David Brown - Academia.edu (original) (raw)

Papers by David Brown

The Journal of Neuroscience, 2003

KCNQ2 and KCNQ3 potassium-channel subunits can form both homomeric and heteromeric channels; the ... more KCNQ2 and KCNQ3 potassium-channel subunits can form both homomeric and heteromeric channels; the latter are thought to constitute native ganglionic M channels. We have tried to deduce the stoichiometric contributions of KCNQ2 and KCNQ3 subunits to currents generated by the coexpression of KCNQ2 and KCNQ3 cDNA plasmids in Chinese hamster ovary (CHO) cells, and to native M currents in dissociated rat superior cervical ganglion (SCG) neurons, by comparing the block of these currents produced by tetraethylammonium (TEA) with the block of currents generated by a tandem KCNQ3/2 construct. TEA concentration-inhibition curves against coexpressed KCNQ2 plus KCNQ3 currents, and against native M currents in SCG neurons from 6-week-old [postnatal day 45 (P45)] rats, were indistinguishable from those for the expressed tandem construct, and fully accorded with a 1:1 stoichiometry. Inhibition curves in neurons from younger (P17) rats could be better fitted assuming an additional small proportion of current carried by KCNQ2 homomultimers. Single-cell PCR yielded signals for KCNQ2, KCNQ3, and KCNQ5 mRNAs in all SCG neurons tested from both P17 and P45 rats. Quantitative PCR of whole-ganglion mRNA revealed stable levels of KCNQ2 and KCNQ5 mRNA between P7 and P45, but excess and incrementing levels of KCNQ3 mRNA. Increasing levels of KCNQ3 protein between P17 and P45 were confirmed by immunocytochemistry. We conclude that coexpressed KCNQ2 plus KCNQ3 cDNAs generate channels with 1:1 (KCNQ2:KCNQ3) stoichiometry in CHO cells and that native M channels in SCG neurons adopt the same conformation during development, assisted by the increased expression of KCNQ3 mRNA and protein.

The Journal of Neuroscience, 2003

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M... more Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [I K(M) ] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of I K(M) , have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. I K(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC 50 , 2.1 M) and XE991 (IC 50 , 0.26 M) and enhanced by retigabine (10 M). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and A␦ fibermediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that I K(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target.

The Journal of Physiology, 2001

1. The region of alternative splicing in the KCNQ2 potassium channel gene was determined by RNase... more 1. The region of alternative splicing in the KCNQ2 potassium channel gene was determined by RNase protection analysis of KCNQ2 mRNA transcripts. 2. Systematic analysis of KCNQ2 alternative splice variant expression in rat superior cervical ganglia revealed multiple variant isoforms. 3. One class of KCNQ2 splice variants, those that contained exon 15a, was found to have significantly different kinetics to those of the other isoforms. These transcripts encoded channel subunits that, when co-expressed with the KCNQ3 subunit, activated and deactivated approximately 2•5 times more slowly than other isoforms. Deletion of exon 15a in these isoforms produced a reversion to the faster kinetics. 4. Comparison of the kinetic properties of the cloned channel splice variants with those of the native M-current suggests that alternative splicing of the KCNQ2 gene may contribute to the variation in M-current kinetics seen in vivo.

Journal of cardiovascular pharmacology and therapeutics, 2014

We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and ... more We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia's cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 minutes prior to reperfusion (0.05 mg/kg/h, intravenously) reduced myocardial infarct size by ∼50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 minutes after the onset of reperfusion, the protection against infarction and no-reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates....

