ORCID Profile
0000-0002-3318-0410
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Nanomaterials | Nanomedicine | Nanotechnology | Nanobiotechnology |
Industrial Chemicals and Related Products not elsewhere classified | Plastic Products (incl. Construction Materials) | Expanding Knowledge in the Medical and Health Sciences
Publisher: SAGE Publications
Date: 04-2013
Publisher: Cold Spring Harbor Laboratory
Date: 21-03-2017
Abstract: Large numbers of long noncoding RNAs have been discovered in recent years, but only a few have been characterized. NEAT1 (nuclear paraspeckle assembly transcript 1) is a mammalian long noncoding RNA that is important for the reproductive physiology of mice, cancer development, and the formation of subnuclear bodies termed paraspeckles. The two major isoforms of NEAT1 (3.7 kb NEAT1_1 and 23 kb NEAT1_2 in human) are generated from a common promoter and are produced through the use of alternative transcription termination sites. This gene structure has made the functional relationship between the two isoforms difficult to dissect. Here we used CRISPR-Cas9 genome editing to create several different cell lines: total NEAT1 knockout cells, cells that only express the short form NEAT1_1, and cells with twofold more NEAT1_2. Using these reagents, we obtained evidence that NEAT1_1 is not a major component of paraspeckles. In addition, our data suggest NEAT1_1 localizes in numerous nonparaspeckle foci we termed “microspeckles,” which may carry paraspeckle-independent functions. This study highlights the complexity of lncRNA and showcases how genome editing tools are useful in dissecting the structural and functional roles of overlapping transcripts.
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.BIOCEL.2014.09.028
Abstract: The "stem cell" has become arguably one of the most important biological tools in the arsenal of translational research directed at regeneration and repair. It remains to be seen whether every tissue has its own stem cell niche, although relatively recently a large amount of research has focused on isolating and characterizing tissue-specific stem cell populations, as well as those that are able to be directed to transdifferentiate into a variety of different lineages. Traditionally, stem cells are isolated from the viable tissue of embryonic, fetal, or adult living hosts from "fresh" donated tissues that have been surgically or otherwise removed (biopsies), or obtained directly from tissues within minutes to several hours post mortem (PM). These human progenitor/stem cell sources remain potentially highly controversial, since they are accompanied by various still-unresolved ethical, social, moral and legal challenges. Due to the limited number of "live" donors, the small amount of material obtained from biopsies and difficulties during purification processes, harvesting from cadaveric material presents itself as an alternative strategy that could provide a hitherto untapped source of stem cells. However, PM stem cells are not without their own unique set of limitations including difficulty of obtaining s les, limited supply of material, variations in delay between death and s le collection, possible lack of medication history and suboptimal retrospective assignment of diagnostic and demographic data. This article is part of a Directed Issue entitled: Regenerative Medicine: The challenge of translation.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2003
Publisher: Elsevier BV
Date: 04-2000
Publisher: Elsevier
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 22-04-2005
DOI: 10.1007/S00441-005-1102-Z
Abstract: Dramatic clinical success in the treatment of chronic inflammatory diseases has resulted from the use of anti-cytokine therapies including specific blocking antibodies, soluble receptors and traps to silence the actions of inflammatory cytokines such as tumour necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1). Two agents used clinically to block the functional activity of TNFalpha protein are Remicade (an antibody) and Enbrel (a soluble TNF receptor). These tools are now being extended to many other clinical disorders. We have a specific interest in the treatment of muscle diseases. In order to study the effects of novel anti-cytokine drugs on mouse models of human disease, such drugs must be investigated to determine whether they are indeed effective in blocking the inflammatory response in mouse. This has been carried out by means of a simple in vivo bioassay. Histological examination of transverse sections from whole muscle autografts in C57BL/10ScSn mice s led at 5 days after transplantation provides an excellent assay model and clearly shows that Remicade and Enbrel block the acute inflammatory cell response in vivo. This graft model has also been used to show that a single intraperitoneal injection of Remicade (10 microg/g) is long-lived and effective when administered at 1 week and even 4 weeks prior to the assay. Enbrel is highly effective when injected twice at -3 days and -1 day (2 x 100 microg) before muscle grafting but shows no inhibition of the inflammatory response after a single injection (100 microg) 1 week prior to grafting. This striking ablation of inflammation by pharmacological blockage of TNFalpha is in marked contrast to the lack of any effect in TNFalpha null mice. This simple reproducible in vivo assay model in mice can be used to evaluate the efficacy of many novel anti-cytokine interventions designed to block inflammation.
