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Deltex proteins are a family of E3 ubiquitin ligases that encode C‐terminal RING and DTC domains that mediate interactions with E2 ubiquitin‐conjugating enzymes and recognize ubiquitination substrates. DTX3L is unique among the Deltex proteins based on its N‐terminal domain architecture. The N‐terminal D1 and D2 domains of DTX3L mediate homo‐oligomerization, and the D3 domain interacts with PARP9, a protein that contains tandem macrodomains with ADP‐ribose reader function. While DTX3L and PARP9 are known to heterodimerize, and assemble into a high molecular weight oligomeric complex, the nature of the oligomeric structure, including whether this contributes to the ADP‐ribose reader function is unknown. Here, we report a crystal structure of the DTX3L N‐terminal D2 domain and show that it forms a tetramer with, conveniently, D2 symmetry. We identified two interfaces in the structure: a major, conserved interface with a surface of 973 Å2 and a smaller one of 415 Å2. Using native mass spectrometry, we observed molecular species that correspond to monomers, dimers and tetramers of the D2 domain. Reconstitution of DTX3L knockout cells with a D1‐D2 deletion mutant showed the domain is dispensable for DTX3L‐PARP9 heterodimer formation, but necessary to assemble an oligomeric complex with efficient reader function for ADP‐ribosylated androgen receptor. Our results suggest that homo‐oligomerization of DTX3L is important for the DTX3L‐PARP9 complex to read mono‐ADP‐ribosylation on a ligand‐regulated transcription factor. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that cellular premature senescence of the glomerulus, including endothelial cells, mesangial cells, and podocytes leads to diabetic nephropathy (DN), and DN is regarded as a clinical model of premature senescence. However, the role of cellular senescence‐associated genes in the glomerulus in DN progression remains unclear. Therefore, this work aims to identify and validate potential cellular aging‐related genes in the glomerulus in DN to provide novel clues for DN treatment based on anti‐aging. The microarray GSE96804 dataset, including 41 diabetic glomeruli and 20 control glomeruli, is retrieved from the Gene Expression Omnibus (GEO) database and cellular senescence‐related genes (CSRGs) are obtained from the GeneCards database and literature reports. Subsequently, PPI, GO, and KEGG enrichment are analyzed by screening the intersection between differentially expressed genes (DEGs) and CSRGs. scRNA‐seq dataset GSE127235 is used to verify core genes expression in glomerulocytes of mice. Finally, db/db mice are utilized to validate the hub gene expression in the glomeruli, and high glucose‐induced mesangial cells are used to confirm key gene expression. This study reveals that FOS and ZFP36 may play an anti‐aging role in DN to ameliorate cell intracellular premature aging in mesangial cells of glomeruli. [ABSTRACT FROM AUTHOR]

Background: Translocator protein (TSPO) is a biomarker of neuroinflammation and brain injury. This study aimed to ascertain the potential of serum TSPO as a predictor of cognitive impairment after acute intracerebral hemorrhage (ICH).Methods: In this prospective observational cohort study, 276 patients with supratentorial ICH were randomly assigned to two groups (184 patients in the study group and 92 in the validation group) in a 2:1 ratio. Serum TSPO levels were gauged at admission, and cognitive status was assessed using the Montreal Cognitive Assessment Scale (MoCA) post-stroke 3 months. A MoCA score of < 26 was considered indicative of cognitive impairment.Results: Serum TSPO levels were inversely correlated with MoCA scores (ρ=− 0.592; P< 0.001). Multivariate linear regression analysis showed that serum TSPO levels were independently associated with MoCA scores (β, − 0.934; 95% confidence interval (CI), − 1.412--0.455; VIF, 1.473; P< 0.001). Serum TSPO levels were substantially higher in patients with cognitive impairment than in the remaining patients (median, 2.7 versus 1.6 ng/mL; P< 0.001). Serum TSPO levels were linearly correlated with the risk of cognitive impairment under a restricted cubic spline (P=0.325) and independently predicted cognitive impairment (odds ratio, 1.589; 95% CI, 1.139– 2.216; P=0.016). Subgroup analysis showed that the relationship between serum TSPO levels and cognitive impairment was not markedly influenced by other parameters, such as age, sex, drinking, smoking, hypertension, diabetes mellitus, body mass index, and dyslipidemia (all P for interaction > 0.05). The model, which contained serum TSPO, National Institutes of Health Stroke Scale scores and hematoma volume, performed well under the receiver operating characteristic curve, calibration curve and decision curve, and using the Hosmer–Lemeshow test. This model was validated in the validation group.Conclusion: Serum TSPO level upon admission after ICH was independently associated with cognitive impairment, substantializing serum TSPO as a reliable predictor of post-ICH cognitive impairment. [ABSTRACT FROM AUTHOR]