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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.

Two complementary regiodivergent C–H alkynylations of 2-arylthiazoles are reported. When RuII catalysis is employed, an aryl ortho-alkynylation process is favored. The alkynylated products are gained in good yields. With the use of PdII catalysis, a thiazole C5-alkynylation process is developed, allowing for the construction of C5-alkynylated products. This strategy not only expands the methods for the functionalization of 2-arylthiazoles, but also provides new opportunities for the rapid assembly of complex molecular structures, which may have great potential in organic synthesis, medicinal chemistry, and materials science. [ABSTRACT FROM AUTHOR]

We report an innovative synthetic strategy for the generation of polysubstituted indoles from indolines, aryldiazonium salts, and azoles. The methodology encompasses an electrophilic substitution reaction affording C5-indoline intermediates which undergo an iodine-mediated oxidative transformation coupled with C–H functionalization to yield the indole derivatives. [ABSTRACT FROM AUTHOR]

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]

A directing-group-free strategy for oxidative regioselective aminochalcogenation of indolines with amines and dichalconides is presented. This strategy combines tandem coupling sequences and oxidative dehydrogenation methods in a multi-component reaction, enabling the fast construction of a series of C2,3- or C2,5-aminochalcogenated indole derivatives. Moreover, the application of this synthetic approach is demonstrated through the late-stage modification of pharmaceuticals and the derivatization of the products, highlighting its potential and significance. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: A one‐pot synthesis of vicinal diamines using indoles, azoles and phenothiazines in a tandem multi‐component reaction is developed. The utilization of a copper‐iodine co‐catalytic system enables the generation of a diverse range of vicinal diaminoindoles with good selectivity and moderate to good yields. An attractive aspect of this method is that it can be conducted under mild and environmentally friendly conditions, showcasing its potential as an alternative approach for synthesizing vicinal diamines. Moreover, the use of a multicomponent tandem reaction highlights the power and versatility of such strategies in synthetic chemistry. [ABSTRACT FROM AUTHOR]

The development of a rational protocol to realize the complete regioselectivity and the capability to switch regioselectivity is an appealing yet challenging task. Herein, a regiodivergent C−H arylation of 2‐pyridylthiophenes has been demonstrated via the choice of RuII and PdII catalysts. The reactions proceeded smoothly in a good regioselective manner to afford the corresponding C3‐ and C5‐arylated thiophenes. Late‐stage diversification of biologically relevant scaffold derived from estrone and successful transformation of the products further highlighted the potential utility and importance of this synthetic strategy. [ABSTRACT FROM AUTHOR]

A novel and effective RhIII- and PdII-controlled switchable C–H alkenylation of 2-pyridylthiophenes with alkenes is realized. The alkenylation reactions proceeded smoothly in a highly regio- and stereo-selective manner to afford a broad range of C3- and C5-alkenylated products. Depending on the catalyst employed, the reactions involve two typical approaches: C3-alkenylation via chelation-assisted rhodation and C5-alkenylation via electrophilic palladation. This regiodivergent synthetic protocol was successfully applied for the straightforward building of π-conjugated difunctionalized 2-pyridylthiophenes, which may show great potential in organic electronic materials. [ABSTRACT FROM AUTHOR]

With over 300 million severe cases and 1.5 million deaths annually, invasive fungal diseases (IFDs) are a major medical burden and source of global morbidity and mortality. The World Health Organization (WHO) recently released the first-ever fungal priority pathogens list including 19 fungal pathogens, considering the perceived public health importance. Most of the pathogenic fungi are opportunistic and cause diseases in patients under immunocompromised conditions such as HIV infection, cancer, chemotherapy, transplantation, and immune suppressive drug therapy. Worryingly, the morbidity and mortality caused by IFDs are continuously on the rise due to the limited available antifungal therapies, the emergence of drug resistance, and the increase of population that is vulnerable to IFDs. Moreover, the COVID-19 pandemic worsened IFDs as a globe health threat as it predisposes the patients to secondary life-threatening fungi. In this mini-review, we provide a perspective on the advances and strategies for combating IFDs with antifungal therapies. [ABSTRACT FROM AUTHOR]

