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Song R.,University of Technology, Sydney | Liu Q.,University of Technology, Sydney | Liu T.,Childrens Cancer Institute Australia for Medical Research | Li J.,University of Technology, Sydney
BMC Genomics | Year: 2015

Background: Intensive research based on the inverse expression relationship has been undertaken to discover the miRNA-mRNA regulatory modules involved in the infection of Hepatitis C virus (HCV), the leading cause of chronic liver diseases. However, biological studies in other fields have found that inverse expression relationship is not the only regulatory relationship between miRNAs and their targets, and some miRNAs can positively regulate a mRNA by binding at the 5' UTR of the mRNA.Results: This work focuses on the detection of both inverse and positive regulatory relationships from a paired miRNA and mRNA expression data set of HCV patients through a 'change-to-change' method which can derive connected discriminatory rules. Our study uncovered many novel miRNA-mRNA regulatory modules. In particular, it was revealed that GFRA2 is positively regulated by miR-557, miR-765 and miR-17-3p that probably bind at different locations of the 5' UTR of this mRNA. The expression relationship between GFRA2 and any of these three miRNAs has not been studied before, although separate research for this gene and these miRNAs have all drawn conclusions linked to hepatocellular carcinoma. This suggests that the binding of mRNA GFRA2 with miR-557, miR-765, or miR-17-3p, or their combinations, is worthy of further investigation by experimentation. We also report another mRNA QKI which has a strong inverse expression relationship with miR-129 and miR-493-3p which may bind at the 3' UTR of QKI with a perfect sequence match. Furthermore, the interaction between hsa-miR-129-5p (previous ID: hsa-miR-129) and QKI is supported with CLIP-Seq data from starBase. Our method can be easily extended for the expression data analysis of other diseases.Conclusion: Our rule discovery method is useful for integrating binding information and expression profile for identifying HCV miRNA-mRNA regulatory modules and can be applied to the study of the expression profiles of other complex human diseases. © 2015 Song et al.; licensee BioMed Central Ltd.

Lynch G.W.,University of Sydney | Selleck P.,CSIRO | Church W.B.,University of Sydney | Sullivan J.S.,University of Sydney | Sullivan J.S.,Childrens Cancer Institute Australia for Medical Research
Immunology and Cell Biology | Year: 2012

Fundamentally new approaches are required for the development of vaccines to pre-empt and protect against emerging and pandemic influenzas. Current strategies involve post-emergent homotypic vaccines that are modelled upon select circulating seasonal influenzas, but cannot induce cross-strain protection against newly evolved or zoonotically introduced highly pathogenic influenza (HPI). Avian H5N1 and the less-lethal 2009 H1N1 and their reassortants loom as candidates to seed a future HPI pandemic. Therefore, more universal seasoned vaccine approaches are urgently needed for heterotypic protection ahead of time. Pivotal to this is the need to understand mechanisms that can deliver broad strain protection. Heterotypic and heterosubtypic humoral immunities have largely been overlooked for influenza cross-protection, with most seasoned vaccine efforts for humans focussed on heterotypic cellular immunity. However, 5 years ago we began to identify direct and indirect indicators of humoral-herd immunity to protein sites preserved among H1N1, H3N2 and H5N1 influenzas. Since then the evidence for cross-protective antibodies in humans has been accumulating. Now proposed is a rationale to stimulate and enhance pre-existing heterotypic humoral responses that, together with cell-mediated initiatives, will deliver pre-emptive and universal human protection against emerging epidemic and pandemic influenzas. © 2012 Australasian Society for Immunology Inc. All rights reserved.

McDonald W.J.,Dalhousie University | Sangster S.M.,Dalhousie University | Moffat L.D.,Dalhousie University | Henderson M.J.,Childrens Cancer Institute Australia for Medical Research | Too C.K.L.,Dalhousie University
Journal of Cellular Biochemistry | Year: 2010

