ORCID Profile
0000-0002-7264-8602
Current Organisation
Monash University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Biological Mathematics | Applied Mathematics | Simulation And Modelling | Signal Transduction | Other Information, Computing And Communication Sciences | Systems Biology | Artificial Intelligence and Image Processing | Pattern Recognition
Clinical health not specific to particular organs, diseases and conditions | Information processing services | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Mathematical Sciences |
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.PBIOMOLBIO.2014.11.006
Abstract: Understanding the complexity of cardiac physiology requires system-level studies of multiple cardiac cell types. Frequently, however, the end result of published research lacks the detail of the collaborative and integrative experimental design process, and the underlying conceptual framework. We review the recent progress in systems modelling and omics analysis of the heterocellular heart environment through complementary forward and inverse approaches, illustrating these conceptual and experimental frameworks with case studies from our own research program. The forward approach begins by collecting curated information from the niche cardiac biology literature, and connecting the dots to form mechanistic network models that generate testable system-level predictions. The inverse approach starts from the vast pool of public omics data in recent cardiac biological research, and applies bioinformatics analysis to produce novel candidates for further investigation. We also discuss the possibility of combining these two approaches into a hybrid framework, together with the benefits and challenges. These interdisciplinary research frameworks illustrate the interplay between computational models, omics analysis, and wet lab experiments, which holds the key to making real progress in improving human cardiac wellbeing.
Publisher: IEEE
Date: 09-2015
Publisher: Elsevier BV
Date: 06-2010
Publisher: Elsevier BV
Date: 07-2005
Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.MOLIMM.2007.07.008
Abstract: Complement is a central component of host defence, but unregulated activation can contribute to disease. The system can be initiated by three pathways: classical, alternative and lectin. The classical and lectin pathways are initiated by the C1 and mannose-binding lectin (MBL) or ficolin complexes, respectively, with C1s the executioner protease of the C1 complex and MASP-2 its counterpart in the lectin complexes. These proteases in turn cleave the C4 and C2 components of the system. Here we have elucidated the cleavage specificity of MASP-2 using a randomised substrate phage display library. Apart from the crucial P1 position, the MASP-2 S2 and S3 subsites (in that order) play the greatest role in determining specificity, with Gly residues preferred at P2 and Leu or hydrophobic residues at P3. Cleavage of peptide substrates representing the known physiological cleavage sequences in C2, C4 or the serpin C1-inhibitor (a likely regulator of MASP-2) revealed that MASP-2 is up to 1000 times more catalytically active than C1s. C1-inhibitor inhibited MASP-2 50-fold faster than C1s and much faster than any other protease tested to date, implying that MASP-2 is a major physiological target of C1-inhibitor.
Publisher: Springer Science and Business Media LLC
Date: 09-2009
DOI: 10.1038/NBT0909-864D
Publisher: American Chemical Society (ACS)
Date: 11-11-2011
DOI: 10.1021/BI201333G
Abstract: Understanding the active site preferences of an enzyme is critical to the design of effective inhibitors and to gaining insights into its mechanisms of action on substrates. While the subsite specificity of thrombin is understood, it is not clear whether the enzyme prefers in idual amino acids at each subsite in isolation or prefers to cleave combinations of amino acids as a motif. To investigate whether preferred peptide motifs for cleavage could be identified for thrombin, we exposed a phage-displayed peptide library to thrombin. The resulting preferentially cleaved substrates were analyzed using the technique of association rule discovery. The results revealed that thrombin selected for amino acid motifs in cleavage sites. The contribution of these hypothetical motifs to substrate cleavage efficiency was further investigated using the B1 IgG-binding domain of streptococcal protein G as a model substrate. Introduction of a P(2)-P(1)' LRS thrombin cleavage sequence within a major loop of the protein led to cleavage of the protein by thrombin, with the cleavage efficiency increasing with the length of the loop. Introduction of further P(3)-P(1) and P(1)-P(1)'-P(3)' amino acid motifs into the loop region yielded greater cleavage efficiencies, suggesting that the susceptibility of a protein substrate to cleavage by thrombin is influenced by these motifs, perhaps because of cooperative effects between subsites closest to the scissile peptide bond.