Publisher: MDPI AG
Date: 14-01-2015
DOI: 10.3390/JCM4010193
Publisher: Springer Science and Business Media LLC
Date: 08-06-2017
DOI: 10.1007/S10522-017-9714-8
Abstract: The ability of resistance exercise, initiated from mid-life, to prevent age-related changes in old sciatic nerves, was investigated in male and female C57BL/6J mice. Aging is associated with cellular changes in old sciatic nerves and also loss of skeletal muscle mass and function (sarcopenia). Mature adult mice aged 15 months (M) were subjected to increasing voluntary resistance wheel exercise (RWE) over a period of 8 M until 23 M of age. This prevented sarcopenia in the old 23 M aged male and female mice. Nerves of control sedentary (SED) males at 3, 15 and 23 M of age, showed a decrease in the myelinated axon numbers at 15 and 23 M, a decreased g-ratio and a significantly increased proportion of myelinated nerves containing electron-dense aggregates at 23 M. Myelinated axon and nerve diameter, and axonal area, were increased at 15 M compared with 3 and 23 M. Exercise increased myelinated nerve profiles containing aggregates at 23 M. S100 protein, detected with immunoblotting was increased in sciatic nerves of 23 M old SED females, but not males, compared with 15 M, with no effect of exercise. Other neuronal proteins showed no significant alterations with age, gender or exercise. Overall the RWE had no cellular impact on the aging nerves, apart from an increased number of old nerves containing aggregates. Thus the relationship between cellular changes in aging nerves, and their sustained capacity for stimulation of old skeletal muscles to help maintain healthy muscle mass in response to exercise remains unclear.
Publisher: Elsevier BV
Date: 05-2007
Publisher: Walter de Gruyter GmbH
Date: 2013
Publisher: Public Library of Science (PLoS)
Date: 09-08-2013
Publisher: Elsevier BV
Date: 09-2015
Publisher: Wiley
Date: 2001
Publisher: Wiley
Date: 06-2001
DOI: 10.1046/J.1440-1711.2001.01006.X
Abstract: Myoblast transfer therapy (MTT) is a potential cell therapy for myopathies such as Duchenne Muscular Dystrophy and involves the injection of cultured muscle precursor cells ('myoblasts') isolated from normal donor skeletal muscles into dystrophic host muscle. The failure of donor myoblast survival following MTT is widely accepted as being due to the immune response of the host. The role of complement as one possible mechanism for the initial, very rapid death of myoblasts following MTT was investigated. Donor male myoblasts were injected into the tibialis anterior (TA) muscles of female host mice that were: (i) untreated (ii) depleted of C3 complement (24 h prior to MTT) using cobra venom factor (CVF) and/or (iii) deficient in C5 complement. Quantification of surviving male donor myoblast DNA was performed using the Y-chromosome specific (Y1) probe on slot blots for s les taken at 0 h, 1 h, 24 h, 1 week and 3 weeks after MTT. Peripheral depletion of C3 was confirmed using double immunodiffusion, and local depletion of C3 in host TA muscles was confirmed by immunostaining of muscle s les. Cobra venom factor treatment significantly increased the initial survival of donor myoblasts, but there was a marked decline in myoblast numbers after 1 h and little long-term benefit by 3 weeks. Strain specific variation in the immediate survival of donor male myoblasts following MTT in untreated C57BL/10Sn, DBA-1 and DBA-2 (C5-deficient) female hosts was observed. Cobra venom factor depletion of C3 increased initial donor male myoblast survival (approximately twofold at 0 h) in C57BL/10Sn and DBA-1 host mice and approximately threefold in DBA-2 hosts at 0 h and 1 h after MTT. The rapid and extensive number (approximately 90%) of donor male myoblasts in untreated DBA-2 mice (that lack C5) indicates that activation of the membrane attack complex (MAC) plays no role in this massive initial cell death. The observation that myoblast survival was increased in all mice treated with CVF suggests that CVF may indirectly enhance donor myoblast survival by a mechanism possibly involving activated C3 fragments.
