Experience-dependent Tip60 nucleocytoplasmic transport is regulated by its NLS/NES sequences for neuroplasticity gene control.

Nucleocytoplasmic transport (NCT) in neurons is critical for enabling proteins to enter the nucleus and regulate plasticity genes in response to environmental cues. Such experience-dependent (ED) neural plasticity is central for establishing memory formation and cognitive function and can influence the severity of neurodegenerative disorders like Alzheimer's disease (AD). ED neural plasticity is driven by histone acetylation (HA) mediated epigenetic mechanisms that regulate dynamic activity-dependent gene transcription profiles in response to neuronal stimulation. Yet, how histone acetyltransferases (HATs) respond to extracellular cues in the in vivo brain to drive HA-mediated activity-dependent gene control remains unclear. We previously demonstrated that extracellular stimulation of rat hippocampal neurons in vitro triggers Tip60 HAT nuclear import with concomitant synaptic gene induction. Here, we focus on investigating Tip60 HAT subcellular localization and NCT specifically in neuronal activity-dependent gene control by using the learning and memory mushroom body (MB) region of the Drosophila brain as a powerful in vivo cognitive model system. We used immunohistochemistry (IHC) to compare the subcellular localization of Tip60 HAT in the Drosophila brain under normal conditions and in response to stimulation of fly brain neurons in vivo either by genetically inducing potassium channels activation or by exposure to natural positive ED conditions. Furthermore, we found that both inducible and ED condition-mediated neural induction triggered Tip60 nuclear import with concomitant induction of previously identified Tip60 target genes and that Tip60 levels in both the nucleus and cytoplasm were significantly decreased in our well-characterized Drosophila AD model. Mutagenesis of a putative nuclear localization signal (NLS) sequence and nuclear export signal (NES) sequence that we identified in the Drosophila Tip60 protein revealed that both are functionally required for appropriate Tip60 subcellular localization. Our results support a model by which neuronal stimulation triggers Tip60 NCT via its NLS and NES sequences to promote induction of activity-dependent neuroplasticity gene transcription and that this process may be disrupted in AD.

Hip Range of Motion During Passive and 1-Leg Exercises Is Greater in Women: A Meta-analysis and Systematic Review.

PURPOSE: To summarize sex-related differences in hip range of motion (ROM), including flexion, extension, abduction, adduction, internal rotation, and external rotation. METHODS: We performed a systematic search of 3 databases (PubMed, CINAHL [Cumulative Index to Nursing and Allied Health Literature], and Embase). The search terms were as follows: hip, pelvis, range of motion, kinematic, men, and women. Included studies reported sex-specific data on hip ROM in healthy, uninjured adults. To generate hip ROM mean differences, a DerSimonian-Laird random-effects model was used. Effect sizes were pooled for each exercise. Subgroup analyses compared hip ROM by physical activity group: passive ROM, 1-leg hop or jump, 2-leg hop or jump, 2-leg drop or landing, 1-leg squat, 2-leg squat, walking, and jogging/running. Positive effect sizes represent greater ROM in women. RESULTS: Thirty-eight studies with 3,234 total subjects were included; of these subjects, 1,639 were women (50.1%). The mean age was 25.3 years. An effect difference was considered statistically significant if P < .05 and clinically significant if the mean difference was greater than 4.0°. Women showed statistically and clinically significantly greater hip flexion in passive ROM (mean difference, 6.4°) and during the 1-leg hop or jump exercise (mean difference, 6.5°). Women also showed statistically and clinically significantly greater hip adduction during the 1-leg hop or jump (mean difference, 4.5°) and 1-leg squat (mean difference, 4.4°) exercises, as well as statistically and clinically significantly greater hip internal rotation in passive ROM (mean difference, 8.2°). In contrast, men showed statistically and clinically significantly greater flexion during the 2-leg hop or jump exercise (mean difference, -9.1°). No clinically significant differences in extension, abduction, or external rotation were found between women and men. CONCLUSIONS: On average, women showed statistically and clinically significantly greater flexion, adduction, and internal rotation during passive and 1-leg exercises whereas men showed statistically and clinically significantly greater flexion during the 2-leg hop or jump exercise. LEVEL OF EVIDENCE: Level IV, meta-analysis and systematic review of Level II-IV studies.