Maurice Wilkins Center

Wellington, New Zealand

Maurice Wilkins Center

Wellington, New Zealand
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Mester B.,Malaghan Institute of Medical Research | Bauer E.,Malaghan Institute of Medical Research | Wood C.E.,Malaghan Institute of Medical Research | Wood C.E.,Capital and Coast District Health Board | And 4 more authors.
PLoS ONE | Year: 2015

Ex vivo generated monocyte-derived dendritic cell (moDC)-vaccines have long been touted as promising immunotherapeutic agents for cancer treatment, although the response rate generally remains low. The reasons for this are still unclear and confounded by the diversity in manufacturing protocols that may affect moDC function. Preclinical studies have shown that the stimulatory function of dendritic cells can be improved by engaging invariant NKT cells in vivo through the presentation of the glycolipid alpha-galactosylceramide via CD1d. However, expression of CD1d on moDC has been shown to be negatively correlated with expression of CD1a, which in turn has been suggested to be a surrogate marker for IL-12 secreting type-1 polarized moDC, the preferred functional characteristics for cancer vaccines. Here we challenge this notion by showing that plasma-derived lipids drive functional levels of CD1d expression, while CD1a expression can vary considerably in these cells without being correlated with a loss of polarization or immunogenicity. © 2015 Mester et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Mittelstadt G.,Maurice Wilkins Center | Moggre G.-J.,Maurice Wilkins Center | Parker E.J.,Maurice Wilkins Center
Protein Science | Year: 2016

Adenosine triphosphate phosphoribosyltransferase (ATP-PRT) catalyzes the first committed step of the histidine biosynthesis in plants and microorganisms. Here, we present the functional and structural characterization of the ATP-PRT from the pathogenic ε-proteobacteria Campylobacter jejuni (CjeATP-PRT). This enzyme is a member of the long form (HisGL) ATP-PRT and is allosterically inhibited by histidine, which binds to a remote regulatory domain, and competitively inhibited by AMP. In the crystalline form, CjeATP-PRT was found to adopt two distinctly different hexameric conformations, with an open homohexameric structure observed in the presence of substrate ATP, and a more compact closed form present when inhibitor histidine is bound. CjeATP-PRT was observed to adopt only a hexameric quaternary structure in solution, contradicting previous hypotheses favoring an allosteric mechanism driven by an oligomer equilibrium. Instead, this study supports the conclusion that the ATP-PRT long form hexamer is the active species; the tightening of this structure in response to remote histidine binding results in an inhibited enzyme. © 2016 The Protein Society.


Trevarton A.J.,University of Auckland | Mann M.B.,Methodist Hospital Research Institute | Knapp C.,University of Auckland | Araki H.,Kyushu University | And 7 more authors.
Frontiers in Oncology | Year: 2013

Despite on-going research, metastatic melanoma survival rates remain low and treatment options are limited. Researchers can now access a rapidly growing amount of molecular and clinical information about melanoma. This information is becoming difficult to assemble and interpret due to its dispersed nature, yet as it grows it becomes increasingly valuable for understanding melanoma. Integration of this information into a comprehensive resource to aid rational experimental design and patient stratification is needed. As an initial step in this direction, we have assembled a web-accessible melanoma database, MelanomaDB, which incorporates clinical and molecular data from publically available sources, which will be regularly updated as new information becomes available. This database allows complex links to be drawn between many different aspects of melanoma biology: genetic changes (e.g., mutations) in individual melanomas revealed by DNA sequencing, associations between gene expression and patient survival, data concerning drug targets, biomarkers, druggability, and clinical trials, as well as our own statistical analysis of relationships between molecular pathways and clinical parameters that have been produced using these data sets. The database is freely available at http://genesetdb.auckland.ac.nz/melanomadb/about.html. A subset of the information in the database can also be accessed through a freely available web application in the Illumina genomic cloud computing platform BaseSpace at http://www.biomatters.com/apps/melanoma-profiler-for-research. The MelanomaDB database illustrates dysregulation of specific signaling pathways across 310 exome-sequenced melanomas and in individual tumors and identifies the distribution of somatic variants in melanoma. We suggest that MelanomaDB can provide a context in which to interpret the tumor molecular profiles of individual melanoma patients relative to biological information and available drug therapies. © 2013 Trevarton, Mann, Knapp, Araki, Wren, Stones-Havas, Black and Print.