Publisher: Springer Science and Business Media LLC
Date: 14-04-2016
Publisher: The Company of Biologists
Date: 15-10-2003
DOI: 10.1242/JCS.00721
Abstract: There is a massive and rapid death of donor myoblasts (& % surviving) within hours after intramuscular injection in myoblast transfer therapy (MTT), due to host immune cells, especially natural killer (NK) cells. To investigate the role of host immune cells in the dramatic death of donor myoblasts, MTT experiments were performed in irradiated host mice. Cultured normal C57BL/10ScSn male donor myoblasts were injected into muscles of female C57BL/10ScSn-Dmdmdx host mice after one of three treatments: whole body irradiation (WBI) to eliminate all circulating leukocytes, WBI and bone marrow reconstitution (BMR), or local irradiation (or protection) of one limb. Similar experiments were performed in host mice after antibody depletion of NK cells. Numbers of male donor myoblasts were quantified using a Y-chromosome-specific (male) probe following total DNA extraction of injected muscles. WBI prior to MTT resulted in dramatically enhanced survival (∼80%) of donor myoblasts at 1 hour after MTT, supporting a central role for host inflammatory cells in the initial death of donor myoblasts seen in untreated host mice. BMR restored the massive and rapid loss (∼25% surviving) of donor myoblasts at 1 hour after MTT. Local pre-irradiation also resulted in increased donor myoblast numbers (∼35-40%) compared with untreated controls (∼10%) at 3 weeks after MTT. Preirradiation of host muscle with 10 Gy did not significantly stimulate proliferation of the injected donor myoblasts. Serum protein levels of TNFα, IL-1β, IL-6 and IL-12 fluctuated following irradiation treatments. These combined results strongly reinforce a major role for host immune cells in the rapid death of injected cultured donor myoblasts.
Publisher: American Chemical Society (ACS)
Date: 09-02-2015
DOI: 10.1021/NN506607X
Abstract: The use of programmed electrical signals to influence biological events has been a widely accepted clinical methodology for neurostimulation. An optimal biocompatible platform for neural activation efficiently transfers electrical signals across the electrode-cell interface and also incorporates large-area neural guidance conduits. Inherently conducting polymers (ICPs) have emerged as frontrunners as soft biocompatible alternatives to traditionally used metal electrodes, which are highly invasive and elicit tissue damage over long-term implantation. However, fabrication techniques for the ICPs suffer a major bottleneck, which limits their usability and medical translation. Herein, we report that these limitations can be overcome using colloidal chemistry to fabricate multimodal conducting polymer nanoparticles. Furthermore, we demonstrate that these polymer nanoparticles can be precisely assembled into large-area linear conduits using surface chemistry. Finally, we validate that this platform can act as guidance conduits for neurostimulation, whereby the presence of electrical current induces remarkable dendritic axonal sprouting of cells.
