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Papers by James Parker

increases in isolated mouse lungs metabolites modulate ventilator-induced permeability and arachi... more increases in isolated mouse lungs metabolites modulate ventilator-induced permeability and arachidonic acid 2 Cytosolic phospholipase A You might find this additional info useful... physiology, especially those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a publishes original papers that deal with diverse area of research in applied

Journal of Applied Physiology, 1998

We determined whether drugs which modulate the state of protein tyrosine phosphorylation could al... more We determined whether drugs which modulate the state of protein tyrosine phosphorylation could alter the threshold for high airway pressure-induced microvascular injury in isolated perfused rat lungs. Lungs were ventilated for successive 30-min periods with peak inflation pressures (PIP) of 7, 20, 30, and 35 cmH2O followed by measurement of the capillary filtration coefficient ( Kfc), a sensitive index of hydraulic conductance. In untreated control lungs, Kfcincreased by 1.3- and 3.3-fold relative to baseline (7 cmH2O PIP) after ventilation with 30 and 35 cmH2O PIP. However, in lungs treated with 100 μM phenylarsine oxide (a phosphotyrosine phosphatase inhibitor), Kfcincreased by 4.7- and 16.4-fold relative to baseline at these PIP values. In lungs treated with 50 μM genistein (a tyrosine kinase inhibitor), Kfcincreased significantly only at 35 cmH2O PIP, and the three groups were significantly different from each other. Thus phosphotyrosine phosphatase inhibition increased the susc...

American Journal of Physiology - Lung Cellular and Molecular Physiology, 2002

The response of segmental filtration coefficients ( K f) to high peak inflation pressure (PIP) in... more The response of segmental filtration coefficients ( K f) to high peak inflation pressure (PIP) injury was determined in isolated perfused rat lungs. Total ( K f,t), arterial ( K f,a), and venous ( K f,v) filtration coefficients were measured under baseline conditions and after ventilation with 40–45 cmH2O PIP. K f,a and K f,v were measured under zone I conditions by increasing airway pressure to 25–27 cmH2O. The microvascular segment K f ( K f,mv) was then calculated by: K f,mv = K f,t − K f,a − K f,v. The baseline K f,twas 0.090 ± 0.022 ml · min−1 · cmH2O−1 · 100 g−1 and segmentally distributed 18% arterial, 41% venous, and 41% microvascular. After high PIP injury, K f,t increased by 680%, whereas K f,a, K f,v, and K f,mv increased by 398, 589, and 975%, respectively. Pretreatment with 50 μM gadolinium chloride prevented the high PIP-induced increase in K f in all vascular segments. These data imply a lower hydraulic conductance for microvascular endothelium due to its large surfac...

Mechanosensitivity and Mechanotransduction, 2010

The transient receptor potential vanilloid 4 (TRPV4) non-selective cation channel has emerged as ... more The transient receptor potential vanilloid 4 (TRPV4) non-selective cation channel has emerged as a critical channel for initiating the increased vascular permeability induced by high airway or vascular pressures in the lung. TRPV4 gating is regulated by multiple factors: mechanical stress, heat, epoxyeicosatrienoic acids (EETs) – the arachidonic acid metabolites of P450 epoxygenases, and phorbol esters. Increased pulmonary venous pressure

Journal of Neurochemistry, 2015

Cyanide is a life threatening, bioterrorist agent, preventing cellular respiration by inhibiting ... more Cyanide is a life threatening, bioterrorist agent, preventing cellular respiration by inhibiting cytochrome c oxidase, resulting in cardiopulmonary failure, hypoxic brain injury, and death within minutes. However, even after treatment with various antidotes to protect cytochrome oxidase, cyanide intoxication in humans can induce a delayed-onset neurological syndrome that includes symptoms of Parkinsonism. Additional mechanisms are thought to underlie cyanide-induced neuronal damage, including generation of reactive oxygen species (ROS). This may account for the fact that antioxidants prevent some aspects of cyanide-induced neuronal damage. Here, as a potential preemptive countermeasure against a bioterrorist attack with cyanide, we tested the CNS protective effect of carnosic acid (CA), a pro-electrophilic compound found in the herb rosemary. CA crosses the blood-brain-barrier to upregulate endogenous antioxidant enzymes via activation of the Nrf2 transcriptional pathway. We demonstrate that CA exerts neuroprotective effects on cyanide-induced brain damage in cultured rodent and human induced pluripotent stem cell (hiPSC)-derived neurons in vitro, and in vivo in various brain areas of a non-Swiss albino (NSA) mouse model of cyanide poisoning that simulates damage observed in the human brain.

