A quantum mechanics/molecular mechanics study on the hydrolysis mechanism of New Delhi metallo-β-lactamase-1

New Delhi metallo-β-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known β-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing β-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C–N bond within the β-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem β-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.     

Studies on the Synthesis and Antiproliferative Activities of 13‐cis‐Retinoyl Sugar Derivatives

New retinoyl sugar derivatives of 13‐cis‐retinoic acid were synthesized in three ways in this paper in order to enhance pharmacal effects, especially antiproliferative activities of 13‐cis‐retinoic acid. Their structures were confirmed by IR, ¹H‐NMR, ¹³C‐NMR, and MS spectra and their antiproliferative activities were determined in vitro using human cancer lines. Results showed that some compounds possessed potential antitumor activities.     

On a problem of Hornik

In 1991,Hornik proved that the collection of single hidden layer feedforward neural networks(SLFNs)with continuous,bounded,and non-constant activation functionσis dense in C(K)where K is a compact set in R~s(see Neural Networks,4(2),251-257(1991)).Meanwhile,he pointed out"Whether or not the continuity assumption can entirely be dropped is still an open quite challenging problem".This paper replies in the affirmative to the problem and proves that for bounded and continuous almost everywhere(a.e.)activation functionσon R,the collection of SLFNs is dense in C(K)if and only ifσis un-constant a.e..     

A one-pot tandem synthesis of various 1,2-disubstituted benzimidazoles

A facile method to synthesize various 1,2-disubstituted benzimidazoles is developed. It is suggested that formation of a Meisenheimer adduct between the substrate, amine, and solvent aids the N-arylation process. The generality of the protocol is demonstrated by the efficient reactions involving numerous substituents ranging from electron-withdrawing groups to electron-donating groups.     

Pd-catalyzed assembly of phenanthridines from aryl ketone O-acetyloximes and arynes through C–H bond activation

Pd-catalyzed annulation of aryne and aryl ketone O-acetyloxime via C–H bond activation was realized. Through the C–H bond activation/insertion/cyclization/elimination reaction sequence, phenanthridines are successfully constructed, providing an attractive strategy to approach substituted heterocycle without preactivation of starting materials.     

Self-calibration method for cerium-doped lanthanum bromide scintillator detector in the 0.1–2.0 MeV energy range

In recent years, the cerium-doped lanthanum bromide, LaBr₃ (Ce = 5 %) detector is increasingly playing an important role in radiation measurements because of its higher energy resolution (~3 % at 662 keV), faster luminescence decay time (~35 ns) and higher detection efficiency compared to 7.65 cm × 7.65 cm NaI(Tl) detector. Intrinsic spectra between 1,800 and 3,000 keV derived from internal radioactivity within LaBr₃(Ce) scintillators have been investigated in some literatures, and these results are confirmed by the experiments in this work. In this paper, a new method for LaBr₃(Ce) detector energy calibration from 100 to 2,000 keV is proposed using the intrinsic spectra (self-calibration) instead of the standard gamma sources. Proof-of-concept experiment results show that self-calibration can guarantee energy accuracy of better than 0.815 % and can be applied outside the laboratory. The stability and applicability of this method are also investigated systematically.     

Neutral 1D Perovskite-Type ABX3 Phase Transition Material with a Narrowband Emission and Semiconductor Property

Cyclic organic amines are emerging as excellent building blocks to assemble organic–inorganic hybrid phase transition materials due to their flexible cyclic structure. Here, we have assembled a 1D organic-inorganic hybrid dielectric material C₅H₆NOPbBr₃ ( 1 ) by alloying the cyclic organic amine 3-hydroxypyridine. 1 displays a remarkable switchable dielectric response induced by an order-disorder transformation of the organic moiety, this transformation behaviour is confirmed by DSC and Hirshfeld surface measurements. More interestingly, 1 has a narrowband emission (FWHM=4.64 nm) at 590 nm; FWHM is a major quality figure for narrowband photodetectors. In addition, 1 exhibits semiconducting properties with an indirect bandgap of 2.78 eV by the analysis of the UV-Vis absorption results.     

Improved Stabilities of Labeling Probes for the Selective Modification of Endogenous Proteins in Living Cells and In Vivo

To date, various affinity-based protein labeling probes have been developed and applied in biological research to modify endogenous proteins in cell lysates and on the cell surface. However, the reactive groups on the labeling probes are also the cause of probe instability and nonselective labeling in a more complex environment, e. g., intracellular and in vivo. Here, we show that labeling probes composed of a sterically stabilized difluorophenyl pivalate can achieve efficient and selective labeling of endogenous proteins on the cell surface, inside living cells and in vivo. As compared with the existing protein labeling probes, probes with the difluorophenyl pivalate exhibit several advantages, including long-term stability in stock solutions, resistance to enzymatic hydrolysis and can be customized easily with diverse fluorophores and protein ligands. With this probe design, endogenous hypoxia biomarker in living cells and nude mice were successfully labeled and validated by in vivo, ex vivo, and immunohistochemistry imaging.