Discovery of TIGIT inhibitors based on DEL and machine learning

Drug discovery has entered a new period of vigorous development with advanced technologies such as DNA-encoded library (DEL) and artificial intelligence (AI). The previous DEL-AI combination has been successfully applied in the drug discovery of classical kinase and receptor targets mainly based on the known scaffold. So far, there is no report of the DEL-AI combination on inhibitors targeting protein-protein interaction, including those undruggable targets with few or unknown active scaffolds. Here, we applied DEL technology on the T cell immunoglobulin and ITIM domain (TIGIT) target, resulting in the unique hit compound 1 (IC50 = 20.7 μM). Based on the screening data from DEL and hit derivatives a1-a34, a machine learning (ML) modeling process was established to address the challenge of poor sample distribution uniformity, which is also frequently encountered in DEL screening on new targets. In the end, the established ML model achieved a satisfactory hit rate of about 75% for derivatives in a high-scored area

Evaluation of the Hair Cell Regeneration in Zebrafish Larvae by Measuring and Quantifying the Startle Responses

The zebrafish has become an established model organism for the study of hearing and balance systems in the past two decades. The classical approach to examine hair cells is to use dye to conduct selective staining, which shows the number and morphology of hair cells but does not reveal their function. Startle response is a behavior closely related to the auditory function of hair cells; therefore it can be used to measure the function of hair cells. In this study, we developed a device to measure the startle response of zebrafish larvae. By applying various levels of stimulus, it showed that the system can discern a 10 dB difference. The hair cell in zebrafish can regenerate after damage due to noise exposure or drug treatment. With this device, we measured the startle response of zebrafish larvae during and after drug treatment. The results show a similar trend to the classical hair cell staining method. The startle response was reduced with drug treatment and recovered after removal of the drug. Together it demonstrated the capability of this behavioral assay in evaluating the hair cell functions of fish larvae and its potential as a high-throughput screening tool for auditory-related gene and drug discovery

Electrochemical Reduction of CO2 to CO on Hydrophobic Zn Foam Rod in a Microchannel Electrochemical Reactor

Due to CO2 mass transfer limitation as well as the competition of hydrogen evolution reaction in electroreduction of CO2 in the aqueous electrolyte, Zn-based electrodes normally exhibit unsatisfying selectivity for CO production, especially at high potentials. In this work, we introduced a zinc myristate (Zn [CH3(CH2)12COO]2) hydrophobic layer on the surface of zinc foam electrode by an electrodeposition method. The obtained hydrophobic zinc foam electrode showed a high Faradaic efficiency (FE) of 91.8% for CO at −1.9 V (vs. saturated calomel electrode, SCE), which was a remarkable improvement over zinc foam (FECO = 81.87%) at the same potentials. The high roughness of the hydrophobic layer has greatly increased the active surface area and CO2 mass transfer performance by providing abundant gas-liquid-solid contacting area. This work shows adding a hydrophobic layer on the surface of the catalyst is an effective way to improve the electrochemical CO2 reduction performance

Determination of pyraclostrobin residue in wax gourd and its dietary risk assessment

Abstract To study the residue behavior of pyraclostrobin in wax gourd, and evaluate the risk of dietary intake. Wax gourd samples were extracted with acetonitrile, purified with PSA and C18, detected by HPLC-MS/MS. In 2017, the supervised field trials of pyraclostrobin in wax gourd were carried out in Henan, Jiangsu, Sichuan, Beijing, Hunan, and Guangxi. The STMR of pyraclostrobin in wax gourd was acquired, and then the risk of dietary intake was evaluated. At the three spiked levels of 0.01, 0.1 and 1.0 mg kg-1, the average recoveries ranged from 95% to 104%, the RSDs ranged from 2.1% to 3.8%, and LOQ was 0.01 mg kg-1. The dissipation of pyraclostrobin in wax gourd in Sichuan fitted to the first order kinetics with the half-life of 4.1d. The 250 gL-1 emulsifiable concentrate of pyraclostrobin was sprayed at 150 and 225 g a.i./hm2 for 2-3 times on wax gourd. The final residue level of pyraclostrobin in wax gourd was between <LOQ and 0.11 mgkg-1. The national estimated daily intake (NEDI) of pyraclostrobin was 0.3722 mg, accounting for 19.69% of the acceptable daily intake (ADI) for general population, which means that it will not pose unacceptable risks to the health of the general population

Assessment of radio frequency heating on composition, microstructure, flowability and rehydration characteristics of milk powder

<div><p>Abstract Radio frequency heating (RFH) provides higher efficiency and more uniform heating zone compared with conventional method. The aim of present work is to evaluate the effect of RFH (at 90 °C for 5 or 10 min) on the changes in composition (protein oxidation and fat distribution), microstructure, flow characteristic and rehydration property of infant milk powder. The results indicate that the concentration of protein dityrosine was slightly enhanced, more free fat appeared on powder surfaces (> 50% increase), and porosity in powder matrix as tested by SEM was increased after RFH treatment. For powder flowability, raw sample had low cohesiveness (specific energy = 4.39 mJ/g), and RFH provided better flowability and decreased compressibility. Moreover, RFH had some negative impacts on wettability and solubility of powder particles with contact angle increase at least 5% and solubility decrease of 2%~4%, indicating worse rehydration abilities. Guggenheim-Anderson-de Boer (GAB) model was applied to fit moisture vapor sorption isotherms, and longer RFH duration leading to higher c values (about 63% increase at 10 min). In addition, the RFH initiated browning reaction as CIE a* values increased from -1.8 to -1.3.</p></div