ORCID Profile
0000-0001-7188-5035
Current Organisation
Murdoch University
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Publisher: OMICS Publishing Group
Date: 2017
Publisher: Wiley
Date: 18-03-2016
DOI: 10.1111/JAN.12953
Abstract: To describe an integrative review protocol to analyse and synthesize peer-reviewed research evidence in relation to engagement of patients and their families in communication during transitions of care to, in and from acute care settings. Communication at transitions of care in acute care settings can be complex and challenging, with important information about patients not always clearly transferred between responsible healthcare providers. Involving patients and their families in communication during transitions of care may improve the transfer of clinical information and patient outcomes and prevent adverse events during hospitalization and following discharge. Recently, optimizing patient and family participation during care transitions has been acknowledged as central to the implementation of patient-centred care. Integrative review with potential for meta-analysis and application of framework synthesis. The review will evaluate and synthesize qualitative and quantitative research evidence identified through a systematic search. Primary studies will be selected according to inclusion criteria. Data collection, quality appraisal and analysis of the evidence will be conducted by at least two authors. Nine electronic databases (including CINAHL and Medline) will be searched. The search will be restricted to 10 years up to December 2013. Data analysis will include content and thematic analysis. The review will seek to identify all types of patient engagement activities employed during transitions of care communication. The review will identify enablers for and barriers to engagement for patients, families and health professionals. Key strategies and tools for improving patient engagement, clinical communication and promoting patient-centred care will be recommended based on findings.
Publisher: Springer Science and Business Media LLC
Date: 25-10-2021
Publisher: Springer Science and Business Media LLC
Date: 18-10-2017
DOI: 10.1007/S00414-016-1464-7
Abstract: The rate of decomposition and insect succession onto decomposing pig carcasses were investigated following burning of carcasses. Ten pig carcasses (40-45 kg) were exposed to insect activity during autumn (March-April) in Western Australia. Five replicates were burnt to a degree described by the Crow-Glassman Scale (CGS) level #2, while five carcasses were left unburnt as controls. Burning carcasses greatly accelerated decomposition in contrast to unburnt carcasses. Physical modifications following burning such as skin discolouration, splitting of abdominal tissue and leathery consolidation of skin eliminated evidence of bloat and altered microambient temperatures associated with carcasses throughout decomposition. Insect species identified on carcasses were consistent between treatment groups however, a statistically significant difference in insect succession onto remains was evident between treatments (PERMANOVA F
Publisher: Springer Science and Business Media LLC
Date: 23-07-2021
DOI: 10.1038/S41598-021-94639-X
Abstract: Antisense oligomers (AOs) are increasingly being used to modulate RNA splicing in live cells, both for research and for the development of therapeutics. While the most common intended effect of these AOs is to induce skipping of whole exons, rare ex les are emerging of AOs that induce skipping of only part of an exon, through activation of an internal cryptic splice site. In this report, we examined seven AO-induced cryptic splice sites in six genes. Five of these cryptic splice sites were discovered through our own experiments, and two originated from other published reports. We modelled the predicted effects of AO binding on the secondary structure of each of the RNA targets, and how these alterations would in turn affect the accessibility of the RNA to splice factors. We observed that a common predicted effect of AO binding was disruption of the exon definition signal within the exon’s excluded segment.
Publisher: MDPI AG
Date: 31-10-2019
DOI: 10.3390/IJMS20215434
Abstract: Spinocerebellar ataxia type 3 (SCA3) is a devastating neurodegenerative disease for which there is currently no cure, nor effective treatment strategy. One of nine polyglutamine disorders known to date, SCA3 is clinically heterogeneous and the main feature is progressive ataxia, which in turn affects speech, balance and gait of the affected in idual. SCA3 is caused by an expanded polyglutamine tract in the ataxin-3 protein, resulting in conformational changes that lead to toxic gain of function. The expanded glutamine tract is located at the 5′ end of the penultimate exon (exon 10) of ATXN3 gene transcript. Other studies reported removal of the expanded glutamine tract using splice switching antisense oligonucleotides. Here, we describe improved efficiency in the removal of the toxic polyglutamine tract of ataxin-3 in vitro using phosphorodiamidate morpholino oligomers, when compared to antisense oligonucleotides composed of 2′-O-methyl modified bases on a phosphorothioate backbone. Significant downregulation of both the expanded and non-expanded protein was induced by the morpholino antisense oligomer, with a greater proportion of ataxin-3 protein missing the polyglutamine tract. With growing concerns over toxicity associated with long-term administration of phosphorothioate oligonucleotides, the use of a phosphorodiamidate morpholino oligomer may be preferable for clinical application. These results suggest that morpholino oligomers may provide greater therapeutic benefit for the treatment of spinocerebellar ataxia type 3, without toxic effects.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-10-2021
Publisher: MDPI AG
Date: 11-10-2019
DOI: 10.3390/IJMS20205030
Abstract: The process of pre-mRNA splicing is a common and fundamental step in the expression of most human genes. Alternative splicing, whereby different splice motifs and sites are recognised in a developmental and/or tissue-specific manner, contributes to genetic plasticity and ersity of gene expression. Redirecting pre-mRNA processing of various genes has now been validated as a viable clinical therapeutic strategy, providing treatments for Duchenne muscular dystrophy (inducing specific exon skipping) and spinal muscular atrophy (promoting exon retention). We have designed and evaluated over 5000 different antisense oligonucleotides to alter splicing of a variety of pre-mRNAs, from the longest known human pre-mRNA to shorter, exon-dense primary gene transcripts. Here, we present our guidelines for designing, evaluating and optimising splice switching antisense oligomers in vitro. These systematic approaches assess several critical factors such as the selection of target splicing motifs, choice of cells, various delivery reagents and crucial aspects of validating assays for the screening of antisense oligonucleotides composed of 2′-O-methyl modified bases on a phosphorothioate backbone.