The Journal of Physiology, 2003

In mammalian sympathetic neurones several membrane ion channels are regulated by intracellular ca... more In mammalian sympathetic neurones several membrane ion channels are regulated by intracellular calcium (Ca 2+). Thus, the influx of Ca 2+ during action potentials activates two types of Ca 2+-dependent K + channel: one (the 'BK' channel) accelerates spike repolarisation and induces a fast after-hyperpolarisation (Belluzzi & Sacchi, 1990; Marsh & Brown, 1991; Davies et al. 1996), while the other (the 'SK' channel) induces a slow after-hyperpolarisation and spike train accommodation (Kawai & Watanabe, 1986; Sacchi et al. 1995; Davies et al. 1996). Elevation of intracellular Ca 2+ can also activate two species of chloride current, a fast current gated directly by Ca 2+ (Sanchez-Vivas et al. 1994a) and a delayed current triggered by activation of protein kinase C (Marsh et al. 1995). Finally, M-type K + channels are inhibited by intracellular Ca 2+ with an IC 50 around 100 nM (Selyanko & Brown, 1996), and there is evidence to suggest that the release of Ca 2+ from internal stores following activation of certain G-protein-coupled receptors may contribute to M channel inhibition in these cells (Cruzblanca et al. 1998; Bofill-Cardona et al. 2000). For these reasons, it seems essential to understand what processes regulate intracellular Ca 2+ levels in mammalian sympathetic neurones. To date, the only information available derives from experiments on caffeine-induced Ca 2+ release (Thayer et al. 1988; Hernandez-Cruz et al. 1995, 1997). In contrast, very little is known regarding the magnitude or duration of the Ca 2+ transients, or the factors that affect these transients, following the entry of Ca 2+ through voltage-gated Ca 2+ channels, which are most pertinent to the physiological effects referred to above. In the present experiments, therefore, we have measured the Ca 2+ transients in dissociated rat sympathetic neurones following activation of voltage-gated Ca 2+ channels, and have investigated some of the processes that determine the duration of, and recovery from, these transients. We provide evidence that the plasma membrane Ca 2+-ATPase (PMCA; Carafoli, 1994) is primarily responsible for recovery following modest elevations of [Ca 2+ ] i but that it is supplemented by other mechanisms (principally a Na +-Ca 2+ exchanger (NCX) and mitochondrial uptake) following larger elevations. We also show that PMCA is active at rest, extruding Ca 2+ that enters through a lanthanum (La 3+)sensitive 'leak' channel, and that these neurones have a high Ca 2+-binding capacity. Parts of this work have been published in abstract form (Wanaverbecq et al. 2000, 2001).

IEEE Aerospace and Electronic Systems Magazine, 2020

While large-scale research and development initiatives are reshaping the future of aviation and s... more While large-scale research and development initiatives are reshaping the future of aviation and space operations, avionics systems are becoming cyber-physical and progressively evolving into a variety of autonomous, intelligent and closed-loop human-machine systems. This article provides the IEEE Aerospace & Electronic Systems Society (AESS) Avionics Systems Panel (ASP) views on avionics systems evolutionary pathways, with an identification of key research challenges and industry-focused innovation opportunities. The ever-increasing density of air traffic and the rise of Unmanned Aircraft Systems (UAS) are prompting a rapid evolution of Communication, Navigation, Surveillance/Air Traffic Management (CNS/ATM) and Avionics (CNS+A) technologies that will provide unprecedented enhancements in terms of safety and efficiency, thus unleashing additional airspace and airport capacity. Several of the underlying CNS technologies have already hit the market, while other more advanced capabilit...

Biophysical journal, Jan 19, 2018

Pulsed electric fields with microsecond pulse width (μsPEFs) are used clinically; namely, irrever... more Pulsed electric fields with microsecond pulse width (μsPEFs) are used clinically; namely, irreversible electroporation/Nanoknife is used for soft tissue tumor ablation. The μsPEF pulse parameters used in irreversible electroporation (0.5-1 kV/cm, 80-100 pulses, ∼100 μs each, 1 Hz frequency) may cause an internal field to develop within the cell because of the disruption of the outer cell membrane and subsequent penetration of the electric field. An internal field may disrupt voltage-sensitive mitochondria, although the research literature has been relatively unclear regarding whether such disruptions occur with μsPEFs. This investigation reports the influence of clinically used μsPEF parameters on mitochondrial respiration in live cells. Using a high-throughput Agilent Seahorse machine, it was observed that μsPEF exposure comprising 80 pulses with amplitudes of 600 or 700 V/cm did not alter mitochondrial respiration in 4T1 cells measured after overnight postexposure recovery. To rec...

