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The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In the PROTAC process, a heterobifunctional degrader forms a ternary complex with a target protein of interest (POI) and an E3 ligase, which results in ubiquitination and proteasomal degradation of the POI. While ternary complex formation is a key attribute of PROTAC degraders, modification of the PROTAC molecule to optimize ternary complex formation and protein degradation can be a labor-intensive and tedious process. In this study, we take advantage of DNA-encoded library (DEL) technology to efficiently synthesize a vast number of possible PROTAC molecules and describe a parallel screening approach that utilizes DNA barcodes as reporters of ternary complex formation and cooperative binding. We use a designed PROTAC DEL against BRD4 and CRBN to describe a dual protein affinity selection method and the direct discovery of novel, potent BRD4 PROTACs that importantly demonstrate clear SAR. Such an approach evaluates all the potential PROTACs simultaneously, avoids the interference of PROTAC solubility and permeability, and uses POI and E3 ligase proteins in an efficient manner.

This paper examines how to improve the problems of low user satisfaction and low recommendation efficiency. A method of intelligent recommendation system for products, taking nixing Tao products as an example, was proposed based on gradient boosting decision tree algorithm in machine learning and Zernike features extraction of machine vision. The overall structure of the recommendation system for products was formed with user shopping module, system management module, database module and visualisation module. The key features of products were extracted by Zernike moment, and they were analysed by clustering in order to obtain the association rules between products and users. We embedded the association rules into recommendation model based on gradient extension decision tree algorithm. The experimental results show our method had short recommendation time and good user satisfaction.

Over the past 20 years, the toolbox for discovering small-molecule therapeutic starting points has expanded considerably. Pharmaceutical researchers can now choose from technologies that, in addition to traditional high-throughput knowledge-based and diversity screening, now include the screening of fragment and fragment-like libraries, affinity selection mass spectrometry, and selection against DNA-encoded libraries (DELs). Each of these techniques has its own unique combination of advantages and limitations that makes them more, or less, suitable for different target classes or discovery objectives, such as desired mechanism of action. Layered on top of this are the constraints of the drug-hunters themselves, including budgets, timelines, and available platform capacity; each of these can play a part in dictating the hit identification strategy for a discovery program. In this article, we discuss some of the factors that we use to govern our building of a hit identification roadmap for a program and describe the increasing role that DELs are playing in our discovery strategy. Furthermore, we share our learning during our initial exploration of DEL and highlight the approaches we have evolved to maximize the value returned from DEL selections. Topics addressed include the optimization of library design and production, reagent validation, data analysis, and hit confirmation. We describe how our thinking in these areas has led us to build a DEL platform that has begun to deliver tractable matter to our global discovery portfolio.

Over the past 20 years, the toolbox for discovering small-molecule therapeutic starting points has expanded considerably. Pharmaceutical researchers can now choose from technologies that, in addition to traditional high-throughput knowledge-based and diversity screening, now include the screening of fragment and fragment-like libraries, affinity selection mass spectrometry, and selection against DNA-encoded libraries (DELs). Each of these techniques has its own unique combination of advantages and limitations that makes them more, or less, suitable for different target classes or discovery objectives, such as desired mechanism of action. Layered on top of this are the constraints of the drug-hunters themselves, including budgets, timelines, and available platform capacity; each of these can play a part in dictating the hit identification strategy for a discovery program. In this article, we discuss some of the factors that we use to govern our building of a hit identification roadmap for a program and describe the increasing role that DELs are playing in our discovery strategy. Furthermore, we share our learning during our initial exploration of DEL and highlight the approaches we have evolved to maximize the value returned from DEL selections. Topics addressed include the optimization of library design and production, reagent validation, data analysis, and hit confirmation. We describe how our thinking in these areas has led us to build a DEL platform that has begun to deliver tractable matter to our global discovery portfolio.

