Crystal structure of tyrosine hydroxylase at 2.3 A and its implications for inherited neurodegenerative diseases

Tyrosine hydroxylase (TyrOH) catalyzes the conversion of tyrosine to L-DOPA, the rate-limiting step in the biosynthesis of the catecholamines dopamine, adrenaline, and noradrenaline. TyrOH is highly homologous in terms of both protein sequence and catalytic mechanism to phenylalanine hydroxylase (PheOH) and tryptophan hydroxylase (TrpOH). The crystal structure of the catalytic and tetramerization domains of TyrOH reveals a novel alpha-helical basket holding the catalytic iron and a 40 A long anti-parallel coiled coil which forms the core of the tetramer. The catalytic iron is located 10 A below the enzyme surface in a 17 A deep active site pocket and is coordinated by the conserved residues His 331, His 336 and Glu 376. The structure provides a rationale for the effect of point mutations in TyrOH that cause L-DOPA responsive parkinsonism and Segawa's syndrome. The location of 112 different point mutations in PheOH that lead to phenylketonuria (PKU) are predicted based on the TyrOH structure.     

Rapid and selective depletion of CD4+ T lymphocytes and preferential loss of memory cells on interaction of mononuclear cells with HIV-1 glycoprotein-expressing cells

Apigenin is a plant flavonoid that has been shown to significantly inhibit ultraviolet-induced mouse skin tumorigenesis when applied topically and may be an alternative sunscreen agent for humans. A long-term goal of our laboratory is to elucidate the molecular mechanism or mechanism by which apigenin inhibits skin tumorigenesis. In a previous publication, we characterized the mechanism by which apigenin induced G2/M arrest in keratinocytes. More recent studies in our laboratory have provided evidence that apigenin can induce G1 arrest in addition to arresting cells at G2/M. Here we describe the mechanism of the apigenin-induced G1 arrest in human diploid fibroblasts (HDF). Treatment of asynchronous HDF for 24 h with 10-50 microM apigenin resulted in dose-dependent cell-cycle arrest at both the G0/G1 and G2/M phases as measured by flow cytometry. The G0/G1 arrest was more clearly defined by using HDF that were synchronized in G0 and then released from quiescence by replating at subconfluent densities in medium containing 10-70 microM apigenin. The cells were analyzed for cell-cycle progression or cyclin D1 expression 24 h later. A dose of apigenin as low as 10 microM reduced the percentage of cells in S phase by 20% compared with control cultures treated with solvent alone. Western blot analysis of apigenin-treated HDF indicated that cyclin D1 was expressed at higher levels than in untreated cells, which signifies that they were arrested in G1 phase rather than in a G0 quiescent state. The G1 arrest was further studied by cyclin-dependent kinase 2 (cdk2) immune complex-kinase assays of apigenin-treated asynchronous HDF, which demonstrated a dose-dependent inhibition of cdk2 by apigenin. Inhibition of cdk2 kinase activity in apigenin-treated cells was associated with the accumulation of the hypophosphorylated form of the retinoblastoma (Rb) protein as measured by western blot analysis. The cdk inhibitor p21/WAF1 was also induced in a dose-dependent manner, with a 22-fold induction of p21/WAF1 in 70 microM apigenin-treated cells. In conclusion, apigenin treatment produced a G1 cell-cycle arrest by inhibiting cdk2 kinase activity and the phosphorylation of Rb and inducing the cdk inhibitor p21/WAF1, all of which may mediate its chemopreventive activities in vivo. To our knowledge this is the first report of a chemopreventive agent inducing p21/WAF1, a known downstream effector of the p53 tumor suppressor protein.     

The development and application of a scale of acculturation

As Australia is one of the most multicultural societies in the world, acculturation of migrants and changes in migrants' health status should be an important focus of public health research. The absence of an accepted measure of acculturation is one barrier to exploring the relationship between acculturation and health. This paper presents data from a study of 851 Arabic-speaking adults attending 20 Arabic-speaking general practitioners in Canterbury, Sydney. An eight-item scale assessing acculturation was developed with a structural equation modelling program (LISREL). This acculturation scale was based on similar scales used with Hispanic populations, was theoretically grounded and had high internal consistency and criterion-related validity. To show the application of a scale of acculturation, patients' preferences for participation in medical decision making, according to level of acculturation, were examined. After adjustment for age, sex and highest level of formal education, significant inverse associations between acculturation and preferences for patient (versus family) involvement in medical decision making were found. Mechanisms for how acculturation affects health need to be explored.     