Pflugers Archiv : European journal of physiology, Jan 24, 2018

Kv7 channels determine the resting membrane potential of neurons and regulate their excitability.... more Kv7 channels determine the resting membrane potential of neurons and regulate their excitability. Even though dysfunction of Kv7 channels has been linked to several debilitating childhood neuronal disorders, the ontogeny of the constituent genes, which encode Kv7 channels (KNCQ), and expression of their subunits have been largely unexplored. Here, we show that developmentally regulated expression of specific KCNQ mRNA and Kv7 channel subunits in mouse and human striatum is crucial to the functional maturation of mouse striatal neurons and human-induced pluripotent stem cell-derived neurons. This demonstrates their pivotal role in normal development and maturation, the knowledge of which can now be harnessed to synchronise and accelerate neuronal differentiation of stem cell-derived neurons, enhancing their utility for disease modelling and drug discovery.

Advances in nutrition (Bethesda, Md.), 2018

Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a ... more Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization. The composition and molecular organization of these membranes are crucial to the maintenance and function of mitochondria. In this review, we first present a general overview of mitochondrial membrane biochemistry and biophysics followed by the role of different dietary saturated and unsaturated fatty acids in modulating mitochondrial membrane structure-function. We focus extensively on long-chain n-3 (ω-3) polyunsaturated fatty acids and their underlying mechanisms of action. Finally, we discuss implications of understanding molecular mechanisms by which dietary n-3 fatty acids target mitochondrial structure-fun...

Nature reviews. Cardiology, Apr 22, 2016

Heart failure is a pressing worldwide public-health problem with millions of patients having wors... more Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the me...

Frontiers in Physiology, 2015

Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial dise... more Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial disease and manifests as chronic limb pain at rest and/or tissue necrosis. Current clinical interventions are largely ineffective and therapeutic angiogenesis based trials have shown little efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. Despite a decade of research related to skeletal muscle as a determinant of morbidity and mortality outcomes in CLI, very little progress has been made toward an effective therapy aimed directly at the muscle myopathies of this disease. Within the muscle cell, mitochondria are well positioned to modulate the ischemic cellular response, as they are the principal sites of cellular energy production and the major regulators of cellular redox charge and cell death. In this mini review, we update the crucial importance of skeletal muscle to CLI pathology and examine the evolving influence of muscle and endothelial cell mitochondria in the complex ischemic microenvironment. Finally, we discuss the novelty of muscle mitochondria as a therapeutic target for ischemic pathology in the context of the complex co-morbidities often associated with CLI.

PloS one, 2015

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels ... more The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC-1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels alt...

Robotics and Autonomous Systems, 2015

Audio event detection (AED) and recognition is a signal processing and analysis domain used in a ... more Audio event detection (AED) and recognition is a signal processing and analysis domain used in a wide range of applications including surveillance, home automation and behavioral assessment. The field presents numerous challenges to the current state-of-the-art due to its highly nonlinear nature. High false alarm rates (FARs) in such applications particularly limit the capabilities of vision-based perimeter monitoring systems by inducing high operator dependence. On the other hand, conventional fence-based vibration detectors and pressure-driven "taut wires" offer high sensitivity at the cost of a high FAR due to debris, animals and weather. This work reports an audio event identification methodology implemented as a test-bed system for a surveillance application to reduce FAR, maximize blind-spot coverage and improve audio event classification accuracy. The first phase utilizes a nonlinear autoregressive classifier to locate and classify discrete audio events via an exogenous sound direction variable to improve classifier confidence. The second phase implements a time-series-based system to recognize various audio activity groups from nominal everyday sound events such as traffic and muffled speech. The discretely labeled data is thus trained with HMM and Conditional Random Field classifiers and reports a substantial improvement in classification accuracies of indoor human activities.

RSC Adv., 2015

We present an alternative synthetic route to acrylic acid, starting from the platform chemical la... more We present an alternative synthetic route to acrylic acid, starting from the platform chemical lactic acid and using heterogeneous catalysis.

