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Pyrazinamidase (PZase) is a member of Fe-dependent amidohydrolases that activates pyrazinamide (PZA) into active pyrazinoic acid (POA). PZA, a nicotinamide analogue, is an essential first-line drug...

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.

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.

Half of the world population is infected by the Gram-negative bacterium Helicobacter pylori (H. pylori). It colonizes in the stomach and is associated with severe gastric pathologies including gastric cancer and peptic ulceration. The most virulent factor of H. pylori is the cytotoxin-associated gene A (CagA) that is injected into the host cell. CagA interacts with several host proteins and alters their function, thereby causing several diseases. The most well-known target of CagA is the tumor suppressor protein ASPP2. The subdomain I at the N-terminus of CagA interacts with the proline-rich motif of ASPP2. Here, in this study, we carried out alanine scanning mutagenesis and an extensive molecular dynamics simulation summing up to 3.8 μs to find out hot spot residues and discovered some new protein-protein interaction (PPI)-modulating molecules. Our findings are in line with previous biochemical studies and further suggested new residues that are crucial for binding. The alanine scanning showed that mutation of Y207 and T211 residues to alanine decreased the binding affinity. Likewise, dynamics simulation and molecular mechanics with generalized Born surface area (MMGBSA) analysis also showed the importance of these two residues at the interface. A four-feature pharmacophore model was developed based on these two residues, and top 10 molecules were filtered from ZINC, NCI, and ChEMBL databases. The good binding affinity of the CHEMBL17319 and CHEMBL1183979 molecules shows the reliability of our adopted protocol for binding hot spot residues. We believe that our study provides a new insight for using CagA as the therapeutic target for gastric cancer treatment and provides a platform for a future experimental study.

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.

Aluminum cables are playing an increasingly important role in power transmission system, in which the “rare-earth high-iron aluminum alloy power cables were developed in China. In this paper, the effects of B on grain refinement of high-iron aluminum alloy were studied by using OM (optical microscopy), SEM (scanning electron microscopy), EDX (energy dispersive X-Ray spectroscopy) and XRD (X-ray diffraction). And the conductivity of high-iron aluminum alloy was also tested. The results showed that B could take significant effects on grain refinement and promote the increase of conductivity. The refinement may be mainly due to the eutectic reaction in solidification process and the formation of AlB2 particles. The optimal concentration of B was determined as 0.06 wt. %.

It is generally believed that the etiology of Alzheimer's disease (AD) is closely related to the amyloid-β polypeptides, produced from γ-secretase cleavage of C99. There is preliminary evidence that cholesterol directly activates γ-secretase cleavage of C99 through mechanisms that have not been understood so far. In this article, coarse-grained (CG) and all-atom (AT) simulations were employed to investigate the association between C99 and cholesterol, which is essential for our understanding of the role of cholesterol in the amyloidogenic pathway. Firstly, we find that both the N-terminus and the C-terminus of the C99 transmembrane domain (TMD) show interactions with cholesterol. Secondly, a multi-site dynamic cholesterol binding model was captured from the simulations, where 6 binding sites in the C99 TMD were presented. The analyses of the binding energies show that cholesterol prefers the site no. 1, 2, 4 and 5 over others. The most favorable binding energy of nearly −58.857 kJ mol−1 is from site 1, the repeat GxxxG motif. There are two pathways and two binding states of cholesterol binding to this site. Ser697 and Phe690 contribute most to the stabilization of the tightly binding state and the loosely binding state, respectively. The other binding sites described may also be potential drug targets. Thirdly, the residues GAVILMTKF, especially IVKF play a key role in this association. The C99 model appears to suggest a new mechanism for cholesterol binding. Finally, the multiple-site dynamic cholesterol binding model better explains the hypotheses that cholesterol promotes the amyloidogenic AβPP route. The GxxxA motif in the middle of the C99 transmembrane domain is completely exposed without cholesterol sheltering, which might help γ-secretase identify the cleavage sites and then promote γ-cleavage. Our results provide a detailed picture of dynamic cholesterol binding, which is crucial to our recognition of the potential influence of cholesterol on the C99 process and the etiology of AD.

To increase the industrial applicability of hypereutectic Al-Si alloys, various methods have been used to refine primary silicon. The addition and refinement effects of phosphorus (P), rare earth metals (RE) on primary Si have been studied widely, But they have been testified be with some disadvantages, that is, the pollution to the environment of P and the high cost of RE, etc. Now, a new refiner - ZnS and the corresponding processing technology were researched. Microstructures of hypereutectic Al-Si alloy (Si wt. 24%) with fine primary Si were successfully obtained. And the primary Si can be refined from more than 80μm to 20μm. And the distribution of primary silicon is getting more uniform.

Magnesium oxychloride cement sawdust concrete box caused great harm to the environment. This article introduced the method to recycle the box. Magnesium oxychloride cement sawdust concrete was gradually heated, in the range of 0 ~ 800°C, and then the residue was calcined at 700 ° C. Studies showed that the 5•1•8 and sawdust in the box was decomposed into MgO in high temperature conditions. The X-ray diffraction examination results showed that the content of this MgO reached 90%. The application the MgO is very wide.

The DAP12-NKG2C activating immunoreceptor complex is one of the multisubunit transmembrane protein complexes in which ligand-binding receptor chains assemble with dimeric signal-transducing modules through non-covalent associations in their transmembrane (TM) domains. In this work, both coarse grained and atomistic molecular dynamic simulation methods were applied to investigate the self-assembly dynamics of the transmembrane domains of the DAP12-NKG2C activating immunoreceptor complex. Through simulating the dynamics of DAP12-NKG2C TM heterotrimer and point mutations, we demonstrated that a five-polar-residue motif including: 2 Asps and 2 Thrs in DAP12 dimer, as well as 1 Lys in NKG2C TM plays an important role in the assembly structure of the DAP12-NKG2C TM heterotrimer. Furthermore, we provided clear evidences to exclude the possibility that another NKG2C could stably associate with the DAP12-NKG2C heterotrimer. Based on the simulation results, we proposed a revised model for the self-assembly of DAP12-NKG2C activating immunoreceptor complex, along with a plausible explanation for the association of only one NKG2C with a DAP12 dimer.