Early induction of chalpains in rotenone-mediated neuronal apoptosis

Rotenone is an inhibitor of mitochondrial complex I that produces a model of Parkinson's disease (PD), where neurons undergo apoptosis by caspase-dependent and/or caspase-independent pathways. Inhibition of calpains has recently been shown to attenuate neuronal apoptosis. This study aims to establish for the first time, the time-point of calpain activation with respect to the caspase activation and the possibility of cell cycle re-entry in rotenone-mediated cell death. Immunoblot results revealed calpain activation occurred at 5, 10 h prior to caspase-3 activation (at 15 h), suggesting calpain activation was an earlier cellular event compared to caspase activation in the rotenone-mediated apoptosis. In addition, an upregulation of phospho-p53 was observed at 21 h. However, no expression or upregulation of cell cycle regulatory proteins including cdc25a, cyclin-D1 and cyclin-D3 were observed, strongly suggesting that cell cycle re-entry did not occur. These findings provide new insights into the differential patterns of calpain and caspase activation that result from rotenone poisoning and which may be relevant to the therapeutic management of PD.

Induction of propranolol metabolism by Ginkgo biloba extract EGb 761 in rats

Ginkgo biloba is one of the most popular herbal medicines in the world, due to its purported pharmacological effects, including memory-enhancing, cognition-improving, and antiplatelet effects. When used in the elderly, Ginkgo has a high potential for interactions with cardiovascular drugs. This study aimed to investigate the effects of the standard Ginkgo biloba extract (EGB 761) treatment on the pharmacokinetics of propranolol and its metabolism to form Ndesisopropylpropranolol (NDP) in rats. We also examined the activity and expression of cytochrome P450 (CYP) 1A and other CYPs in rats treated with EGb 761 at 10 and 100 mg/kg/day for 10 days. A single oral dose of propranolol (10 mg/kg) was administered on day 11 and the concentrations of both propranolol and NDP were determined using validated liquid chromatography-mass spectrometry (LC-MS) methods. The levels of mRNA and protein of various CYPs were determined by RT-PCR and Western blotting analysis, respectively. Pretreatment of EGb 761 at 100 mg/kg, but not 10 mg/kg, for 10 days significantly reduced the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max) of propranolol, whereas those values of NDP were significantly increased. CYP1A1, 1A2, 2B1/2, and 3A1 activities and gene expression in the rat liver were significantly increased in a dose-dependent manner by pretreatment with EGb 761. The ex-vivo formation of NDP in liver microsomes from rats pretreated with EGb 761 was markedly enhanced. The formation of NDP from propranolol in liver microsomes was significantly inhibited by α- naphthoflavone (ANF, a selective CYP1A2 inhibitor), but not by quinidine (a CYP2D inhibitor). These results indicated that EGb 761 pretreatment decreased the plasma concentrations of propranolol by accelerated conversion of parental drug to NDP due to induction of CYP1A2. EGb 761 pretreatment also significantly induced CYP2B1/2 and CYP3A1, suggesting potential interactions with substrate drugs for these two enzymes. Further study is needed to explore the potential for gingko-drug interactions and the clinical impact.

Convex hulls in concept induction

Classification learning is dominated by systems which induce large numbers of small axis-orthogonal decision surfaces. This strongly biases such systems towards particular hypothesis types but there is reason believe that many domains have underlying concepts which do not involve axis orthogonal surfaces. Further, the multiplicity of small decision regions mitigates against any holistic appreciation of the theories produced by these systems, notwithstanding the fact that many of the small regions are individually comprehensible. This thesis investigates modeling concepts as large geometric structures in n-dimensional space. Convex hulls are a superset of the set of axis orthogonal hyperrectangles into which axis orthogonal systems partition the instance space. In consequence, there is reason to believe that convex hulls might provide a more flexible and general learning bias than axis orthogonal regions. The formation of convex hulls around a group of points of the same class is shown to be a usable generalisation and is more general than generalisations produced by axis-orthogonal based classifiers, without constructive induction, like decision trees, decision lists and rules. The use of a small number of large hulls as a concept representation is shown to provide classification performance which can be better than that of classifiers which use a large number of small fragmentary regions for each concept. A convex hull based classifier, CH1, has been implemented and tested. CH1 can handle categorical and continuous data. Algorithms for two basic generalisation operations on hulls, inflation and facet deletion, are presented. The two operations are shown to improve the accuracy of the classifier and provide moderate classification accuracy over a representative selection of typical, largely or wholly continuous valued machine learning tasks. The classifier exhibits superior performance to well-known axis-orthogonal-based classifiers when presented with domains where the underlying decision surfaces are not axis parallel. The strengths and weaknesses of the system are identified. One particular advantage is the ability of the system to model domains with approximately the same number of structures as there are underlying concepts. This leads to the possibility of extraction of higher level mathematical descriptions of the induced concepts, using the techniques of computational geometry, which is not possible from a multiplicity of small regions.

Transitional issues of induction into design education for international undergraduate students : a case study analysis of architecture

The overarching aim of this paper is to present and discuss a collaborative undertaking between the School of Architecture and Building and the Academic Skills Unit at Deakin University, Australia in a programme called The Integrated Support Programme for Architecture. It does this in the following ways. It provides a justification for the setting up of an integrated programme for international architecture students. It describes the programme that was set up and outlines the reasons for collaboration between an academic School and an Academic Skills support services unit to prepare students both nationally and internationally as graduates of architecture. It then reports on a study undertaken to evaluate the programme in terms of student response and perception. Following this, it highlights directions for effective and strategic transition of past and present learning for international students. Using a case study analysis, the thrust of this paper is to advance knowledge and understanding of the pertinent issues related to international students either commencing or articulating into the professional course of architecture. It is envisaged that in this discussion matters may be raised for a strategic and effective transition of generic and internationalised learning for international students.