Hickey A.J.R.,Maurice Wilkins Center | Hickey A.J.R.,University of Auckland | Chai C.C.,University of Auckland | Delahunt B.,University of Otago | And 4 more authors.
HPB | Year: 2011

Introduction: Multiple organ dysfunction is the main cause of death in severe acute pancreatitis. Primary mitochondrial dysfunction plays a central role in the development and progression of organ failure in critical illness. The present study investigated mitochondrial function in seven tissues during early experimental acute pancreatitis. Methods: Twenty-eight male Wistar rats (463 ± 2 g; mean ± SEM) were studied. Group 1 (n= 8), saline control; Group 2 (n= 6), caerulein-induced mild acute pancreatitis; Group 3 (n= 7) sham surgical controls; and Group 4 (n= 7), taurocholate-induced severe acute pancreatitis. Animals were euthanased at 6 h from the induction of acute pancreatitis and mitochondrial function was assessed in the heart, lung, liver, kidney, pancreas, duodenum and jejunum by mitochondrial respirometry. Results: Significant early mitochondrial dysfunction was present in the pancreas, lung and jejunum in both models of acute pancreatitis, however, the Heart, liver, kidney and duodenal mitochondria were unaffected. Conclusions: The present study provides the first description of early organ-selective mitochondrial dysfunction in the lung and jejunum during acute pancreatitis. Research is now needed to identify the underlying pathophysiology behind the organ selective mitochondrial dysfunction, and the potential benefits of early mitochondrial-specific therapies in acute pancreatitis. © 2011 International Hepato-Pancreato-Biliary Association.


Mittelstadt G.,Maurice Wilkins Center | Mittelstadt G.,University of Canterbury | Moggre G.-J.,Maurice Wilkins Center | Moggre G.-J.,University of Canterbury | And 5 more authors.
Protein Science | Year: 2016

Adenosine triphosphate phosphoribosyltransferase (ATP-PRT) catalyzes the first committed step of the histidine biosynthesis in plants and microorganisms. Here, we present the functional and structural characterization of the ATP-PRT from the pathogenic ε-proteobacteria Campylobacter jejuni (CjeATP-PRT). This enzyme is a member of the long form (HisGL) ATP-PRT and is allosterically inhibited by histidine, which binds to a remote regulatory domain, and competitively inhibited by AMP. In the crystalline form, CjeATP-PRT was found to adopt two distinctly different hexameric conformations, with an open homohexameric structure observed in the presence of substrate ATP, and a more compact closed form present when inhibitor histidine is bound. CjeATP-PRT was observed to adopt only a hexameric quaternary structure in solution, contradicting previous hypotheses favoring an allosteric mechanism driven by an oligomer equilibrium. Instead, this study supports the conclusion that the ATP-PRT long form hexamer is the active species; the tightening of this structure in response to remote histidine binding results in an inhibited enzyme. © 2016 The Protein Society


Gibbins J.D.,Malaghan Institute of Medical Research | Gibbins J.D.,Victoria University of Wellington | Ancelet L.R.,Malaghan Institute of Medical Research | Ancelet L.R.,Maurice Wilkins Center | And 5 more authors.
Journal of Immunotherapy | Year: 2015

Circulating antigens released from tumor cells can drain into the spleen and be acquired by resident antigen-presenting cells (APCs). Here, we examined the ability of splenic dendritic cells to cross-present tumor antigens to CD8 + T cells and investigated the effects that this has on T-cell therapy in a murine model of lymphoma. In the presence of established lymphoma, langerin (CD207)-expressing CD8+ dendritic cells acquired, processed, and cross-presented tumor antigens to naive CD8 + T cells. Although this resulted in initial T-cell proliferation, the T-cell population failed to expand measurably over the following days, and tumor-free survival was actually improved when langerin-expressing cells were depleted. In contrast, following adoptive T-cell therapy with in vitro-Activated CD8 + T cells, marked antitumor activity was observed and associated with accumulation of activated antigen-specific CD8 + T cells in the spleen and blood, whereas tumor protection and T-cell accumulation were significantly reduced in animals depleted of langerin-expressing cells. Therefore, although resident APCs that acquire tumor antigens may induce tolerance in naive cells in the absence of further stimuli, they can play an important role in promoting antitumor immunity during the course of T-cell therapy. It is possible that further therapeutic benefit will result from improving the activation status of these APCs. © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Smith G.C.,University of Auckland | Smith G.C.,University of New South Wales | McEwen H.,University of Auckland | McEwen H.,Maurice Wilkins Center | And 3 more authors.
Psychopharmacology | Year: 2014

The second generation antipsychotic drug clozapine is a much more effective therapy for schizophrenia than first generation compounds, but the reasons for this are poorly understood. We have previously shown that one distinguishing feature of clozapine is its ability to raise glucagon levels in animal models and thus causes prolonged hyperinsulinemia without inducing hypoglycaemia. Previous studies have provided evidence that defects in Akt/PKB and GSK3 signalling can contribute to development of psychiatric diseases. Clozapine is known to activate Akt/PKB in the brain, and some studies have indicated that this is due to a direct effect of the drug on the neurons. However, we provide strong evidence that elevated insulin levels induced by clozapine are in fact the real cause of the drug's effects on Akt/PKB and GSK3 in the brain. This suggests that the elevated levels of insulin induced by clozapine may contribute to this drug's therapeutic efficacy. © 2014 Springer-Verlag Berlin Heidelberg.


