JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation.

Janus tyrosine kinase 3 (JAK3) is primarily expressed in immune cells and is needed for signaling by the common gamma chain (γc) family of cytokines. Abnormal JAK3 signal transduction can manifest as hematological disorders, e.g., leukemia, severe combined immunodeficiency (SCID) and autoimmune disease states. While regulatory JAK3 phosphosites have been well studied, here a functional proteomics approach coupling a JAK3 autokinase assay to mass spectrometry revealed ten previously unreported autophosphorylation sites (Y105, Y190, Y238, Y399, Y633, Y637, Y738, Y762, Y824, and Y841). Of interest, Y841 was determined to be evolutionarily conserved across multiple species and JAK family members, suggesting a broader role for this residue. Phospho-substitution mutants confirmed that Y841 is also required for STAT5 tyrosine phosphorylation. The homologous JAK1 residue Y894 elicited a similar response to mutagenesis, indicating the shared importance for this site in JAK family members. Phospho-specific Y841-JAK3 antibodies recognized activated kinase from various T-cell lines and transforming JAK3 mutants. Computational biophysics analysis linked Y841 phosphorylation to enhanced JAK3 JH1 domain stability across pH environments, as well as to facilitated complementary electrostatic JH1 dimer formation. Interestingly, Y841 is not limited to tyrosine kinases, suggesting it represents a conserved ubiquitous enzymatic function that may hold therapeutic potential across multiple kinase families.

Exercise-Based Cardiac Rehabilitation Improves Cognitive Function Among Patients With Cardiovascular Disease.

PURPOSE: To investigate the effects of cardiac rehabilitation (CR) exercise training on cognitive performance and whether the changes are associated with alterations in prefrontal cortex (PFC) oxygenation among patients with cardiovascular disease. METHODS: Twenty (men: n = 15; women: n = 5) participants from an outpatient CR program were enrolled in the study. Each participant completed a cognitive performance test battery and a submaximal graded treadmill evaluation on separate occasions prior to and again upon completion of 18 individualized CR sessions. A functional near-infrared spectroscopy (fNIRS) device was used to measure left and right prefrontal cortex (LPFC and RPFC) oxygenation parameters (oxyhemoglobin [O2Hb], deoxyhemoglobin [HHb], total hemoglobin [tHb], and oxyhemoglobin difference [Hbdiff]) during the cognitive test battery. RESULTS: Patients showed improvements in cardiorespiratory fitness (+1.4 metabolic equivalents [METs]) and various cognitive constructs. A significant increase in PFC oxygenation, primarily in the LPFC region, occurred at post-CR testing. Negative associations between changes in cognition (executive function [LPFC O2Hb: r = -0.45, P = .049; LPFC tHb: r = -0.49, P = .030] and fluid composite score [RPFC Hbdiff: r = -0.47, P = .038; LPFC Hbdiff: r = -0.45, P = .048]) and PFC changes were detected. The change in cardiorespiratory fitness was positively associated with the change in working memory score (r = 0.55, P = .016). CONCLUSION: Cardiovascular disease patients enrolled in CR showed significant improvements in multiple cognitive domains along with increased cortical activation. The negative associations between cognitive functioning and PFC oxygenation suggest an improved neural efficiency.

Exercise-Based Cardiac Rehabilitation Modulates Prefrontal Cortex Oxygenation during Submaximal Exercise Testing in Cardiovascular Disease Patients.

The purpose of this study was to investigate if prefrontal cortex (PFC) oxygenation during incremental exercise is altered among cardiovascular disease (CVD) patients who completed 6 weeks of exercise-based cardiac rehabilitation (CR). Nineteen (male = 14, female = 5; 65.5 ± 11.5 years) participants from an outpatient CR program were enrolled in the study. Each participant completed a submaximal graded treadmill evaluation at intake and again upon completion of 18 individualized CR sessions. Functional near-infrared spectroscopy (fNIRS) imaging was used to measure left- and right- PFC (LPFC and RPFC) oxygenation parameters during the submaximal exercise evaluations. Patients showed improvements in cardiorespiratory capacity (pre 5.5 ± 2.5 vs. post 6.9 ± 2.8 metabolic equivalents (METs)). A significant decrease in LPFC and RPFC oxygenation was observed during the post-CR exercise test compared to pre-CR. CVD patients enrolled in 6 weeks of CR showed significant improvements in functional capacity along with decreased cortical oxygenation during submaximal exercise. Exercise training may cause distribution of cortical resources to motor regions that support sustained exercise.