ORCID Profile
0000-0003-0770-4935
Current Organisations
University of Tasmania School of Medicine
,
Alfred Health
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Publisher: Society for Neuroscience
Date: 28-01-2004
DOI: 10.1523/JNEUROSCI.2586-03.2004
Abstract: In the present study, we examined the ability of estrogen to enhance cholinergic neurite arborization in vitro and identified the signal transduction cascade associated with this effect. Basal forebrain primordia collected from rat pups on postnatal day 1 were cultured for 2 weeks and then treated with 5 n m 17β-estradiol for 24 hr. Cholinergic neurons were identified immunocytochemically with an antibody against the vesicular acetylcholine transporter and digitally photographed. Morphological analysis indicated that female cultures respond to estrogen treatment with an increase in total neurite length per neuron (4.5-fold over untreated controls) and in total branch segment number per neuron (2.3-fold over controls). In contrast, there was no change in total neurite length per neuron in male cultures, and we also observed a decrease in total branch segment number per neuron (0.5-fold below controls). Detailed histograms indicated that estrogen increases primary and secondary branch length and number and also increases terminal neuritic branches to the seventh order in female cultures. In a second set of experiments, we investigated the signal transduction cascade involved in this response, and found that an upstream extracellular signal-regulated kinase (ERK) inhibitor blocked the ability of estrogen to enhance outgrowth in female cultures. Our study provides strong evidence in support of the fact that the ERK pathway is required for estrogen-induced structural plasticity in the cholinergic system of female rats. Understanding the intracellular processes that underlie the response of cholinergic neurons to estrogen provides a necessary step in elucidating how cholinergic neurons can be particularly susceptible to degeneration in postmenopausal women.
Publisher: Society for Neuroscience
Date: 04-2009
DOI: 10.1523/JNEUROSCI.0550-09.2009
Abstract: 17-β-Estradiol (E2) is a steroid hormone involved in numerous bodily functions, including several brain functions. In particular, E2 is neuroprotective against excitotoxicity and other forms of brain injuries, a property that requires the extracellular signal-regulated kinase (ERK) pathway and possibly that of other signaling molecules. The mechanism and identity of the receptor(s) involved remain unclear, although it has been suggested that E2 receptor α (ERα) and G proteins are involved. We, therefore, investigated whether E2-mediated neuroprotection and ERK activation were linked to pertussis toxin (PTX)-sensitive G-protein-coupled effector systems. Biochemical and image analysis of organotypic hippoc al slices and cortical neuronal cultures showed that E2-mediated neuroprotection as well as E2-induced ERK activation were sensitive to PTX. The sensitivity to PTX suggested a possible role of G-protein- and β-arrestin-mediated mechanisms. Western immunoblots from E2-treated cortical neuronal cultures revealed an increase in phosphorylation of both G-protein-coupled receptor-kinase 2 and β-arrestin-1, a G-protein-coupled receptor adaptor protein. Transfection of neurons with β-arrestin-1 small interfering RNA prevented E2-induced ERK activation. Coimmunoprecipitation experiments indicated that E2 increased the recruitment of β-arrestin-1 and c-Src to ERα. These findings suggested that ERα is regulated by a mechanism associated with receptor desensitization and downregulation. In support of this idea, we found that E2 treatment of cortical synaptoneurosomes resulted in internalization of ERα, whereas treatment of cortical neurons with the ER agonists E-6-BSA-FITC [β-estradiol-6-(O-carboxymethyl)oxime-bovine serum albumin conjugated with fluorescein isothiocyanate] and E-6-biotin [1,3,5(10)-estratrien-3,17β-diol-6-one-6-carboxymethloxime-NH-propyl-biotin] resulted in agonist internalization. These results demonstrate that E2-mediated neuroprotection and ERK activation involve ERα activation of G-protein- and β-arrestin-mediated mechanisms.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.JOCN.2019.11.039
