Morphine-3-glucuronide's neuro-excitatory effects are mediated via indirect activation of N-methyl-D-aspartic acid receptors: Mechanistic studies in embryonic cultured hippocampal neurones

Indirect evidence indicates that morphine-3-glucuronide (M3G) may contribute significantly to the neuro-excitatory side effects (myoclonus and allodynia) of large-dose systemic morphine. To gain insight into the mechanism underlying M3G' s excitatory behaviors, We used fluo-3 fluorescence digital imaging techniques to assess the acute effects of M3G (5-500 muM) on the cytosolic calcium concentration ([Ca2+](CYT)) in cultured embryonic hippocampal neurones. Acute (3 min) exposure of neurones to M3G evoked [Ca2+](CYT) transients that were typically either (a) transient oscillatory responses characterized by a rapid increase in [Ca2+](CYT) oscillation amplitude that was sustained for at least similar to30 s or (b) a sustained increase in [Ca2+](CYT) that slowly recovered to baseline. Naloxone-pretreatment decreased the proportion of M3G-responsive neurones by 10%-25%, implicating a predominantly non-opioidergic mechanism. Although the naloxone-insensitive M3G-induced increases in [Ca2+](CYT) were completely blocked by N-methyl-D-aspartic acid (NMDA) antagonists and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (alphaamino-3-hydroxy-5-methyl-4-isoxazolepropiordc acid/ kainate antagonist), CNQX did not block the large increase in [Ca2+](CYT) evoked by NMDA (as expected), confirming that N13G indirectly activates the NMDA receptor. Additionally, tetrodotoxin (Na+ channel blocker), baclofen (gamma-aminobutyric acid, agonist), MVIIC (P/Q-type calcium channel blocker), and nifedipine (L-type calcium channel blocker) all abolished M3G-induced increases in [Ca2+](CYT), suggesting that M3G may produce its neuro-excitatory effects by modulating neurotransmitter release. However, additional characterization is required.

Comparative mechanistic studies of de novo RNA synthesis by flavivirus RNA-dependent RNA polymerases

Flavivirus protein NS5 harbors the RNA-dependent RNA polymerase (RdRp) activity. In contrast to the RdRps of hepaci- and pestiviruses, which belong to the same family of Flaviviridae, NS5 carries two activities, a methyltransferase (MTase) and a RdRp. RdRp domains of Dengue virus (DV) and West Nile virus (WNV) NS5 were purified in high yield relative to full-length NS5 and showed full RdRp activity. Steady-state enzymatic parameters were determined on homopolymeric template poly(rC). The presence of the MTase domain does not affect the RdRp activity. Flavivirus RdRp domains might bear more than one GTP binding site displaying positive cooperativity. The kinetics of RNA synthesis by four Flaviviridae RdRps were compared. In comparison to Hepatitis C RdRp, DV and WNV as well as Bovine Viral Diarrhea virus RdRps show less rate limitation by early steps of short-product fort-nation. This suggests that they display a higher conformational flexibility upon the transition from initiation to elongation. (c) 2006 Elsevier Inc. All rights reserved.

Lung cancer rates in men and women with comparable histories of smoking

Background: Recent case-control studies suggest that, given equal smoking exposure, women may have a higher relative risk of developing lung cancer than men. Despite prospective data that conflict with this hypothesis, mechanistic studies to find a biologic basis for a sex difference continue. Methods: We addressed the hypothesis directly by analyzing prospective data from former and current smokers in two large cohorts-the Nurses' Health Study of women and the Health Professionals Follow-up Study of men. We calculated incidence rates and hazard ratios of lung cancer in women compared with men, adjusting for age, number of cigarettes smoked per day, age at start of smoking, and time since quitting, using Cox proportional hazards models. We also reviewed published results from prospective analyses. Results: From 1986 through 2000, 955 and 311 primary lung cancers were identified among 60 296 women and 25 397 men, respectively, who ranged in age from 40 to 79 years. Incidence rates per 100 000 person-years for women and men were 253 and 232, respectively, among current smokers and 81 and 73, respectively, among former smokers. The hazard ratio in women ever smokers compared with men was 1.11 (95% confidence interval = 0.95 to 1.31). Six published prospective cohort studies allowed assessment of comparative susceptibility to lung cancer by sex. None supported an excess risk of lung cancer for women. Conclusions: Women do not appear to have a greater susceptibility to lung cancer than men, given equal smoking exposure. Research should be focused on enhancing preventive interventions for all.

