Involvement of C4 Protein of Beet Severe Curly Top Virus (Family Geminiviridae) in Virus Movement

Background: Beet severe curly top virus (BSCTV) is a leafhopper transmitted geminivirus with a monopartite genome. C4 proteins encoded by geminivirus play an important role in virus/plant interaction. Methods and Findings: To understand the function of C4 encoded by BSCTV, two BSCTV mutants were constructed by introducing termination codons in ORF C4 without affecting the amino acids encoded by overlapping ORF Rep. BSCTV mutants containing disrupted ORF C4 retained the ability to replicate in Arabidopsis protoplasts and in the agro-inoculated leaf discs of N. benthamiana, suggesting C4 is not required for virus DNA replication. However, both mutants did not accumulate viral DNA in newly emerged leaves of inoculated N. benthamiana and Arabidopsis, and the inoculated plants were asymptomatic. We also showed that C4 expression in plant could help C4 deficient BSCTV mutants to move systemically. C4 was localized in the cytosol and the nucleus in both Arabidopsis protoplasts and N. benthamiana leaves and the protein appeared to bind viral DNA and ds/ssDNA nonspecifically, displaying novel DNA binding properties. Conclusions: Our results suggest that C4 protein in BSCTV is involved in symptom production and may facilitate virus movement instead of virus replication

The complete plastid genome of Delonix regia (Hook.) Raf. (Leguminosae)

Delonix regia, a plant species of the legume family native to Madagascar, has been widely cultivated in the tropical and subtropical regions as an ornamental tree due to its remarkable showy orange-red flowers over summer. Here we report for the first time the complete plastid genome of this species, which has a typical circular structure with a total length of 162,756 bp and contains two inverted repeat regions (IRs, 25,544 bp), a large single copy region (LSC, 92,490 bp), and a small single copy region (SSC, 19,178 bp). The phylogenetic analysis based on the complete plastome sequences of this species and those of the related species from GenBank strongly suggested that D. regia is nested in the subfamily Caesalpinioideae and is sister to a clade consisting of Erythrophlium fordii and the old-sense Mimosoideae

Hierarchical graph transformer with contrastive learning for protein function prediction.

MOTIVATION: In recent years, high-throughput sequencing technologies have made large-scale protein sequences accessible. However, their functional annotations usually rely on low-throughput and pricey experimental studies. Computational prediction models offer a promising alternative to accelerate this process. Graph neural networks have shown significant progress in protein research, but capturing long-distance structural correlations and identifying key residues in protein graphs remains challenging. RESULTS: In the present study, we propose a novel deep learning model named Hierarchical graph transformEr with contrAstive Learning (HEAL) for protein function prediction. The core feature of HEAL is its ability to capture structural semantics using a hierarchical graph Transformer, which introduces a range of super-nodes mimicking functional motifs to interact with nodes in the protein graph. These semantic-aware super-node embeddings are then aggregated with varying emphasis to produce a graph representation. To optimize the network, we utilized graph contrastive learning as a regularization technique to maximize the similarity between different views of the graph representation. Evaluation of the PDBch test set shows that HEAL-PDB, trained on fewer data, achieves comparable performance to the recent state-of-the-art methods, such as DeepFRI. Moreover, HEAL, with the added benefit of unresolved protein structures predicted by AlphaFold2, outperforms DeepFRI by a significant margin on Fmax, AUPR, and Smin metrics on PDBch test set. Additionally, when there are no experimentally resolved structures available for the proteins of interest, HEAL can still achieve better performance on AFch test set than DeepFRI and DeepGOPlus by taking advantage of AlphaFold2 predicted structures. Finally, HEAL is capable of finding functional sites through class activation mapping. AVAILABILITY AND IMPLEMENTATION: Implementations of our HEAL can be found at https://github.com/ZhonghuiGu/HEAL

Discovery of a Potential Anti-Inflammatory Agent: 3‑Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile

