ORCID Profile
0000-0003-2384-2983
Current Organisation
Saint Vincent's Institute of Medical Research
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Biochemistry and Cell Biology | Signal Transduction | Structural Biology (incl. Macromolecular Modelling) | Cell Metabolism
Publisher: Cambridge University Press (CUP)
Date: 11-2011
DOI: 10.1017/S0950268811002135
Abstract: Infectious diarrhoea caused by bacterial pathogens contributes to the high level of mortality in developing countries like Bangladesh. Following standard bacteriological procedures, a total of 14 428 bacterial pathogens were isolated from 56 132 stool s les and rectal swabs collected from diarrhoeal patients between 2005 and 2008. The rate of isolation and antimicrobial susceptibility data were retrospectively analysed for these isolates and among them Vibrio spp. (42·9%) were the most predominant, followed by Shigella spp. (20·3%), Aeromonas spp. (12·8%) and Salmonella spp. (6·4%). A decreasing trend in isolation of Vibrio spp. ( P ·001) and Salmonella spp. ( P ·001) was observed. While Vibrio cholerae isolates remained susceptible to ciprofloxacin, an increase in resistance was observed in C ylobacter spp. and Shigella flexneri . Variations in susceptibility to other tested antibiotics were observed among the isolated pathogens. Access to this current data will help in understanding the local burden of diarrhoeal disease and contribute to better design of prevention programmes.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
DOI: 10.1038/S42255-019-0157-1
Abstract: Central to cellular metabolism and cell proliferation are highly conserved signalling pathways controlled by mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK)
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.IJFOODMICRO.2010.07.019
Abstract: Cronobacter spp. formerly known as Enterobacter sakazakii is an occasional contaminant of powdered infant formula (PIF). This pathogen has been associated with out-breaks of a rare form of infant meningitis, necrotizing enterocolitis (NEC), bacteremia and neonate deaths. The organism is ranked by the International Commission for Microbiological Specifications for Foods (ICMSF) as a 'Severe hazard for restricted populations, life threatening or substantial chronic sequelae or long duration'. Present study aimed to isolate Cronobacter spp. from PIF and clinical s les, such as blood, stool and CSF collected from 93 neonates and child patients, age ranged from 0 to 24months. We did not detect Cronobacter spp. in any of these s les. Later 32 PIF s les collected from retail markets in Bangladesh were tested for the presence of Cronobacter spp. Of these only one was found to be contaminated with Cronobacter sp. This is the first case of Cronobacter contaminated PIF found in Bangladesh to be reported. The organism was successfully identified based on its typical culture characteristics, producing blue-green colonies on chromogenic DFI agar and also by a standardized conventional PCR assay targeting the alpha glucosidase and 16S rRNA gene sequence of Cronobacter sp. The 16S rRNA gene was partially sequenced to provide for the phylogenetic analysis of this isolate (DA01) and found to cluster with some other Cronobacter isolates in the phylogram.
