Molecular Insights into the Heterotropic Allosteric Mechanism in Cytochrome P450 3A4-Mediated Midazolam Metabolism

Cytochrome P450 3A4 (CYP3A4) is the main P450 enzyme for drug metabolism and drug–drug interactions (DDIs), as it is involved in the metabolic process of approximately 50% of drugs. A detailed mechanistic elucidation of DDIs mediated by CYP3A4 is commonly believed to be critical for drug optimization and rational use. Here, two typical probes, midazolam (MDZ, substrate) and testosterone (TST, allosteric effector), are used to investigate the molecular mechanism of CYP3A4-mediated heterotropic allosteric interactions, through conventional molecular dynamics (cMD) and well-tempered metadynamics (WT-MTD) simulations. Distance monitoring shows that TST can stably bind in two potential peripheral sites (Site 1 and Site 2) of CYP3A4. The binding of TST at these two sites can induce conformational changes in CYP3A4 flexible loops on the basis of conformational analysis, thereby promoting the transition of the MDZ binding mode and affecting the ratio of MDZ metabolites. According to the results of the residue interaction network, multiple allosteric communication pathways are identified that can provide vivid and applicable insights into the heterotropic allostery of TST on MDZ metabolism. Comparing the regulatory effects and the communication pathways, the allosteric effect caused by TST binding in Site 2 seems to be more pronounced than in Site 1. Our findings could provide a deeper understanding of CYP3A4-mediated heterotropic allostery at the atomic level and would be helpful for rational drug use as well as the design of new allosteric modulators

Additional file 1 of Effects of electroconvulsive therapy on functional brain networks in patients with schizophrenia

Additional file 1

Synthesis, liquid crystalline mesophases and morphologies of diblock copolymers composed of a poly(dimethylsiloxane) block and a nematic liquid crystalline block

<p>In this study, a series of liquid crystalline diblock copolymers, composed of a soft poly(dimethylsiloxane) (PDMS) block with a defined length and a side-on liquid crystalline poly(3ʹʹ-acryloyloxypropyl 2,5-di(4ʹ-butyloxybenzoyloxy) benzoate) (P3ADBB) block with different lengths, are synthesised by the atom transfer radical polymerisation. The macromolecular structures, liquid crystalline properties and the microphase-separated morphologies of the diblock copolymer are investigated by ¹H NMR, FT-IR, GPC, POM, DSC and TEM. The results show that the well-defined diblock copolymers (PDMS_n-<i>b</i>-P3ADBB_m) possess four different soft/rigid ratios (<i>n</i> = 58, <i>m</i> = 10, 25, 42, 66) and relatively narrow molecular distributions (PDI ≤ 1.30). P3ADBB blocks of the copolymers show nematic sub-phases, which are identical to the mesomorphic behaviour of the homopolymer P3ADBB. After being annealed at 90°C in a vacuum oven for 48 h, the copolymers form a lamellar morphology when <i>m</i> = 10 and morphologies of PDMS spheres embedded in P3ADBB matrix when <i>m</i> = 25, 42 and 66.</p

Filtration efficiency analysis of fibrous filters: Experimental and theoretical study on the sampling of agglomerate particles emitted from a GDI engine

<p>Fibrous filters are commonly used for aerosol purification and sampling. The filtration efficiency has been extensively studied using standard aerosol generators, yet the literature on experimental data and theoretical study concerning the filtration of agglomerates from real engines remains scarce. A filtration efficiency test system was developed to determine the filtration efficiency of two types of filters (uncoated and fluorocarbon coated) loaded by particulate matter (PM) emissions from a gasoline direct injection (GDI) engine. The experimental results showed that the filtration efficiency in terms of PM mass and number increased over time for both types of filters. The fractional efficiency (penetration efficiency) curves for the test fibrous filters rendered a U-shaped curve for particle sizes from 70 to 500 nm, and the most penetrating particulate size (MPPS) decreased over time. A small fraction of accumulation mode particles with the size between 70 nm to 500 nm penetrated the filters while almost all nucleation mode particles with the size below 50 nm were captured by the filters. The filtration efficiency derived from an empirical model based on classical single-fiber theory for laden filters generally agreed with the experimental data for the first 500 s, but suffered a significant deviation by approximately one order of magnitude at 948 s. A better estimate of the filtration efficiency trend with the maximum deviation of about 20% (except for large particles at the high end of the measurement spectra) was obtained by using a revised model which incorporates the effects of the increase in filter solidity, local velocity, dynamic shape factor and effective total length of fibers during the filtration process.</p> <p>© 2017 American Association for Aerosol Research</p

Self-Assembly Hierarchical Silica Nanotubes with Vertically Aligned Silica Nanorods and Embedded Platinum Nanoparticles

We report a simple method for the fabrication of hierarchical silica-Pt nanotubes. In the system, initial Pt NPs can be obtained via the reduction of H₂PtCl₆ with trisodium citrate as reductant. The self-assembled SiO₂@Pt@SiO₂ spheres were stuck together and etched through the “surface-protected etching” strategy. Many vertically aligned silica branches <i>in situ</i> grew from the inlaid SiO₂@Pt@SiO₂ spheres, fabricating the hierarchical silica-Pt nanotubes automatically. TEM and SEM were conducted to monitor the morphological evolution. The effects of the PVP concentration and molar ratios of NH₄OH to TEOS have also been investigated with a series of contrast experiments. Furthermore, in this work, several potential applications of HSNs have been investigated, such as the synthesis of Pt-CeO₂ nanotubes and other single or double metal nanotubes. Besides, the hierarchical silica-Pt nanotubes exhibited a high thermal stability and excellent catalytic performance in the reaction of propane dehydrogenation, suggesting their potential application in various high-temperature reactions