Rainfall variability at decadal and longer time scales: signal or noise?

Rainfall variability occurs over a wide range of temporal scales. Knowledge and understanding of such variability can lead to improved risk management practices in agricultural and other industries. Analyses of temporal patterns in 100 yr of observed monthly global sea surface temperature and sea level pressure data show that the single most important cause of explainable, terrestrial rainfall variability resides within the El Nino-Southern Oscillation (ENSO) frequency domain (2.5-8.0 yr), followed by a slightly weaker but highly significant decadal signal (9-13 yr), with some evidence of lesser but significant rainfall variability at interclecadal time scales (15-18 yr). Most of the rainfall variability significantly linked to frequencies tower than ENSO occurs in the Australasian region, with smaller effects in North and South America, central and southern Africa, and western Europe. While low-frequency (LF) signals at a decadal frequency are dominant, the variability evident was ENSO-like in all the frequency domains considered. The extent to which such LF variability is (i) predictable and (ii) either part of the overall ENSO variability or caused by independent processes remains an as yet unanswered question. Further progress can only be made through mechanistic studies using a variety of models.

Mechanism and kinetics of dithiobenzoate-mediated RAFT polymerization. I. The current situation

Investigations into the kinetics and mechanism of dithiobenzoate-mediated Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerizations, which exhibit nonideal kinetic behavior, such as induction periods and rate retardation, are comprehensively reviewed. The appreciable uncertainty in the rate coefficients associated with the RAFT equilibrium is discussed and methods for obtaining RAFT-specific rate coefficients are detailed. In addition, mechanistic studies are presented, which target the elucidation of the fundamental cause of rate retarding effects. The experimental and theoretical data existing in the literature are critically evaluated and apparent discrepancies between the results of different studies into the kinetics of RAFT polymerizations are discussed. Finally, recommendations for further work are given. (c) 2006 Wiley Periodicals, Inc.

Synthesis, characterization and DFT studies of the cobalt(III) complex of a tetrapodal pentadentate N4S donor ligand

The synthesis of the pentadentate ligand 2,6-bis(3,3-dimethyl-2,4-dioxocyclohexanyl)-4-thiaheptane (N(4)Samp) is described. The synthetic pathway involves the coupling of two 1,3-(dimethylenedioxy)-2-methyl-2-(methylene-p-toluenesulfonyl)propane moieties with sodium sulfide and subsequent synthetic elaboration to prepare the final N4S donor system. The cobalt(III) complex [Co(N(4)Samp)Cl](2+) has been prepared and subsequently crystallized as the tetrachlorozincate salt. The X-ray structure analysis confirms the pentadentate nature of the ligand and shows the thioether donor occupying one apex with four equivalent amine donors effectively occupying the equatorial plane of the molecule. The sixth coordination site is occupied by a chloro ligand. The electronic absorption and C-13 NMR spectra have been studied. DFT calculations have been employed to explore structural and mechanistic comparisons between [Co(N(4)Samp)Cl](2+) and an analogous pentaamine complex.

Mechanistic modelling of pilling. Part II: Individual-fibre computational model

A one-dimensional computational model of pilling of a fibre assembly has been created. The model follows a set of individual fibres, as free ends and loops appear as fuzz and arc progressively withdrawn from the body of the assembly, and entangle to form pills, which eventually break off or are pulled out. The time dependence of the computation is given by ticks, which correspond to cycles of a wear and laundering process. The movement of the fibres is treated as a reptation process. A set of standard values is used as inputs to the computation. Predictions arc given of the change with a number Of cycles of mass of fuzz, mass of pills, and mass removed from the assembly. Changes in the standard values allow sensitivity studies to be carried out.