Journal of NeuroEngineering and Rehabilitation, 2015

Background: Individuals post-stroke select slow comfortable walking speeds (CWS) and the major fa... more Background: Individuals post-stroke select slow comfortable walking speeds (CWS) and the major factors used to select their CWS is unknown. Objective: To determine the extent to which slow CWS post-stroke is achieved through matching a relative force output or targeting a particular walking speed. Methods: Ten neurologically nonimpaired individuals and fourteen chronic stroke survivors with hemiplegia were recruited. Participants were instructed to "walk at the speed that feels most comfortable" on a treadmill against 12 progressively increasing horizontal resistive force levels applied at the pelvis using a robotic system that allowed participant to self-select their walking speed. We compared slope coefficients of the simple linear regressions between the observed normalized force vs. normalized speed relationship in each group to a slope of-1.0 (i.e. ideal slope for a constant relative force output) and 0.0 (i.e. ideal slope for a constant relative speed). We also compared slope coefficients between groups. Results: The slope coefficients were significantly greater than-1.0 (p < 0.001 for both) and significantly less than 0 (p < 0.001 for both). However, compared with nonimpaired individuals, people post-stroke were less able to maintain their walking speed (p = 0.003). Conclusions: The results of this study provide evidence for a complex interaction between the regulation of relative force output and intention to move at a particular speed in the selection of the CWS for individuals post-stroke. This would suggest that therapeutic interventions should not only focus on task specific lower-limb strengthening exercises (e.g. walking against resistance), but should also focus on increasing the range of speeds at which people can safely walk.

PloS one, 2014

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physio... more Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as be...

Chem. Commun., 2014

Here we describe a simple route to creating conformal sulphated zirconia monolayers throughout an... more Here we describe a simple route to creating conformal sulphated zirconia monolayers throughout an SBA-15 architecture that confers efficient acid-catalysed one-pot conversion of glucose to ethyl levulinate.

MNRAS, Aug 1, 2014

Using a sample of 68 planet-hosting stars, I carry out a comparison of isochrone fitting and gyro... more Using a sample of 68 planet-hosting stars, I carry out a comparison of isochrone fitting and gyrochronology to investigate whether tidal interactions between the stars and their planets are leading to underestimated ages using the latter method. I find a slight tendency for isochrones to produce older age estimates but find no correlation with tidal time-scale, although for some individual systems the effect of tides might be leading to more rapid rotation than expected from the stars' isochronal age, and therefore an underestimated gyrochronology age. By comparing to planetary systems in stellar clusters, I also find that in some cases isochrone fitting can overestimate the age of the star. The evidence for any bias on a sample-wide level is inconclusive. I also consider the subset of my sample for which the sky-projected alignment angle between the stellar rotation axis and the planet's orbital axis has been measured, finding similar patterns to those identified in the f...

The Journal of Physiology, 2001

KCNQ2 and KCNQ3 subunits form heteromeric potassium channels that underlie slow, subthreshold M-t... more KCNQ2 and KCNQ3 subunits form heteromeric potassium channels that underlie slow, subthreshold M-type potassium currents in autonomic (and possibly central) neurones (Wang et al. 1998). They are related to KCNQ1 (Yang et al. 1997) and KCNQ4 (Kubisch et al. 1999) subunits, mutations of which produce one form of the cardiac long QT syndrome and deafness, respectively. KCNQ2 and KCNQ3 subunits are expressed exclusively in the nervous system and their mutations produce a benign form of epilepsy in newborns (

Gold Bulletin, 1988

The aim of what we now call restorative dentistry is to replace teeth lost by either accidental o... more The aim of what we now call restorative dentistry is to replace teeth lost by either accidental or intentional extraction, or to replace parts of teeth lost due to decay or accident. In this short review, aimed at the general reader, the author describes gold's important role in dentistry. Fillings and Castings Modem techniques and materials enable the dental surgeon and dental technician to create a wide range of restorations. Some materials, such as dental amalgam, cements and composites, are manipulated as pastes directly in the mouth of the patient, and set to become strong and rigid parts of the tooth's anatomy. Modem dental alloys, however, many of which are based on gold, are cast in the laboratory and then cemented into place in the mouth.