Publisher: Springer Science and Business Media LLC
Date: 03-2019
DOI: 10.1038/S41419-019-1445-0
Abstract: Excitotoxicity, caused by overstimulation or dysregulation of ionotropic glutamate receptors (iGluRs), is a pathological process directing neuronal death in many neurological disorders. The aberrantly stimulated iGluRs direct massive influx of calcium ions into the affected neurons, leading to changes in expression and phosphorylation of specific proteins to modulate their functions and direct their participation in the signalling pathways that induce excitotoxic neuronal death. To define these pathways, we used quantitative proteomic approaches to identify these neuronal proteins (referred to as the changed proteins) and determine how their expression and/or phosphorylation dynamically changed in association with excitotoxic cell death. Our data, available in ProteomeXchange with identifier PXD008353, identified over 100 changed proteins exhibiting significant alterations in abundance and/or phosphorylation levels at different time points (5–240 min) in neurons after glutamate overstimulation. Bioinformatic analyses predicted that many of them are components of signalling networks directing defective neuronal morphology and functions. Among them, the well-known neuronal survival regulators including mitogen-activated protein kinases Erk1/2, glycogen synthase kinase 3 (GSK3) and microtubule-associated protein (Tau), were selected for validation by biochemical approaches, which confirmed the findings of the proteomic analysis. Bioinformatic analysis predicted Protein Kinase B (Akt), c-Jun kinase (JNK), cyclin-dependent protein kinase 5 (Cdk5), MAP kinase kinase (MEK), Casein kinase 2 (CK2), Rho-activated protein kinase (Rock) and Serum/glucocorticoid-regulated kinase 1 (SGK1) as the potential upstream kinases phosphorylating some of the changed proteins. Further biochemical investigation confirmed the predictions of sustained changes of the activation states of neuronal Akt and CK2 in excitotoxicity. Thus, future investigation to define the signalling pathways directing the dynamic alterations in abundance and phosphorylation of the identified changed neuronal proteins will help elucidate the molecular mechanism of neuronal death in excitotoxicity.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2020
DOI: 10.1186/S12964-020-0528-Y
Abstract: Eukaryotic elongation factor-2 kinase (eEF2K) is a Ca 2+ /calmodulin (CaM)-dependent protein kinase that inhibits protein synthesis. However, the role of eEF2K in cancer development was reported paradoxically and remains to be elucidated. Herein, A549 cells with eEF2K depletion or overexpression by stably transfected lentivirus plasmids were used in vitro and in vivo study. MTT and colony assays were used to detect cell proliferation and growth. Extracellular glucose and lactate concentration were measured using test kit. Immunoblot and co-immunoprecipitation assays were used to examine the molecular biology changes and molecular interaction in these cells. LC-MS/MS analysis and [γ- 32 P] ATP kinase assay were used to identify combining protein and phosphorylation site. Nude mice was utilized to study the correlation of eEF2K and tumor growth in vivo. We demonstrated that eEF2K inhibited lung cancer cells proliferation and affected the inhibitory effects of EGFR inhibitor gefitinib. Mechanistically, we showed that eEF2K formed a complex with PKM2 and STAT3, thereby phosphorylated PKM2 at T129, leading to reduced dimerization of PKM2. Subsequently, PKM2 impeded STAT3 phosphorylation and STAT3-dependent c-Myc expression. eEF2K depletion promoted the nuclear translocation of PKM2 and increased aerobic glycolysis reflected by increased lactate secretion and glucose. Our findings define a novel mechanism underlying the regulation of cancer cell proliferation by eEF2K independent of its role in protein synthesis, disclosing the erse roles of eEF2K in cell biology, which lays foundation for the development of new anticancer therapeutic strategies.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Wiley
Date: 09-04-2020
DOI: 10.1111/BDI.12901
Publisher: Elsevier BV
Date: 02-2022
Publisher: Springer Science and Business Media LLC
Date: 05-03-2018
DOI: 10.1038/S41420-018-0042-9
Abstract: Human induced pluripotent stem cells (iPSCs) are a valuable tool for studying the cardiac developmental process in vitro, and cardiomyocytes derived from iPSCs are a putative cell source for personalized medicine. Changes in mitochondrial morphology have been shown to occur during cellular reprogramming and pluripotent stem cell differentiation. However, the relationships between mitochondrial dynamics and cardiac mesoderm commitment of iPSCs remain unclear. Here we demonstrate that changes in mitochondrial morphology from a small granular fragmented phenotype in pluripotent stem cells to a filamentous reticular elongated network in differentiated cardiomyocytes are required for cardiac mesodermal differentiation. Genetic and pharmacological inhibition of the mitochondrial fission protein, Drp1, by either small interfering RNA or M i-1, respectively, increased cardiac mesoderm gene expression in iPSCs. Treatment of iPSCs with M i-1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. Furthermore, Drp1 gene silencing was accompanied by increased mitochondrial respiration and decreased aerobic glycolysis. Our findings demonstrate that shifting the balance of mitochondrial morphology toward fusion by inhibition of Drp1 promoted cardiac differentiation of human iPSCs with a metabolic shift from glycolysis towards oxidative phosphorylation. These findings suggest that Drp1 may represent a new molecular target for future development of strategies to promote the differentiation of human iPSCs into cardiac lineages for patient-specific cardiac regenerative medicine.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 04-2016
