TLPs) of customers and grouping them into classes according to their load characteristics. When using ...clustering techniques to obtain the load patterns of electricity customers, choosing a suitable clustering algorithm and determining an appropriate cluster number are always important and difficult issues. Therefore, this paper proposes a stability index for choosing the most suitable clustering algorithm and a priority index (based on the stability index) for determining the priority rank of clusters. Based on three known clustering algorithms, an analysis approach is presented to demonstrate the use of these indices. In the approach, all load curves of customers are first clustered with the clustering algorithms under a serial given number of clusters. The two above-mentioned indices are then calculated. Following this, the most suitable clustering algorithm is chosen and the optimal number of clusters can be determined from the rank list for special application purposes. A case study with large electricity customers connected to a distribution network in Northern China illustrates the approach. The results prove the efficiency of the approach using the proposed indices in the classification and generation of the TLPs of large electricity customers.
A new Pb-free Ag paste containing a Bi2O3-B2O3-ZnO glass frit was developed for Al2O3 substrate metallization. First, Bi2O3-B2O3-ZnO glass frits with various compositions and glass transition ...temperatures (Tg) of 322 °C–440 °C were synthesized by using a traditional melt-quenching method. Then, silver pastes containing different contents of the glass frit were sintered on an Al2O3 substrate at temperatures ranging from 450 °C to 600 °C. The glass frit content and the sintering temperature had significant impacts on the electrical resistivity and shear strength of the product. The experimental results indicated that the silver film formed from the paste containing 7 wt.% glass frit and sintered at 600 °C for 15 min had a low electrical resistivity of 2.5 μΩ cm and a high strength of 28.5 MPa. These properties resulted from the formation of a stable glass network that supported the Ag network. Furthermore, ZnAl2O4 was observed to form close to the interface of the Al2O3 substrate, which could improve the shear strength. Moreover, the Bi-based glass frit could be a suitable substitute for Pb-based glass frits in the preparation of environmentally friendly silver pastes for forming thick Ag films on Al2O3 substrates.
CDK6 plays a key role in the regulation of the cell cycle and is considered a crucial target for cancer therapy. In this work, conformational transitions of CDK6 were identified by using Gaussian ...accelerated molecular dynamics (GaMD), deep learning (DL), and free energy landscapes (FELs). DL finds that the binding pocket as well as the T-loop binding to the Vcyclin protein are involved in obvious differences of conformation contacts. This result suggests that the binding pocket of inhibitors (LQQ and AP9) and the binding interface of CDK6 to the Vcyclin protein play a key role in the function of CDK6. The analyses of FELs reveal that the binding pocket and the T-loop of CDK6 have disordered states. The results from principal component analysis (PCA) indicate that the binding of the Vcyclin protein affects the fluctuation behavior of the T-loop in CDK6. Our QM/MM-GBSA calculations suggest that the binding ability of LQQ to CDK6 is stronger than AP9 with or without the binding of the Vcyclin protein. Interaction networks of inhibitors with CDK6 were analyzed and the results reveal that LQQ contributes more hydrogen binding interactions (HBIs) and hot interaction spots with CDK6. In addition, the binding pocket endures flexibility changes from opening to closing states and the Vcyclin protein plays an important role in the stabilizing conformation of the T-loop. We anticipate that this work could provide useful information for further understanding the function of CDK6 and developing new promising inhibitors targeting CDK6.
The phosphorylation of different sites produces a significant effect on the conformational dynamics of KRAS. Gaussian accelerated molecular dynamics (GaMD) simulations were combined with deep ...learning (DL) to explore the molecular mechanism of the phosphorylation-mediated effect on conformational dynamics of the GTP-bound KRAS. The DL finds that the switch domains are involved in obvious differences in conformation contacts and suggests that the switch domains play a key role in the function of KRAS. The analyses of free energy landscapes (FELs) reveal that the phosphorylation of pY32, pY64, and pY137 leads to more disordered states of the switch domains than the wild-type (WT) KRAS and induces conformational transformations between the closed and open states. The results from principal component analysis (PCA) indicate that principal motions PC1 and PC2 are responsible for the closed and open states of the phosphorylated KRAS. Interaction networks were analyzed and the results verify that the phosphorylation alters interactions of GTP and magnesium ion Mg
with the switch domains. It is concluded that the phosphorylation pY32, pY64, and pY137 tune the activity of KRAS through changing conformational dynamics and interactions of the switch domains. We anticipated that this work could provide theoretical aids for deeply understanding the function of KRAS.
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Electronic cigarettes (e-cigarettes) have rapidly gained popularity as alternatives to traditional combustible cigarettes. However, their long-term health impact remains uncertain. ...This study aimed to investigate the effects of chronic exposure to e-cigarette aerosol (ECA) in mice compared to conventional cigarette smoke (CS) exposure. The mice were exposed to air (control), low, medium, or high doses of ECA, or a reference CS dose orally and nasally for eight months. Various cardiovascular and pulmonary assessments have been conducted to determine the biological and prosthetic effects. Histopathological analysis was used to determine structural changes in the heart and lungs. Biological markers associated with fibrosis, inflammation, and oxidative stress were investigated. Cardiac proteomic analysis was applied to reveal the shared and unique protein expression changes in ECA and CS groups, which related to processes such as immune activation, lipid metabolism, and intracellular transport. Overall, chronic exposure to ECA led to adverse cardiovascular and pulmonary effects in mice, although they were less pronounced than those of CS exposure. This study provides evidence that e-cigarettes may be less harmful than combustible cigarettes for the long-term health of the cardiovascular and respiratory systems in mice. However, further human studies are needed to clarify the long-term health risks associated with e-cigarette use.
Abstract
Inkjet-printed electronics have become a popular research topic in recent years. For common drop-on-demand (DOD) inkjet printing technology, uneven edges are a universal problem. Many ...factors, such as the properties of the ink and printing parameters, influence this problem, and numerical methods are better than experimental methods for studying these influences. In this paper, a model based on the Volume of Fluid (VOF) method and user-defined files (UDFs) in Ansys F is established to simulate the formation process of deposited ink droplets. The model and UDFs include the friction effect, and the morphology of a single droplet, two fused droplets, and multiple droplets is simulated to study the influence of different factors; some results can serve as guidelines for improving pattern quality. Finally, the effect of selective treatment is also studied to understand its advantages for inkjet printing.
Electronic cigarette (EC) has been suggested to be less harmful than cigarette smoking, but the research on the full extent of their harm reduction potential is still lacking. This study aimed to ...evaluate the influence of EC aerosol and cigarette smoke (CS) on cardiovascular, gastrointestinal, and renal functions in mice after prolonged exposure. Forty-eight C57BL/6J male mice were randomly grouped and then exposed to fresh air (control), mung bean-flavored EC aerosol with low and high dose (EC1L, 6 mg/kg; EC1H, 12 mg/kg), watermelon-flavored EC aerosol with low and high dose (EC2L, 6 mg/kg; EC2H, 12 mg/kg), and finally a cigarette smoke (CS, 6 mg/kg), respectively. After 10 weeks of exposure, the heart rate increased for both the EC and CS groups, and the effect of CS on blood oxygen saturation was significantly higher than that of the EC group (P < 0.01). Proteomic analysis of the heart tissue showed that the overlapped differential expression protein from the EC and CS exposures was Crip2. For the gastrointestinal system, oral mucosa was significantly damaged in CS group. Compare with CS, EC had significantly fewer negative effects on most of the indictors which focused on in this study.
