Florey Department of Neuroscience and Mental Health - Research Publications
Now showing items 1-12 of 587
Biodiesel synthesis assisted by ultrasonication using engineered thermo-stable Proteus vulgaris lipase
(ELSEVIER SCI LTD, 2017-11-15)
Nature has evolved and designed enzymes to perform an exquisite array of tasks, but in the pursuit of biotechnological interests, these enzymes must often be improved, altered, or even completely redesigned. In the present work, production of biodiesel was carried out using Neem oil and methanol catalysed by “engineered” Proteus vulgaris lipase (PVL). Two major issues have been addressed in this study in order to improve the efficiency of biodiesel synthesis by enzyme catalysis. The thermal stability of PVL was increased by introduction of a disulfide bond in G181 and T238 by mutation to cysteines. The transesterification reaction was carried out using sonication under different ultrasonic experimental conditions using a 20 kHz horn. The results showed that the application of ultrasound, using 20 kHz horn with 1 cm tip diameter, decreased the reaction time from 22–24 h to 30 min at an applied power of 40 W and methanol to oil molar ratio of 5:1. Temperature raised due to sonication had no effect on engineered PVL (PVLC181-238) activity. A comparative study of wild type (WT-PVL) and engineered PVLC181-238 for different temperature has been performed and results showed that introduction of a single disulfide in PVL significantly stabilized it, increasing the half-inactivation temperature (IT1/2) from 37 °C for the WT-PVL to 50 °C for the PVLC181-238 engineered one. In biodiesel synthesis also after immobilization on (Polysulfone) PS beads, PVLC181-238 showed better performance compared to WT-PVL.
Cerebrospinal fluid neurofilament light concentration predicts brain atrophy and cognition in Alzheimer's disease.
Introduction: This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation. Methods: CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). Results: CSF NfL levels as well as NfL/amyloid β (Aβ42) were significantly elevated in AD compared to healthy controls (HC; P < .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P < .001 NfL/Aβ42). CSF NfL and NfL/Aβ42 differentiated AD from HC with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 and 0.90, respectively. CSF NfL and NfL/Aβ42 predicted cortical amyloid load, brain atrophy, and cognition. Discussion: CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology.
Higher levels of α7 nicotinic receptors, but not choline acetyltransferase, in the dorsolateral prefrontal cortex from a sub-group of patients with schizophrenia.
(Elsevier BV, 2020-06-02)
It has been suggested the study of sub-groups within the syndrome of schizophrenia will assist in elucidating the complex pathophysiology of the syndrome. Hence, we have studied a number of cholinergic markers in the cortex from a sub-group of subjects with schizophrenia that have a marked decrease in levels of muscarinic M1 receptors (MRDS). The displacement of [3H]NMS by cortical extracts was used to measure tissue anticholinergic load, [125I]α bungarotoxin binding was used to measure levels of the α7 nicotinic receptor (CHRNA7) and western blotting was used to measure levels of choline acetyltransferase (ChAT) 68 and 82 as well as synaptosome nerve-associated protein 25 (SNAP25). In comparing schizophrenia, MRDS and non-MRDS to controls, there were no differences in levels of ChAT 68 or 82, SNAP 25 or cholinergic load in BA 9. However, levels of CHRNA7 were higher in BA 9, but not BA 6 or 44, from subjects with MRDS. These data argue that there is no change in cholinergic innovation (measured using ChAT), presynaptic neurons (measured using SNAP25) or cholinergic load in schizophrenia, MRDS or non-MRDS. However, increased levels of CHRNA7 may be contributing to a breakdown in cholinergic homeostasis in BA 9, but not BA 6 or 44, in subjects with MRDS.
Muscarinic M1 and M4 receptors: Hypothesis driven drug development for schizophrenia
(ELSEVIER IRELAND LTD, 2020-06-01)
The finding that the drug KarXT, a formulation of xanomeline and tropsium which targets muscarinic receptors, has given a positive result in reducing the positive and negative symptoms of schizophrenia in a phase II trial suggests targeting muscarinic receptors is a new approach to treating the disorder. This review will detail the synergistic interplay between studies to understand the role of muscarinic receptors in the aetiology of schizophrenia and drug development and how this has supported the hypothesis that activating the muscarinic M1 and M4 receptors is critical to the efficacy of KarXT, in schizophrenia. The discovery of an intermediate phenotype within schizophrenia which is characterised by the presence of a marked loss of cortical muscarinic M1 receptors will be reviewed. Highlighted will be progress in understanding the biochemistry of that intermediate phenotype and evidence to suggest that those with the intermediate phenotype may resist treatment with agonist to the orthosteric site on the muscarinic M1 and M4 receptor. Finally, the possibility of using drugs targeting the allosteric binding sites on muscarinic receptors to treat schizophrenia will be discussed. This timely review will therefore highlight how research can influence hypothesis driven drug discovery that should produce new treatments for schizophrenia.