Pharmaceuticals (Basel, Switzerland), Jan 22, 2014

The mitochondrial targeted DNA repair enzyme, 8-oxoguanine DNA glycosylase 1, was previously repo... more The mitochondrial targeted DNA repair enzyme, 8-oxoguanine DNA glycosylase 1, was previously reported to protect against mitochondrial DNA (mtDNA) damage and ventilator induced lung injury (VILI). In the present study we determined whether mitochondrial targeted endonuclease III (EndoIII) which cleaves oxidized pyrimidines rather than purines from damaged DNA would also protect the lung. Minimal injury from 1 h ventilation at 40 cmH2O peak inflation pressure (PIP) was reversed by EndoIII pretreatment. Moderate lung injury due to ventilation for 2 h at 40 cmH2O PIP produced a 25-fold increase in total extravascular albumin space, a 60% increase in W/D weight ratio, and marked increases in MIP-2 and IL-6. Oxidative mtDNA damage and decreases in the total tissue glutathione (GSH) and the GSH/GSSH ratio also occurred. All of these indices of injury were attenuated by mitochondrial targeted EndoIII. Massive lung injury caused by 2 h ventilation at 50 cmH2O PIP was not attenuated by EndoI...

Proceedings of the National Academy of Sciences, 2013

Significance Communication between nerve cells occurs at specialized cellular structures known as... more Significance Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we describe a pathway for synaptic damage whereby amyloid-β 1–42 peptide (Aβ 1–42 ) releases, via stimulation of α7 nicotinic receptors, excessive amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA-type glutamate receptors (eNMDARs) to mediate synaptic damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced synaptic loss, providing hope for disease-modifying intervention in AD.

Microvascular Research, 2006

Endothelial phenotypes derived from different pulmonary vascular segments have markedly different... more Endothelial phenotypes derived from different pulmonary vascular segments have markedly different permeability response to inflammatory agonists, but their responses to mechanical strain have not been characterized. Therefore, we evaluated the effect of cyclical stretch on cell shape, cell membrane wounding, and junctional β-catenin in rat pulmonary artery (RPAEC) and microvascular (RPMVEC) endothelial cell monolayers. After 24 h of 24% uniaxial strain at 40 cycles/min, RPAEC but not RPMVEC reoriented transverse to the axis of strain. Total β-catenin increased in RPAEC but decreased in RPMVEC. Transient plasma membrane wounding was produced by cyclical biaxial strain of 34% or by scratching of monolayers with a needle and was indicated by retention of lysine fixable fluorescent 70 kDa dextran. Junctional β-catenin was quantified by fluorescence intensity and image analysis. β-catenin fluorescence was significantly lower in wounded cells than in adjacent uninjured cells in both phenotypes, and the decrease was significantly greater in RPAEC compared to RPMVEC in both scratched (57% vs. 30%) and stretched (55% vs. 37%) cells. Using immunoprecipitation, VE-cadherin-associated β-catenin decreased significantly in RPAEC (61%) but E-cadherin-associated βcatenin was not significantly decreased in RPMVEC after 34% biaxial cyclical strain. These data suggest that RPAEC more readily remodel cellcell adhesions during cyclical stretch than RPMVEC and that a reduced intercellular adhesion adjacent to wounded cells could serve as transvascular leak sites in both phenotypes.

