Prolonged persistence of mutagenic DNA lesions in somatic cells.

DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours, but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium.

DNA polymerase theta-mediated DNA repair is a functional dependency and therapeutic vulnerability in DNMT3A deficient leukemia cells.

Myeloid malignancies carrying somatic DNMT3A mutations (DNMT3Amut) are usually resistant to standard therapy. DNMT3Amut leukemia cells accumulate toxic DNA double strand breaks (DSBs) and collapsed replication forks, rendering them dependent on DNA damage response (DDR). DNA polymerase theta (Polθ), a key element in Polθ-mediated DNA end-joining (TMEJ), is essential for survival and proliferation of DNMT3Amut leukemia cells.

Clonal hematopoiesis and hematological malignancy.

Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers.

Machine learning-enabled detection of attention-deficit/hyperactivity disorder with multimodal physiological data: a case-control study.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a multifaceted neurodevelopmental psychiatric condition that typically emerges during childhood but often persists into adulthood, significantly impacting individuals' functioning, relationships, productivity, and overall quality of life. However, the current diagnostic process exhibits limitations that can significantly affect its overall effectiveness. Notably, its face-to-face and time-consuming nature, coupled with the reliance on subjective recall of historical information and clinician subjectivity, stand out as key challenges.