Immunoselected STRO-3(+) mesenchymal precursor cells reduce inflammation and improve clinical outcomes in a large animal model of monoarthritis
BACKGROUND: The purpose of this study was to investigate the therapeutic efficacy of intravenously administered immunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine production in an ovine model of monoarthritis. METHODS: Monoarthritis was established in 16 adult merino sheep by administration of bovine type II collagen into the left hock joint following initial sensitization to this antigen. After 24 h, sheep were administered either 150 million allogeneic ovine MPCs (n = 8) or saline (n = 8) intravenously (IV). Lameness, joint swelling and pain were monitored and blood samples for leukocytes and cytokine levels were collected at intervals following arthritis induction. Animals were necropsied 14 days after arthritis induction and gross and histopathological evaluations were undertaken on tissues from the arthritic (left) and contralateral (right) joints. RESULTS: MPC-treated sheep demonstrated significantly reduced clinical signs of lameness, joint pain and swelling compared with saline controls. They also showed decreased cartilage erosions, synovial stromal cell activation and angiogenesis. This was accompanied by decreased infiltration of the synovial tissues by CD4+ lymphocytes and CD14+ monocytes/macrophages. Over the 3 days following joint arthropathy induction, the numbers of neutrophils circulating in the blood and plasma concentrations of activin A were significantly reduced in animals administered MPCs. CONCLUSIONS: The results of this study have demonstrated the capacity of IV-administered MPCs to mitigate the clinical signs and some of the inflammatory mediators responsible for joint tissue destruction in a large animal model of monoarthritis.
Spinal cord thermosensitivity: An afferent phenomenon?
(Informa UK Limited, 2016-04)
We review the evidence for thermoregulatory temperature sensors in the mammalian spinal cord and reach the following conclusions. 1) Spinal cord temperature contributes physiologically to temperature regulation. 2) Parallel anterolateral ascending pathways transmit signals from spinal cooling and spinal warming: they overlap with the respective axon pathways of the dorsal horn neurons that are driven by peripheral cold- and warm-sensitive afferents. 3) We hypothesize that these 'cold' and 'warm' ascending pathways transmit all extracranial thermosensory information to the brain. 4) Cutaneous cold afferents can be activated not only by cooling the skin but also by cooling sites along their axons: we consider that this is functionally insignificant in vivo. 5) By a presynaptic action on their central terminals, local spinal cooling enhances neurotransmission from incoming 'cold' afferent action potentials to second order neurons in the dorsal horn; this effect disappears when the spinal cord is warm. 6) Spinal warm sensitivity is due to warm-sensitive miniature vesicular transmitter release from afferent terminals in the dorsal horn: this effect is powerful enough to excite second order neurons in the 'warm' pathway independently of any incoming sensory traffic. 7) Distinct but related presynaptic mechanisms at cold- and warm-sensitive afferent terminals can thus account for the thermoregulatory actions of spinal cord temperature.
Supervised exercise delivered via telehealth in real time to manage chronic conditions in adults: a protocol for a scoping review to inform future research in stroke survivors
(BMJ PUBLISHING GROUP, 2019-06-01)
INTRODUCTION: Increasing physical activity reduces secondary stroke risk factors, but many stroke survivors have low levels of physical activity. Supervised exercise delivered via telehealth has the potential to overcome barriers to increased physical activity in stroke survivors. Our scoping review will examine the emerging field of supervised exercise delivered via telehealth to map the available evidence in relation to its efficacy, acceptability, safety and feasibility in chronic conditions to inform future research into its ability to increase physical activity. METHODS AND ANALYSIS: The methodological framework of Arksey and O'Malley will be applied to our scoping review. A systematic search of Medline, CINAHL, Scopus, Cochrane, Pedro and Embase; hand searching of pertinent studies' reference lists; and consultation with experts in the field will identify relevant papers. Studies involving participants with a chronic condition who undertake supervised exercise delivered by a health professional via telehealth targeted at improving secondary stroke risk factors or involving lower limb weight-bearing exercise will be included. Study selection and critical appraisal of individual studies will be carried out independently by two authors with discrepancies resolved by a third author. Quantitative and qualitative data will be charted using a standardised form. Results will be tabulated and narratively summarised to highlight findings relevant to the review's research questions and to inform recommendations for future research. ETHICS AND DISSEMINATION: Our review will significantly contribute to the knowledge base of exercise and rehabilitation delivered via telehealth and its application in chronic conditions, including stroke. Findings will be relevant to researchers, healthcare workers and policy-makers and will be disseminated through publication and presentations. Only secondary deidentified data will be included, therefore ethics approval will not be sought. This protocol is not registered as PROSPERO currently excludes scoping reviews.
