Erythropoietin Receptor Signaling Is Membrane Raft Dependent

Upon erythropoietin (Epo) engagement, Epo-receptor (R) homodimerizes to activate JAK2 and Lyn, which phosphorylate STAT5. Although recent investigations have identified key negative regulators of Epo-R signaling, little is known about the role of membrane localization in controlling receptor signal fidelity. Here we show a critical role for membrane raft (MR) microdomains in creation of discrete signaling platforms essential for Epo-R signaling. Treatment of UT7 cells with Epo induced MR assembly and coalescence. Confocal microscopy showed that raft aggregates significantly increased after Epo stimulation (mean, 4.3±1.4(SE) vs. 25.6±3.2 aggregates/cell; p≤0.001), accompanied by a >3-fold increase in cluster size (p≤0.001). Raft fraction immunoblotting showed Epo-R translocation to MR after Epo stimulation and was confirmed by fluorescence microscopy in Epo stimulated UT7 cells and primary erythroid bursts. Receptor recruitment into MR was accompanied by incorporation of JAK2, Lyn, and STAT5 and their activated forms. Raft disruption by cholesterol depletion extinguished Epo induced Jak2, STAT5, Akt and MAPK phosphorylation in UT7 cells and erythroid progenitors. Furthermore, inhibition of the Rho GTPases Rac1 or RhoA blocked receptor recruitment into raft fractions, indicating a role for these GTPases in receptor trafficking. These data establish a critical role for MR in recruitment and assembly of Epo-R and signal intermediates into discrete membrane signaling units

Cough in the Elderly Population: Relationships with Multiple Comorbidity

BACKGROUND: The epidemiology of cough in the elderly population has not been studied comprehensively. The present study aimed to investigate the epidemiology of cough in a community elderly population, particularly in relation with their comorbidity. METHODS: A cross-sectional analysis was performed using a baseline dataset from the Korean Longitudinal Study on Health and Aging, a community-based elderly population cohort study. Three types of cough (frequent cough, chronic persistent cough, and nocturnal cough) were defined using questionnaires. Comorbidity was examined using a structured questionnaire. Health-related quality of life was assessed using the Short Form 36 questionnaire. RESULTS: The prevalence was 9.3% for frequent cough, 4.6% for chronic persistent cough, and 7.3% for nocturnal cough. In multivariate logistic regression analyses, smoking, asthma and allergic rhinitis were found to be risk factors for cough in the elderly. Interestingly, among comorbidities, constipation and uncontrolled diabetes mellitus (HbA1c ≥ 8%) were also found to have positive associations with elderly cough. In the Short Form 36 scores, chronic persistent cough was independently related to impairment of quality of life, predominantly in the mental component. CONCLUSIONS: Cough has a high prevalence and is detrimental to quality of life in the elderly. Associations with smoking, asthma and rhinitis confirmed previous findings in younger populations. Previously unrecognised relationships with constipation and uncontrolled diabetes mellitus suggested the multi-faceted nature of cough in the elderly