Contracting out local government services: A comparative study of two New Zealand regional councils

Studies of New Zealand public sector reforms since the mid-1980s have tended to focus on the application of New Public Management principles to the central government. Yet local government in New Zealand too has experienced drastic restructuring with a view to ensuring greater rationalisation, efficiency and effectiveness. This article examines contracting out in New Zealand local government, focusing on the delivery of plant pest management by Environment Waikato(the Waikato Regional Council) and the Wellington Regional Council. The study reveals distinct differences in approach by the two councils, determined in each case by pragmatic responses to situational context rather than mere adherence to NPM principles

Denial and distancing in discourses of development: shadow of the 'Third World' in New Zealand

Anxieties about development in New Zealand show up in a deep-rooted fear of the 'Third World' in the country. We examine how the term 'Third World' is deployed in media discourses in economic, social and environmental contexts and how this deployment results in a 'discursive distancing' from anything associated with the 'Third World'. Such distancing demonstrates a fragile national identity that struggles with the contradictions between the nation's desire to be part of the 'First World' of global capitalism and the growing disparities in health and wealth within it. The shadow of the 'Third World' prevents New Zealand from confronting the realities of its own inequities, which in turn comes in the way of a sound development agenda

Science, governance, and public participation: An analysis of decision making on genetic modification in Aotearoa/New Zealand

The acceptance of public participation in science and technology governance in liberal democratic contexts is evident in the institutionalization of a variety of mechanisms for participation in recent decades. Yet questions remain about the extent to which institutions have actually transformed their policy practice to embrace democratic governance of techno-scientific decision making. A critical discourse analysis of the response to public participation by the Environmental Risk Management Authority (ERMA), the key decision-making body on genetic modification in Aotearoa/New Zealand, in a specific case demonstrates that ERMA systematically marginalized concerns raised by the public about risk management, ethics, and ecological, economic, and cultural issues in order to give primacy to a positivist, technological worldview. Such delegitimization of public perspectives pre-empts the possibility of the democratic governance of science

Submonomer Synthesis and Structure-activity Relationship Studies of Azapeptide Inhibitors of the Insulin Receptor Tyrosine Kinase

Azapeptides are a class of peptide mimics (peptidomimetics), which have served as valuable tools for the development of peptide based therapeutic agents. The therapeutic promise of azapeptides has been correlated to its primary sequence modification which translates into bio-active secondary structures that improves the pharmacological properties of the native peptide sequence. More specifically, azapeptides contain a semicarbazide within the peptide backbone which restricts the peptide bond torsion angles (φ, ψ) into pre-organized b-turn secondary structures. Thus, azapeptides have been shown to stabilize bio-active b-turn secondary structures responsible for high affinity and selective binding to a target receptor or enzyme in order to modulate its activity for therapeutic purpose. Moreover, azapeptides have been found to be stable in biological media thereby improving their therapeutic indices and pharmacokinetic properties. For example, Goserelin, an aza-Gly peptide analog has received FDA approval in 1989 for the treatment of prostate and breast cancers. Therefore, the systematic substitution of aza amino acid residues within bio-active sequences (aza-amino acid scanning) has been shown to be useful in the conversion of native peptides into lead therapeutic peptidomimetics. The submonomer approach for azapeptides synthesis has been especially useful in aza-amino acid scanning and in the production of diverse azapeptides for structure-activity relationship studies with therapeutic targets. In this thesis, the submonomer approach for azapeptide synthesis is put into practical use for the development of azapeptide inhibitors of the Insulin Receptor Tyrosine Kinase (IRTK) domain. Overexpression or unregulated signal transduction of the IRTK has been associated with increased levels of gene expression and cell proliferation that are hallmarks of tumor progression. Thus, the inhibition of un-regulated tyrosine kinase phosphorylation of the insulin receptor may prove to be an efficient method of cancer therapy. Towards this goal, the synthetic pentapeptide, Ac-DIYET-NH2 derived from the activation loop of the insulin receptor was found to inhibit the autophosphorylation of the IRTK to about 80% at 4 mM. Moreover, molecular docking simulation studies indicated that, Ac-DIYET-NH2, was bound within the active site of the IRTK with a folded peptide structure that was reminiscent of a turn geometry. In order to identify the location and importance of a turn structure on the inhibitory activity of Ac-DIYET-NH2, aza-modifications within the IYE region were developed for structure activity relationship studies. Submonomer solid phase synthesis was used for the production of azapeptides, featuring the introduction of new aza-Ile and aza-DOPA residues. The azapeptides were analyzed and purified by reverse-phase LCMS in order to ascertain purity (\u3e95%) and identity prior to structure-activity relationship studies. Molecular modeling and docking simulation studies revealed that the Ac-DIazaYET-NH2 sequence, adopted a β-turn conformation that bound to the kinase domain of the IRTK. The azapeptide β-turn conformation was also proven by CD and NMR spectroscopy. The inhibitory activity of the peptides, Ac-DIYET-NH2 vs Ac-DIazaYET-NH2, was evaluated in a single dose experiment (400 mM), which indicated minimal inhibitory activity (2, whereas, Ac-DIazaYET-NH2 displayed 50% inhibition of the IRTK autophosphorylation. These results validate the importance of the peptide b-turn geometry on the inhibition of IRTK phosphorylation. This finding is not only important towards the development of potent azapeptide inhibitors of the IRTK for potential anti-cancer applications, but also in the design of novel probes for studying the mechanisms and kinetics associated with this important class of tyrosine kinases