The Journal of Neuroscience, 2003

KCNQ2 and KCNQ3 potassium-channel subunits can form both homomeric and heteromeric channels; the ... more KCNQ2 and KCNQ3 potassium-channel subunits can form both homomeric and heteromeric channels; the latter are thought to constitute native ganglionic M channels. We have tried to deduce the stoichiometric contributions of KCNQ2 and KCNQ3 subunits to currents generated by the coexpression of KCNQ2 and KCNQ3 cDNA plasmids in Chinese hamster ovary (CHO) cells, and to native M currents in dissociated rat superior cervical ganglion (SCG) neurons, by comparing the block of these currents produced by tetraethylammonium (TEA) with the block of currents generated by a tandem KCNQ3/2 construct. TEA concentration-inhibition curves against coexpressed KCNQ2 plus KCNQ3 currents, and against native M currents in SCG neurons from 6-week-old [postnatal day 45 (P45)] rats, were indistinguishable from those for the expressed tandem construct, and fully accorded with a 1:1 stoichiometry. Inhibition curves in neurons from younger (P17) rats could be better fitted assuming an additional small proportion of current carried by KCNQ2 homomultimers. Single-cell PCR yielded signals for KCNQ2, KCNQ3, and KCNQ5 mRNAs in all SCG neurons tested from both P17 and P45 rats. Quantitative PCR of whole-ganglion mRNA revealed stable levels of KCNQ2 and KCNQ5 mRNA between P7 and P45, but excess and incrementing levels of KCNQ3 mRNA. Increasing levels of KCNQ3 protein between P17 and P45 were confirmed by immunocytochemistry. We conclude that coexpressed KCNQ2 plus KCNQ3 cDNAs generate channels with 1:1 (KCNQ2:KCNQ3) stoichiometry in CHO cells and that native M channels in SCG neurons adopt the same conformation during development, assisted by the increased expression of KCNQ3 mRNA and protein.

The Journal of Neuroscience, 2003

Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M... more Neuronal hyperexcitability is a feature of epilepsy and both inflammatory and neuropathic pain. M currents [I K(M) ] play a key role in regulating neuronal excitability, and mutations in neuronal KCNQ2/3 subunits, the molecular correlates of I K(M) , have previously been linked to benign familial neonatal epilepsy. Here, we demonstrate that KCNQ/M channels are also present in nociceptive sensory systems. I K(M) was identified, on the basis of biophysical and pharmacological properties, in cultured neurons isolated from dorsal root ganglia (DRGs) from 17-d-old rats. Currents were inhibited by the M-channel blockers linopirdine (IC 50 , 2.1 M) and XE991 (IC 50 , 0.26 M) and enhanced by retigabine (10 M). The expression of neuronal KCNQ subunits in DRG neurons was confirmed using reverse transcription-PCR and single-cell PCR analysis and by immunofluorescence. Retigabine, applied to the dorsal spinal cord, inhibited C and A␦ fibermediated responses of dorsal horn neurons evoked by natural or electrical afferent stimulation and the progressive "windup" discharge with repetitive stimulation in normal rats and in rats subjected to spinal nerve ligation. Retigabine also inhibited responses to intrapaw application of carrageenan in a rat model of chronic pain; this was reversed by XE991. It is suggested that I K(M) plays a key role in controlling the excitability of nociceptors and may represent a novel analgesic target.

The Journal of Physiology, 2001

1. The region of alternative splicing in the KCNQ2 potassium channel gene was determined by RNase... more 1. The region of alternative splicing in the KCNQ2 potassium channel gene was determined by RNase protection analysis of KCNQ2 mRNA transcripts. 2. Systematic analysis of KCNQ2 alternative splice variant expression in rat superior cervical ganglia revealed multiple variant isoforms. 3. One class of KCNQ2 splice variants, those that contained exon 15a, was found to have significantly different kinetics to those of the other isoforms. These transcripts encoded channel subunits that, when co-expressed with the KCNQ3 subunit, activated and deactivated approximately 2•5 times more slowly than other isoforms. Deletion of exon 15a in these isoforms produced a reversion to the faster kinetics. 4. Comparison of the kinetic properties of the cloned channel splice variants with those of the native M-current suggests that alternative splicing of the KCNQ2 gene may contribute to the variation in M-current kinetics seen in vivo.

Journal of cardiovascular pharmacology and therapeutics, 2014

We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and ... more We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia's cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 minutes prior to reperfusion (0.05 mg/kg/h, intravenously) reduced myocardial infarct size by ∼50% when administered for either 1 or 3 hours of reperfusion. However, when Bendavia perfusion began just 10 minutes after the onset of reperfusion, the protection against infarction and no-reflow was completely lost, indicating that the mechanism of protection is occurring early in reperfusion. Experiments in isolated mouse liver mitochondria found no discernible effect of Bendavia on blocking the permeability transition pore, and studies in isolated heart mitochondria showed no effect of Bendavia on respiratory rates....