Publisher: Elsevier BV
Date: 12-2009
Publisher: Springer Science and Business Media LLC
Date: 08-2009
DOI: 10.1038/NBT.1558
Abstract: Circuit diagrams and Unified Modeling Language diagrams are just two ex les of standard visual languages that help accelerate work by promoting regularity, removing ambiguity and enabling software tool support for communication of complex information. Ironically, despite having one of the highest ratios of graphical to textual information, biology still lacks standard graphical notations. The recent deluge of biological knowledge makes addressing this deficit a pressing concern. Toward this goal, we present the Systems Biology Graphical Notation (SBGN), a visual language developed by a community of biochemists, modelers and computer scientists. SBGN consists of three complementary languages: process diagram, entity relationship diagram and activity flow diagram. Together they enable scientists to represent networks of biochemical interactions in a standard, unambiguous way. We believe that SBGN will foster efficient and accurate representation, visualization, storage, exchange and reuse of information on all kinds of biological knowledge, from gene regulation, to metabolism, to cellular signaling.
Publisher: Frontiers Media SA
Date: 15-03-2017
Publisher: World Scientific Pub Co Pte Lt
Date: 06-2005
DOI: 10.1142/S021972000500117X
Abstract: Proteases play a fundamental role in the control of intra- and extra-cellular processes by binding and cleaving specific amino acid sequences. Identifying these targets is extremely challenging. Current computational attempts to predict cleavage sites are limited, representing these amino acid sequences as patterns or frequency matrices. Here we present PoPS, a publicly accessible bioinformatics tool () that provides a novel method for building computational models of protease specificity, which while still being based on these amino acid sequences, can be built from any experimental data or expert knowledge available to the user. PoPS specificity models can be used to predict and rank likely cleavages within a single substrate, and within entire proteomes. Other factors, such as the secondary or tertiary structure of the substrate, can be used to screen unlikely sites. Furthermore, the tool also provides facilities to infer, compare and test models, and to store them in a publicly accessible database.
Publisher: Elsevier BV
Date: 07-2008
Publisher: Wiley
Date: 30-06-2018
DOI: 10.1111/MEC.14763
Abstract: Spatially adjacent habitats on coral reefs can represent highly distinct environments, often harbouring different coral communities. Yet, certain coral species thrive across ergent environments. It is unknown whether the forces of selection are sufficiently strong to overcome the counteracting effects of the typically high gene flow over short distances, and for local adaptation to occur. We screened the coral genome (using restriction site-associated sequencing) and characterized both the dinoflagellate photosymbiont- and tissue-associated prokaryote microbiomes (using metabarcoding) of a reef flat and slope population of the reef-building coral, Pocillopora damicornis, at two locations on Heron Island in the southern Great Barrier Reef. Reef flat and slope populations were separated by <100 m horizontally and ~5 m vertically, and the two study locations were separated by ~1 km. For the coral host, genetic ergence between habitats was much greater than between locations, suggesting limited gene flow between the flat and slope populations. Consistent with environmental selection, outlier loci primarily belonged to the conserved, minimal cellular stress response, likely reflecting adaptation to the different temperature and irradiance regimes on the reef flat and slope. The prokaryote community differed across both habitat and, to a lesser extent, location, whereas the dinoflagellate photosymbionts differed by habitat but not location. The observed intraspecific ersity associated with ergent habitats supports that environmental adaptation involves multiple members of the coral holobiont. Adaptive alleles or microbial associations present in coral populations from the environmentally variable reef flat may provide a source of adaptive variation for assisted evolution approaches, through assisted gene flow, artificial cross-breeding or probiotic inoculations, with the aim to increase climate resilience in the slope populations.
Publisher: Cold Spring Harbor Laboratory
Date: 04-06-2021
DOI: 10.1101/2021.06.03.446915
Abstract: Organ fibroblasts are essential components of homeostatic and diseased tissues. They participate in sculpting the extracellular matrix, sensing the microenvironment and communicating with other resident cells. Recent studies have revealed transcriptomic heterogeneity among fibroblasts within and between organs. To dissect the basis of inter-organ heterogeneity, we compare the gene expression of fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, gonads) and show that they display distinct positional and organ-specific transcriptome signatures that reflect their embryonic origins. We demonstrate that fibroblasts’ expression of genes typically attributed to the surrounding parenchyma is established in embryonic development and largely maintained in culture, bioengineered tissues, and ectopic transplants. Targeted knockdown of key organ-specific transcription factors affects fibroblasts functions, with modulation of genes related to fibrosis and inflammation. Our data open novel opportunities for the treatment of fibrotic diseases in a more precise, organ-specific manner.
