Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants.

A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.

The genomes of 5 underutilized Papilionoideae crops provide insights into root nodulation and disease resistance.

BACKGROUND: The Papilionoideae subfamily contains a large amount of underutilized legume crops, which are important for food security and human sustainability. However, the lack of genomic resources has hindered the breeding and utilization of these crops. RESULTS: Here, we present chromosome-level reference genomes for 5 underutilized diploid Papilionoideae crops: sword bean (Canavalia gladiata), scarlet runner bean (Phaseolus coccineus), winged bean (Psophocarpus tetragonolobus), smooth rattlebox (Crotalaria pallida), and butterfly pea (Clitoria ternatea), with assembled genome sizes of 0.62 Gb, 0.59 Gb, 0.71 Gb, 1.22 Gb, and 1.72 Gb, respectively. We found that the long period of higher long terminal repeat retrotransposon activity is the major reason that the genome size of smooth rattlebox and butterfly pea is enlarged. Additionally, there have been no recent whole-genome duplication (WGD) events in these 5 species except for the shared papilionoid-specific WGD event (∼55 million years ago). Then, we identified 5,328 and 10,434 species-specific genes between scarlet runner bean and common bean, respectively, which may be responsible for their phenotypic and functional differences and species-specific functions. Furthermore, we identified the key genes involved in root-nodule symbiosis (RNS) in all 5 species and found that the NIN gene was duplicated in the early Papilionoideae ancestor, followed by the loss of 1 gene copy in smooth rattlebox and butterfly pea lineages. Last, we identified the resistance (R) genes for plant defenses in these 5 species and characterized their evolutionary history. CONCLUSIONS: In summary, this study provides chromosome-scale reference genomes for 3 grain and vegetable beans (sword bean, scarlet runner bean, winged bean), along with genomes for a green manure crop (smooth rattlebox) and a food dyeing crop (butterfly pea). These genomes are crucial for studying phylogenetic history, unraveling nitrogen-fixing RNS evolution, and advancing plant defense research.

The genomes of seven economic Caesalpinioideae trees provide insights into polyploidization history and secondary metabolite biosynthesis.

The Caesalpinioideae subfamily contains many well-known trees that are important for economic sustainability and human health, but a lack of genomic resources has hindered their breeding and utilization. Here, we present chromosome-level reference genomes for the two food and industrial trees Gleditsia sinensis (921 Mb) and Biancaea sappan (872 Mb), the three shade and ornamental trees Albizia julibrissin (705 Mb), Delonix regia (580 Mb), and Acacia confusa (566 Mb), and the two pioneer and hedgerow trees Leucaena leucocephala (1338 Mb) and Mimosa bimucronata (641 Mb). Phylogenetic inference shows that the mimosoid clade has a much higher evolutionary rate than the other clades of Caesalpinioideae. Macrosynteny comparison suggests that the fusion and breakage of an unstable chromosome are responsible for the difference in basic chromosome number (13 or 14) for Caesalpinioideae. After an ancient whole-genome duplication (WGD) shared by all Caesalpinioideae species (CWGD, ∼72.0 million years ago [MYA]), there were two recent successive WGD events, LWGD-1 (16.2-19.5 MYA) and LWGD-2 (7.1-9.5 MYA), in L. leucocephala. Thereafter, ∼40% gene loss and genome-size contraction have occurred during the diploidization process in L. leucocephala. To investigate secondary metabolites, we identified all gene copies involved in mimosine metabolism in these species and found that the abundance of mimosine biosynthesis genes in L. leucocephala largely explains its high mimosine production. We also identified the set of all potential genes involved in triterpenoid saponin biosynthesis in G. sinensis, which is more complete than that based on previous transcriptome-derived unigenes. Our results and genomic resources will facilitate biological studies of Caesalpinioideae and promote the utilization of valuable secondary metabolites.

A Biodegradable Nano-Drug Delivery Platform for Co-Delivery of Minocycline and Chitosan to Achieve Efficient and Safe Non-Surgical Periodontitis Therapy.