Publisher: Research Square Platform LLC
Date: 18-01-2021
DOI: 10.21203/RS.3.RS-144809/V1
Abstract: Antisense oligomers (AOs) are increasingly being used for modulating RNA splicing in live cells, both for research and for therapeutic purposes. While the most common intended effect of these AOs is to induce skipping of whole exons, rare ex les are emerging of AOs that induce skipping of only part of an exon, through activation of an internal cryptic splice site. In this report, we examined seven such ex les of AO-induced cryptic splice site activation – five new ex les from our own experiments and three from reports published by others. We modelled the predicted effects that AO binding would have on the secondary structure of each of the RNA targets, and how these alterations would in turn affect the accessibility of the RNA to splice factors. We observed that a common predicted effect of AO binding was a disruption to the exon definition signal within the exon’s excluded segment.
Publisher: Springer Science and Business Media LLC
Date: 20-05-2021
DOI: 10.1186/S40035-021-00240-7
Abstract: Precursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the ersity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans- splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.
Publisher: MDPI AG
Date: 20-10-2021
DOI: 10.3390/BIOMEDICINES9111499
Abstract: Polyglutamine (polyQ) ataxias are a heterogenous group of neurological disorders all caused by an expanded CAG trinucleotide repeat located in the coding region of each unique causative gene. To date, polyQ ataxias encompass six disorders: spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17 and account for a larger group of disorders simply known as polyglutamine disorders, which also includes Huntington’s disease. These diseases are typically characterised by progressive ataxia, speech and swallowing difficulties, lack of coordination and gait, and are unfortunately fatal in nature, with the exception of SCA6. All the polyQ spinocerebellar ataxias have a hallmark feature of neuronal aggregations and share many common pathogenic mechanisms, such as mitochondrial dysfunction, impaired proteasomal function, and autophagy impairment. Currently, therapeutic options are limited, with no available treatments that slow or halt disease progression. Here, we discuss the common molecular and clinical presentations of polyQ spinocerebellar ataxias. We will also discuss the promising antisense oligonucleotide therapeutics being developed as treatments for these devastating diseases. With recent advancements and therapeutic approvals of various antisense therapies, it is envisioned that some of the studies reviewed may progress into clinical trials and beyond.
Publisher: MDPI AG
Date: 12-08-2019
DOI: 10.3390/MOLECULES24162922
Abstract: One of the crucial aspects of screening antisense oligonucleotides destined for therapeutic application is confidence that the antisense oligomer is delivered efficiently into cultured cells. Efficient delivery is particularly vital for antisense phosphorodiamidate morpholino oligomers, which have a neutral backbone, and are known to show poor gymnotic uptake. Here, we report several methods to deliver these oligomers into cultured cells. Although 4D-Nucleofector™ or Neon™ electroporation systems provide efficient delivery and use lower amounts of phosphorodiamidate morpholino oligomer, both systems are costly. We show that some readily available transfection reagents can be used to deliver phosphorodiamidate morpholino oligomers as efficiently as the electroporation systems. Among the transfection reagents tested, we recommend Lipofectamine 3000™ for delivering phosphorodiamidate morpholino oligomers into fibroblasts and Lipofectamine 3000™ or Lipofectamine 2000™ for myoblasts/myotubes. We also provide optimal programs for nucleofection into various cell lines using the P3 Primary Cell 4D-Nucleofector™ X Kit (Lonza), as well as antisense oligomers that redirect expression of ubiquitously expressed genes that may be used as positive treatments for human and murine cell transfections.
No related grants have been discovered for Craig McIntosh.