Medical & Biological Engineering & Computing, 2009

A prototype time cycled, constant volume, closed circuit perfluorocarbon (PFC) total liquid venti... more A prototype time cycled, constant volume, closed circuit perfluorocarbon (PFC) total liquid ventilator system is described. The system utilizes microcontroller-driven display and master control boards, gear motor pumps, and three-way solenoid valves to direct flow. A constant tidal volume and functional residual capacity (FRC) are maintained with feedback control using end-expiratory and end-inspiratory stop-flow pressures. The system can also provide a unique continuous perfusion (bias flow, tracheal insufflation) through one lumen of a double-lumen endotracheal catheter to increase washout of dead space liquid. FRC and arterial blood gases were maintained during ventilation with Rimar 101 PFC over 2-3 h in normal piglets and piglets with simulated pulmonary edema induced by instillation of albumin solution. Addition of tracheal insufflation flow significantly improved the blood gases and enhanced clearance of instilled albumin solution during simulated edema.

Journal of Applied Physiology, 2007

We previously reported that the cytosolic phospholipase A2(cPLA2) pathway is involved in ventilat... more We previously reported that the cytosolic phospholipase A2(cPLA2) pathway is involved in ventilator-induced lung injury (VILI) produced by high peak inflation pressures (PIP) ( J Appl Physiol 98: 1264–1271, 2005), but the relative contributions of the various downstream products of cPLA2on the acute permeability response were not determined. Therefore, we investigated the role of cPLA2and the downstream products of arachidonic acid metabolism in the high-PIP ventilation-induced increase in vascular permeability. We perfused isolated mouse lungs and measured the capillary filtration coefficient ( Kfc) after 30 min of ventilation with 9, 25, and 35 cmH2O PIP. In high-PIP-ventilated lungs, Kfcincreased significantly, 2.7-fold, after ventilation with 35 cmH2O PIP compared with paired baseline values and low-PIP-ventilated lungs. Also, increased phosphorylation of lung cPLA2suggested enzyme activation after high-PIP ventilation. However, treatment with 40 mg/kg arachidonyl trifluoromethy...

Journal of Applied Physiology, 2004

To determine the influence of experimental model and strain differences on the relationship of va... more To determine the influence of experimental model and strain differences on the relationship of vascular permeability to inflammatory cytokine production after high peak inflation pressure (PIP) ventilation, we used isolated perfused mouse lung and intact mouse preparations of Balb/c and B6/129 mice ventilated at high and low PIP. Filtration coefficients in isolated lungs and bronchoalveolar lavage (BAL) albumin in intact mice increased within 20–30 min after initiation of high PIP in isolated Balb/c lungs and intact Balb/c, B6/129 wild-type, and p55 and p75 tumor necrosis factor (TNF) dual-receptor null mice. In contrast, the cytokine response was delayed and variable compared with the permeability response. In isolated Balb/c lungs ventilated with 25–27 cmH2O PIP, TNF-α, interleukin (IL)-1β, IL-1α, macrophage inflammatory protein (MIP)-2, and IL-6 concentrations in perfusate were markedly increased in perfusate at 2 and 4 h, but only MIP-2 was detectable in intact Balb/c mice using...

Journal of Applied Physiology, 2005

Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To ... more Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To determine the roles of mechanically activated cytosolic PLA2(cPLA2) and Clara cell secretory protein (CCSP), a modulator of cPLA2activity, we compared lung injury with and without a PLA2inhibitor in wild-type mice and CCSP-null mice (CCSP−/−) ventilated with high and low peak inflation pressures (PIP) for 2- or 4-h periods. After ventilation with high PIP, we observed significant increases in the bronchoalveolar lavage albumin concentrations, lung wet-to-dry weight ratios, and lung myeloperoxidase in both genotypes compared with unventilated controls and low-PIP ventilated mice. All injury variables except myeloperoxidase were significantly greater in the CCSP−/−mice relative to wild-type mice. Inhibition of cPLA2in wild-type and CCSP−/−mice ventilated at high PIP for 4 h significantly reduced bronchoalveolar lavage albumin and total protein and lung wet-to-dry weight ratios compared wit...