Influenza A virus-specific CD8.sup.+ T-cell responses : from induction to function

Seasonal influenza virus infection is a leading cause of illness and mortality in young children and the elderly each year. Current influenza vaccines generate protective antibody responses; however, these must be given annually to provide protection against serologically distinct viruses. By contrast, CD8.sup.+ T cells are capable of recognizing conserved antigenic determinants within the influenza virion and, as such, may provide protection against a number of variant strains of the virus. CD8.sup.+ T cells play a critical key role in controlling and resolving influenza virus infections via the production of cytokines and cytolytic mediators. This article focuses on the induction of the influenza-specific CD8.sup.+ T-cell response and how these cells acquire and maintain effector function after induction. Moreover, we discuss how cytotoxic T-lymphocyte function correlates with protection following vaccination.

A partnership in induction and mentoring : noticing how we improve our practice

This article focuses on the induction and mentoring of early career teachers. The context is a suburban primary school in Victoria, Australia, as the school develops mentoring networks for graduate and beginning teachers. Instigated from a school–university partnership, the research draws from the traditions of practitioner research. In the research design and likewise in successful mentoring the importance of a genuine commitment to the discipline of reflective practice or what we have come to describe as “ noticing ” (Mason, 2002; Moss et al., 2004) is illustrated. The approach offers a new method for small scale–close up research in teacher education.

HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production

Many viruses have developed mechanisms to evade the IFN response. Here, HIV-1 was shown to induce a distinct subset of IFN-stimulated genes (ISGs) in monocyte-derived dendritic cells (DCs), without detectable type I or II IFN. These ISGs all contained an IFN regulatory factor 1 (IRF-1) binding site in their promoters, and their expression was shown to be driven by IRF-1, indicating this subset was induced directly by viral infection by IRF-1. IRF-1 and -7 protein expression was enriched in HIV p24 antigen-positive DCs. A HIV deletion mutant with the IRF-1 binding site deleted from the long terminal repeat showed reduced growth kinetics. Early and persistent induction of IRF-1 was coupled with sequential transient up-regulation of its 2 inhibitors, IRF-8, followed by IRF-2, suggesting a mechanism for IFN inhibition. HIV-1 mutants with Vpr deleted induced IFN, showing that Vpr is inhibitory. However, HIV IFN inhibition was mediated by failure of IRF-3 activation rather than by its degradation, as in T cells. In contrast, herpes simplex virus type 2 markedly induced IFNβ and a broader range of ISGs to higher levels, supporting the hypothesis that HIV-1 specifically manipulates the induction of IFN and ISGs to enhance its noncytopathic replication in DCs.

The influence of genetic background on the induction of oxidative stress and impaired insulin secretion in mouse islets

Aims/hypothesis We determined whether high-glucose-induced beta cell dysfunction is associated with oxidative stress in the DBA/2 mouse, a mouse strain susceptible to islet failure.

Materials and methods Glucose- and non-glucose-mediated insulin secretion from the islets of DBA/2 and control C57BL/6 mice was determined following a 48-h exposure to high glucose. Flux via the hexosamine biosynthesis pathway was assessed by determining O-glycosylated protein levels. Oxidative stress was determined by measuring hydrogen peroxide levels and the expression of anti-oxidant enzymes.

Results Exposure to high glucose levels impaired glucose-stimulated insulin secretion in DBA/2 islets but not C57BL/6 islets, and this was associated with reduced islet insulin content and lower ATP levels than in C57BL/6 islets. Exposure of islets to glucosamine for 48 h mimicked the effects of high glucose on insulin secretion in the DBA/2 islets. High glucose exposure elevated O-glycosylated proteins; however, this occurred in islets from both strains, excluding a role for O-glycosylation in the impairment of DBA/2 insulin secretion. Additionally, both glucosamine and high glucose caused an increase in hydrogen peroxide in DBA/2 islets but not in C57BL/6 islets, an effect prevented by the antioxidant N-acetyl-l-cysteine. Interestingly, while glutathione peroxidase and catalase expression was comparable between the two strains, the antioxidant enzyme manganese superoxide dismutase, which converts superoxide to hydrogen peroxide, was increased in DBA/2 islets, possibly explaining the increase in hydrogen peroxide levels.

Conclusions/interpretation Chronic high glucose culture caused an impairment in glucose-stimulated insulin secretion in DBA/2 islets, which have a genetic predisposition to failure, and this may be the result of oxidative stress.

Automatic rule induction in Arabic to English machine translation framework

This chapter addresses the exploitation of a supervised machine learning technique to automatically induce Arabic-to-English transfer rules from chunks of parallel aligned linguistic resources. The induced structural transfer rules encode the linguistic translation knowledge for converting an Arabic syntactic structure into a target English syntactic structure. These rules are going to be an integral part of an Arabic-English transfer-based machine translation. Nevertheless, a novel morphological rule induction method is employed for learning Arabic morphological rules that are applied in our Arabic morphological analyzer. To demonstrate the capability of the automated rule induction technique, we conducted rule-based translation experiments that use induced rules from a relatively small data set. The translation quality of the hybrid translation experiments achieved good results in terms of WER.