The DrPolA-NTD deficient strain shows increased sensitivity to UV and gamma-ray radiation. Collectively, our results reveal distinct biochemical characteristics of DrPolA during DNA degradation and re-synthesis, which provide new insight into the outstanding DNA repair capacity of D. radiodurans.Small-molecule inhibitors of enzyme function are critical tools for the study of cell biological processes and for treatment of human disease. Avibactam free acid clinical trial Identifying inhibitors with suitable specificity and selectivity for single enzymes, however, remains a challenge. In this study we describe our serendipitous discovery that NMS-873, a compound that was previously identified as a highly selective allosteric inhibitor of the ATPase valosin-containing protein (VCP/p97), rapidly induces aerobic fermentation in cultured human and mouse cells. Our further investigation uncovered an unexpected off-target effect of NMS-873 on mitochondrial oxidative phosphorylation, specifically as a dual inhibitor of Complex I and ATP synthase. This work points to the need for caution regarding the interpretation of cell survival data associated with NMS-873 treatment and indicates that cellular toxicity associated with its use may be caused by both VCP/p97-dependent and VCP/p97-independent mechanisms.Inteins are intervening polypeptides that interrupt the functional domains of several important proteins across the three domains of life. Inteins excise themselves from the precursor protein, ligating concomitant extein residues in a process called protein splicing. Post-translational auto-removal of inteins remain critical for the generation of active proteins. The perspective of inteins in science is a robust field of research, however fundamental studies centralized upon splicing regulatory mechanism are imperative for addressing more intricate issues. Controlled engineering of intein splicing has many applications; intein inhibition can facilitate novel drug design, while activation of intein splicing is exploited in protein purification. This paper provides a comprehensive review of the past and recent advances in the splicing regulation via metal-intein interaction. We compare the behavior of different metal ions on diverse intein systems. Though metals such as Zn, Cu, Pt, Cd, Co, Ni exhibit intein inhibitory effect heterogeneously on different inteins, divalent metal ions such as Ca and Mg fail to do so. The observed diversity in the metal-intein interaction arises mostly due to intein polymorphism and variations in atomic structure of metals. A mechanistic understanding of intein regulation by metals in native as well as synthetically engineered intein systems may yield potent intein inhibitors via direct or indirect approach.Luteolin (5,7,3',4'-tetrahydroxyflavone) belongs to the flavone subclass of flavonoids. Luteolin and its glycosides are present in many botanical families, including edible plants, fruits, and vegetables. While the beneficial properties of luteolin have been widely studied, fewer studies have investigated its toxicity. In the present study, using human lymphoblastoid TK6 cells and our newly developed TK6-derived cell lines that each stably express a single human cytochrome P450 (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C18, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7), we systematically evaluated luteolin-induced cytotoxicity and genotoxicity, and the role of specific CYPs in the bioactivation of luteolin. Treatments with luteolin for 4-24 h induced cytotoxicity, apoptosis, DNA damage, and chromosome damage in a concentration-dependent manner. Subsequently, we observed that luteolin-induced cytotoxicity and genotoxicity, measured by the high-throughput micronucleus assay, were significantly increased in TK6 cells transduced with CYP1A1 and 1A2. In addition, key apoptosis and DNA damage biomarkers, including cleaved PARP-1, cleaved caspase-3, and phosphorylated histone 2AX (γH2A.X), were all significantly increased in the CYP1A1- and 1A2-expressing cells compared with the empty vector controls. Analysis by LC-MS/MS revealed that TK6 cells biotransformed the majority of luteolin into diosmetin, a less toxic O-methylated flavone, after 24 h; the presence of CYP1A1 and 1A2 partially reversed this process. Altogether, these results indicate that metabolism by CYP1A1 and 1A2 enhanced the toxicity of luteolin in vitro. Our results further support the utility of our TK6 cell system for identification of the specific CYPs responsible for chemical bioactivation and toxicity potential. Malignant cutaneous adnexal tumors (MCATs) are rare and their natural history is poorly understood. Available literature indicates aggressive behavior with a significant risk of metastasis. Retrospective review of our institutional surgical oncology databases was performed for patients diagnosed with MCATs (2001-2020). We hypothesized that most patients have a low risk of lymph node involvement, recurrence, and death. Kaplan-Meier statistical analysis was used to assess risk of recurrence and 5-year survival. We identified 41 patients diagnosed with MCATs (median age 59 years, 68% were men). Most patients had long-standing cutaneous lesions (median 24 months) and no palpable adenopathy. Most patients had stage I or II disease (98%). Primary tumors were treated with wide local excision (n= 28 [68%]), Mohs surgery (n= 5 [12%]), or amputation (n= 8 [19%]). Of 25 patients who underwent SLNB (61%), 1 had lymphatic metastasis. These include apocrine carcinoma (1 of 3), digital papillary adenocarcinoma (0 of 8), porocarcinoma (0 of 4), and additional MCAT sub-types (0 of 10). Three patients (7%) had disease recurrence at a median interval of 3.6 years (interquartile range 1.5 to 4.4 years). Five patients (12%) died at a median interval of 7 years (interquartile range 6.7 to 9.2 years), but only 1 patient was known to have succumbed to MCAT. Overall 5-year survival rate was 96% (95% CI, 75% to 99%). Despite the historical impression that MCATs have a high metastatic potential, most patients have low recurrence rates and excellent 5-year survival rates. Lymphatic disease identified after SLNB in early-stage tumors is rare and the value of this staging procedure in MCAT remains unclear.Despite the historical impression that MCATs have a high metastatic potential, most patients have low recurrence rates and excellent 5-year survival rates. Lymphatic disease identified after SLNB in early-stage tumors is rare and the value of this staging procedure in MCAT remains unclear.