TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice.

PubMed

Oda, Sayaka; Numaga-Tomita, Takuro; Kitajima, Naoyuki; Toyama, Takashi; Harada, Eri; Shimauchi, Tsukasa; Nishimura, Akiyuki; Ishikawa, Tatsuya; Kumagai, Yoshito; Birnbaumer, Lutz; Nishida, Motohiro

2017-08-08

Excess production of reactive oxygen species (ROS) caused by hyperglycemia is a major risk factor for heart failure. We previously reported that transient receptor potential canonical 3 (TRPC3) channel mediates pressure overload-induced maladaptive cardiac fibrosis by forming stably functional complex with NADPH oxidase 2 (Nox2). Although TRPC3 has been long suggested to form hetero-multimer channels with TRPC6 and function as diacylglycerol-activated cation channels coordinately, the role of TRPC6 in heart is still obscure. We here demonstrated that deletion of TRPC6 had no impact on pressure overload-induced heart failure despite inhibiting interstitial fibrosis in mice. TRPC6-deficient mouse hearts 1 week after transverse aortic constriction showed comparable increases in fibrotic gene expressions and ROS production but promoted inductions of inflammatory cytokines, compared to wild type hearts. Treatment of TRPC6-deficient mice with streptozotocin caused severe reduction of cardiac contractility with enhancing urinary and cardiac lipid peroxide levels, compared to wild type and TRPC3-deficient mice. Knockdown of TRPC6, but not TRPC3, enhanced basal expression levels of cytokines in rat cardiomyocytes. TRPC6 could interact with Nox2, but the abundance of TRPC6 was inversely correlated with that of Nox2. These results strongly suggest that Nox2 destabilization through disrupting TRPC3-Nox2 complex underlies attenuation of hyperglycemia-induced heart failure by TRPC6.

Radiometric observations of atmospheric attenuation at 20.6 and 31.65 GHz: The Wave Propagation Laboratory data base

NASA Technical Reports Server (NTRS)

Jacobson, Mark D.; Snider, J. B.; Westwater, E. R.

1993-01-01

The National Oceanic and Atmospheric Administration (NOAA) Wave Propagation Laboratory (WPL) presently operates five dual-channel microwave radiometers, one triple-channel microwave radiometer, and one six-channel microwave radiometer. The dual-channel radiometers operate at frequencies of 20.6 or 23.87 GHz and 31.4 or 31.65 GHz. The triple-channel radiometer operates at 20.6, 31.65, and 90.0 GHz. The six-channel radiometer operates at frequencies of 20.6, 31.65, 52.85, 53.85, 55.45, and 58.8 GHz. Recent brightness temperature measurements and attenuation values from some of the above radiometers are presented. These radiometric measurements, taken in different locations throughout the world, have given WPL a diverse set of measurements under a variety of atmospheric conditions. We propose to do a more complete attenuation analysis on these measurements in the future. In addition, a new spinning reflector was installed recently for the dual-channel radiometer at the Platteville, Colorado site. This reflector will extend our measurement capabilities during precipating conditions. Locating the three-channel and portable dual-channel radiometers at or near Greeley, Colorado to support the Advanced Communications Technology Satellite (ACTS) program is discussed.

Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

PubMed Central

Kiyatkin, Michael E.; Feng, Bin; Schwartz, Erica S.

2013-01-01

The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity. PMID:23989007

Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage.

PubMed

Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Cavaliere, Fabio; Magnus, Tim; Koch-Nolte, Friederich; Scemes, Eliana; Pérez-Samartín, Alberto; Matute, Carlos

2015-05-01

The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to ~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise.

Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice.

PubMed

Tong, Xiaoping; Ao, Yan; Faas, Guido C; Nwaobi, Sinifunanya E; Xu, Ji; Haustein, Martin D; Anderson, Mark A; Mody, Istvan; Olsen, Michelle L; Sofroniew, Michael V; Khakh, Baljit S

2014-05-01

Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.

Protective role of Kv7 channels in oxygen and glucose deprivation-induced damage in rat caudate brain slices

PubMed Central

Barrese, Vincenzo; Taglialatela, Maurizio; Greenwood, Iain A; Davidson, Colin

2015-01-01

Ischemic stroke can cause striatal dopamine efflux that contributes to cell death. Since Kv7 potassium channels regulate dopamine release, we investigated the effects of their pharmacological modulation on dopamine efflux, measured by fast cyclic voltammetry (FCV), and neurotoxicity, in Wistar rat caudate brain slices undergoing oxygen and glucose deprivation (OGD). The Kv7 activators retigabine and ICA27243 delayed the onset, and decreased the peak level of dopamine efflux induced by OGD; and also decreased OGD-induced damage measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Retigabine also reduced OGD-induced necrotic cell death evaluated by lactate dehydrogenase activity assay. The Kv7 blocker linopirdine increased OGD-evoked dopamine efflux and OGD-induced damage, and attenuated the effects of retigabine. Quantitative-PCR experiments showed that OGD caused an ~6-fold decrease in Kv7.2 transcript, while levels of mRNAs encoding for other Kv7 subunits were unaffected; western blot experiments showed a parallel reduction in Kv7.2 protein levels. Retigabine also decreased the peak level of dopamine efflux induced by L-glutamate, and attenuated the loss of TTC staining induced by the excitotoxin. These results suggest a role for Kv7.2 in modulating ischemia-evoked caudate damage. PMID:25966943

