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Rasmiena A.A.,Baker IDI Heart and Diabetes Institute | Rasmiena A.A.,University of Melbourne | Barlow C.K.,Baker IDI Heart and Diabetes Institute | Ng T.W.,Baker IDI Heart and Diabetes Institute | And 4 more authors.
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2016

Objective Oxidised low density lipoprotein (oxLDL) contributes to atherosclerosis, whereas high density lipoprotein (HDL) is known to be atheroprotective due, at least in part, to its ability to remove oxidised lipids from oxLDL. The molecular details of the lipid transfer process are not fully understood. We aimed to identify major oxidised lipid species of oxLDL and investigate their transfer upon co-incubation with HDL with varying levels of oxidation. Approach and results A total of 14 major species of oxidised phosphatidylcholine and oxidised cholesteryl ester from oxLDL were identified using an untargeted mass spectrometry approach. HDL obtained from pooled plasma of normolipidemic subjects (N = 5) was oxidised under mild and heavy oxidative conditions. Non-oxidised (native) HDL and oxidised HDL were co-incubated with oxLDL, re-isolated and lipidomic analysis was performed. Lipoprotein surface lipids, oxidised phosphatidylcholines and oxidised cholesterols (7-ketocholesterol and 7β-hydroxycholesterol), but not internal oxidised cholesteryl esters, were effectively transferred to native HDL. Saturated and monounsaturated lyso-phosphatidylcholines were also transferred from the oxLDL to native HDL. These processes were attenuated when HDL was oxidised under mild and heavy oxidative conditions. The impaired capacities were accompanied by an increase in a ratio of sphingomyelin to phosphatidylcholine and a reduction in phosphatidylserine content in oxidised HDL, both of which are potentially important regulators of the oxidised lipid transfer capacity of HDL. Conclusions Our study has revealed the differential transfer efficiency of surface and internal oxidised lipids from oxLDL and their acceptance onto HDL. These capacities were modulated when HDL was itself oxidised. © 2015 Elsevier B.V.

Crava C.M.,University of Valencia | Bel Y.,University of Valencia | Lee S.F.,Bio21 Institute | Manachini B.,University of Palermo | And 2 more authors.
Insect Biochemistry and Molecular Biology | Year: 2010

Aminopeptidases N (APNs) are a class of ectoenzymes present in lepidopteran larvae midguts, involved in the Bacillus thuringiensis (Bt) toxins mode of action. In the present work, seven aminopeptidases have been cloned from the midgut of Ostrinia nubilalis, the major Lepidopteran corn pest in the temperate climates. Six sequences were identified as APNs because of the presence of the HEXXH(X)18E and GAMEN motifs, as well as the signal peptide and the GPI-anchor sequences. The remaining sequence did not contain the two cellular targeting signals, indicating it belonged to the puromycin-sensitive aminopeptidase (PSA) family. An in silico analysis allowed us to find orthologous sequences in Bombyx mori. A phylogenetic study of lepidopteran aminopeptidase sequences resulted in their clustering into nine classes. Linkage analysis revealed that the onapn genes as well as all bmapn genes clustered in a single linkage group. O. nubilalis aminopeptidases were expressed in all larval instars. In 5th instar larvae tissues, apns transcripts were found mainly in midguts while apn8 was also highly expressed in Malpighian tubules, and psa showed an ubiquitous expression pattern in O. nubilalis and B. mori. The sequence homology and gene organization of apns suggest a single origin from an ancestral lepidopteran apn gene. © 2010 Elsevier Ltd.