The position‐selective functionalization of the poorly reactive benzenoid nucleus of indoles has remained a great challenge in organic chemistry. Here we describe a directing‐group‐free, three‐component tandem C3‐acylation/C5,6‐H disulfenylation of indoles via an iodine‐, Lewis acid‐ and Brønsted acid‐cooperated mediated strategy. This protocol is remarkable for its exceptional regio‐ and chemo‐selectivity, broad substrate scope, good functional group tolerance and mild reaction conditions. Advantageously, the present protocol offers great potential for the development of general site‐selective functionalization at the benzenoid nucleus of indoles, removing the requirement for neighbouring activating groups. [ABSTRACT FROM AUTHOR]

The Fine-Gray proportional sub-distribution hazards (PSH) model is among the most popular regression model for competing risks time-to-event data. This article develops a fast safe feature elimination method, named PSH-SAFE, for fitting the penalized Fine-Gray PSH model with a Lasso (or adaptive Lasso) penalty. Our PSH-SAFE procedure is straightforward to implement, fast, and scales well to ultrahigh dimensional data. We also show that as a feature screening procedure, PSH-SAFE is safe in a sense that the eliminated features are guaranteed to be inactive features in the original Lasso (or adaptive Lasso) estimator for the penalized PSH model. We evaluate the performance of the PSH-SAFE procedure in terms of computational efficiency, screening efficiency and safety, run-time, and prediction accuracy on multiple simulated datasets and a real bladder cancer data. Our empirical results show that the PSH-SAFE procedure possesses desirable screening efficiency and safety properties and can offer substantially improved computational efficiency as well as similar or better prediction performance in comparison to their baseline competitors. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) are organelles with good natural biocompatibility that are abundant in eukaryotic cells and are considered good candidates for use in biological delivery inside cells. Importantly, numerous studies have reported that LDs also participate in immune processes. Here, we investigated whether LDs can also be used as vaccine adjuvants. We designed and prepared a variety of artificial nano-LDs with a nanometer size (200–300 nm) to test this possibility. Artificial nano-LDs have the same monolayer lecithin membrane as natural LDs; in contrast to natural LDs, artificial nano-LDs do not have proteins on their surfaces, which is beneficial to ensure better biocompatibility. Compared with other oil-in-water emulsion adjuvants (MF59 [AddaVax] and AS03 [AddaS03] used in licensed vaccines), vitamin E was used instead of squalene as the oil phase. The artificial nano-LDs (V3, V11, and V12) prepared in this study have structures similar to those of MF59 (AddaVax) and AS03-(AddaS03) under scanning electron microscopy and transmission electron microscopy and have better stability than MF59 (AddaVax) and AS03 (AddaS03); they can even withstand high-temperature sterilization at 120 °C for 30 min. In vivo test results showed that the artificial nano-LDs had good biocompatibility. Recombinant hepatitis B surface antigen and recombinant varicella-zoster virus glycoprotein E were used as model antigens to evaluate the adjuvant effect. We found that our artificial nano-LDs induced excellent humoral and cellular immunity (comparable to that of MF59 [AddaVax]). In addition, apart from the initial increase in the particle size upon high-temperature sterilization, the adjuvant effect of artificial nano-LDs did not decrease. [ABSTRACT FROM AUTHOR]

An efficient intermolecular C−H aminohalogenation of indoles with azoles and NXS (X = F, Cl, Br, I) has been developed. This mild protocol provides a straightforward entry to structurally valuable 2‐azolyl‐3‐halogenated indoles in one single operation. In addition, this attractive route for the synthesis of polyfunctionalized indoles is of great significance due to the product's versatile reactivity for further transformations. [ABSTRACT FROM AUTHOR]