The Journal of Physiology, 2003

In mammalian sympathetic neurones several membrane ion channels are regulated by intracellular ca... more In mammalian sympathetic neurones several membrane ion channels are regulated by intracellular calcium (Ca 2+). Thus, the influx of Ca 2+ during action potentials activates two types of Ca 2+-dependent K + channel: one (the 'BK' channel) accelerates spike repolarisation and induces a fast after-hyperpolarisation (Belluzzi & Sacchi, 1990; Marsh & Brown, 1991; Davies et al. 1996), while the other (the 'SK' channel) induces a slow after-hyperpolarisation and spike train accommodation (Kawai & Watanabe, 1986; Sacchi et al. 1995; Davies et al. 1996). Elevation of intracellular Ca 2+ can also activate two species of chloride current, a fast current gated directly by Ca 2+ (Sanchez-Vivas et al. 1994a) and a delayed current triggered by activation of protein kinase C (Marsh et al. 1995). Finally, M-type K + channels are inhibited by intracellular Ca 2+ with an IC 50 around 100 nM (Selyanko & Brown, 1996), and there is evidence to suggest that the release of Ca 2+ from internal stores following activation of certain G-protein-coupled receptors may contribute to M channel inhibition in these cells (Cruzblanca et al. 1998; Bofill-Cardona et al. 2000). For these reasons, it seems essential to understand what processes regulate intracellular Ca 2+ levels in mammalian sympathetic neurones. To date, the only information available derives from experiments on caffeine-induced Ca 2+ release (Thayer et al. 1988; Hernandez-Cruz et al. 1995, 1997). In contrast, very little is known regarding the magnitude or duration of the Ca 2+ transients, or the factors that affect these transients, following the entry of Ca 2+ through voltage-gated Ca 2+ channels, which are most pertinent to the physiological effects referred to above. In the present experiments, therefore, we have measured the Ca 2+ transients in dissociated rat sympathetic neurones following activation of voltage-gated Ca 2+ channels, and have investigated some of the processes that determine the duration of, and recovery from, these transients. We provide evidence that the plasma membrane Ca 2+-ATPase (PMCA; Carafoli, 1994) is primarily responsible for recovery following modest elevations of [Ca 2+ ] i but that it is supplemented by other mechanisms (principally a Na +-Ca 2+ exchanger (NCX) and mitochondrial uptake) following larger elevations. We also show that PMCA is active at rest, extruding Ca 2+ that enters through a lanthanum (La 3+)sensitive 'leak' channel, and that these neurones have a high Ca 2+-binding capacity. Parts of this work have been published in abstract form (Wanaverbecq et al. 2000, 2001).

IEEE Aerospace and Electronic Systems Magazine, 2020

While large-scale research and development initiatives are reshaping the future of aviation and s... more While large-scale research and development initiatives are reshaping the future of aviation and space operations, avionics systems are becoming cyber-physical and progressively evolving into a variety of autonomous, intelligent and closed-loop human-machine systems. This article provides the IEEE Aerospace & Electronic Systems Society (AESS) Avionics Systems Panel (ASP) views on avionics systems evolutionary pathways, with an identification of key research challenges and industry-focused innovation opportunities. The ever-increasing density of air traffic and the rise of Unmanned Aircraft Systems (UAS) are prompting a rapid evolution of Communication, Navigation, Surveillance/Air Traffic Management (CNS/ATM) and Avionics (CNS+A) technologies that will provide unprecedented enhancements in terms of safety and efficiency, thus unleashing additional airspace and airport capacity. Several of the underlying CNS technologies have already hit the market, while other more advanced capabilit...

Biophysical journal, Jan 19, 2018

Pulsed electric fields with microsecond pulse width (μsPEFs) are used clinically; namely, irrever... more Pulsed electric fields with microsecond pulse width (μsPEFs) are used clinically; namely, irreversible electroporation/Nanoknife is used for soft tissue tumor ablation. The μsPEF pulse parameters used in irreversible electroporation (0.5-1 kV/cm, 80-100 pulses, ∼100 μs each, 1 Hz frequency) may cause an internal field to develop within the cell because of the disruption of the outer cell membrane and subsequent penetration of the electric field. An internal field may disrupt voltage-sensitive mitochondria, although the research literature has been relatively unclear regarding whether such disruptions occur with μsPEFs. This investigation reports the influence of clinically used μsPEF parameters on mitochondrial respiration in live cells. Using a high-throughput Agilent Seahorse machine, it was observed that μsPEF exposure comprising 80 pulses with amplitudes of 600 or 700 V/cm did not alter mitochondrial respiration in 4T1 cells measured after overnight postexposure recovery. To rec...