Changes in BQCA Allosteric Modulation of [H-3]NMS Binding to Human Cortex within Schizophrenia and by Divalent Cations
(NATURE PUBLISHING GROUP, 2016-05-01)
Stimulation of the cortical muscarinic M1 receptor (CHRM1) is proposed as a treatment for schizophrenia, a hypothesis testable using CHRM1 allosteric modulators. Allosteric modulators have been shown to change the activity of CHRMs using cloned human CHRMs and CHRM knockout mice but not human CNS, a prerequisite for them working in humans. Here we show in vitro that BQCA, a positive allosteric CHRM1 modulator, brings about the expected change in affinity of the CHRM1 orthosteric site for acetylcholine in human cortex. Moreover, this effect of BQCA is reduced in the cortex of a subset of subjects with schizophrenia, separated into a discrete population because of a profound loss of cortical [(3)H]pirenzepine binding. Surprisingly, there was no change in [(3)H]NMS binding to the cortex from this subset or those with schizophrenia but without a marked loss of cortical CHRM1. Hence, we explored the nature of [(3)H]pirenzepine and [(3)H]NMS binding to human cortex and showed total [(3)H]pirenzepine and [(3)H]NMS binding was reduced by Zn(2+), acetylcholine displacement of [(3)H]NMS binding was enhanced by Mg(2+) and Zn(2+), acetylcholine displacement of [(3)H]pirenzepine was reduced by Mg(2+) and enhanced by Zn(2+), whereas BQCA effects on [(3)H]NMS, but not [(3)H]pirenzepine, binding was enhanced by Mg(2+) and Zn(2+). These data suggest the orthosteric and allosteric sites on CHRMs respond differently to divalent cations and the effects of allosteric modulation of the cortical CHRM1 is reduced in a subset of people with schizophrenia, a finding that may have ramifications for the use of CHRM1 allosteric modulators in the treatment of schizophrenia.
Changed cortical risk gene expression in major depression and shared changes in cortical gene expression between major depression and bipolar disorders
(SAGE PUBLICATIONS LTD, 2019-12-01)
BACKGROUND: Mood disorders likely occur in someone with a genetic predisposition who encounters a deleterious environmental factor leading to dysregulated physiological processes due to genetic mutations and epigenetic mechanisms altering gene expression. To gain data to support this hypothesis, we measured levels of gene expression in three cortical regions known to be affected by the pathophysiologies of major depression and bipolar disorders. METHODS: Levels of RNA were measured using the Affymetrix™ Human Exon 1.0 ST Array in Brodmann's areas 9, 10 and 33 (left hemisphere) from individuals with major depression, bipolar disorder and age- and sex-matched controls with changed expression taken as a fold change in RNA ⩾1.2 at p < 0.01. Data were analysed using JMP® genomics 6.0 and the probable biological consequences of changes in gene expression determined using Core and Pathway Designer Analyses in Ingenuity Pathway Analysis. RESULTS: There were altered levels of RNA in Brodmann's area 9 (major depression = 424; bipolar disorder = 331), Brodmann's area 10 (major depression = 52; bipolar disorder = 24) and Brodmann's area 33 (major depression = 59 genes; bipolar disorder = 38 genes) in mood disorders. No gene was differentially expressed in all three regions in either disorder. There was a high correlation between fold changes in levels of RNA from 112 genes in Brodmann's area 9 from major depression and bipolar disorder (r2 = 0.91, p < 0.001). Levels of RNA for four risk genes for major depression were lower in Brodmann's area 9 in that disorder. CONCLUSION: Our data argue that there are complex regional-specific changes in cortical gene expression in major depression and bipolar disorder that includes the expression of some risk genes for major depression in those with that disorder. It could be hypothesised that the common changes in gene expression in major depression and bipolar disorder are involved in the genesis of symptoms common to both disorders.