Intensive Care Medicine, 2007

Fertility and Sterility, 2009

OBJECTIVE: Leiomyoma cells reside in an extracellular matrix (ECM) of increased mechanical stress... more OBJECTIVE: Leiomyoma cells reside in an extracellular matrix (ECM) of increased mechanical stress that they create (Rogers et al. 2008), although it is unclear why this transformation occurs. Normal cells respond to increased mechanical stress with activation of Rho signaling, which leads to reorganization of the cell cytoskeleton. Here we tested whether leiomyoma cells appropriately sense ambient mechanical cues. DESIGN: Experimental Investigation. MATERIALS AND METHODS: Immortalized leiomyoma and myometrial cells were cultured on pronectin-coated, flexible silicone substrates (Flex Cell Intl) and levels of active RhoAwere quantified at baseline and after 2 hours of 8.6% uni-axial cyclic strain at 1 Hertz. Next, cells were treated with Y-27632, a selective inhibitor of the Rho-associated kinase (ROCK), then exposed to 18 hours of the same cyclic strain before the cytoskeleton was assessed by cytoimmunofluorescence. To quantify their response to substrate stiffness, cells were cultured on collagen-coated polyacrylamide gels with stiffness ranging from 30 to 140.5 kPa. Cells were then treated with Calcein AM and fluorescent images were obtained at 24 hours. RESULTS: Two hours of cyclic strain resulted in a 1.5-fold increased RhoA activation in myometrial cells, while levels in leiomyoma cells were increased 2-fold at baseline and showed a reduced response to load compared with myometrial cells. Inhibition of ROCK resulted in morphologic changes in myometrial cells, while results with leiomyoma cells were consistent with an attenuated response. Leiomyoma cells exhibited a reduced ability to respond to increasing substrate stiffness compared with myometrial cells. CONCLUSIONS: These data indicate that leiomyoma cells do not sense or respond appropriately to mechanical cues. Altered mechanosensing by leiomyoma cells may play a role in the aberrant structure of the ECM of leiomyoma.

FEBS Letters, 1997

Cactus protein is a Drosophila homologue of the mammalian ΙκΒ family of cytoplasmic anchor protei... more Cactus protein is a Drosophila homologue of the mammalian ΙκΒ family of cytoplasmic anchor proteins. In unstimulated cells they function to retain rel/NFx:B transcription factors in the cytoplasm but are rapidly degraded in response to signalling. The destruction of cactus or ΙκΒα allows the rel/ NFKB transcription factor to relocalise to the nucleus. Cactus is a phosphoprotein and has in its C-terminus a PEST protein stability domain. In this paper we show that, like mammalian ΙκΒα, the PEST domain of cactus is phosphorylated by casein kinase Π. We have localised the site of modification to a single residue, Ser 468 , and find no evidence for additional phosphorylation sites. The conservation of these sites in mammalian and invertebrate cytoplasmic anchor proteins suggests that phosphorylation by casein kinase Π may play a critical functional role, plausibly in the regulation of constitutive or inducible proteolysis.

Cell, 2013

Parkinson's disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substant... more Parkinson's disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patientderived stem cell model of PD allowing comparison of A53T a-synuclein (a-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T a-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1a transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1a pathway as a therapeutic target to combat PD.

The Australian and New Zealand Journal of Obstetrics and Gynaecology, 1995

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in different dimensional configurations and different SQUID area distributions. We have measured ... more in different dimensional configurations and different SQUID area distributions. We have measured the electrical transport characteristics of each array and compare it to computer simulations based on the resistively shunted junction model to investigate the effect of mutual inductance between the SQUIDS within the array. We find there is good agreement between our simulation model and our experimental device when the parallel dimension of the device is less than 15 SQUIDs.

National Laboratory-We report electrical transport measurements of multiferroic/ferromagnet, BiFe... more National Laboratory-We report electrical transport measurements of multiferroic/ferromagnet, BiFeO3 (BFO) / La0.7Sr0.3MnO3 (LSMO), electric field effect devices. The antiferromagnetic (AFM) ordering of the BFO dielectric layer is coupled to the ferromagnetic (FM) ordering of the LSMO channel layer and is observed as exchange bias-a shift of the LSMO magnetic hysteresis curve along the applied field axis. We will present the temperature dependence of this exchange bias between 2K and 100K. Furthermore, we also investigate the exchange bias with respect to multiple gating variables, including channel current and gate pulsing patterns. We have observed that the current in the channel during gating plays an important role in setting the exchange bias.