Pflugers Archiv : European journal of physiology, Jan 24, 2018

Kv7 channels determine the resting membrane potential of neurons and regulate their excitability.... more Kv7 channels determine the resting membrane potential of neurons and regulate their excitability. Even though dysfunction of Kv7 channels has been linked to several debilitating childhood neuronal disorders, the ontogeny of the constituent genes, which encode Kv7 channels (KNCQ), and expression of their subunits have been largely unexplored. Here, we show that developmentally regulated expression of specific KCNQ mRNA and Kv7 channel subunits in mouse and human striatum is crucial to the functional maturation of mouse striatal neurons and human-induced pluripotent stem cell-derived neurons. This demonstrates their pivotal role in normal development and maturation, the knowledge of which can now be harnessed to synchronise and accelerate neuronal differentiation of stem cell-derived neurons, enhancing their utility for disease modelling and drug discovery.

Advances in nutrition (Bethesda, Md.), 2018

Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a ... more Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization. The composition and molecular organization of these membranes are crucial to the maintenance and function of mitochondria. In this review, we first present a general overview of mitochondrial membrane biochemistry and biophysics followed by the role of different dietary saturated and unsaturated fatty acids in modulating mitochondrial membrane structure-function. We focus extensively on long-chain n-3 (ω-3) polyunsaturated fatty acids and their underlying mechanisms of action. Finally, we discuss implications of understanding molecular mechanisms by which dietary n-3 fatty acids target mitochondrial structure-fun...

Nature reviews. Cardiology, Apr 22, 2016

Heart failure is a pressing worldwide public-health problem with millions of patients having wors... more Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the me...

Frontiers in Physiology, 2015

Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial dise... more Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial disease and manifests as chronic limb pain at rest and/or tissue necrosis. Current clinical interventions are largely ineffective and therapeutic angiogenesis based trials have shown little efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. Despite a decade of research related to skeletal muscle as a determinant of morbidity and mortality outcomes in CLI, very little progress has been made toward an effective therapy aimed directly at the muscle myopathies of this disease. Within the muscle cell, mitochondria are well positioned to modulate the ischemic cellular response, as they are the principal sites of cellular energy production and the major regulators of cellular redox charge and cell death. In this mini review, we update the crucial importance of skeletal muscle to CLI pathology and examine the evolving influence of muscle and endothelial cell mitochondria in the complex ischemic microenvironment. Finally, we discuss the novelty of muscle mitochondria as a therapeutic target for ischemic pathology in the context of the complex co-morbidities often associated with CLI.

PloS one, 2015

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels ... more The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC-1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels alt...

Robotics and Autonomous Systems, 2015

Audio event detection (AED) and recognition is a signal processing and analysis domain used in a ... more Audio event detection (AED) and recognition is a signal processing and analysis domain used in a wide range of applications including surveillance, home automation and behavioral assessment. The field presents numerous challenges to the current state-of-the-art due to its highly nonlinear nature. High false alarm rates (FARs) in such applications particularly limit the capabilities of vision-based perimeter monitoring systems by inducing high operator dependence. On the other hand, conventional fence-based vibration detectors and pressure-driven "taut wires" offer high sensitivity at the cost of a high FAR due to debris, animals and weather. This work reports an audio event identification methodology implemented as a test-bed system for a surveillance application to reduce FAR, maximize blind-spot coverage and improve audio event classification accuracy. The first phase utilizes a nonlinear autoregressive classifier to locate and classify discrete audio events via an exogenous sound direction variable to improve classifier confidence. The second phase implements a time-series-based system to recognize various audio activity groups from nominal everyday sound events such as traffic and muffled speech. The discretely labeled data is thus trained with HMM and Conditional Random Field classifiers and reports a substantial improvement in classification accuracies of indoor human activities.

RSC Adv., 2015

We present an alternative synthetic route to acrylic acid, starting from the platform chemical la... more We present an alternative synthetic route to acrylic acid, starting from the platform chemical lactic acid and using heterogeneous catalysis.