Publisher: Elsevier BV
Date: 10-2006
DOI: 10.1016/J.NMD.2006.06.011
Abstract: Necrosis of skeletal muscle fibres in the lethal childhood myopathy Duchenne Muscular Dystrophy results from deficiency of the cell membrane associated protein, dystrophin. We test the hypothesis in dystrophin-deficient mice, that the initial sarcolemmal breakdown resulting from dystrophin deficiency is exacerbated by inflammatory cells, specifically neutrophils, and that cytokines, specifically Tumour Necrosis Factor alpha (TNFalpha), contribute to myofibre necrosis. Antibody depletion of host neutrophils resulted in a delayed and significantly reduced amount of skeletal muscle breakdown in young dystrophic mdx mice. A more striking and prolonged protective effect was seen after pharmacological blockade of TNFalpha bioactivity using Etanercept. The extent of exercise induced myofibre necrosis in adult mdx mice after voluntarily wheel exercise was also reduced after Etanercept administration. These data show a clear role for neutrophils and TNFalpha in necrosis of dystrophic mdx muscle in vivo. Etanercept is a highly specific anti-inflammatory drug, widely used clinically, and potential application to muscular dystrophies is suggested by this reduced breakdown of mdx skeletal muscle.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.NEUROSCIENCE.2016.10.005
Abstract: Combinations of Ca
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3CC41523F
Abstract: The self-assembly of nanoparticles is an efficient and precise method to fabricate nanoscale devices. By manipulating iron oxide nanoparticles in suspension with an external field to form magnetically directed linear assemblies, we demonstrate the feasibility of using this structure to template the synthesis of PEDOT:PSS conducting polymer nanowires in suspension. Furthermore these conducting wires can be assembled on interdigitated electrodes to form an array of conducting nanowires.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2018
DOI: 10.1007/S10522-018-9765-5
Abstract: Age-related changes in ventral lumbar spinal cord (L3-L5) were compared in young [3 month, (M)] and old (27 M) C57BL/6J male mice. The aged mice had previously been shown to exhibit sarcopenia and changes to peripheral nerve morphology. The putative connectivity of β-III tubulin positive α-motor neurons was compared in immunostained transverse sections using excitatory and inhibitory terminal markers vesicular glutamate transporter-1 (VGLUT1) and vesicular GABA transporter (VGAT). Glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to monitor changes in astrocyte and microglial phenotype respectively. For a given motor neuron, the neuronal perimeter was outlined and terminals immunoreactive for VGLUT1 or VGAT in close apposition to the soma were identified. By 27 M, the percentage coverage and total number of VGLUT1 immunoreactive terminals immediately adjacent to the soma of α-motor neurons was significantly decreased compared with young mice. However, percentage coverage of immunoreactive VGAT inhibitory terminals did not change significantly with age. The gray matter of 27 M spinal cords showed increased astrocytic and microglial activity. The loss of VGLUT1 terminals on α-motor neurons, terminals known to be derived from proprioceptive muscle afferents, may further impair sensorimotor control of hind limb skeletal muscle function in old mice.
Publisher: Elsevier
Date: 2009
Publisher: Hindawi Limited
Date: 06-08-2018
DOI: 10.1155/2018/9828725
Abstract: Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bi cis tronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTF mCherry ) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTF mCherry , as well as with AAV-CNTF mCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTF mCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTF mCherry versus AAV-GFP groups. After AAV-CNTF mCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations.
Publisher: Elsevier
Date: 2017
Publisher: Oxford University Press (OUP)
Date: 30-03-2016
DOI: 10.1093/JNEN/NLW019
Abstract: To elucidate the neural basis for age-related sarcopenia, we quantified morphologic and molecular changes within sciatic nerves of aging male and female C57BL/6J mice aged between 3 and 27 months using immunoblotting, immunohistochemistry, and electron microscopy. Protein analyses by immunoblotting of nerves of male mice aged 4, 15, 18, 22, and 24 months showed increased levels of heavy chain SMI-32-positive neurofilaments, vimentin, tau5, choline acetyltransferase (ChAT), and p62 by 18-22 months. Similar protein increases were seen in 26-month-old compared with 3-month-old female mice. Immunostaining of longitudinal sections of old (27-month-old) male sciatic nerves revealed intense staining for tau5 and p62 that was increased compared with that at 3 months, but there were decreased numbers of axon profiles stained for ChAT or isolectin B4 (motor and sensory axons, respectively). Ultrastructural analysis revealed electron-dense aggregates within axons in peripheral nerves of old male mice the proportion of axons that contained aggregates more than doubled between 15 and 27 months. Overall, the observed age-related accumulation of many proteins from about 18 months of age onward suggests impaired mechanisms for axonal transport and protein turnover. These peripheral nerve changes may contribute to the morphological and functional muscle deficits associated with sarcopenia.
No related organisations have been discovered for Stuart Hodgetts.
Start Date: 2019
End Date: 12-2022
Amount: $382,000.00
Funder: Australian Research Council
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