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More than 60% of pharmaceuticals are related to natural products (NPs), chemicals produced by living organisms. Despite this, the rate of NP discovery has slowed over the past few decades. In many cases the rate-limiting step in NP discovery is structural characterization. Here we report the use of microcrystal electron diffraction (MicroED), an emerging cryogenic electron microscopy (CryoEM) method, in combination with genome mining to accelerate NP discovery and structural elucidation. As proof of principle we rapidly determine the structure of a new 2-pyridone NP, Py-469, and revise the structure of fischerin, an NP isolated more than 25 years ago, with potent cytotoxicity but hitherto ambiguous structural assignment. This study serves as a powerful demonstration of the synergy of MicroED and synthetic biology in NP discovery, technologies that when taken together will ultimately accelerate the rate at which new drugs are discovered.

In order to study the water infiltration and self-weight collapse deformation characteristics of Jingyuan loess with large thickness under the condition of immersion, a field immersion test without water injection holes was carried out in the self-weight collapsed loess site of Jingyuan North Station along the Zhongwei−Lanzhou Railway. The surface and underground collapsible deformation, cracks, water content and vertical stress in the soil around the test pit were monitored and analyzed. The water diffusion, self-weight collapsible characteristics and vertical stress in the soil were studied, and the regional correction coefficient β0 value and wetting angle were discussed. The results showed that: the change of volumetric water content was divided into four stages: immersion stabilization (two), rapid increase (one) and slow increase (one). In the immersion process, the vertical infiltration of water was accelerated and the radial diffusion was slowed down at 21 m, and the final shape of the wetting front was presented as elliptical. According to the water content test results of exploratory wells and boreholes, the maximum wetting angle was calculated to be 41°. The self-weight collapse process of loess in the site went through three stages: severe collapse, slow collapse and consolidation stabilization. At the end of the test, a total of 13 ring cracks were developed, and the farthest point of the cracks was 26 m from the edge of the test pit. According to the laboratory test and field test results, it was suggested that the regional correction coefficient should be corrected along the depth of the soil layer, and the β0 value was taken as 1.05 within 0−10 m and 0.95 within 10−27 m. In the depth range from the surface to 21 m, the foundation soil was saturated and fully collapsed. The vertical stress in the soil increased linearly along the depth, and the vertical stress in the soil was close to the saturated self-weight stress. The foundation soil below 21 m failed to collapse entirely, and the vertical stress in the soil decreased gradually. The research results could be applied to the later construction of Zhongwei−Lanzhou Railway and provide a reference for other regional engineering projects.

The pericyclases are a growing superfamily of enzymes that catalyze pericyclic reactions. We report a pericyclase IccD catalyzing an inverse-electron demand Diels-Alder (IEDDA) reaction with a rate acceleration of 3 × 105-fold in the biosynthesis of fungal natural product ilicicolin H. We demonstrate IccD is highly periselective toward the IEDDA cycloaddition over a competing normal electron demand Diels-Alder (NEDDA) reaction from an ambimodal transition state. A predicted flavoenzyme IccE was identified to epimerize the IEDDA product 8- epi-ilicicolin H to ilicicolin H, a step that is critical for the observed antifungal activity of ilicicolin H. Our results reveal the ilicicolin H biosynthetic pathway and add to the collection of pericyclic reactions that are catalyzed by pericyclases.

For the dynamic takeout delivery vehicle routing problem, which faces fluctuating order demand and time-varying speeds, this study presents a novel approach. We analyze the time distribution of takeout orders and apply a Receding Horizon Control (RHC) strategy to convert the dynamic challenge into a static one. The driving speed of delivery vehicles on different roads at different times is determined based on the subdivision criteria of the urban road network and a traffic congestion measurement method. We propose a dynamic takeout delivery vehicle routing optimization model and a time-varying subdivision road network is established to minimize the total delivery cost. We validated the model through simulation examples. The optimization results show that the total distribution cost is reduced after considering the time-varying subdivision road network, with the penalty cost decreasing by 39%. It is evident that considering the subdivision of the road network can enhance order delivery efficiency and optimize the overall dining experience. The sensitivity analysis of various parameters reveals that the delivery platform must appropriately determine the time domain and allocate the number of delivery personnel based on order scale to avoid escalating delivery costs. These findings provide theoretical guidance for vehicle routing planning in the context of delivery platforms. [ABSTRACT FROM AUTHOR]

Objective To determine the median effective dose (ED50) of prophylactic intravenous lidocaine for the prevention of propofol medium-chain triglyceride/long-chain triglyceride (MCT/LCT) emulsion injection pain. Design Prospective trial, Dixon up-and-down sequential method. Setting Operating room of a single hospital. Patients Thirty patients aged 18–65 years with American Society of Anesthesiologists (ASA) status I or II who were scheduled for elective surgery under general anesthesia (GA) were included. Interventions The initial dose of prophylactic lidocaine before propofol MCT/LCT emulsion injection was set at 0.5 mg/kg lean body weight (LBW). The lidocaine dose was adjusted according to the degree of patients' injection pain using the Dixon up-and-down sequential method. Measurements The ED50 and 95% confidence intervals (CIs) of lidocaine were calculated using the Dixon–Massey formula. Vital signs and adverse effects were recorded. In the postanesthesia care unit (PACU), patients were asked if they recalled feeling any injection pain with visual analog scale (VAS) evaluation. Results The ED50 of lidocaine for the prevention of propofol MCT/LCT emulsion injection pain was 0.306 mg/kg LBW (95% CI, 0.262–0.357 mg/kg LBW). No adverse reactions to lidocaine occurred. In the PACU, 90.9% of patients who experienced injection pain recalled this pain (VAS score, 2.8±1.8). Conclusions Prophylactic intravenous lidocaine (0.306 mg/kg LBW) effectively prevented propofol MCT/LCT emulsion injection pain in 50% of patients scheduled for elective surgery under GA with no adverse reaction occurring. [ABSTRACT FROM AUTHOR]