ROLE OF NORMAL PERFUSION TIME ON FUNCTIONAL ENZYME ACTIVITIES AND PHYSIOLOGY OF INTERFIBRILLAR AND SUB-SARCOLEMMAL MITOCHONDRIA FROM ISOLATED RAT HEART

Objective: Obvious lack of interfibrillar mitochondria (IFM) subpopulation in isolated mitochondria attributed to limitations in the isolation procedure. In this manuscript, we compared the functional activities of mitochondrial sub-populations namely, IFM and sub-sarcolemmal (SSM) mitochondria.Methods: IFM and SSM were obtained from isolated rat heart subjected to different perfusion time namely (minutes) 0.5,5,10,25,60 and 120 through Langendroff perfusion system.Results: Prolonged perfusion of isolated rat heart reduced oxidative phosphorylation capacity in both IFM and SSM, but were distinct among the sub-populations. However, mRNA expression level of ND4, CYT B and ATP 6 and resazurin activity was similar in both IFM and SSM.Conclusion: Even though overall function of myocardium is unchanged, mitochondrial sub- populations were distinct in electron transport chain activities, emphasizes the requirement to assess mitochondrial function as distinct subpopulation rather than whole entity.Â

Submonomer Synthesis and Structure-activity Relationship Studies of Azapeptide Inhibitors of the Insulin Receptor Tyrosine Kinase