Inhibition studies of purple acid phosphatases: Implications for the catalytic mechanism

Purple acid phosphatases (PAPs) belong to the family of binuclear metallohydrolases and catalyse the hydrolysis of a large group of phosphoester substrates at acidic pH. Despite structural conservation in their active sites PAPs appear to display mechanistic versatility. Here, aspects of the catalytic mechanism of two PAPs are investigated using the inhibitors vanadate and fluoride as probes. While the magnitude of their vanadate inhibition constants are similar the two enzymes differ with respect to the mode of inhibition; vanadate interacts in a non-competitive fashion with pig PAP (K-i = 40 mu mol L-1) while it inhibits red kidney bean PAP competitively (K-i = 30 mu mol L-1). Similarly, fluoride also acts as a competitive inhibitor for red kidney bean PAP, independent of pH, while the inhibition of pig PAP by fluoride is uncompetitive at low pH and non-competitive at higher pH, independent of metal ion composition. Furthermore, while fluoride acts as a slow-binding inhibitor in pig PAP it binds rapidly to the catalytic site of the red kidney bean enzyme. Since vanadate and fluoride are proposed to act as transition state and nucleophile mimics, respectively, the observed differences in inhibition kinetics indicate subtle but distinct variations in the reaction mechanism of these enzymes.

Aboriginal and Torres Strait Islander Studies Unit Annual Report

Welcome to the 2002 Aboriginal and Torres Strait Islander Studies Unit Annual Report. This report is a brief summary of Unit activities during the 2002 calendar year. The Unit provides personal and academic support for Aboriginal and Torres Strait Islander students and specifically aims to increase the recruitment, retention, academic performance and graduation rates of Indigenous students. The Unit also administers schemes to help Indigenous students gain access to, and receive support in, tertiary studies such as the Alternative Entry scheme and the federally funded Aboriginal Tutorial Assistance Scheme (ATAS). The Unit is also the focus for teaching and research in Aboriginal and Torres Strait Islander Studies at the University of Queensland.

Aboriginal and Torres Strait Islander Studies Unit Annual Report 2003

Welcome to the 2003 Aboriginal and Torres Strait Islander Studies Unit Annual Report. This report is a brief summary of Unit activities during the 2003 calendar year. The Unit provides personal and academic support for Aboriginal and Torres Strait Islander students and specifically aims to increase the recruitment, retention, academic performance and graduation rates of Indigenous students. The Unit also administers schemes to help Indigenous students gain access to, and receive support in, tertiary studies such as the Alternative Entry scheme and the federally funded Aboriginal Tutorial Assistance Scheme (ATAS). The Unit is also the focus for teaching and research in Aboriginal and Torres Strait Islander Studies at the University of Queensland.

Aboriginal and Torres Strait Islander Studies Unit Annual Report 2005

Welcome to the 2005 Aboriginal and Torres Strait Islander Studies Unit Annual Report. This report is a brief summary of Unit activities during the 2005 calendar year. The Unit provides personal and academic support for Aboriginal and Torres Strait Islander students and specifically aims to increase the recruitment, retention, academic performance and graduation rates of Indigenous students. The Unit also administers schemes to help Indigenous students gain access to, and receive support in, tertiary studies such as the Alternative Entry scheme and the federally-funded Indigenous Tutorial Assistance Scheme (ITAS). The Unit is also the focus for teaching and research in Aboriginal and Torres Strait Islander Studies at the University of Queensland.

Cross-sectional and prospective relationships of interleukin-6 and C-reactive protein with physical performance in elderly persons: MacArthur Studies of Successful aging

Although IL-6 has been shown to predict onset of disability in older persons and both IL-6 and CRP are associated with motality risk, these markers of inflammation have only limited associations with physical performance, except for walking measures and grip strength at baseline, and do not predict change in performance 7 years later in a high-functioning subset of older adults.