Sulfone-Rhodamines: A New Class of Near-Infrared Fluorescent Dyes for Bioimaging

Given the wavelength dependence of tissue transparency and the requirement for sufficiently low background autofluorescence, the development of fluorescent dyes with excitation and emission maxima beyond 700 nm is highly desired, but it is a challenging task. Herein, a new class of fluorescent dyes, named sulfone-rhodamines (SO₂Rs), was developed on the basis of the one-atom replacement of the rhodamine 10-position O atom by a sulfone group. Such a modification makes their absorption and emission maxima surprisingly reach up to 700–710 and 728–752 nm, respectively, much longer than their O-, C-, and Si-rhodamine analogs, due to the unusual d*−π* conjugation. Among these dyes, <b>SO</b>_<b>2</b><b>R4</b> and <b>SO</b>_<b>2</b><b>R5</b>, bearing disubstituted <i>meso</i>-phenyl groups, show the greatest potentials for bioimaging applications in view of their wide pH range of application, high photostability, and big extinction coefficients and fluorescence quantum yields. They could quickly penetrate cells to give stable NIR fluorescence, even after continuous irradiation by a semiconductor laser, making them suitable candidates for time-lapse and long-term bioimaging applications. Moreover, they could specifically localize in lysosomes independent of alkylmorpholine targeted group, thus avoiding the problematic alkalization effect suffered by most LysoTrackers. Further imaging assays of frozen slices of rat kidney reveal that their tissue imaging depth is suprior to the widely used NIR labeling agent Cy5.5

Fabrication of Ellipsoidal Silica Yolk–Shell Magnetic Structures with Extremely Stable Au Nanoparticles as Highly Reactive and Recoverable Catalysts

A novel strategy was reported for the fabrication of yolk–shell magnetic MFSVmS-Au nanocomposites (NCs) consisting of double-layered ellipsoidal mesoporous silica shells, numerous sub-4 nm Au nanoparticles (NPs), and magnetic Fe central cores. The hierarchical FSVmS NCs with ellipsoidal α-Fe₂O₃@mSiO₂/mSiO₂ as yolks/shells were first prepared through the facile sol–gel template-assisted method, and plenty of extremely stable ultrafine Au NPs were postencapsulated within interlayer cavities through the unique deposition–precipitation method mediated with Au­(en)₂Cl₃ compounds. Notably, ethylenediamine ligands were used to synthesize the stable cationic complexes, [Au­(en)₂]³⁺, that readily underwent the deprotonation reaction to chemically modify negatively charged mesoporous silica under alkaline conditions. The subsequent two-stage programmed hydrogen annealing initiated the in situ formation of Au NPs and the reduction of α-Fe₂O₃ to magnetic Fe, where the synthesized Au NPs were highly resistant to harsh thermal sintering even at 700 °C. Given its structural superiority and magnetic nature, the MFSVmS-Au was demonstrated to be a highly efficient and recoverable nanocatalyst with superior activity and reusability toward the reduction of 4-nitrophenol to 4-aminophenol, and the pristine morphology was retained after six recycling tests

Individual genotyping results for the two SNPs of Neurexin 3.

*<p>For combined samples.</p

Top 10 SNPs associated with DEACMP in the pooling-based GWA in both genders.

<p>Top 10 SNPs associated with DEACMP in the pooling-based GWA in both genders.</p

Data_Sheet_1_Plantaricin BM-1 decreases viability of SW480 human colorectal cancer cells by inducing caspase-dependent apoptosis.docx

Plantaricin BM-1 is a class IIa bacteriocin produced by Lactobacillus plantarum BM-1 that has significant antimicrobial activity against food-borne bacteria. In this study, a cell proliferation assay and scanning electron microscopy were used to detect changes in the viability of SW480, Caco-2, and HCT-116 colorectal cancer cells treated with plantaricin BM-1. We found that plantaricin BM-1 significantly reduced the viability of all colorectal cancer cell lines tested, especially that of the SW480 cells. Scanning electron microscopy showed that plantaricin BM-1 treatment reduced the number of microvilli and slightly collapsed the morphology of SW480 cells. Fluorescence microscopy and flow cytometry demonstrated that plantaricin BM-1 induced apoptosis of SW480 cells in a concentration-dependent manner. Western blotting further showed that plantaricin BM-1-induced apoptosis of SW480 cells was mediated by the caspase pathway. Finally, transcriptomic analysis showed that 69 genes were differentially expressed after plantaricin BM-1 treatment (p < 0.05), of which 65 were downregulated and four were upregulated. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that expression levels of genes involved in the TNF, NF-κB, and MAPK signaling pathways, as well as functional categories such as microRNAs in cancer and transcriptional misregulation in cancer, were affected in SW480 cells following the treatment with plantaricin BM-1. In conclusion, plantaricin BM-1 induced death in SW480 cells via the caspase-dependent apoptosis pathway. Our study provides important information for further development of plantaricin BM-1 for potential applications in anti-colorectal cancer.</p