GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells.

Amino acid availability is crucial for cancer cells' survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation.

Semi-occluded Nasal Tract Exercises (SONTEs): Nasal Tube in Water Exercises Using Nasal Consonants.

OBJECTIVE: This study analyzes the effects of the vocal exercises called semi-occluded nasal tract exercises (SONTEs), which were carried out with a new appliance that extends the nasal cavity as a part of the vocal tract. The acoustic, aerodynamic and electroglottographic (EGG) measurements were compared with those of the traditional semi-occluded vocal tract exercises (SOVTEs) of phonation in water. METHODS: In this study, 34 women were randomly asked to perform phonation in water for 5 min through the nasal and oral routes with the sounds /m/ and /ɔ/, respectively, using a tube with a submersion depth of 5 cm. The acoustic, aerodynamic and EGG measurements before and after the exercises were analyzed using the appropriate statistical methods. RESULTS: No significant difference was found in the time and frequency domain parameters before and after the exercises, except for the amplitude perturbation quotient (APQ) values, which decreased after both exercises. In addition, there was no significant difference in any aerodynamic parameters before and after the exercises, but the mean SPL values significantly increased after both exercises. The oral and nasal peak inspiratory flow rates increased after both exercises, but the increase peaked after the SONTEs implementation. As expected, the EGG-jitter and EGG-periodicity values had a reciprocal interaction with each other, while differences were observed between the values of the vocal fold movements measured in both exercises. CONCLUSIONS: SONTEs may be as effective as the conventional SOVTEs because it made tube phonation into water possible through artificial extension of the nasal cavity and increased the resonant effect by using the positive effects based on the principles of SOVTEs.