Publisher: Microbiology Society
Date: 07-2012
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.BRAINRES.2014.10.040
Abstract: Src-family kinases (SFKs) are involved in neuronal survival and their aberrant regulation contributes to neuronal death. However, how they control neuronal survival and death remains unclear. To define the effect of inhibition of Src activity and expression on neuronal survival. In agreement with our previous findings, we demonstrated that Src was cleaved by calpain to form a 52-kDa truncated fragment in neurons undergoing excitotoxic cell death, and expression of the recombinant truncated Src fragment induced neuronal death. The data confirm that the neurotoxic signaling pathways are intact in the neurons we used for our study. To define the functional role of neuronal SFKs, we treated these neurons with SFK inhibitors and discovered that the treatment induced cell death, suggesting that the catalytic activity of one or more of the neuronal SFKs is critical to neuronal survival. Using small hairpin RNAs that suppress Src expression, we demonstrated that Src is indispensable to neuronal survival. Additionally, we found that neuronal death induced by expression of the neurotoxic truncated Src mutant, treatment of SFK inhibitors or knock-down of Src expression caused inhibition of the neuroprotective protein kinases Erk1/2, or Akt. Src is critical to both neuronal survival and death. Intact Src sustains neuronal survival. However, in the excitotoxic condition, calpain cleavage of Src generates a neurotoxic truncated Src fragment. Both intact Src and the neurotoxic truncated Src fragment exert their biological actions by controlling the activities of neuroprotective protein kinases.
Publisher: Elsevier BV
Date: 12-2022
Publisher: Springer Science and Business Media LLC
Date: 27-07-2020
Publisher: Wiley
Date: 21-11-2019
DOI: 10.1111/JNC.14900
Abstract: Perception of our environment entirely depends on the close interaction between the central and peripheral nervous system. In order to communicate each other, both systems must develop in parallel and in coordination. During development, axonal projections from the CNS as well as the PNS must extend over large distances to reach their appropriate target cells. To do so, they read and follow a series of axon guidance molecules. Interestingly, while these molecules play critical roles in guiding developing axons, they have also been shown to be critical in other major neurodevelopmental processes, such as the migration of cortical progenitors. Currently, a major hurdle for brain repair after injury or neurodegeneration is the absence of axonal regeneration in the mammalian CNS. By contrasts, PNS axons can regenerate. Many hypotheses have been put forward to explain this paradox but recent studies suggest that hacking neurodevelopmental mechanisms may be the key to promote CNS regeneration. Here we provide a seminar report written by trainees attending the second Flagship school held in Alpbach, Austria in September 2018 organized by the International Society for Neurochemistry (ISN) together with the Journal of Neurochemistry (JCN). This advanced school has brought together leaders in the fields of neurodevelopment and regeneration in order to discuss major keystones and future challenges in these respective fields.
Publisher: Springer Science and Business Media LLC
Date: 23-02-2017
DOI: 10.1038/SREP43264
Abstract: The Ca 2+ -calmodulin dependent protein kinase kinase-2 (CaMKK2) is a key regulator of neuronal function and whole-body energy metabolism. Elevated CaMKK2 activity is strongly associated with prostate and hepatic cancers, whereas reduced CaMKK2 activity has been linked to schizophrenia and bipolar disease in humans. Here we report the functional effects of nine rare-variant point mutations that were detected in large-scale human genetic studies and cancer tissues, all of which occur close to two regulatory phosphorylation sites and the catalytic site on human CaMKK2. Four mutations (G87R, R139W, R142W and E268K) cause a marked decrease in Ca 2+ -independent autonomous activity, however S137L and P138S mutants displayed increased autonomous and Ca 2+ -CaM stimulated activities. Furthermore, the G87R mutant is defective in Thr85-autophosphorylation dependent autonomous activity, whereas the A329T mutation rendered CaMKK2 virtually insensitive to Ca 2+ -CaM stimulation. The G87R and R139W mutants behave as dominant-negative inhibitors of CaMKK2 signaling in cells as they block phosphorylation of the downstream substrate AMP-activated protein kinase (AMPK) in response to ionomycin. Our study provides insight into functionally disruptive, rare-variant mutations in human CaMKK2, which have the potential to influence risk and burden of disease associated with aberrant CaMKK2 activity in human populations carrying these variants.