Mammalian α4 phosphoprotein, the homolog of yeast Tap42, is a component of the mammalian target-of-rapamycin (mTOR) pathway that regulates ribogenesis, the initiation of translation, and cell-cycle progression. α4 is known to interact with the catalytic subunit of protein phosphatase 2A (PP2Ac) and to regulate PP2A activity. Using α4 as bait in yeast two-hybrid screening of a human K562 erythroleukemia cDNA library, EDD (E3 isolated by differential display) E3 ubiquitin ligase was identified as a new protein partner of α4. EDD is the mammalian ortholog of Drosophila hyperplastic discs gene (hyd) that controls cell proliferation during development. The EDD protein contains a PABC domain that is present in poly(A)-binding protein (PABP), suggesting that PABP may also interact with α4. PABP recruits translation factors to the poly(A)-tails of mRNAs. In the present study, immunoprecipitation/immunoblotting (IP/IB) analyses showed a physical interaction between α4 and EDD in rat Nb2 T-lymphoma and human MCF-7 breast cancer cell lines. α4 also interacted with PABP in Nb2, MCF-7 and the human Jurkat T-leukemic and K562 myeloma cell lines. COS-1 cells, transfected with Flag-tagged-pSG5-EDD, gave a (Flag)-EDD-α4 immunocomplex. Furthermore, deletion mutants of α4 were constructed to determine the binding site for EDD. IP/IB analysis showed that EDD bound to the C-terminal region of α4, independent of the α4-PP2Ac binding site. Therefore, in addition to PP2Ac, α4 interacts with EDD and PABP, suggesting its involvement in multiple steps in the mTOR pathway that leads to translation initiation and cell-cycle progression. © 2010 Wiley-Liss, Inc.

McCarroll J.,University of Massachusetts Medical School | McCarroll J.,Childrens Cancer Institute Australia for Medical Research | Baigude H.,University of Massachusetts Medical School | Baigude H.,Burnham Institute for Medical Research | And 4 more authors.
Bioconjugate Chemistry | Year: 2010

Single-walled carbon nanotubes (SWNT) have unique electronic, mechanical, and structural properties as well as chemical stability that make them ideal nanomaterials for applications in materials science and medicine. Here, we report the design and creation of a novel strategy for functionalizing SWNT to systemically silence a target gene in mice by delivering siRNA at doses of <1 mg/kg. SWNT were functionalized with lipids and natural amino acid-based dendrimers (TOT) and complexed to siRNA. Our model study of the silencing efficiency of the TOT-siRNA complex showed that, in mice injected at 0.96 mg/kg, an endogenous gene for apoliproprotein B (ApoB) was silenced in liver, plasma levels of ApoB decreased, and total plasma cholesterol decreased. TOT-siRNA treatment was nontoxic and did not induce an immune response. Most (80%) of the RNA trigger molecules assembled with TOT were cleared from the body 48 h after injection, suggesting that the nanotubes did not cause siRNA aggregation or inhibit biodegradation and drug clearance in vivo. These results provide the first evidence that nanotubes can be functionalized with lipids and amino acids to systemically deliver siRNA. This new technology not only can be used for systemic RNAi, but may also be used to deliver other drugs in vivo. © 2010 American Chemical Society.

Wong L.,University of New South Wales | Kavallaris M.,Childrens Cancer Institute Australia for Medical Research | Bulmus V.,University of New South Wales
Polymer Chemistry | Year: 2011

Doxorubicin (Dox)-conjugated, poly(ethylene glycol) (PEG) shielded, reversibly crosslinked particles were prepared by a one-pot thiol-ene reaction from a RAFT-synthesized well-defined homopolymer scaffold, poly(pyridyldisulfide ethylmethacrylate) (PPDSM). Dox and PEG modified with maleimide end-groups (mal-Dox and mal-PEG), were covalently attached in one pot to free thiol groups of PPDSM (M n = 8900 g mol -1 and PDI = 1.18) in the presence of a disulfide reducing agent. ∼ 50% of the total pyridyldisulfide units were conjugated with Dox and PEG (with an equal mol ratio). Particles with an average hydrodynamic diameter of 192 ± 28 nm were observed to form after conjugation. Incubation of these particles with a disulfide reducing agent resulted in the disassociation of the particles. The release of Dox from the particles was pH dependent. The Dox-conjugated PEGylated particles (with a Dox content of 8 wt%) inhibited the viability of human cervical carcinoma cells (HeLa) with an IC 50 value of 8 × 10 -7 M, determined by an Alamar Blue assay, while the IC 50 of free Dox was 1 × 10 -7 M. The fluorescence microscopy analyses of the HeLa cells after incubation with the particles for varying times showed that the Dox carried by the particles is taken up efficiently by the cells. © 2011 The Royal Society of Chemistry.

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