Abstract: The authors perform a retrospective trauma registry study to compare clinical, surgical and radiographical variables between anterior and posterior approaches in the management of AO Type B1 and B2 traumatic thoracolumbar fractures. Consecutive patients with surgically-managed AO Type B1 and B2 thoracolumbar fractures were included. Baseline demographics, surgical outcomes (including duration of surgery, postoperative morbidity etc.), neurological outcomes and radiographical outcomes (Cobb angle, Gardner angle) were compared between the anterior and posterior approaches. A total of 108 patients (anterior: n = 25, posterior: n = 83) were included. There were no significant between-group differences in baseline demographics and co-morbidities. Duration of surgery was longer in the anterior compared to posterior group (251 ± 91 min vs. 175 ± 69 min respectively, p < 0.00003). At six-months post-surgery, there was a trend towards improvement of at least one AIS grade in the posterior compared to the anterior group (85.7% vs. 33.3% respectively, p = 0.08). Postoperative complication profile showed no difference between approaches. The posterior approach resulted in better sagittal correction (Cobb angle anterior: +1.05 ± 8.61 deg, posterior: -3.87 ± 9.88 deg, p = 0.03) and smaller loss of correction at 6-months post-surgery (Cobb angle anterior: 8.36 ± 9.47 deg, posterior: 4.88 ± 6.62 deg, p = 0.048). This is the first study investigating surgical approach in flexion-distraction thoracolumbar fractures. Besides a shorter operative duration, the posterior approach seems to portend more favourable radiological correction at 6 months when compared to the anterior approach. Given the inherent selection bias of this study, definitive recommendations regarding the anterior versus posterior approach cannot be made. Further well-defined, prospective studies are necessary.
Publisher: Elsevier BV
Date: 08-2009
Publisher: Elsevier BV
Date: 06-2013
Publisher: Cold Spring Harbor Laboratory
Date: 24-03-2016
DOI: 10.1101/045450
Abstract: Recently, measurement of RNA at single cell resolution has yielded surprising insights. Methods for single-cell RNA sequencing (scRNA-seq) have received considerable attention, but the broad reliability of single cell methods and the factors governing their performance are still poorly known. Here, we conducted a large-scale control experiment to assess the transfer function of three scRNA-seq methods and factors modulating the function. All three methods detected greater than 70% of the expected number of genes and had a 50% probability of detecting genes with abundance greater than 2 to 4 molecules. Despite the small number of molecules, sequencing depth significantly affected gene detection. While biases in detection and quantification were qualitatively similar across methods, the degree of bias differed, consistent with differences in molecular protocol. Measurement reliability increased with expression level for all methods and we conservatively estimate the measurement transfer functions to be linear above ~5-10 molecules. Based on these extensive control studies, we propose that RNA-seq of single cells has come of age, yielding quantitative biological information.
Publisher: AME Publishing Company
Date: 12-2019
Publisher: Wiley
Date: 13-08-2007
Publisher: Elsevier BV
Date: 02-2016
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.SPINEE.2019.09.013
Abstract: There are three phases in prophylaxis of surgical site infections (SSI): preoperative, intraoperative and postoperative. There is lack of consensus and paucity of evidence with SSI prophylaxis in the postoperative period. To systematically evaluate the literature, and provide evidence-based summaries on postoperative measures for SSI prophylaxis in spine surgery. Systematic review, meta-analysis, evidence synthesis. A systematic review conforming to PRIMSA guidelines was performed utilizing PubMed (MEDLINE), EMBASE, and the Cochrane Database from inception to January 2019. The GRADE approach was used for quality appraisal and synthesis of evidence. Six postoperative care domains with associated key questions were identified. Included studies were extracted into evidence tables, data synthesized quantitatively and qualitatively, and evidence appraised per GRADE approach. Forty-one studies (nine RCT, 32 cohort studies) were included. In the setting of preincisional antimicrobial prophylaxis (AMP) administration, use of postoperative AMP for SSI reduction has not been found to reduce rate of SSI in lumbosacral spine surgery. Prolonged administration of AMP for more than 48 hours postoperatively does not seem to reduce the rate of SSI in decompression-only or lumbar spine fusion surgery. Utilization of wound drainage systems in lumbosacral spine and adolescent idiopathic scoliosis corrective surgery does not seem to alter the overall rate of SSI in spine surgery. Concomitant administration of AMP in the presence of a wound drain does not seem to reduce the overall rate of SSI, deep SSI, or superficial SSI in