Publisher: Elsevier BV
Date: 09-2017
Publisher: Spandidos Publications
Date: 19-03-2018
Abstract: In contrast to healthy intervertebral discs (IVDs), degenerate IVDs become vascularized. Here, we determined the role of an angiogenesis promoter, angiopoietin (Ang)-2, in the pathology of IVD degeneration (IDD). We evaluated degree of IDD using the Pfirrmann grading system. We used quantitative real-time polymerase chain reaction and western blotting to analyze ANG2 gene expression and Ang-2 protein levels, respectively. The involvement of Ang-2 in IVD degradation and regulation of nuclear factor-κB (NF-κB) signaling was examined by immunohistochemistry, western blotting and immunofluorescence. As a result, 10 s les with grades II and III IDD were categorized as the mild IDD group for comparison, another 10 specimens with grades IV and V constituted the severe IDD group. Ang-2 expression was significantly higher in severe IDD than in mild IDD. Exogenous Ang-2 administration led to increased production of catabolic proteinases and loss of aggrecan and collagen II in degenerative NP cell cultures, which was mediated by the NF-κB signaling pathway. Elevated Ang-2 levels also increased interleukin-1β expression in degenerative NP cells. We conclude that the release of Ang-2 aggravates NP cell degradation and plays an important role in IDD. Ang-2 may thus constitute a novel therapeutic target for the treatment of IVD.
Publisher: Elsevier BV
Date: 06-2018
Publisher: EMBO
Date: 15-09-2020
Publisher: Springer Science and Business Media LLC
Date: 17-03-2012
DOI: 10.1007/S10096-012-1601-2
Abstract: The main objective of this study was to investigate the prevalence of bla (NDM-1) in Gram-negative bacteria in Bangladesh. In October 2010 at the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) laboratories, 1,816 consecutive clinical s les were tested for imipenem-resistant Gram-negative organisms. Imipenem-resistant isolates were tested for the bla (NDM-1) gene. Among 403 isolates, 14 (3.5 %) were positive for bla (NDM-1), and the predominant species were Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli. All bla (NDM-1)-positive isolates were resistant to multiple antibiotics. Among β-lactamase genes, bla (CTX-M-1-group) was detected in ten isolates (eight bla (CTX-M-15)), bla (OXA-1-group) in six, bla (TEM) in nine, bla (SHV) in seven, and bla (VIM) and bla (CMY) in two isolates each. The 16S rRNA methylase gene, armA, was detected in five K. pneumoniae isolates and in one E. coli isolate. rmtB and rmtC were detected in a Citrobacter freundii and two K. pneumoniae isolates, respectively. qnr genes were detected in two K. pneumoniae isolates (one qnrB and one qnrS) and in an E. coli isolate (qnrA). Transferable plasmids (60-100 MDa) carrying bla (NDM-1) were detected in 7 of the 11 plasmid-containing isolates. Pulsed-field gel electrophoresis (PFGE) analysis grouped K. pneumoniae isolates into three clusters, while E. coli isolates differed significantly from each other. This study reports that approximately 3.5 % of Gram-negative clinical isolates in Bangladesh are NDM-1-producing.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CHEMBIOL.2018.03.008
Abstract: The AMP-activated protein kinase (AMPK) αβγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2β2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates α2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose "importagog" to define a substance that induces or augments cellular uptake of another substance. Three-dimensional structures of the glucose importagog SC4 bound to activated α2β2γ1 and α2β1γ1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and β2-Asp111, which provide a design paradigm for β2-AMPK therapeutics. The α2β2γ1/SC4 structure reveals an interaction between a β2 N-terminal α helix and the α2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, β2-AMPK therapeutics.
