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

Research on deformation mechanism of AZ31 magnesium alloy sheet with non-basal texture during uniaxial tension at room temperature: A visco-plastic self-consistent analysis

The relationship between activities of involved deformation mechanisms and the evolution of microstructure and texture during uniaxial tension of AZ31 magnesium alloy with a rare non-basal texture has been thoroughly investigated in the present study by means of electron backscattered diffraction (EBSD) measurement and visco-plastic self-consistent (VPSC) modeling. These results show that except basal slip and prismatic slip, {101¯2} extension twin (ET) also plays a significant role during plastic deformation. With the increasing tilted angle between loading direction and rolling direction (RD) of sheet, the activity of {101¯2} ET possesses a decreasing tendency and its role in plastic deformation changes from the one mainly sustaining plastic strain to the one mainly accommodating local strain between individual grains. When {101¯2} ET serves as a carrier of plastic strain, it mainly results in the formation of basal texture component (c-axis//ND, normal direction). By comparison, when the role of {101¯2} ET is to accommodate local strain, it mainly brings about the formation of prismatic texture component (c-axis//TD, transverse direction). At large plastic deformation, the competition between basal slip and pyramidal slip is responsible for the concentration of tilted basal poles towards ND within all deformed samples. The larger difference is between the activities of basal slip and pyramidal slip, the smaller separation is between these two tilted basal poles. Besides, VPSC modeling overestimates volume fractions of {101¯2} ET in samples with angle of 0 to 30° between loading direction and RD of sheet because interactions between twin variants are not included in VPSC modeling procedure at the present form. In addition, as compatible deformation between individual grains cannot be considered in VPSC modeling, the predicted volume fractions of {101¯2} ET in samples with angle of 45 to 90° between loading direction and RD of sheet are smaller than the correspondingly measured results

Genome-Wide Identification of the Rose <i>SWEET</i> Gene Family and Their Different Expression Profiles in Cold Response between Two Rose Species

Sugars Will Eventually be Exported Transporter (SWEET) gene family plays indispensable roles in plant physiological activities, development processes, and responses to biotic and abiotic stresses, but no information is known for roses. In this study, a total of 25 RcSWEET genes were identified in Rosa chinensis ‘Old Blush’ by genome-wide analysis and clustered into four subgroups based on their phylogenetic relationships. The genomic features, including gene structures, conserved motifs, and gene duplication among the chromosomes of RcSWEET genes, were characterized. Seventeen types of cis-acting elements among the RcSWEET genes were predicted to exhibit their potential regulatory roles during biotic and abiotic stress and hormone responses. Tissue-specific and cold-response expression profiles based on transcriptome data showed that SWEETs play widely varying roles in development and stress tolerance in two rose species. Moreover, the different expression patterns of cold-response SWEET genes were verified by qRT-PCR between the moderately cold-resistant species R. chinensis ‘Old Blush’ and the extremely cold-resistant species R. beggeriana. Especially, SWEET2a and SWEET10c exhibited species differences after cold treatment and were sharply upregulated in the leaves of R. beggeriana but not R. chinensis ‘Old Blush’, indicating that these two genes may be the crucial candidates that participate in cold tolerance in R. beggeriana. Our results provide the foundation for function analysis of the SWEET gene family in roses, and will contribute to the breeding of cold-tolerant varieties of roses

A Robust Pyro-phototronic Route to Markedly Enhanced Photocatalytic Disinfection

Photocatalysis offers a direct, yet robust, approach to eradicate pathogenic bacteria. However, the practical implementation of photocatalytic disinfection faces a significant challenge due to low-efficiency photogenerated carrier separation and transfer. Here, we present an effective approach to improve photocatalytic disinfection performance by exploiting the pyro-phototronic effect through a synergistic combination of pyroelectric properties and photocatalytic processes. A set of comprehensive studies reveals that the temperature fluctuation-induced pyroelectric field promotes photoexcited carrier separation and transfer and thus facilitates the generation of reactive oxygen species and ultimately enhances photocatalytic disinfection performance. It is worth highlighting that the constructed film demonstrated an exceptional antibacterial efficiency exceeding 95% against pathogenic bacteria under temperature fluctuations and light irradiation. Moreover, the versatile modulation role of the pyro-phototronic effect in boosting photocatalytic disinfection was corroborated. This work paves the way for improving photocatalytic disinfection efficiency by harnessing the synergistic potential of various inherent material properties