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 mutational spectrum of brachydactyly type C

Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.     

2-O-methylisohemigossylic acid lactone, a sesquiterpene, isolated from roots of mokumen (Gossampinus malabarica) induces cell death and morphological change indicative of apoptotic chromatin condensation in human promyelotic leukemia HL-60 cells

2-O-methylisohemigossylic acid lactone, a sesquiterpene, was purified from roots of mokumen (Gossampinus malabarica) and identified by Mass, and (1)H- and (13)-NMR. This sesquiterpene displayed strong growth inhibitory effect against human promyelotic leukemia HL-60 cells. Apoptotic morphological change of the nucleus, including chromatin condensation was induced in the HL-60 cells treated with the sesquiterpene. The fragmentation of DNA by the sesquiterpene to oligonucleosomal-sized fragments, a characteristic of apoptosis, was observed to be dose- and time-dependent in the HL-60 cells. Inhibitors of caspases suppressed the DNA fragmentation induced by the sesquiterpene. These findings suggest that growth inhibition by the sesquiterpene of HL-60 cells results from the induction of apoptosis by the sesqui-terpene, and that caspase cascade is involved in the induction of apoptosis by the compound in the HL-60 cells.     

Preparation of Iron Carbon Composite Material by Extracting Iron from Bauxite Residue and Its Adsorption of Heavy Metal Cd(II)

Bulletin of Environmental Contamination and Toxicology - An effective method of iron extraction from bauxite residue was explored, and iron was used to prepare iron carbon composite material, which...     

Beta-adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes.

cAMP-dependent phosphorylation clearly increases current through cardiac L-type Ca channels, but the molecular manifestation of this effect remains controversial. Previous work implicates either an increase in the number of functional channels or graded changes in the gating of individual channels. We now find that single cardiac Ca channels display three patterns of activity ("modes") and that isoproterenol or 8-bromoadenosine 3',5'-cyclic monophosphate redistributes the relative proportions of modes such that the two most active (mode 1, bursts of brief openings; mode 2, very long-lasting openings) are favored (P less than 0.05; n = 7). Conversely, a pattern of sparse brief openings (mode 0a) is selectively inhibited (P less than 0.01). Despite differences in the relative frequencies of the various modes before and during drug exposure, the gating within each mode is not detectably changed. We conclude that potentiation of highly active modes of Ca channel gating underlies the enhancement of calcium influx by beta-adrenergic stimulation.     

喉大部切除术后喉功能重建

为 ２３ 例喉癌患者行喉大部分切除术,采用下列方法重建喉功能,（１）重建声门关闭功能;（２）重建会厌覆盖功能;（３）保留或重建梨状窝;（４）保护喉上神经和喉返神经;（５）保持宽大的下咽部;（６）切断环咽肌。２３ 例中２１ 例获得随访,术后均能发音,术后２～４ 周拔除鼻饲管,无误吸及呛咳。５ 年生存１１ 例,生存率 ４７８％ 。     

Skin test inhibition by astemizole.

For the purpose of evaluating the therapeutic effect of antihistamines, we have set up an assay method called the "Skin Test Inhibition Index" (STII). Twenty subjects with hay fever were given astemizole (10 mg/d) for 7 days. Skin titration tests were carried out before and after treatment. Significant inhibition of the skin test reaction by astemizole was demonstrated (STII = 91). Another group of 6 hay fever patients was given astemizole (10 mg/d) for 10 days, and STII was determined on days 5 and 10 and on days 7, 14 and 21 after treatment. STII were calculated as 12, 108, 90, 10 and 7, respectively. These results demonstrate that astemizole is a long-acting antihistamine.