Silicon is one of the most promising anode materials for lithium-ion batteries due to its high theoretical capacity and low cost. However, significant capacity fading caused by severe structural degradation during cycling limits its practical implication. To overcome this barrier, we design a covalently bonded nanocomposite of silicon and poly(vinyl alcohol) (Si–PVA) by high-energy ball-milling of a mixture of micron-sized Si and PVA. The obtained Si nanoparticles are wrapped by resilient PVA coatings that covalently bond to the Si particles. In such nanostructures, the soft PVA coatings can accommodate the volume change of the Si particles during repeated lithiation and delithiation. Simultaneously, as formed covalent bonds enhance the mechanical strength of the coatings. Due to the significantly improved structural stability, the Si–PVA composite delivers a lifespan of 100 cycles with a high capacity of 1526 mAh g–1. In addition, a high initial Coulombic efficiency of over 86% and an average value of 99.2% in subsequent cycles can be achieved. This reactive ball-milling strategy provides a low-cost and scalable route to fabricate high-performance anode materials.

DNA-encoded library (DEL) technology has been used as an ultra-high-throughput screening approach for hit identification of drug targets. This process is an affinity-based selection and requires incubation of DEL molecules with the target. Currently, in most reported cases, the input (i.e., the copy number) of individual DEL molecules varies from 105to 107. With the ever-increasing DEL size and screening cost, lowering the input of DEL molecules while maintaining an appropriate signal-to-noise ratio in a selection is of paramount importance. In this article, we varied the input of DEL ranging from 103to 105in selections with two different protein targets to explore the lower limit of DEL molecule input. The results could facilitate the optimization of the DEL selection process and reduce costs related to library consumption.

DNA-encoded library (DEL) technology has been used as an ultra-high-throughput screening approach for hit identification of drug targets. This process is an affinity-based selection and requires incubation of DEL molecules with the target. Currently, in most reported cases, the input (i.e., the copy number) of individual DEL molecules varies from 105to 107. With the ever-increasing DEL size and screening cost, lowering the input of DEL molecules while maintaining an appropriate signal-to-noise ratio in a selection is of paramount importance. In this article, we varied the input of DEL ranging from 103to 105in selections with two different protein targets to explore the lower limit of DEL molecule input. The results could facilitate the optimization of the DEL selection process and reduce costs related to library consumption.

Owing to its abundance and high theoretical capacity, phosphorus has attracted intense research interest as anode material for lithium-ion batteries. However, the adaption of phosphorus for batteries is still limited by its poor electrochemical performance, which is associated with its poor electronic conductivity and large volume change during charging and discharging. We herein report a facile and cost-effective method, which is based on high-energy mechanical milling, for the synthesis of phosphorus nanoparticles within carbon matrix as high-performance anode materials. Red phosphorus was readily transformed into orthorhombic black phosphorus at ambient temperature and pressure, forming phosphorus nanocrystals homogenously dispersed in carbon matrix. Such composites provide superior electrochemical performance, exhibiting reversible capacity of 1000 mA h g−1after 300 cycles. Full cells based on such phosphorus-carbon composites against LiNi1/3Co1/3Mn1/3O2cathode offer a capacity retention of 92% after 200 cycles at 0.5 C.

Extraction of lead and antimony from their sulfides without SO2 emission is of great significance to tackle the air pollution caused by the conventional metallurgical routes. In the paper, solid PbS and Sb2S3 are respectively electrochemically reduced to Pb and Sb in a 50 wt% NaOH solution. Thermodynamic analysis is conducted to illustrate the feasibility of extracting metals from their sulfides in the alkaline solution. Moreover, a home-made graphite cavity working electrode was employed to study the electrochemical reduction behaviors of PbS and Sb2S3, and their reduction processes were in situ recorded by a camera in a transparent cell. The results show that the strong alkaline solution is able to electrochemically convert PbS and Sb2S3 into Pb and Sb with a current efficiency higher than 90%.

