Dziubinski, M. | Search bioRxiv

bioRxiv2024

Somatomotor disconnection links sleep duration with socioeconomic context, screen time, cognition, and psychopathology

BackgroundSleep is critical for healthy brain development and emotional wellbeing, especially during adolescence when sleep, behavior, and neurobiology are rapidly evolving. Theoretical reviews and empirical research have historically focused on how sleep influences mental health through its impact on higher-order brain systems. No studies have leveraged data-driven network neuroscience methods to uncover interpretable, brain-wide signatures of sleep duration in adolescence, their socio-environmental origins, or their consequences for cognition and mental health. MethodsHere, we implement graph theory and component-based predictive modeling to examine how a multimodal index of sleep duration is associated with intrinsic brain architecture in 3,173 youth (11-12 years) from the Adolescent Brain Cognitive DevelopmentSM Study. ResultsWe demonstrate that network integration/segregation exhibit a strong, generalizable multivariate association with sleep duration. We next identify a single component of brain architecture centered on a single network as the dominant contributor of this relationship. This component is characterized by increasing disconnection of a lower-order system - the somatomotor network - from other systems, with shorter sleep duration. Finally, greater somatomotor disconnection is associated with lower socioeconomic resources, longer screen times, reduced cognitive/academic performance, and elevated externalizing problems. ConclusionsThese findings reveal a novel neural signature of shorter sleep in adolescence that is intertwined with environmental risk, cognition, and psychopathology. By robustly elucidating the key involvement of an understudied brain system in sleep, cognition, and psychopathology, this study can inform theoretical and translational research directions on sleep to promote neurobehavioral development and mental health during the adolescent transition.

neuroscience↗

bioRxiv2022

Small molecule mediated stabilization of PP2A modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death

High-Grade Serous Carcinoma (HGSC) is the most common and lethal ovarian cancer subtype. PARP-inhibitors (PARPi) have become the mainstay of HGSC targeted therapy, given that these tumors are driven by a high degree of genomic instability and Homologous Recombination (HR) defects. Nonetheless, only [~]30% of patients initially respond to treatment, ultimately relapsing with resistant disease. Thus, despite recent advances in drug development and increased understanding of genetic alterations driving HGSC progression, mortality has not declined, highlighting the need for novel therapies. Using a Small Molecule Activator of Protein Phosphatase 2A (PP2A) (SMAP-061), we investigated the mechanism by which PP2A stabilization induces apoptosis in Patient-Derived HGSC cells and Xenograft (PDX) models alone or in combination with PARPi. We uncovered that PP2A genes essential for transformation (B56,B56{gamma} and PR72) and basal phosphatase activity (PP2A-A and -C) are heterozygously lost in the majority of HGSC. Moreover, loss of these PP2A genes correlates with worse overall patient survival. We show that SMAP-061 stabilization of PP2A inhibits the HR output by targeting RAD51, leading to chronic accumulation of DNA damage and ultimately apoptosis. Furthermore, combination of SMAP-061 and PARPi leads to enhanced apoptosis in both HR-proficient and -deficient cells and in patient-derived xenograft models. Our studies identify PP2A as novel regulator of HR and introduces PP2A activators as a potential treatment for HGSC tumors. Our studies further emphasize the potential of PP2A modulators to overcome PARPi insensitivity, given that targeting RAD51 has presented benefits in overcoming PARPi-resistance driven by BRCA1/2 mutation reversions.

cancer biology↗