Fifteen novel derivatives of glycyrrhetinic acid (GA) were synthesized and evaluated for anti-inflammatory activities. It was found that the introduction of 1-en-3-one and 9(11),12-diene and 2,20-dinitrile functionalities into the scaffold of GA led to the discovery of potent compound <b>19</b> for inhibition of LPS-induced NO production. Furthermore, <b>19</b> effectively inhibited the protein and mRNA expression of inducible NO synthase (iNOS) and the mRNA expression of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW 264.7 macrophages. Mechanistically, <b>19</b> exerted inhibitory effects on the activation of the three main MAPKs and phosphorylation and degradation of IκB-α, as well as the ratio of nuclear/cytosolic content of p65. Importantly, <b>19</b> significantly decreased the mortality rate in the mouse model of LPS-induced sepsis shock. It is noteworthy that inhibitory effect of <b>19</b> on NO production was not blocked by the glucocorticoid receptor antagonist mifepristone, indicating that it does not act through the glucocorticoid receptor

Effective Virtual Screening Strategy toward Covalent Ligands: Identification of Novel NEDD8-Activating Enzyme Inhibitors

The NEDD8-activating enzyme (NAE) is an emerging target for cancer therapy, which regulates the degradation and turnover of a variety of cancer-related proteins by activating the cullin-RING E3 ubiquitin ligases. Among a limited number of known NAE inhibitors, the covalent inhibitors have demonstrated the most potent efficacy through their covalently linked adducts with NEDD8. Inspired by this unique mechanism, in this study, a novel combined strategy of virtual screening (VS) was adopted with the aim to identify diverse covalent inhibitors of NAE. To be specific, a docking-enabled pharmacophore model was first built from the possible active conformations of chosen covalent inhibitors. Meanwhile, a dynamic structure-based phamacophore was also established based on the snapshots derived from molecular dynamic simulation. Subsequent screening of a focused ZINC database using these pharmacophore models combined with covalent docking discovered three novel active compounds. Among them, compound <b>LZ3</b> exhibited the most potent NAE inhibitory activity with an IC₅₀ value of 1.06 ± 0.18 μM. Furthermore, a cell-based washout experiment proved the proposed covalent binding mechanism for compound <b>LZ3</b>, which confirmed the successful application of our combined VS strategy, indicating it may provide a viable solution to systematically discover novel covalent ligands

Water depth affecting thaumarchaeol production in Lake Qinghai, northeastern Qinghai-Tibetan plateau: Implications for paleo lake levels and paleoclimate

Archaeal glycerol dialkyl glycerol tetraethers (GDGTs) are increasingly popular and versatile tool for palaeolimnology studies, but their applications in paleohydrology are scarce, especially for thaumarchaeol which is specific for the newly proposed phylum Thaumarchaeota. After investigating our published GDGT data of Lake Qinghai, we found that both the concentration of thaumarchaeol and the relative abundance of thaumarchaeol to total archaeal GDGTs (%thaum) in core-top sediments increased significantly with increasing water depth (R=0.88 and 0.95, respectively), with lower concentrations of 5+/-5 ng/g in shallow areas (water depth&lt;5m) and higher concentrations of 121+/-65ng/g in deep areas (water depth&gt;10m). This is likely because that the producers of thaumarchaeol, Thaumarchaeota, prefer living in the relative deeper zone in lacustrine systems, where probably both competition of ammonium (the substrate) from other microbes and light intensity are low. Therefore, we proposed that thaumarchaeol was mainly produced in situ and changes in % thaum might reflect water-depth variations in this closed-basin lake. The application of % thaum as a water-depth indicator in a Holocene sediment sequence of core QH-2011 provided a high-resolution relative lake-level history of Lake Qinghai which resembles that inferred from the delta C-13(org) value obtained in the same core. This supports the use of %thaumas an indicator of lakewater depth in paleohydrology studies, especially for medium lakes. Moreover, the records of the two independent proxies in core QH-2011 confirmed a shallow Lake Qinghai in the early Holocene and a late-Holocene highstand, highlighting the importance of local temperature (and evaporation loss) in controlling effective moisture in the arid/semi-arid region.</p

BSCTV C2 Attenuates the Degradation of SAMDC1 to Suppress DNA Methylation-Mediated Gene Silencing in Arabidopsis[W][OA]

This work shows that a geminivirus-encoded silencing suppressor C2 interacts with a plant host cellular component SAMDC1 and attenuates its fast turnover mediated by the 26S proteasome. As a result, it interferes with the host plant’s DNA methylation-related gene silencing mechanism and facilitates geminivirus infection