Publisher: Mary Ann Liebert Inc
Date: 15-12-2017
Abstract: Cardiac stem cell (CSC) therapy is a promising approach to treat ischemic heart disease. However, the poor survival of transplanted stem cells in the ischemic myocardium has been a major impediment in achieving an effective cell-based therapy against myocardial infarction. Inhibiting mitochondrial fission has been shown to promote survival of several cell types. However, the role of mitochondrial morphology in survival of human CSC remains unknown. In this study, we investigated whether mitochondrial ision inhibitor-1 (M i-1), an inhibitor of mitochondrial fission protein dynamin-related protein-1 (Drp1), can improve survival of a novel population of human W8B2
Publisher: Cold Spring Harbor Laboratory
Date: 15-06-2020
DOI: 10.1101/2020.06.15.151456
Abstract: Excitotoxicity, a neuronal death process in neurological disorders, is initiated by over-stimulation of neuronal ionotropic glutamate receptors. The over-stimulated receptors dysregulate proteases, protein kinases and phosphatases, which in turn modify target neuronal proteins to induce cell death. To decipher this cell death mechanism, we used quantitative proteomics, phosphoproteomics and N-terminomics to identify modified proteins in excitotoxic neurons. Data, available in ProteomeXchange (identifiers: PXD019527 and PXD019211), enabled us to identify over one thousand such proteins with calpains, cathepsins and over twenty protein kinases as their major modifiers. These protein modification events can potentially perturb signalling pathways governing cell survival, synaptogenesis, axonal guidance and mRNA processing. Importantly, blocking the modification of Src protein kinase, a signalling hub in excitotoxic neurons, protected against neuronal loss in vivo in a rat model of neurotoxicity. Besides offering new insights into excitotoxic neuronal death mechanism, our findings suggest potential neuroprotective therapeutic targets for treating neurological disorders. Multi-dimensional proteomic analysis identified proteins modified by proteolysis and altered phosphorylation in neurons undergoing excitotoxic cell death. Calpains, cathepsins and over twenty protein kinases are major modifiers of these proteins. These protein modification events are predicted to impact cell survival, axonal guidance, synaptogenesis and mRNA processing. Blocking modification of an identified protein Src, which acts as a major signalling hub in neurons, was protective against excitotoxic injury in vivo . Using multidimensional proteomic approaches, Ameen, et al . mapped the changes of proteome, phosphoproteome and N-terminome of cultured primary neurons during excitotoxicity, a crucial neuronal death process in neurological disorders. These proteomic changes document new excitotoxicity-associated molecular events, and offer insights into how these events are organized to induce neuronal death. Potential therapeutic relevance of these molecular events is illustrated by the demonstration that in vivo blockade of one of these events could protect against excitotoxic neuronal loss.
Publisher: Springer Science and Business Media LLC
Date: 18-09-2017
DOI: 10.1038/S41467-017-00628-Y
Abstract: AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for maintaining cellular energy homeostasis. Activation of AMPK by salicylate and the thienopyridone A-769662 is critically dependent on phosphorylation of Ser108 in the β1 regulatory subunit. Here, we show a possible role for Ser108 phosphorylation in cell cycle regulation and promotion of pro-survival pathways in response to energy stress. We identify the autophagy initiator Unc-51-like kinase 1 (ULK1) as a β1-Ser108 kinase in cells. Cellular β1-Ser108 phosphorylation by ULK1 was dependent on AMPK β-subunit myristoylation, metabolic stress associated with elevated AMP/ATP ratio, and the intrinsic energy sensing capacity of AMPK features consistent with an AMP-induced myristoyl switch mechanism. We further demonstrate cellular AMPK signaling independent of activation loop Thr172 phosphorylation, providing potential insight into physiological roles for Ser108 phosphorylation. These findings uncover new mechanisms by which AMPK could potentially maintain cellular energy homeostasis independently of Thr172 phosphorylation.
Location: Bangladesh
Location: No location found
Start Date: 10-2022
End Date: 10-2025
Amount: $554,000.00
Funder: Australian Research Council
View Funded Activity