美国UCC公司项目实施八段法

国外工程公司的项目实施工作法是科技发展和经济发展的产物。公司为谋求生存和发展,必须采取先进的技术和科学管理,同时获得适当的利润回报。本文介绍美国UCC公司的项目工作八段法。     

3 cases of post-stapedectomy labyrinthine fistula

Three cases are presented of labyrinthine fistula which suddenly arose in patients who had undergone stapedectomy interposing a vein graft from the back of the hand. These patients had all enjoyed 12-15 years apparently problem free period before the fistula occurred. In all three cases the fistula was accompanied by objective dizziness and varying degrees of sensorineural or mixed hearing loss. The patients underwent revision surgery which identified the fistula and the endolymph oozing out of the graft from the previously installed prosthesis. The authors present the cases, describe how the symptoms arose and the results obtained with revision surgery. Finally, they discuss the need to first perform stapedotomy with a platinar hole; they indicate that the number of cases of total or partial stapedectomy should be limited only to those cases characterized by anatomical variations and/or whenever complications arise during surgery.     

Design of fault-tolerant ATM switch based on parallel architecture

A fault-tolerant ATM switch comprising a distribution network and several routing networks in parallel is proposed. As the distribution network carries out part of the routing process, the routing networks are truncated, giving low overall complexity. A performance evaluation of the switch is presented. The switch outperforms replicated networks but requires lower complexity     

Dopamine and the regulation of cell proliferation in gerbil (Meriones unguiculatus) pyloric mucosa

The epithelium of the digestive system mucosa consists of a highly dynamic cell population. The conditions under which mitotic activity in the gastrointestinal epithelium is regulated is as yet poorly understood. Nevertheless, it is assumed that some biogenic amines might be involved. Having demonstrated that dopaminergic cells occur in the stomach of gerbils (Meriones unguiculatus), in the present study we examined the influence of dopamine antagonist haloperidol on the proliferation of epithelial cells in the mucosa of the stomach. Proliferating cells were detected immunocytochemically and quantified after in-vivo labeling with 5-bromo-2'-desoxyuridine in both haloperidol- and saline-treated animals. The results show that acute doses of haloperidol significantly increases the proliferation rate in the pyloric mucosa, suggesting that dopamine plays a probable modulatory role in the regulation of mitotic activity. These findings are discussed with regard to the role of paraneurons in regulating epithelial mitosis.     

Infrequent association: massive inguinoscrotal bladder hernia, multiple scrotal lithiasis, and bilateral obstructive uropathy]

BACKGROUND AND AIMS OF THE STUDY: Surgical treatment of functional tricuspid regurgitation associated with advanced valvular disease remains controversial, mainly due to the difficulty in choosing between valve replacement or reconstructive surgery. Failure to correct tricuspid regurgitation during valvular surgery carries a poor prognosis, as reoperation may represent a significant risk to the patient. Thus correct tricuspid valve surgery is vital to achieve improved early and long-term clinical results. METHODS: A total of 142 patients underwent concomitant tricuspid annuloplasty with mitral valve replacement and their clinical outcome was assessed. RESULTS: Overall hospital mortality rate was 11.3%. Seven patients died during follow up. The overall actuarial survival rate for 10 years was 74.1 +/- 14.2%. Postoperatively, 75.8% of the patients had no residual tricuspid insufficiency, while 24.2% had first- or second-degree tricuspid insufficiency and were treated medically. All patients were in NHYA functional class I or II postoperatively. CONCLUSION: Clinically, it is important to assess the severity of functional tricuspid insufficiency before and/or during the operation. Bicuspidalization annuloplasty for functional tricuspid insufficiency has provided good results, with a low incidence of reoperation and significant clinical improvement. The technique could be used in most patients with functional tricuspid regurgitation.