4E-binding protein phosphorylation and eukaryotic initiation factor-4E release are required for airway smooth muscle hypertrophy

The molecular mechanisms of airway smooth muscle hypertrophy, a feature of severe asthma, are poorly understood. We previously established a conditionally immortalized human bronchial smooth muscle cell line with a temperature-sensitive SV40 large T antigen. Temperature shift and loss of large T cause G1-phase cell cycle arrest that is accompanied by increased airway smooth muscle cell size. In the present study, we hypothesized that phosphorylation of eukaryotic initiation factor-4E (eIF4E)-binding protein (4E-BP), which subsequently releases eIF4E and initiates cap-dependent mRNA translation, was required for airway smooth muscle hypertrophy. Treatment of cells with chemical inhibitors of PI 3-kinase and mammalian target of rapamycin blocked protein synthesis and cell growth while decreasing the phosphorylation of 4E-BP and increasing the binding of 4E-BP to eIF4E, consistent with the notion that 4E-BP1 phosphorylation and eIF4E function are required for hypertrophy. To test this directly, we infected cells with a retrovirus encoding a phosphorylation site mutant of 4E-BP1 (AA-4E-BP-1) that dominantly inhibits eIF4E. Upon temperature shift, cells infected with AA-4E-BP-1, but not empty vector, failed to undergo hypertrophic growth. We conclude that phosphorylation of 4E-BP, eIF4E release, and cap-dependent protein synthesis are required for hypertrophy of human airway smooth muscle cells.     

The effect of membrane fixed charges on diffusion potentials and streaming potentials

1. Electrical potential differences (p.d.''s) have been measured across an in vitro preparation of rabbit gall-bladder.2. When the gall-bladder separates identical bathing solutions, the p.d. is always zero, regardless of the composition of the bathing solution. Hence the gall-bladder is symmetrical: i.e. the mucosal and serosal cell membranes have the same relative permeability coefficients.3. Osmotic water flow causes streaming potentials of up to 20 mV, of a sign indicating greater permeability to cations than to anions.4. At constant osmolarity, streaming potentials increase slightly with NaCl concentration. Streaming potentials decrease considerably with changes in osmolarity resulting from changes in NaCl concentration.5. Diffusion potentials resulting from electrolyte concentration gradients are fitted well by the constant-field equation with the relative permeability coefficients P_Na = 1·00, P_Cl = 0·33, P_K = 2·3. These permeability coefficients are independent of osmolarity and of salt concentration.6. Relative to 0·25 mM-Ca, 5 mM-Ca reduces streaming potentials by 40%, NaCl diffusion potentials by 62%, and potassium diffusion potentials by 43%.7. The aqueous channels through which water and electrolytes traverse the cell membranes of the gall-bladder contain negative fixed charges, which are blocked by Ca. The physiological significance of the charges may be to reduce chloride permeability and thereby to increase the effectiveness of the gall-bladder in concentrating bile.8. The effect of pH, and analogy with surface charges of other cells, suggest that the charges are organic acids of low pK_a.     

Homeostasis of memory T cells

Summary: The pool of memory T cells is regulated by homeostatic mechanisms to persist for prolonged periods at a relatively steady overall size. Recent work has shown that two members of the common γ chain (γc) family of cytokines, interleukin‐7 (IL‐7) and IL‐15, govern homeostasis of memory T cells. These two cytokines work in conjunction to support memory T‐cell survival and intermittent background proliferation. Normal animals contain significant numbers of spontaneously arising memory‐phenotype (MP) cells, though whether these cells are representative of true antigen‐specific memory T cells is unclear. Nevertheless, it appears that the two types of memory cells do not display identical homeostatic requirements. For antigen‐specific memory CD8⁺ T cells, IL‐7 is primarily important for survival while IL‐15 is crucial for their background proliferation. For memory CD4⁺ T cells, IL‐7 has an important role, whereas the influence of IL‐15 is still unclear.     

Regulation of hepatocyte activator inhibitor-1 expression by androgen and oncogenic transformation in the prostate

Hepatocyte activator inhibitor-1 (HAI-1) is a transmembrane serine protease inhibitor that regulates the conversion of latent to active hepatocyte growth factor (HGF). Studies supporting a role for the HGF pathway in prostate carcinogenesis prompted an analysis of HAI-1 expression in the prostate. Here we analyze the regulation of HAI-1 expression by androgen, oncogenic transformation, and cancer progression. Immunohistochemical analysis revealed that HAI-1 expression was restricted to prostate epithelium, where staining occurred primarily in basal and atrophic luminal epithelial cells. Compared to normal glands, HAI-1 expression was significantly increased in localized prostate cancer and was present in most prostate cancer metastases. HAI-1 protein expression levels were sensitive to androgen in normal epithelium but not in cancer. Although androgen did not increase HAI-1 protein expression levels in LNCaP cells, it decreased HAI-1 surface expression, consistent with previous data from our group (Martin DB, Gifford DR, Wright ME, Keller A, Yi E, Goodlett DR, Aebersold R, Nelson PS: Quantitative proteomic analysis of proteins released by neoplastic prostate epithelium. Cancer Res 2004, 64:347-355). HAI-1 overexpression in cancer was predictive of prostate-specific antigen recurrence (relative risk, 1.24). These results suggest that HAI-1 regulates the HGF Met axis on prostate epithelial cells and influences HGF mediated tumor invasion and metastasis.     

Vitamin A deficiency and the acute phase response among HIV-1-infected and -uninfected women in Kenya

Among HIV-1-infected individuals, vitamin A deficiency has been associated with faster disease progression and greater infectivity in observational studies, but randomized clinical trials have shown no effect of vitamin A supplementation. We conducted a cross-sectional study of 400 HIV-1-infected and 200 HIV-1-uninfected women in Mombasa, Kenya to examine the relations between vitamin A deficiency (serum retinol <30 microg/dL) and HIV-1 status, HIV-1 disease stage, and the acute phase response (serum C-reactive protein >or=10 mg/L and/or alpha1-acid glycoprotein >or=1.2 g/L). Among the HIV-1-infected women, the effect of vitamin A supplementation was examined in a randomized trial. Vitamin A deficiency was independently associated with HIV-1 infection (OR = 2.7, 95% CI: 1.9-4.0) and the acute phase response (OR = 2.8, 95% CI: 1.9-4.1). Among HIV-1-infected women, vitamin A deficiency and the acute phase response were associated with each other and were both independently associated with higher HIV-1 plasma viral load and lower CD4 count. HIV-1-infected women having an acute phase response had no increase in serum vitamin A levels after supplementation. Serum levels increased significantly among women without an acute phase response, although not to normal levels among women who were deficient at baseline. Among HIV-1-infected individuals, it is likely that low serum vitamin A concentrations reflect more active infection and the acute phase response. These results provide possible explanations for the disparity between observational studies and randomized trials of vitamin A for HIV-1 infection.     

Postpartum U.S. Women's Oral Health Knowledge,Attitudes, and Practices During Pregnancy

Maternal and Child Health Journal - The purpose of this study was to assess oral health knowledge, attitudes, and practices of women who had given birth in the United States within the past 2...     

Correction to: Health Literacy Within a Diverse Community-Based Cohort: The Multi-Ethnic Study of Atherosclerosis

Journal of Immigrant and Minority Health - The original version of this article unfortunately contained a typo in co-author name.