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Colorectal cancer is considered one of the leading causes of death that is linked with the Kirsten Rat Sarcoma (KRAS) harboring codons 13 and 61 mutations. The objective for this study is to search for clinically important codon 61 mutations and analyze how they affect the protein structural dynamics. Additionally, a deep-learning approach is used to carry out a similarity search for potential compounds that might have a comparatively better affinity. Public databases like The Cancer Genome Atlas and Genomic Data Commons were accessed for obtaining the data regarding mutations that are associated with colon cancer. Multiple analysis such as genomic alteration landscape, survival analysis, and systems biology-based kinetic simulations were carried out to predict dynamic changes for the selected mutations. Additionally, a molecular dynamics simulation of 100 ns for all the seven shortlisted codon 61 mutations have been conducted, which revealed noticeable deviations. Finally, the deep learning-based predicted compounds were docked with the KRAS 3D conformer, showing better affinity and good docking scores as compared to the already existing drugs. Taking together the outcomes of systems biology and molecular dynamics, it is observed that the reported mutations in the SII region are highly detrimental as they have an immense impact on the protein sensitive sites' native conformation and overall stability. The drugs reported in this study show increased performance and are encouraged to be used for further evaluation regarding the situation that ascends as a result of KRAS mutations.

The Linghu Au deposit is located within the northeastern part of the Xiaoqinling region in the southern margin of the North China Craton. Field investigations, cross-cutting relationships, and mineral paragenetic associations have identified three stages of hydrothermal activity. To determine the origin and evolution of ore-forming fluids, and better understand genesis of the Linghu Au deposit, we have undertaken a series of studies including fluid inclusion and He–Ar–H–O–S–Pb isotope systematics. Fluid inclusion study indicates that the early stage of gold mineralization was characterized by a high-temperature and low-salinity H2O–CO2–NaCl hydrothermal fluids that have δD values of – 82.0 to – 78.6‰ and δ18OH2O values of 5.3 to 6.4‰. The intermediate stage of gold mineralization involved moderate temperature H2O–CO2–NaCl hydrothermal fluids with δD and δ18OH2O values of – 92.7‰ to – 87.9‰ and – 1.4‰ to 0‰, respectively. Pyrite samples from this mineralization stage have 3He/4He and 40Ar/36Ar ratios of 0.26–0.31 Ra and 2834.7–4300.6, respectively. The last mineralization stage involved (low-temperature and low-salinity NaCl–H2O system of hydrothermal fluids with relatively lower δD values of – 93.1 to – 92.3‰ and δ18OH2O values of – 5.7 to – 5.2‰. Moreover, sulfides in ores yielded δ34S values of – 3.6 to 5.9‰, with an average of 2.65‰. The sulfides have 206Pb/204Pb ratios of 17.101–17.804, 207Pb/204Pb ratios of 15.438–15.554, and 208Pb/204Pb ratios of 37.438–38.654. The results of fluid inclusions and H–O, S–Pb, and He–Ar isotopes indicate that hydrothermal fluids associated with the early stage of mineralization originated from magmatic fluids, with sulfur and lead being derived from both units of the Taihua Group and a Late Triassic magmatic–hydrothermal system. All of these data indicate that the Linghu gold deposit formed as a result of magmatic–hydrothermal mineralizing processes.

Helicobacter pylori (H. pylori) is one of the most extensively studied Gram-negative bacteria due to its implication in gastric cancer. The oncogenicity of H. pylori is associated with cytotoxin-associated gene A (CagA), which is injected into epithelial cells lining the stomach. Both the C- and N-termini of CagA are involved in the interaction with several host proteins, thereby disrupting vital cellular functions, such as cell adhesion, cell cycle, intracellular signal transduction, and cytoskeletal structure. The N-terminus of CagA interacts with the tumor-suppressing protein, apoptosis-stimulating protein of p53 (ASPP2), subsequently disrupting the apoptotic function of tumor suppressor gene p53. Here, we present the in-depth molecular dynamic mechanism of the CagA–ASPP2 interaction and highlight hot-spot residues through in silico mutagenesis. Our findings are in agreement with previous studies and further suggest other residues that are crucial for the CagA–ASPP2 interaction. Furthermore, the ASPP2-binding pocket possesses potential druggability and could be engaged by decoy peptides, identified through a machine-learning system and suggested in this study. The binding affinities of these peptides with CagA were monitored through extensive computational procedures and reported herein. While CagA is crucial for the oncogenicity of H. pylori, our designed peptides possess the potential to inhibit CagA and restore the tumor suppressor function of ASPP2.