Publisher: Oxford University Press (OUP)
Date: 08-10-2008
DOI: 10.1093/NAR/GKN683
Publisher: Public Library of Science (PLoS)
Date: 16-12-2015
Publisher: Springer Science and Business Media LLC
Date: 05-2015
Publisher: Walter de Gruyter GmbH
Date: 10-04-2009
DOI: 10.1515/BC.2009.064
Abstract: Complement is a key component of the immune system, but can contribute to inflammatory diseases. The substrate specificity of C1s protease has been successfully investigated using a combinatorial approach, while a positional scanning method failed. The lack of success of the latter approach is possibly due to cooperativity in the active site, which could confound such analyses. With a panel of peptides devised using factorial design, we show pronounced cooperativity between the S 4 and S 1 ′ subsites in the active site of the enzyme, and weaker cooperativity between the S 1 ′ and S 3 ′ subsites. The use of factorial design has promise as a methodology for determining cooperativity in protease active sites.
Publisher: Walter de Gruyter GmbH
Date: 10-04-2009
DOI: 10.1515/BC.2009.065
Abstract: Proteases play vital roles in a range of biological processes, such as cell cycle, cell growth and differentiation, apoptosis, haemostasis and signalling. Fundamental to our knowledge of protease action is an understanding of how the active site operates this has been examined through extensive studies of the substrate specificity of the enzymes. Kinetic and structural analyses have shown that the binding of a particular substrate residue at a protease subsite can have either a positive or negative influence on the binding of particular residues at other subsites. This phenomenon has been termed subsite cooperativity and has been observed in a wide range of proteases, often between non-adjacent subsites. This review aims to highlight studies where subsite cooperativity has been observed, experimental techniques used in the past and potential methods that can be employed to comprehensively examine this phenomenon. Further understanding of how the protease active site recognises and chooses its substrates for cleavage will have a significant impact on the development of pharmaceuticals that target these enzymes.
Publisher: Wiley
Date: 23-01-2007
DOI: 10.1111/J.1365-2222.2007.02651.X
Abstract: The cysteine protease Der p 1 from the house dust mite Dermatophagoides pteronyssinus is one of the most potent allergens known. An attractive mechanism for a component of Der p 1 allergenicity lies in its ability to cleave key regulatory molecules from leucocyte surfaces, subverting cellular function and driving abnormal immunoglobulin E (IgE) responses. Although CD23, CD25 and CD40 have already been identified as major Der p 1 targets, other significant substrates may also exist. To investigate this, knowledge of the proteolytic properties of Der p 1 was used to perform in silico digestion of human dendritic cell surface proteins, using the prediction of protease specificity (PoPS) bioinformatics tool, in conjunction with cellular in vitro analysis and cleavage site determination. Targets identified included DC-SIGN and DC-SIGNR, two C-type lectins implicated mostly in pathogen trafficking. Treatment of positively expressing cells with Der p 1 led to loss of detectable surface DC-SIGN and DC-SIGNR. Digestion of purified soluble recombinant DC-SIGN and DC-SIGNR, followed by N-terminal sequencing and MALDI mass spectrometry, indicated in each case one major cleavage site and several minor sites, the former correlating well with Der p 1 enzymology and the folded state of the substrate proteins. Loss of DC-SIGN from the cell surface led to reduced binding of intracellular adhesion molecule-3, an endogenous DC-SIGN ligand expressed on naïve T cells which is thought to be involved in T-helper type 1 cytokine signalling. These data provide evidence of lectin involvement in the initiation of the allergic response and the value of using genome-wide in silico digestion tools.
Publisher: Springer Science and Business Media LLC
Date: 27-07-2012
Publisher: Public Library of Science (PLoS)
Date: 30-03-2012
Publisher: Portland Press Ltd.
