Comprehensive whole-genome sequencing reveals origins of mutational signatures associated with aging, mismatch repair deficiency and temozolomide chemotherapy.

In a comprehensive study to decipher the multi-layered response to the chemotherapeutic agent temozolomide (TMZ), we analyzed 427 genomes and determined mutational patterns in a collection of ∼40 isogenic DNA repair-deficient human TK6 lymphoblast cell lines. We first demonstrate that the spontaneous mutational background is very similar to the aging-associated mutational signature SBS40 and mainly caused by polymerase zeta-mediated translesion synthesis (TLS). MSH2-/- mismatch repair (MMR) knockout in conjunction with additional repair deficiencies uncovers cryptic mutational patterns.

Plasma Alzheimer's disease biomarker variability: Amyloid-independent and amyloid-dependent factors.

Introduction: We aimed to investigate which factors affect plasma biomarker levels via amyloid beta (Aβ)-independent or Aβ-dependent effects and improve the predictive performance of these biomarkers for Aβ positivity on positron emission tomography (PET).

Methods: A total of 2935 participants underwent blood sampling for measurements of plasma Aβ42/40 ratio, phosphorylated tau 217 (p-tau217; ALZpath), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels using single-molecule array and Aβ PET. Laboratory findings were collected using a routine blood test battery.

Socioeconomic mobility, metabolic health, and diet: mediation via subjective socioeconomic status.

Objective: Socioeconomic mobility, i.e., changing socioeconomic status (SES) between adolescence and adulthood, may impact health through changing resources, social status, and health-related behaviors.