Castell, S. | bioRxiv Science

bioRxiv2026

Exposure to childhood adversity and adult alcohol, nicotine, and illicit drug use in Germany: a cross-sectional analysis of the German National Cohort (NAKO)

Rationale: Exposure to adversity in childhood and adolescence (i.e., "early-life stress"; ELS) is a well-established risk factor for substance use. Objectives: The aim of this study was to investigate associations between ELS exposure and substance use across subtypes of ELS, different substance classes, and behavioral profiles of substance use. Methods: In this cross-sectional study, we examined associations between ELS exposure and substance use in a population-based sample of 172,173 adults aged 19-74 years from the German National Cohort (NAKO). ELS exposure was assessed using the Childhood Trauma Screener. Substance use included nicotine, alcohol, and illicit drug use. Associations were examined using regression models evaluating overall ELS exposure, cumulative trauma load, and ELS subtypes. Latent class analysis (LCA) was conducted to identify substance use profiles. Results: ELS exposure was associated with higher odds of smoking, greater smoking severity, heavier alcohol consumption among drinkers, and higher odds of lifetime illicit drug use. Overall, the strongest associations were observed for opioid and stimulant use. Dose-response analyses revealed higher risk with increasing numbers of ELS subtypes. Abuse-related subtypes, particularly exposure to physical and sexual abuse, consistently showed strongest independent associations across substances, whereas neglect exhibited weaker, more variable associations. LCA identified four substance use profiles, with ELS exposure predicting membership in more severe polysubstance classes. Conclusions: ELS emerged as a robust risk factor for adult substance use, underscoring the need for trauma-informed approaches in clinical practice, public health, and policy to mitigate the long-term consequences of early adversity.

neuroscience↗

bioRxiv2024

Low fidelity DNA polymerase IV accelerates genome evolution in Pseudomonas aeruginosa

Specialized DNA polymerases are crucial for bypassing lesions and facilitating various cellular processes. Despite extensive research, the mutagenic effects of these error-prone enzymes on genomes are still not fully understood. In this study, we examined the genomic instability caused by Pol IV in the bacterial pathogen Pseudomonas aeruginosa. Pol IV mutagenesis primarily involved the misincorporation of oxidized guanine nucleotides opposite template adenine. This activity led to a distinctive mutational signature, characterized by A to C transversions occurring preferentially at AT sites flanked by a 5G and/or 3C. Furthermore, Pol IV preferentially targeted specific chromosomal locations near the replication termination region and rRNA-encoding operons. Several genes associated with virulence, motility, antibiotic resistance and chemotaxis are located in these difficult-to-replicate regions, making them hotspots for Pol IV-mutagenesis. Notably, half of the mutation events catalyzed by Pol IV effectively impaired gene function. This can be attributed to the strong bias of Pol IV for mutating specific codons with its preferred sequence contexts, leading to substitutions primarily to the unreactive Ala and Gly residues. Remarkably, mutation signatures identified for Pol IV were also present in genomes from clinical isolates of P. aeruginosa, providing compelling evidence for its role in genetic diversification during pathogen adaptation.

genomics↗