Date: 25-03-2014
DOI: 10.1042/BSR20140025
Abstract: Caspase-2 is an evolutionarily conserved but enigmatic protease whose biological role remains poorly understood. To date, research into the functions of caspase-2 has been h ered by an absence of reagents that can distinguish its activity from that of the downstream apoptotic caspase, caspase-3. Identification of protein substrates of caspase-2 that are efficiently cleaved within cells may also provide clues to the role of this protease. We used a yeast-based transcriptional reporter system to define the minimal substrate specificity of caspase-2. The resulting profile enabled the identification of candidate novel caspase-2 substrates. Caspase-2 cleaved one of these proteins, the cancer-associated transcription factor Runx1, although with relatively low efficiency. A fluorogenic peptide was derived from the sequence most efficiently cleaved in the context of the transcriptional reporter. This peptide, Ac-VDTTD-AFC, was efficiently cleaved by purified caspase-2 and auto-activating caspase-2 in mammalian cells, and exhibited better selectivity for caspase-2 relative to caspase-3 than reagents that are currently available. We suggest that this reagent, used in parallel with the traditional caspase-3 substrate Ac-DEVD-AFC, will enable researchers to monitor caspase-2 activity in cell lysates and may assist in the determination of stimuli that activate caspase-2 in vivo.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.STEM.2017.06.003
Abstract: Organ growth requires a careful balance between stem cell self-renewal and lineage commitment to ensure proper tissue expansion. The cellular and molecular mechanisms that mediate this balance are unresolved in most organs, including skeletal muscle. Here we identify a long-lived stem cell pool that mediates growth of the zebrafish myotome. This population exhibits extensive clonal drift, shifting from random deployment of stem cells during development to reliance on a small number of dominant clones to fuel the vast majority of muscle growth. This clonal drift requires Meox1, a homeobox protein that directly inhibits the cell-cycle checkpoint gene ccnb1. Meox1 initiates G
Publisher: The Company of Biologists
Date: 02-2016
DOI: 10.1242/DEV.120576
Abstract: In the adult, tissue repair after injury is generally compromised by fibrosis, which maintains tissue integrity with scar formation but does not restore normal architecture and function. The process of regeneration is necessary to replace the scar and rebuild normal functioning tissue. Here, we address this problem in the context of heart disease, and discuss the origins and characteristics of cardiac fibroblasts, as well as the crucial role that they play in cardiac development and disease. We discuss the dual nature of cardiac fibroblasts, which can lead to scarring, pathological remodelling and functional deficit, but can also promote heart function in some contexts. Finally, we review current and proposed approaches whereby regeneration could be fostered by interventions that limit scar formation.
Publisher: World Scientific Pub Co Pte Ltd
Date: 02-2011
DOI: 10.1142/S0219720011005288
Abstract: Proteases have central roles in "life and death" processes due to their important ability to catalytically hydrolyze protein substrates, usually altering the function and/or activity of the target in the process. Knowledge of the substrate specificity of a protease should, in theory, dramatically improve the ability to predict target protein substrates. However, experimental identification and characterization of protease substrates is often difficult and time-consuming. Thus solving the "substrate identification" problem is fundamental to both understanding protease biology and the development of therapeutics that target specific protease-regulated pathways. In this context, bioinformatic prediction of protease substrates may provide useful and experimentally testable information about novel potential cleavage sites in candidate substrates. In this article, we provide an overview of recent advances in developing bioinformatic approaches for predicting protease substrate cleavage sites and identifying novel putative substrates. We discuss the advantages and drawbacks of the current methods and detail how more accurate models can be built by deriving multiple sequence and structural features of substrates. We also provide some suggestions about how future studies might further improve the accuracy of protease substrate specificity prediction.
Publisher: Oxford University Press (OUP)
Date: 03-02-2010
DOI: 10.1093/BIOINFORMATICS/BTQ043
Abstract: Motivation: The caspase family of cysteine proteases play essential roles in key biological processes such as programmed cell death, differentiation, proliferation, necrosis and inflammation. The complete repertoire of caspase substrates remains to be fully characterized. Accordingly, systematic computational screening studies of caspase substrate cleavage sites may provide insight into the substrate specificity of caspases and further facilitating the discovery of putative novel substrates. Results: In this article we develop an approach (termed Cascleave) to predict both classical (i.e. following a P1 Asp) and non-typical caspase cleavage sites. When using local sequence-derived profiles, Cascleave successfully predicted 82.2% of the known substrate cleavage sites, with a Matthews correlation coefficient (MCC) of 0.667. We found that prediction performance could be further improved by incorporating information such as predicted solvent accessibility and whether a cleavage sequence lies in a region that is most likely natively unstructured. Novel bi-profile Bayesian signatures were found to significantly improve the prediction performance and yielded the best performance with an overall accuracy of 87.6% and a MCC of 0.747, which is higher accuracy than published methods that essentially rely on amino acid sequence alone. It is anticipated that Cascleave will be a powerful tool for predicting novel substrate cleavage sites of caspases and shedding new insights on the unknown caspase-substrate interactivity relationship. Availability: sunflower.kuicr.kyoto-u.ac.jp/∼sjn/Cascleave/ Contact: jiangning.song@med.monash.edu.au takutsu@kuicr.kyoto-u.ac.jp james whisstock@med.monash.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 11-2005
Start Date: 04-2013
End Date: 12-2016
Amount: $270,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2007
End Date: 12-2009
Amount: $249,000.00
Funder: Australian Research Council
View Funded Activity