Improving cycling stability while maintaining a high initial Coulombic efficiency (ICE) of the antimony (Sb) anode is always a trade-off for the design of electrodes of sodium-ion batteries (SIBs). Herein, we prepare a carbon-free Sb8Bi1anode with an ICE of 87.1% at 0.1 A g–1by a one-step electrochemical reduction of Sb2O3and Bi2O3in alkaline solutions. The improved ICE of the Sb8Bi1anode is due to the alloying of bismuth (Bi) that prevents irreversible interfacial reactions during the sodiation process. Unlike carbon buffers, the use of Bi will reduce the number of side reactions between the carbon buffer and sodium. Moreover, Bi2O3can promote the reduction of Sb2O3and reduce the particle size of Sb from ∼20 μm to below 300 nm. The electrolytic products can be modulated by controlling the cell voltages and electrolysis time. The electrolytic Sb8Bi1anode delivered a capacity of 625 mAh g–1after 200 cycles with an ICE of 87.1% at 0.1 A g–1and even 625 mAh g–1at 1 A g–1over 100 cycles. Hence, alloying Bi into Sb is an effective way to make a long-lasting Sb anode while maintaining a high Coulombic efficiency.

Shoot regeneration from leaf tissue requires the de-differentiation of cells from a highly differentiated state into an actively dividing state, but it remains unclear how this physiological transition occurs and is regulated, especially at the epigenetic level. Here, we characterized the DNA methylome represented by 5-methylcytosine (5mC) in leaf and callus tissue derived from leaf explants of woodland strawberry, Fragaria vesca. We detected an overall increase in DNA methylation and distinct 5mC enrichment patterns in the CG, CHG, and CHH sequence contexts in genes and transposable elements. Our analyses revealed an intricate relationship between DNA methylation and gene expression level in leaves or leaf-derived callus. However, when considering the genes involved in callus formation and shoot regeneration, e.g. FvePLT3/7, FveWIND3, FveWIND4, FveLOG4and FveIAA14, their dynamic transcription levels were associated with differentially methylated regions located in the promoters or gene bodies, indicating a regulatory role of DNA methylation in the transcriptional regulation of pluripotency acquisition in strawberry. Furthermore, application of the DNA methyltransferase inhibitor 5′-azacytidine (5′-Aza) hampered both callus formation and shoot regeneration from the leaf explants. We further showed that 5′-Aza downregulated the expression of genes involved in cell wall integrity, such as expansin, pectin lyase, and pectin methylesterasegenes, suggesting an essential role of cell wall metabolism during callus formation. This study reveals the contribution of DNA methylation to callus formation capacity and will provide a basis for developing a strategy to improve shoot regeneration for basic and applied research applications.

Li metal anode (LMA) for practical Li-metal batteries suffers from safety hazards and capacity deterioration caused by its high reactivity and infinite volume change. Herein, a stable LMA with highly uniform surface potential distribution was demonstrated by coating Li with a negatively charged artificial solid electrolyte interphase (ASEI), which is formed by spontaneous in-situpolymerization of 2,3,7,8-tetrakis((trimethylsilyl)ethynyl)pyrazino[2,3-g]quinoxaline-5,10-dione (PPQ) at room temperature. As an ion-transport regulator, such an ASEI with negatively charged moieties provides preferential Li-ion transport with high Li-ion transference number (tLi+= 0.74). As a robust artificial layer, the PPQ-stabilized Li (PPQ-Li) maintains high mechanical strength (Young’s modulus of 7.39 GPa) after being immersed in electrolyte, which readily suppresses formation of hazardous Li dendrites and diminishes parasitic reactions on LMA, leading to dendrite-free morphology after long-term Li stripping-plating tests. Such a multi-functional interphase could potentially promote more tailorable coating designs for practically durable LMA.

Extraction of lead and antimony from their sulfides without SO2emission is of great significance to tackle the air pollution caused by the conventional metallurgical routes. In the paper, solid PbS and Sb2S3are respectively electrochemically reduced to Pb and Sb in a 50 wt% NaOH solution. Thermodynamic analysis is conducted to illustrate the feasibility of extracting metals from their sulfides in the alkaline solution. Moreover, a home-made graphite cavity working electrode was employed to study the electrochemical reduction behaviors of PbS and Sb2S3, and their reduction processes were in situ recorded by a camera in a transparent cell. The results show that the strong alkaline solution is able to electrochemically convert PbS and Sb2S3into Pb and Sb with a current efficiency higher than 90%.