Journal of NeuroEngineering and Rehabilitation, 2015

Background: Individuals post-stroke select slow comfortable walking speeds (CWS) and the major fa... more Background: Individuals post-stroke select slow comfortable walking speeds (CWS) and the major factors used to select their CWS is unknown. Objective: To determine the extent to which slow CWS post-stroke is achieved through matching a relative force output or targeting a particular walking speed. Methods: Ten neurologically nonimpaired individuals and fourteen chronic stroke survivors with hemiplegia were recruited. Participants were instructed to "walk at the speed that feels most comfortable" on a treadmill against 12 progressively increasing horizontal resistive force levels applied at the pelvis using a robotic system that allowed participant to self-select their walking speed. We compared slope coefficients of the simple linear regressions between the observed normalized force vs. normalized speed relationship in each group to a slope of-1.0 (i.e. ideal slope for a constant relative force output) and 0.0 (i.e. ideal slope for a constant relative speed). We also compared slope coefficients between groups. Results: The slope coefficients were significantly greater than-1.0 (p < 0.001 for both) and significantly less than 0 (p < 0.001 for both). However, compared with nonimpaired individuals, people post-stroke were less able to maintain their walking speed (p = 0.003). Conclusions: The results of this study provide evidence for a complex interaction between the regulation of relative force output and intention to move at a particular speed in the selection of the CWS for individuals post-stroke. This would suggest that therapeutic interventions should not only focus on task specific lower-limb strengthening exercises (e.g. walking against resistance), but should also focus on increasing the range of speeds at which people can safely walk.

PloS one, 2014

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physio... more Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as be...

Chem. Commun., 2014

Here we describe a simple route to creating conformal sulphated zirconia monolayers throughout an... more Here we describe a simple route to creating conformal sulphated zirconia monolayers throughout an SBA-15 architecture that confers efficient acid-catalysed one-pot conversion of glucose to ethyl levulinate.

MNRAS, Aug 1, 2014

Using a sample of 68 planet-hosting stars, I carry out a comparison of isochrone fitting and gyro... more Using a sample of 68 planet-hosting stars, I carry out a comparison of isochrone fitting and gyrochronology to investigate whether tidal interactions between the stars and their planets are leading to underestimated ages using the latter method. I find a slight tendency for isochrones to produce older age estimates but find no correlation with tidal time-scale, although for some individual systems the effect of tides might be leading to more rapid rotation than expected from the stars' isochronal age, and therefore an underestimated gyrochronology age. By comparing to planetary systems in stellar clusters, I also find that in some cases isochrone fitting can overestimate the age of the star. The evidence for any bias on a sample-wide level is inconclusive. I also consider the subset of my sample for which the sky-projected alignment angle between the stellar rotation axis and the planet's orbital axis has been measured, finding similar patterns to those identified in the f...

The Journal of Physiology, 2001

KCNQ2 and KCNQ3 subunits form heteromeric potassium channels that underlie slow, subthreshold M-t... more KCNQ2 and KCNQ3 subunits form heteromeric potassium channels that underlie slow, subthreshold M-type potassium currents in autonomic (and possibly central) neurones (Wang et al. 1998). They are related to KCNQ1 (Yang et al. 1997) and KCNQ4 (Kubisch et al. 1999) subunits, mutations of which produce one form of the cardiac long QT syndrome and deafness, respectively. KCNQ2 and KCNQ3 subunits are expressed exclusively in the nervous system and their mutations produce a benign form of epilepsy in newborns (

Gold Bulletin, 1988

The aim of what we now call restorative dentistry is to replace teeth lost by either accidental o... more The aim of what we now call restorative dentistry is to replace teeth lost by either accidental or intentional extraction, or to replace parts of teeth lost due to decay or accident. In this short review, aimed at the general reader, the author describes gold's important role in dentistry. Fillings and Castings Modem techniques and materials enable the dental surgeon and dental technician to create a wide range of restorations. Some materials, such as dental amalgam, cements and composites, are manipulated as pastes directly in the mouth of the patient, and set to become strong and rigid parts of the tooth's anatomy. Modem dental alloys, however, many of which are based on gold, are cast in the laboratory and then cemented into place in the mouth.