Attenuation of Phosphorylation-dependent Activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Disease-causing Mutations at the Transmission Interface*

PubMed Central

Chin, Stephanie; Yang, Donghe; Miles, Andrew J.; Eckford, Paul D. W.; Molinski, Steven; Wallace, B. A.; Bear, Christine E.

2017-01-01

Cystic fibrosis transmembrane conductance regulator (CFTR) is a multidomain membrane protein that functions as a phosphorylation-regulated anion channel. The interface between its two cytosolic nucleotide binding domains and coupling helices conferred by intracellular loops extending from the channel pore domains has been referred to as a transmission interface and is thought to be critical for the regulated channel activity of CFTR. Phosphorylation of the regulatory domain of CFTR by protein kinase A (PKA) is required for its channel activity. However, it was unclear if phosphorylation modifies the transmission interface. Here, we studied purified full-length CFTR protein using spectroscopic techniques to determine the consequences of PKA-mediated phosphorylation. Synchrotron radiation circular dichroism spectroscopy confirmed that purified full-length wild-type CFTR is folded and structurally responsive to phosphorylation. Intrinsic tryptophan fluorescence studies of CFTR showed that phosphorylation reduced iodide-mediated quenching, consistent with an effect of phosphorylation in burying tryptophans at the transmission interface. Importantly, the rate of phosphorylation-dependent channel activation was compromised by the introduction of disease-causing mutations in either of the two coupling helices predicted to interact with nucleotide binding domain 1 at the interface. Together, these results suggest that phosphorylation modifies the interface between the catalytic and pore domains of CFTR and that this modification facilitates CFTR channel activation. PMID:28003367

Physical and functional interactions between a glioma cation channel and integrin-β1 require α-actinin

PubMed Central

Rooj, Arun K.; Liu, Zhiyong; McNicholas, Carmel M.

2015-01-01

Major plasma membrane components of the tumor cell, ion channels, and integrins play crucial roles in metastasis. Glioma cells express an amiloride-sensitive nonselective cation channel composed of acid-sensing ion channel (ASIC)-1 and epithelial Na+ channel (ENaC) α- and γ-subunits. Inhibition of this channel is associated with reduced cell migration and proliferation. Using the ASIC-1 subunit as a reporter for the channel complex, we found a physical and functional interaction between this channel and integrin-β1. Short hairpin RNA knockdown of integrin-β1 attenuated the amiloride-sensitive current, which was due to loss of surface expression of ASIC-1. In contrast, upregulation of membrane expression of integrin-β1 increased the surface expression of ASIC-1. The link between the amiloride-sensitive channel and integrin-β1 was mediated by α-actinin. Downregulation of α-actinin-1 or -4 attenuated the amiloride-sensitive current. Mutation of the putative binding site for α-actinin on the COOH terminus of ASIC-1 reduced the membrane localization of ASIC-1 and also resulted in attenuation of the amiloride-sensitive current. Our data suggest a novel interaction between the amiloride-sensitive glioma cation channel and integrin-β1, mediated by α-actinin. This interaction may form a mechanism by which channel activity can regulate glioma cell proliferation and migration. PMID:26108662

Nutrient attenuation in rivers and streams, Puget Sound Basin, Washington

USGS Publications Warehouse

Sheibley, Rich W.; Konrad, Christopher P.; Black, Robert W.

2015-01-01

From a management perspective, preservation and improvement of instream nutrient attenuation should focus on increasing the travel time through a reach and contact time of water sediment (reactive) surfaces and lowering nutrient concentrations (and loads) to avoid saturation of instream attenuation and increase attenuation efficiency. These goals can be reached by maintaining and restoring channel-flood plain connectivity, maintaining and restoring healthy riparian zones along streams, managing point and nonpoint nutrient loads to streams and rivers, and restoring channel features that promote attenuation such as the addition of woody debris and maintaining pool-riffle morphologies. Many of these management approaches are already being undertaken during projects aimed to restore quality salmon habitat. Therefore, there is a dual benefit to these projects that also may lead to enhanced potential for nitrogen and phosphorus attenuation.

L-type calcium channel blockade attenuates morphine withdrawal: in vivo interaction between L-type calcium channels and corticosterone.