Chen K.,Walter and Eliza Hall Institute of Medical Research | Chen K.,University of Melbourne | Hu J.,Queensland Institute of Medical Research Berghofer Medical Research Institute | Hu J.,Queensland University of Technology | And 27 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

Structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is an epigenetic repressor with described roles in X inactivation and genomic imprinting, but Smchd1 is also critically involved in the pathogenesis of facioscapulohumeral dystrophy. The underlying molecular mechanism by which Smchd1 functions in these instances remains unknown. Our genome-wide transcriptional and epigenetic analyses show that Smchd1 binds cis-regulatory elements, many of which coincide with CCCTC-binding factor (Ctcf) binding sites, for example, the clustered protocadherin (Pcdh) genes, where we show Smchd1 and Ctcf act in opposing ways. We provide biochemical and biophysical evidence that Smchd1-chromatin interactions are established through the homodimeric hinge domain of Smchd1 and, intriguingly, that the hinge domain also has the capacity to bind DNA and RNA. Our results suggest Smchd1 imparts epigenetic regulation via physical association with chromatin, which may antagonize Ctcf-facilitated chromatin interactions, resulting in coordinated transcriptional control.

The study, published today in Nature Microbiology, holds promise for a new treatment method against antibiotic-resistant bacteria (commonly known as superbugs). The star-shaped structures, are short chains of proteins called 'peptide polymers', and were created by a team from the Melbourne School of Engineering. The team included Professor Greg Qiao and PhD candidate Shu Lam, from the Department of Chemical and Biomolecular Engineering, as well as Associate Professor Neil O'Brien-Simpson and Professor Eric Reynolds from the Faculty of Medicine, Dentistry and Health Sciences and Bio21 Institute. Professor Qiao said that currently the only treatment for infections caused by bacteria is antibiotics. However, over time bacteria mutate to protect themselves against antibiotics, making treatment no longer effective. These mutated bacteria are known as 'superbugs'. "It is estimated that the rise of superbugs will cause up to ten million deaths a year by 2050. In addition, there have only been one or two new antibiotics developed in the last 30 years," he said. Professor Qiao and his team have been working with peptide polymers in the past few years. Recently, the team created a star-shaped peptide polymer that was extremely effective at killing Gram-negative bacteria – a major class of bacteria known to be highly prone to antibiotic resistance – while being non-toxic to the body. In fact, tests undertaken on red blood cells showed that the star-shaped polymer dosage rate would need to be increased by a factor of greater than 100 to become toxic. The star-shaped peptide polymer is also effective in killing superbugs when tested in animal models. Furthermore, superbugs showed no signs of resistance against these peptide polymers. The team discovered that their star-shaped peptide polymers can kill bacteria with multiple pathways, unlike most antibiotics which kill with a single pathway. They believe that this accounts for the superior performance of the star-shaped peptide polymers over antibiotics. One of these pathways includes 'ripping apart' the bacteria cell wall. (see image). While more research is needed, Professor Qiao and his team believe that their discovery is the beginning of unlocking a new treatment for antibiotic-resistant pathogens. More information: Shu J. Lam et al. Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers, Nature Microbiology (2016). DOI: 10.1038/nmicrobiol.2016.162

Colinet H.,Catholic University of Louvain | Colinet H.,Bio21 Institute | Hoffmann A.,Bio21 Institute
Insect Biochemistry and Molecular Biology | Year: 2010

In Drosophila melanogaster, the sole member of the Bcl-2-associated anthanogene (BAG)-family proteins, called Starvin (Stv), has only been recently described. BAG proteins regulate a large range of physiological processes including life/death cell balance and stress response. The role of Stv has been poorly studied in the context of abiotic stress and particularly during and after cold stress. In this study we investigated the temporal expression of Stv gene and protein in adult flies during both the cold stress (up to 9 h at 0 °C) and the subsequent recovery phase (up to 8 h at 25 °C). Because BAG proteins can regulate positively and negatively the function of Hsp70/Hsc70, we also checked whether Stv expression was related to Hsp70 and Hsc70. Stv mRNA and Stv protein both showed a similar expression pattern: no modulation during the cold period followed by a significant up-regulation during the recovery period. A coordinated response of Stv and Hsp70 mRNA was observed, but not for Hsc70. Our findings indicate that Stv expression is part of a stress-induced program in D. melanogaster. It probably acts as a co-chaperone modulating the activity of Hsp70 chaperone machinery during recovery from cold stress. Finally our results support the suggestion that Stv and human BAG3 may be functional homologs. © 2010 Elsevier Ltd. All rights reserved.

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