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Here, we report the complete genome sequence of Sphingobacterium sp. PAMC25397, isolated from Ny-Ålesund, Spitsbergen, Norway. The genome is 5.2 Mb in length with a GC content of 37%. This genome harbors biodegradation-related genes involved in benzoate degradation.
AIM: The aim was to characterize the taxonomic and functional composition of the microbiome involved in primary endodontic infections and to evaluate their association with the periapical lesion size using shotgun metagenomic sequencing. METHODOLOGY: Samples from primary root canal infections diagnosed with apical periodontitis were analysed with shotgun sequencing. Samples were classified according to the lesion size as small (< 3 mm) or large (> 7 mm). The bacterial DNA copies in each group were quantified by qPCR. Taxonomic and functional annotations were made using Bracken/Kraken2 and HUMAnN3 software. Species richness, Shannon, Simpson and Pielou indices were used to measure alpha diversity. The similarity of the bacterial communities between study groups was evaluated by Principal Coordinate Analysis based on Bray-Curtis distances. The ALDEx2 package was used to infer the differences between species, and the edgeR package for KEGG pathways. For all statistical analyses, p < 0.05 was considered as significant. RESULTS: A total of 49 samples were analysed, 27 with small lesions and 22 with large lesions. Species richness and Shannon indices showed differences between both groups, whereas no differences were seen according to Simpson and Pielou indices. A different community composition (PERMANOVA, p = 0.0019) was observed between the two groups. Three species were significantly enriched in the large lesion samples, Filifactor alocis, Lachnospiraceae bacterium oral taxon 500 and Olsenella uli, while three others were enriched in small lesion samples, Acinetobacter baumannii, Acinetobacter pittii and Cutibacterium acnes. Functionally, benzoate, flavonoid and steroid degradation, the sphingolipid signalling pathway and proteasome function were enriched in samples with large lesions. Monoterpenoid biosynthesis, phospholipase D signalling, the sulphur relay system and staurosporine biosynthesis were enriched in small lesions. CONCLUSIONS: Teeth with large periapical lesions harbour greater bacterial loads and exhibit a more diverse microbial community than those with small lesions. Differences in species-level taxonomic composition were observed between both groups. Functionally, large lesions are enriched in pathways associated with immune evasion and pro-inflammatory activity, whereas small lesions are characterized by pathways related to apoptosis, metabolic adaptation and anti-inflammatory processes. These findings suggest that lesion severity is also shaped by the functional potential of the microbiome to modulate host inflammation.
Targeted protein degradation (TPD) has emerged as a powerful therapeutic strategy, with proteolysis-targeting chimeras (PROTACs) leading efforts to address previously undruggable targets. However, PROTACs face challenges such as low bioavailability and poor pharmacokinetic properties which limit their biological applications. Here, we report a strategy termed post-translational chemical modification targeting chimera (PTcM-TAC), which integrates ligand-directed chemistry into the PROTAC framework to achieve sustained target protein degradation through covalent modification of E3 ligases. PTcM-TAC incorporates an electrophilic dibromophenyl benzoate warhead into the linker connecting the E3 ligase ligand and the protein-of-interest (POI) ligand, enabling selective transfer of the POI ligand onto the recruited E3 ligase while releasing the E3-binding moiety. Mechanistic studies, including LC-MS/MS peptide mapping, pull-down assays, and structural modeling, demonstrated site-selective modification of CRBN by the PTcM-TAC. The resulting ligand-labeled E3 ligase enables sustained pseudo-catalytic target recognition through a simplified binary interaction, thereby maintaining degradation activity even after compound washout. Furthermore, we successfully applied the PTcM-TAC strategy to another representative E3 ligase, von Hippel-Lindau (VHL), which exhibited substantially sustained degradation activity compared with conventional PROTACs. To our knowledge, PTcM-TAC represents the first ligand-directed chemical strategy that converts transient PROTAC-mediated ternary complex formation into binary target recognition via post-translational chemical modification of an E3 ligase. We believe that PTcM-TAC could provide a platform for next-generation targeted protein degraders to overcome the current limitation of PROTAC approach.