INTRODUCTION: Mesoporous silica nanoparticles (MSN) are widely used as ideal nanovehicles for the delivery of chemotherapeutic drugs. However, the balance between high anti-periodontitis activity and low biotoxicity has been challenging to maintain in most relevant studies owing to the slow degradation of silica in living organisms. METHOD: In this study, -responsive hydroxyapatite (HAP) was doped into the MSN skeleton, and the chemotherapeutic drug minocycline hydrochloride (MH) was loaded into the pores of MSN, forming a negatively charged drug delivery system. Cationic chitosan (COS) is a biodegradable material with high antibacterial performance and good biosafety. In this study, COS was immobilized on the surface of the drug-loaded particles through stable charge interaction to construct a composite drug delivery system (MH@MSNion@COS). RESULTS: In vitro and cellular experiments demonstrated effective degradation of the nanocarrier system and synchronized controlled release of the drug. Notably, compared with single MH administration, this system, in which MH and COS jointly regulated the expression levels of periodontitis- associated inflammatory factors (TNF-α, IL-6, IL-1ß, and iNOS), better inhibited the progress of periodontitis and induced tissue regeneration without showing significant toxic side effects in cells. CONCLUSION: This system provides a promising strategy for the design of intelligent, efficient, and safe anti-periodontitis drug delivery systems.

Comparison of muscle metabolomics between two Chinese horse breeds.

With their enormous muscle mass and athletic ability, horses are well-positioned as model organisms for understanding muscle metabolism. There are two different types of horse breeds-Guanzhong (GZ) horses, an athletic breed with a larger body height (~148.7 cm), and the Ningqiang pony (NQ) horses, a lower height breed generally used for ornamental purposes-both inhabited in the same region of China with obvious differences in muscle content. The main objective of this study was to evaluate the breed-specific mechanisms controlling muscle metabolism. In this study, we observed muscle glycogen, enzyme activities, and LC-MS/MS untargeted metabolomics in the gluteus medius muscle of six, each of GZ and NQ horses, to explore differentiated metabolites that are related to the development of two muscles. As expected, the glycogen content, citrate synthase, and hexokinase activity of muscle were significantly higher in GZ horses. To alleviate the false positive rate, we used both MS1 and MS2 ions for metabolite classification and differential analysis. As a result, a total of 51,535 MS1 and 541 MS2 metabolites were identified, and these metabolites can separate these two groups from each other. Notably, 40% of these metabolites were clustered into lipids and lipid-like molecules. Furthermore, 13 significant metabolites were differentially detected between GZ and NQ horses (fold change [FC] value ≥ 2, variable important in projection value ≥1, and Q value ≤ 0.05). They are primarily clustered into glutathione metabolism (GSH, p = 0.01), taurine, and hypotaurine metabolism (p < 0.05) pathways. Seven of the 13 metabolites were also found in thoroughbred racing horses, suggesting that metabolites related to antioxidants, amino acids, and lipids played a key role in the development of skeleton muscle in horses. Those metabolites related to muscle development shed a light on racing horses' routine maintenance and improvement of athletic performance.

Diversity of the fecal microbiota in Chinese ponies.

Introduction: The gut microbiomes of equine are plentiful and intricate, which plays an important part in the growth. However, there is a relative lack of information on the microbial diversity in the pony's gut. Methods: In this article, 118 fecal samples from DeBa pony, NiQi pony and GuZh horse were studied by 16S rRNA amplicon sequencing. Results: Diversity analysis was used to determine the difference of gut microbiota composition among different breeds. Alpha diversity analysis showed that the gut microbiota of NiQi ponies were abundant and various. Beta diversity analysis showed that the microorganisms constitution of DeBa ponies was more similar to that of NiQi ponies. LDA Effect Size (LEfSe) analysis result that the microorganism biomarkers for NiQi pony at the genus level were Phascolarctobacterium, Paludibacter, and Fibrobacter; the bacterial biomarker for DeBa pony was Streptococcus and Prevotella; and the bacterial biomarkers for GuZh horses was Treponema, Treponema Mogibacterium, Adlercreutzia, and Blautia. The correlation analysis between genera with >1% abundance and horse height found that Streptococcus (P < 0.01), Treponema (P < 0.01), Coprococcus (P < 0.01), Prevotella (P < 0.01), Phascolarctobacterium (P < 0.01), and Mogibacterium (P < 0.01) were significantly associated with horses' height. The functional prediction results indicated that DeBa pony have a microbiota functional more similar to NiQi pony. Discussion: For the first time, our results announce the species composition and structure of the gut microbiota in Chinese ponies. At the same time, our results can provide theoretical reference for further understanding the healthy breeding, feeding management and disease prevention of horses.

An Aqueous Facile Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives by Reverse Zinc Oxide Micelles as Nanoreactor.

A green synthetic protocol has been developed for the efficient preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives with excellent yield in aqueous media. Reverse zinc oxide micelles catalyzed the reactions efficiently and selectively as the hallow nanoreactor. Moreover, the catalyst was reusable without significant loss of catalytic efficiency. The notable advantages of the procedure are high yields and mild reaction conditions, simple operation, nonchromatographic purification, environmentally friendly and good versatile substrates.