The last 18 months, or more, have seen a profound shift in our global experience, with many of us navigating a once-in-100-year pandemic. To date, COVID-19 remains a life-threatening pandemic with little to no targeted therapeutic recourse. The discovery of novel antiviral agents, such as vaccines and drugs, can provide therapeutic solutions to save human beings from severe infections; however, there is no specifically effective antiviral treatment confirmed for now. Thus, great attention has been paid to the use of natural or artificial antimicrobial peptides (AMPs) as these compounds are widely regarded as promising solutions for the treatment of harmful microorganisms. Given the biological significance of AMPs, it was obvious that there was a significant need for a single platform for identifying and engaging with AMP data. This led to the creation of the dbAMP platform that provides comprehensive information about AMPs and facilitates their investigation and analysis. To date, the dbAMP has accumulated 26 447 AMPs and 2262 antimicrobial proteins from 3044 organisms using both database integration and manual curation of >4579 articles. In addition, dbAMP facilitates the evaluation of AMP structures using I-TASSER for automated protein structure prediction and structure-based functional annotation, providing predictive structure information for clinical drug development. Next-generation sequencing (NGS) and third-generation sequencing have been applied to generate large-scale sequencing reads from various environments, enabling greatly improved analysis of genome structure. In this update, we launch an efficient online tool that can effectively identify AMPs from genome/metagenome and proteome data of all species in a short period. In conclusion, these improvements promote the dbAMP as one of the most abundant and comprehensively annotated resources for AMPs. The updated dbAMP is now freely accessible at http://awi.cuhk.edu.cn/dbAMP.

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC ( 21c ) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC 50 = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c . Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.

Human alkyladenine DNA glycosylase (AAG) is a key enzyme that corrects a broad range of alkylated and deaminated nucleobases to maintain genomic integrity. When encountering the lesions, AAG adopts a base-flipping strategy to extrude the target base from the DNA duplex to its active site, thereby cleaving the glycosidic bond. Despite its functional importance, the detailed mechanism of such base extrusion and how AAG distinguishes the lesions from an excess of normal bases both remain elusive. Here, through the Markov state model constructed on extensive all-atom molecular dynamics simulations, we find that the alkylated nucleobase (N3-methyladenine, 3MeA) everts through the DNA major groove. Two key AAG motifs, the intercalation and E131-N146 motifs, play active roles in bending/pressing the DNA backbone and widening the DNA minor groove during 3MeA eversion. In particular, the intercalated residue Y162 is involved in buckling the target site at the early stage of 3MeA eversion. Our traveling-salesman based automated path searching algorithm further revealed that a non-target normal adenine tends to be trapped in an exo site near the active site, which however barely exists for a target base 3MeA. Collectively, these results suggest that the Markov state model combined with traveling-salesman based automated path searching acts as a promising approach for studying complex conformational changes of biomolecules and dissecting the elaborate mechanism of target recognition by this unique enzyme.

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The objective of this study was to explore the heterosis of partial interspecific hybrids between African rice (Oryza glaberrima Steud.) and Asian rice (Oryza sativa L.) and its correlation with genetic distance. Sixty‐nine rice accessions including 57 introgression lines (ILs) were tested for population structure and genetic distance. Forty‐nine crosses between ILs and a test variety, Shengtai1 (ST1), were evaluated for midparent heterosis of nine agronomic traits. Population structure, genetic distance, and the proportion of O. glaberrima genome (PGG) of ILs and heterosis of the test crosses were estimated and analyzed. The PGG of the ILs ranged from 1.22 to 49.71%, with an average of 15.29%. The genetic distance between parents of the tested crosses was positively correlated to the PGG of ILs (r = .95, P < .01). Positive heterosis was scored on plant height (12.23%), panicles per plant (19.97%), panicle length (10.37%), spikelets per panicle (24.06%), thousand‐grain weight (14.00%), length/width ratio of grain (0.03%), and grain yield per plant (60.77%) of the partial interspecific hybrids. Although the introgression of more African genomic genes could effectively increase the genetic distance between ILs and the test variety that lead to positive heterosis for most agronomic traits, it could also increase the possibility of the occurrence of interspecific sterility that might decrease the seed setting rate and result in negative heterosis (−2.57%). These data indicated that the introgression of African rice genes into the genome of Asian rice could effectively broaden the genetic diversity, and the deployment of ILs as parents could be a potential way for exploiting interspecific heterosis in rice.