Development and validation of a mental health screening tool for asylum-seekers and refugees: the STAR-MH
(BIOMED CENTRAL LTD, 2018-03-16)
BACKGROUND: There is no screening tool for major depressive disorder (MDD) or post-traumatic stress disorder (PTSD) in asylum-seekers or refugees (ASR) that can be readily administered by non-mental health workers. Hence, we aimed to develop a brief, sensitive and rapidly administrable tool for non-mental health workers to screen for MDD and PTSD in ASR. METHODS: The screening tool was developed from an extant dataset (n = 121) of multiply screened ASR and tested prospectively (N = 192) against the M.I.N.I. (Mini International Neuropsychiatric Interview) structured psychiatric interview. Rasch, Differential Item Functioning and ROC analyses evaluated the psychometric properties and tool utility. RESULTS: A 9-item tool with a median administration time of six minutes was generated, comprising two 'immediate screen-in' items, and a 7-item scale. The prevalence of PTSD &/or MDD using the M.I.N.I. was 32%, whilst 99% of other diagnosed mental disorders were comorbid with one or both of these. Using a cut-score of ≥2, the tool provided a sensitivity of 0.93, specificity of 0.75 and predictive accuracy of 80.7%. CONCLUSIONS: A brief sensitive screening tool with robust psychometric properties that was easy to administer at the agency of first presentation was developed to facilitate mental health referrals for asylum-seekers and new refugees.
Assessment of longitudinal hippocampal atrophy in the first year after ischemic stroke using automatic segmentation techniques
(ELSEVIER SCI LTD, 2019-01-01)
We assessed first-year hippocampal atrophy in stroke patients and healthy controls using manual and automated segmentations: AdaBoost, FIRST (fsl/v5.0.8), FreeSurfer/v5.3 and v6.0, and Subfields (in FreeSurfer/v6.0). We estimated hippocampal volumes in 39 healthy controls and 124 stroke participants at three months, and 38 controls and 113 stroke participants at one year. We used intra-class correlation, concordance, and reduced major axis regression to assess agreement between automated and 'Manual' estimations. A linear mixed-effect model was used to characterize hippocampal atrophy. Overall, hippocampal volumes were reduced by 3.9% in first-ever stroke and 9.2% in recurrent stroke at three months post-stroke, with comparable ipsi-and contra-lesional reductions in first-ever stroke. Mean atrophy rates between time points were 0.5% for controls and 1.0% for stroke patients (0.6% contra-lesionally, 1.4% ipsi-lesionally). Atrophy rates in left and right-hemisphere strokes were comparable. All methods revealed significant volume change in first-ever and ipsi-lesional stroke (p < 0.001). Hippocampal volume estimation was not impacted by hemisphere, study group, or scan time point, but rather, by the interaction between the automated segmentation method and hippocampal size. Compared to Manual, Subfields and FIRST recorded the lowest bias. FreeSurfer/v5.3 overestimated volumes the most for large hippocampi, while FIRST was the most accurate in estimating small volumes. AdaBoost performance was average. Our findings suggest that first-year ipsi-lesional hippocampal atrophy rate especially in first-ever stroke, is greater than atrophy rates in healthy controls and contra-lesional stroke. Subfields and FIRST can complementarily be effective in characterizing the hippocampal atrophy in healthy and stroke cohorts.
Sensorimotor circuitry involved in the higher brain control of coughing
(BioMed Central, 2013-03-06)
There is an overwhelming body of evidence to support the existence of higher brain circuitries involved in the sensory detection of airways irritation and the motor control of coughing. The concept that cough is purely a reflex response to airways irritation is now superseded by the recognition that perception of an urge-to-cough and altered behavioral modification of coughing are key elements of cough disorders associated with airways disease. Understanding the pathways by which airway sensory nerves ascend into the brain and the patterns of neural activation associated with airways irritation will undoubtedly provide new insights into disordered coughing. This brief review aims to explore our current understanding of higher order cough networks by summarizing data from recent neuroanatomical and functional studies in animals and humans. We provide evidence for the existence of distinct higher order network components involved in the discrimination of signals arising from the airways and the motor control of coughing. The identification of these network components provides a blueprint for future research and the development of targeted managements for cough and the urge-to-cough.