PubMed | University of Canterbury, Australian Synchrotron and Maurice Wilkins Center
Type: Journal Article | Journal: Protein science : a publication of the Protein Society | Year: 2016

Adenosine triphosphate phosphoribosyltransferase (ATP-PRT) catalyzes the first committed step of the histidine biosynthesis in plants and microorganisms. Here, we present the functional and structural characterization of the ATP-PRT from the pathogenic -proteobacteria Campylobacter jejuni (CjeATP-PRT). This enzyme is a member of the long form (HisGL ) ATP-PRT and is allosterically inhibited by histidine, which binds to a remote regulatory domain, and competitively inhibited by AMP. In the crystalline form, CjeATP-PRT was found to adopt two distinctly different hexameric conformations, with an open homohexameric structure observed in the presence of substrate ATP, and a more compact closed form present when inhibitor histidine is bound. CjeATP-PRT was observed to adopt only a hexameric quaternary structure in solution, contradicting previous hypotheses favoring an allosteric mechanism driven by an oligomer equilibrium. Instead, this study supports the conclusion that the ATP-PRT long form hexamer is the active species; the tightening of this structure in response to remote histidine binding results in an inhibited enzyme.


Abdul Rahman N.,University of Auckland | Abdul Rahman N.,University Putra Malaysia | Feisst V.,University of Auckland | Dickinson M.E.,University of Auckland | And 5 more authors.
Materials Chemistry and Physics | Year: 2013

Conductive polymer poly(aniline-co-m-aminobenzoic acid) (P(ANI-co-m-ABA)) and polyaniline (PANI) were blended with a biodegradable, biocompatible polymer, poly(l-lactic acid) and were electrospun into nanofibres to investigate their potential application as a scaffold for human adipose-derived stem cells (hASCs). These polymers, in both conductive and non-conductive form, were electrospun with average fibre diameters of less than 400 nm. Novel nanoindentation results obtained on the individual nanofibres revealed that the elastic moduli of the nanofibres are much higher at the surface (4-10 GPa, hmax <75 nm) than in the inner fibre core (2-4 GPa, h max >75 nm). The composite nanofibres showed great promise as a scaffold for hASCs as they supported the cell adhesion and proliferation. After 1 week of cell culture hASCs were well spread on the substrates with abundant focal adhesions. The electrospun mats provide the cells with comparably stiff, sub-micron sized fibres as anchoring points on a substrate of high porosity. The conductive nature of these composite nanofibres offers exciting opportunities for electrical stimulation of the cells. © 2012 Elsevier B.V. All rights reserved.


Slatter T.L.,University of Otago | Wilson M.,University of Otago | Tang C.,University of Otago | Campbell H.G.,University of Sydney | And 9 more authors.
OncoImmunology | Year: 2016

ABSTRACT: Activated antigen-presenting cells (APC) deliver the three signals cytotoxic T cells require to differentiate into effector cells that destroy the tumor. These comprise antigen, co-stimulatory signals and cytokines. Once these cells have carried out their function, they apoptose. We hypothesized that the tumor suppressor protein, p53, played an important role in generating the antitumor response facilitated by APC. CD11c+APC derived from p53 wild-type (wt) mouse (wt p53) GM-CSF bone marrow cultures (BMAPC) and activated had reduced survival compared to BMAPC from p53 null consistent with p53-mediated apoptosis following activation. There was a lower percentage of antigenic peptide/MHC I complexes on antigen-pulsed p53 null cells suggesting p53 played a role in antigen processing but there was no difference in antigen-specific T cell proliferative responses to these cells in vivo. In contrast, antigen-specific cytotoxicity in vivo was markedly reduced in response to p53 null BMAPC. When these cells were pulsed with a model tumor antigen and delivered as a prophylactic vaccination, they provided no protection against melanoma cell growth whereas wt BMAPC were very effective. This suggested that p53 might regulate the requisite third signal and, indeed, we found that p53 null BMAPC produced less IL-12 than wt p53 BMAPC and that p53 bound to the promoter region of IL-12. This work suggests that p53 in activated BMAPC is associated with the generation of IL-12 required for the differentiation of cytotoxic immune responses and an effective antitumor response. This is a completely new role for this protein that has implications for BMAPC-mediated immunotherapy. © 2016, © Taylor & Francis Group, LLC.

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