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New antimalarial drugs are needed. The benzoxaborole AN13762 showed excellent activity against cultured Plasmodium falciparum, against fresh Ugandan P. falciparum isolates, and in murine malaria models. To gain mechanistic insights, we selected in vitro for P. falciparum isolates resistant to AN13762. In all of 11 independent selections with 100 to 200 nM AN13762, the 50% inhibitory concentration (IC50) increased from 18-118 nM to 180-890 nM, and whole-genome sequencing of resistant parasites demonstrated mutations in prodrug activation and resistance esterase (PfPARE). The introduction of PfPARE mutations led to a similar level of resistance, and recombinant PfPARE hydrolyzed AN13762 to the benzoxaborole AN10248, which has activity similar to that of AN13762 but for which selection of resistance was not readily achieved. Parasites further selected with micromolar concentrations of AN13762 developed higher-level resistance (IC50, 1.9 to 5.0 μM), and sequencing revealed additional mutations in any of 5 genes, 4 of which were associated with ubiquitination/sumoylation enzyme cascades; the introduction of one of these mutations, in SUMO-activating enzyme subunit 2, led to a similar level of resistance. The other gene mutated in highly resistant parasites encodes the P. falciparum cleavage and specificity factor homolog PfCPSF3, previously identified as the antimalarial target of another benzoxaborole. Parasites selected for resistance to AN13762 were cross-resistant with a close analog, AN13956, but not with standard antimalarials, AN10248, or other benzoxaboroles known to have different P. falciparum targets. Thus, AN13762 appears to have a novel mechanism of antimalarial action and multiple mechanisms of resistance, including loss of function of PfPARE preventing activation to AN10248, followed by alterations in ubiquitination/sumoylation pathways or PfCPSF3.IMPORTANCE Benzoxaboroles are under study as potential new drugs to treat malaria. One benzoxaborole, AN13762, has potent activity and promising features, but its mechanisms of action and resistance are unknown. To gain insights into these mechanisms, we cultured malaria parasites with nonlethal concentrations of AN13762 and generated parasites with varied levels of resistance. Parasites with low-level resistance had mutations in PfPARE, which processes AN13762 into an active metabolite; PfPARE mutations prevented this processing. Parasites with high-level resistance had mutations in any of a number of enzymes, mostly those involved in stress responses. Parasites selected for AN13762 resistance were not resistant to other antimalarials, suggesting novel mechanisms of action and resistance for AN13762, a valuable feature for a new class of antimalarial drugs.

From the view of the mill main driving control system,instability model of the electromechanical system and control strategy were researched. In the premise of ensuring the steady and dynamic performance of the control system,the model of main drive of two inertial systems was simplified,the inside and outside disturbance of the system was observed by linear extended state observer. By linear feedback and dynamic error feedback method,the detection and control of electromechanical system failure were achieved. The closed loop controller design method based on simplified differential equation model was proposed,and validated by simulation and experiment. The results show that this study has a significant effect on solving the instability caused by load changes of rolling mill system.

Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg-1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.

Designing earth‐abundant metal complexes as efficient molecular photocatalysts for visible light‐driven CO2 reduction is a key challenge in artificial photosynthesis. Here, we demonstrated the first example of a mononuclear iron pyridine‐thiolate complex that functions both as a photosensitizer and catalyst for CO2 reduction. This single‐component bifunctional molecular photocatalyst efficiently reduced CO2 to formate and CO with a total turnover number (TON) of 46 and turnover frequency (TOF) of 11.5 h−1 in 4 h under visible light irradiation. Notably, the quantum yield was determined to be 8.4 % for the generation of formate and CO at 400 nm. Quenching experiments indicate that high photocatalytic activity is mainly attributed to the rapid intramolecular quenching protocol. The mechanism investigation by DFT calculation and electrochemical studies revealed that the protonation of Febpy(pyS)2 is indispensable step for photocatalytic CO2 reduction. [ABSTRACT FROM AUTHOR]