Papermaking technique was applied to fabricate the centrifuged glassfiber mat (CGM). This paper discussed the influence of the number of beating revolutions on the morphology, drainability and abso...

A drug may be metabolized by multiple cytochrome P450 (CYP450) isoforms. Predicting the metabolic fate of drugs is very important to prevent drug-drug interactions in the development of novel pharmaceuticals. Prediction of CYP450 enzyme-substrate selectivity is formulized as a multilabel learning task in this study. First, we compared the performance of feature combinations based on four different categories of features, which are physiochemical property descriptors, mol2vec descriptors, extended connectivity fingerprints, and molecular access system key fingerprints on modeling. After identifying the best combination of features, we applied seven different multilabel models, which are multilabel

Rivaroxaban (RIV) is a direct oral anticoagulant (DOAC) targeting activated coagulation factor X (FXa). An earlier study reported the F174A mutant of FXa resistant to a RIV-like inhibitor, Apixaban. In current study, the detailed molecular mechanism of the resistance has been explored by molecular dynamics simulations on the impaired interactions between RIV and FXa in the damaged S4 pocket of F174A mutant. Besides, an unexpected relative stable binding mode of S1'S1 was revealed, which required dynamic motions of Gln192 and Gln61 to allow the morpholinone moiety of RIV to shift into the S1' pocket and form strong interactions. These dynamic motions of RIV and critical residues might be important in drug design for direct inhibitors of coagulation factors.

The LaF3-coated Li[Li0.2Mn0.54Ni0.13Co0.13]O2 nanoparticles were synthesized via co-precipitation method followed by simple chemical deposition process. The crystal structure, particle morphology, and electrochemical properties of the bare and coated materials were studied by XRD, SEM, TEM, charge–discharge tests. The results showed that the surface coating on Li[Li0.2Mn0.54Ni0.13Co0.13]O2 nanoparticles were amorphous LaF3 layer with a thickness of about 10–30 nm. After the surface modification with LaF3 films, the coating layer served as a protective layer to suppress the side reaction between the positive electrode and electrolyte, and the Li[Li0.2Mn0.54Ni0.13Co0.13]O2 oxide demonstrated the improved electrochemical properties. The LaF3-coated Li[Li0.2Mn0.54Ni0.13Co0.13]O2 electrode delivered the capacities of 270.5, 247.9, 197.1, 170.0, 142.7, and 109.5 mAh g−1 at current rates of 0.1, 0.2, 0.5, 1, 2, and 5 C rate, respectively. Besides, the capacity retention was increased from 85.1 to 94.8 % after 100 cycles at 0.5 C rate. It implied surface modification with LaF3 played an important role to improve the cyclic stability and rate capacity of the Li-rich nickel manganese oxides.

The FeF3-coated Li[Li0.2Mn0.54Ni0.13Co0.13]O2 cathode materials were synthesized via a wet chemical process followed by a solid state reaction. The physical properties of the as-prepared samples were conducted using X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The results indicated that the surface of cathode particles was covered by FeF3 film (about 5–15 nm thick). Compared with the bare cathode, the FeF3-coated Li[Li0.2Mn0.54Ni0.13Co0.13]O2 one delivered the higher coulombic efficiency, better rate capability, longer cycle life, and better structure stability. A high capacity retention of 95% (190 mAh g− 1) after 100 cycles at 0.5 C rate was obtained for the FeF3-coated Li[Li0.2Mn0.54Ni0.13Co0.13]O2 cathode. Besides, the results from cyclic voltammetry and electrochemical impedance spectra revealed that the noteworthy enhanced electrochemical properties of the surface-modified sample were due to the presence of FeF3 coating layer, which suppressed the side reaction between the Li[Li0.2Mn0.54Ni0.13Co0.13]O2 particles with electrolyte and further stabilized the Li[Li0.2Mn0.54Ni0.13Co0.13]O2 structure with cycling.

C99 is the immediate precursor of amyloid-β (Aβ) and therefore is a central intermediate in the pathway that is believed to result in Alzheimer's disease (AD). Recent studies have shown that C99 dimerization changes the Aβ ratio, but the mechanism remains unclear. Previous studies of the C99 dimer have produced controversial structure models. To address these questions, we investigated C99 dimerization using molecular dynamics (MD) simulations. A helix-switch model was revealed in the formation and transition of the C99 dimer, and six types of conformations were identified. The different conformations show differential exposures of γ-cleavage sites and insertion depths in the bilayer, which may modulate γ-cleavage of C99 and lead to different Aβ levels. Our results redefine C99 dimerization, provide a framework to mediate the current controversial results, and give insights into the understanding of the relationship between C99 dimerization and Aβ formation.