thoracolumbar fusion performed for degenerative and deformity spine pathologies, and in adolescent idiopathic scoliosis corrective surgery. Enhanced-recovery after surgery clinical pathways and infection-specific protocols do not seem to reduce rate of SSI in spine surgery. Insufficient evidence exists for other types of spine surgery not mentioned above, and also for non-AMP pharmacological measures, dressing type and duration, suture and staple management, and postoperative nutrition for SSI prophylaxis in spine surgery. Despite the postoperative period being key in SSI prophylaxis, the literature is sparse and without consensus on optimum postoperative care for SSI prevention in spine surgery. The current best evidence is presented with its limitations. High quality studies addressing high risk cohorts such as the elderly, obese, and diabetic populations, and for traumatic and oncological indications are urgently required.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2016
Publisher: Wiley
Date: 04-01-2007
Publisher: Elsevier BV
Date: 2006
Publisher: Society for Neuroscience
Date: 22-09-2010
DOI: 10.1523/JNEUROSCI.1038-10.2010
Abstract: Estrogen receptors (ERs) and estrogen-binding proteins have been localized intracellularly and on the cell surface. The membrane-associated proteins initiate signaling that activates a myriad of cellular responses including the modulation of ion channels and ultimately transcription. Although many of the downstream actions of membrane ERs, including ERα and ERβ, have been characterized, the mechanisms regulating membrane ER levels have remained elusive in the nervous system. In the present study, we used surface biotinylation to identify and study the estradiol regulation of membrane ERα in mixed-sex, cultured hypothalamic neurons from rat. Following surface biotinylation, Western blot analysis revealed full-length 66 kDa ERα and several ERα splice variants, most notably a biotinylated 52 kDa ERα-immunoreactive protein. Treatment of the neurons with estradiol caused a rapid and transient increase of the biotinylated 52 kDa and 66 kDa ERα proteins in the plasma membrane. Exposure of the neurons to estradiol also significantly increased internalization of 52 kDa and 66 kDa ERα membrane proteins, a measure of receptor activation. In the hypothalamus, membrane ERα signaling depends on transactivation of metabotropic glutamate receptor-1a (mGluR1a). Estradiol treatment increased the internalization of mGluR1a in parallel with ERα, a finding consistent with the hypothesis of an ERα-mGluR1a signaling unit. These results demonstrate that estradiol regulates the amount of ERα in the membrane, suggesting estradiol can regulate its own membrane signaling.
Publisher: Springer New York
Date: 2016
DOI: 10.1007/978-1-4939-3127-9_14
Abstract: Trafficking studies of plasma membrane-localized intracellular estrogen receptors have mainly relied on biochemical and histological techniques to locate the receptor before and after estradiol stimulation. More often than not these experiments were performed using postmortem, lysed, or fixed tissue s les, whose tissue or cellular structure is typically severely altered or at times completely lost, making the definitive localization of estrogen receptors difficult to ascertain. To overcome this limitation we began using total internal reflection fluorescence microscopy (TIRFM) to study the trafficking of plasma membrane estrogen receptors. This real-time imaging approach, described in this chapter, permits observation of live, intact cells while allowing visualization of the steps (in time and spatial distribution) involved in receptor activation by estradiol and movements on and near the membrane. TIRFM yields high-contrast real-time images of fluorescently labeled E6BSA molecules on and just below the cell surface and is ideal for studying estrogen receptor trafficking in living cells.
Publisher: Elsevier BV
Date: 07-2018
Location: United States of America
Location: United States of America
Location: United States of America
Start Date: 2012
End Date: 2013
Funder: National Institutes of Health
View Funded ActivityStart Date: 2010
End Date: 2012
Funder: National Institutes of Health
View Funded ActivityStart Date: 2008
End Date: 2010
Funder: National Institutes of Health
View Funded ActivityStart Date: 2008
End Date: 2010
Funder: National Institutes of Health
View Funded ActivityStart Date: 2006
End Date: 2008
Funder: National Institutes of Health
View Funded ActivityStart Date: 2000
End Date: 2003
Funder: National Institutes of Health
View Funded ActivityStart Date: 2000
End Date: 2003
Funder: National Institutes of Health
View Funded Activity