There is a need for new antimalarials, ideally with novel mechanisms of action. Benzoxaboroles have been shown to be active against bacteria, fungi, and trypanosomes. Therefore, we investigated the antimalarial activity and mechanism of action of 3-aminomethyl benzoxaboroles against Plasmodium falciparum Two 3-aminomethyl compounds, AN6426 and AN8432, demonstrated good potency against cultured multidrug-resistant (W2 strain) P. falciparum (50% inhibitory concentration [IC50] of 310 nM and 490 nM, respectively) and efficacy against murine Plasmodium berghei infection when administered orally once daily for 4 days (90% effective dose [ED90], 7.4 and 16.2 mg/kg of body weight, respectively). To characterize mechanisms of action, we selected parasites with decreased drug sensitivity by culturing with stepwise increases in concentration of AN6426. Resistant clones were characterized by whole-genome sequencing. Three generations of resistant parasites had polymorphisms in the predicted editing domain of the gene encoding a P. falciparum leucyl-tRNA synthetase (LeuRS; PF3D7_0622800) and in another gene (PF3D7_1218100), which encodes a protein of unknown function. Solution of the structure of the P. falciparum LeuRS editing domain suggested key roles for mutated residues in LeuRS editing. Short incubations with AN6426 and AN8432, unlike artemisinin, caused dose-dependent inhibition of [(14)C]leucine incorporation by cultured wild-type, but not resistant, parasites. The growth of resistant, but not wild-type, parasites was impaired in the presence of the unnatural amino acid norvaline, consistent with a loss of LeuRS editing activity in resistant parasites. In summary, the benzoxaboroles AN6426 and AN8432 offer effective antimalarial activity and act, at least in part, against a novel target, the editing domain of P. falciparum LeuRS.

Selective laser sintering technology is not limited by the shape of the parts, and can form parts with complex structures. Selective laser sintering technology is widely used in rapid prototyping manufacturing and new product design and development. It is particularly important to explore the dimensional accuracy of its forming. Aiming at the problem of low dimensional accuracy and shape accuracy of thin-walled shell parts, this paper proposes a method of preprocessing and precompensation based on part features to improve printing accuracy. Taking polystyrene as raw material, under the combination of simulation and experiment, in order to compensate the deformation, the method of adding support and offset margin is used to correct the feature size, which is easy to warp and deform, and the laser parameters are adjusted to improve the heat accumulation in the printing process. By verifying the printing results, the results show that under the same process conditions, the change of the geometric features of the part directly affects the dimensional accuracy of the part. After adding support settings and predeformation compensation to the part features, the printed parts are compared with the 3D model with good detection results, and the actual error can basically be controlled within 0.3 mm. [ABSTRACT FROM AUTHOR]

As novel generated 2D materials, metal‐organic layers (MOLs) have recently emerged as a potential platform for photocatalytic CO2 reduction reaction (PCO2RR). Such 2D structures negate the blemish of low‐density catalytic sites and low electron transmission efficiency on the surface of metal organic frameworks (MOFs), while retaining the advantage of low expenditure when using earth‐abundant metal nodes and meritorious applicability in the PCO2RR. Herein, it is reported that the 2D ultrathin layer material with bis‐metallic catalytic sites (Ni−O metal node and the Ni−N metal site) from bidentate ligand 2,2'‐bipyridine‐5,5'‐dicarboxylate (H2bpydc) and nickel(II) remarkably boosts the visible light‐driven PCO2RR performance with a CO yield of 2400 mmol g−1 for 18 h and a selectivity up to 99 %. Consequently, the effects of morphology, catalytic sites and intrinsic properties on PCO2RR efficiency have been investigated in detail. In this context, the ultrathin layer structure has been elucidated as the key point to facilitate electron transfer efficiency. Notably, the bis‐metallic catalytic sites with reasonable distance between two adjacent metals presumably induce synergistic effect and offer a guiding ideology for further designing high performance photocatalysts. [ABSTRACT FROM AUTHOR]

We propose a design for a novel broadband polarization splitter based on an asymmetric dual-core square-lattice photonic-crystal fiber. The fiber is designed such that index-matched coupling between the two cores can be achieved for one polarization state, while only a part of the energy could be coupled for the other polarization state. Numerical results demonstrate that a device length of 5.9 mm shows extinction ratios as low as -20 dB with bandwidths as great as 101 nm. OCIS codes: 060.5295, 060.1810, 060.2420.