Azapeptides are a class of peptide mimics (peptidomimetics), which have served as valuable tools for the development of peptide based therapeutic agents. The therapeutic promise of azapeptides has been correlated to its primary sequence modification which translates into bio-active secondary structures that improves the pharmacological properties of the native peptide sequence. More specifically, azapeptides contain a semicarbazide within the peptide backbone which restricts the peptide bond torsion angles (φ, ψ) into pre-organized b-turn secondary structures. Thus, azapeptides have been shown to stabilize bio-active b-turn secondary structures responsible for high affinity and selective binding to a target receptor or enzyme in order to modulate its activity for therapeutic purpose. Moreover, azapeptides have been found to be stable in biological media thereby improving their therapeutic indices and pharmacokinetic properties. For example, Goserelin, an aza-Gly peptide analog has received FDA approval in 1989 for the treatment of prostate and breast cancers. Therefore, the systematic substitution of aza amino acid residues within bio-active sequences (aza-amino acid scanning) has been shown to be useful in the conversion of native peptides into lead therapeutic peptidomimetics. The submonomer approach for azapeptides synthesis has been especially useful in aza-amino acid scanning and in the production of diverse azapeptides for structure-activity relationship studies with therapeutic targets. In this thesis, the submonomer approach for azapeptide synthesis is put into practical use for the development of azapeptide inhibitors of the Insulin Receptor Tyrosine Kinase (IRTK) domain. Overexpression or unregulated signal transduction of the IRTK has been associated with increased levels of gene expression and cell proliferation that are hallmarks of tumor progression. Thus, the inhibition of un-regulated tyrosine kinase phosphorylation of the insulin receptor may prove to be an efficient method of cancer therapy. Towards this goal, the synthetic pentapeptide, Ac-DIYET-NH2 derived from the activation loop of the insulin receptor was found to inhibit the autophosphorylation of the IRTK to about 80% at 4 mM. Moreover, molecular docking simulation studies indicated that, Ac-DIYET-NH2, was bound within the active site of the IRTK with a folded peptide structure that was reminiscent of a turn geometry. In order to identify the location and importance of a turn structure on the inhibitory activity of Ac-DIYET-NH2, aza-modifications within the IYE region were developed for structure activity relationship studies. Submonomer solid phase synthesis was used for the production of azapeptides, featuring the introduction of new aza-Ile and aza-DOPA residues. The azapeptides were analyzed and purified by reverse-phase LCMS in order to ascertain purity (\u3e95%) and identity prior to structure-activity relationship studies. Molecular modeling and docking simulation studies revealed that the Ac-DIazaYET-NH2 sequence, adopted a β-turn conformation that bound to the kinase domain of the IRTK. The azapeptide β-turn conformation was also proven by CD and NMR spectroscopy. The inhibitory activity of the peptides, Ac-DIYET-NH2 vs Ac-DIazaYET-NH2, was evaluated in a single dose experiment (400 mM), which indicated minimal inhibitory activity (2, whereas, Ac-DIazaYET-NH2 displayed 50% inhibition of the IRTK autophosphorylation. These results validate the importance of the peptide b-turn geometry on the inhibition of IRTK phosphorylation. This finding is not only important towards the development of potent azapeptide inhibitors of the IRTK for potential anti-cancer applications, but also in the design of novel probes for studying the mechanisms and kinetics associated with this important class of tyrosine kinases

Precision medicine for genetic childhood movement disorders

Increasingly effective targeted precision medicine is either already available or in development for a number of genetic childhood movement disorders. Patient-centred, personalized approaches include the repurposing of existing treatments for specific conditions and the development of novel therapies that target the underlying genetic defect or disease mechanism. In tandem with these scientific advances, close collaboration between clinicians, researchers, affected families, and stakeholders in the wider community will be key to successfully delivering such precision therapies to children with movement disorders

Benign Hereditary Chorea: An Update

Benign hereditary chorea (BHC) is a childhood-onset, hyperkinetic movement disorder normally with little progression of motor symptoms into adult life. The disorder is caused by mutations to the NKX2.1 (TITF1) gene and also forms part of the “brain–lung–thyroid syndrome”, in which additional developmental abnormalities of lung and thyroid tissue are observed. In this review, we summarize the main clinical findings in “classical” BHC syndrome and discuss more recently reported atypical features, including non-choreiform movement phenotypes. We highlight additional non-motor characteristics such as cognitive impairment and psychiatric symptoms, while discussing the evidence for BHC as a developmental disorder involving impaired neural migration and other multisystem developmental abnormalities. Finally, we will discuss the efficacy of available therapies in both affected pediatric and adult cohorts. Delineation of the BHC disease spectrum will no doubt expand our understanding of this disorder, facilitating better targeting of genetic testing and establish a framework for future clinical trials

Cancer Biology

This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist focuses on DNA mutations that cause cancer, abnormal regulation of cell growth and death, and metastasis. Updated March 2016 version posted March 28, 2017.https://escholarship.umassmed.edu/cancer_concepts/1005/thumbnail.jp