PubMed

Esmaeili-Mahani, Saeed; Fathi, Yadollah; Motamedi, Fereshteh; Hosseinpanah, Farhad; Ahmadiani, Abolhassan

2008-02-01

Both opioids and calcium channel blockers could affect hypothalamic-pituitary-adrenal (HPA) axis function. Nifedipine, as a calcium channel blocker, can attenuate the development of morphine dependence; however, the role of the HPA axis in this effect has not been elucidated. We examined the effect of nifedipine on the induction of morphine dependency in intact and adrenalectomized (ADX) male rats, as assessed by the naloxone precipitation test. We also evaluated the effect of this drug on HPA activity induced by naloxone. Our results showed that despite the demonstration of dependence in both groups of rats, nifedipine is more effective in preventing of withdrawal signs in ADX rats than in sham-operated rats. In groups that received morphine and nifedipine concomitantly, naloxone-induced corticosterone secretion was attenuated. Thus, we have shown the involvement of the HPA axis in the effect of nifedipine on the development of morphine dependency and additionally demonstrated an in vivo interaction between the L-type Ca2+ channels and corticosterone.

Teleportation of a general two-mode coherent-state superposition via attenuated quantum channels with ideal and/or threshold detectors

NASA Astrophysics Data System (ADS)

An, Nguyen Ba

2009-04-01

Three novel probabilistic yet conclusive schemes are proposed to teleport a general two-mode coherent-state superposition via attenuated quantum channels with ideal and/or threshold detectors. The calculated total success probability is highest (lowest) when only ideal (threshold) detectors are used.

Global gene expression in channel catfish after vaccination with an attenuated Edwardsiella ictaluri

USDA-ARS?s Scientific Manuscript database

To understand the global gene expression in channel catfish after immersion vaccination with an attenuated Edwardsiella ictaluri (AquaVac ESCTM), microarray analysis of 65,182 UniGene transcripts were performed. With a filter of false-discovery rate less than 0.05 and fold change greater than 2, a t...

Retigabine, a Kv7.2/Kv7.3-Channel Opener, Attenuates Drug-Induced Seizures in Knock-In Mice Harboring Kcnq2 Mutations.

PubMed

Ihara, Yukiko; Tomonoh, Yuko; Deshimaru, Masanobu; Zhang, Bo; Uchida, Taku; Ishii, Atsushi; Hirose, Shinichi

2016-01-01

The hetero-tetrameric voltage-gated potassium channel Kv7.2/Kv7.3, which is encoded by KCNQ2 and KCNQ3, plays an important role in limiting network excitability in the neonatal brain. Kv7.2/Kv7.3 dysfunction resulting from KCNQ2 mutations predominantly causes self-limited or benign epilepsy in neonates, but also causes early onset epileptic encephalopathy. Retigabine (RTG), a Kv7.2/ Kv7.3-channel opener, seems to be a rational antiepileptic drug for epilepsies caused by KCNQ2 mutations. We therefore evaluated the effects of RTG on seizures in two strains of knock-in mice harboring different Kcnq2 mutations, in comparison to the effects of phenobarbital (PB), which is the first-line antiepileptic drug for seizures in neonates. The subjects were heterozygous knock-in mice (Kcnq2Y284C/+ and Kcnq2A306T/+) bearing the Y284C or A306T Kcnq2 mutation, respectively, and their wild-type (WT) littermates, at 63-100 days of age. Seizures induced by intraperitoneal injection of kainic acid (KA, 12mg/kg) were recorded using a video-electroencephalography (EEG) monitoring system. Effects of RTG on KA-induced seizures of both strains of knock-in mice were assessed using seizure scores from a modified Racine's scale and compared with those of PB. The number and total duration of spike bursts on EEG and behaviors monitored by video recording were also used to evaluate the effects of RTG and PB. Both Kcnq2Y284C/+ and Kcnq2A306T/+ mice showed significantly more KA-induced seizures than WT mice. RTG significantly attenuated KA-induced seizure activities in both Kcnq2Y284C/+ and Kcnq2A306T/+ mice, and more markedly than PB. This is the first reported evidence of RTG ameliorating KA-induced seizures in knock-in mice bearing mutations of Kcnq2, with more marked effects than those observed with PB. RTG or other Kv7.2-channel openers may be considered as first-line antiepileptic treatments for epilepsies resulting from KCNQ2 mutations.

NGP1-01, a multi-targeted polycyclic cage amine, attenuates brain endothelial cell death in iron overload conditions.

PubMed

Lockman, J A; Geldenhuys, W J; Jones-Higgins, M R; Patrick, J D; Allen, D D; Van der Schyf, C J

2012-12-13

Development and progression of neurodegenerative disorders have, amongst other potential causes, been attributed to a disruption of iron regulatory mechanisms and iron accumulation. Excess extracellular iron may enter cells via nontraditional routes such as voltage-gated calcium channels and N-methyl-d-aspartate (NMDA) receptors leading to intracellular oxidative damage and ultimately mitochondrial failure. Nimodipine, an L-type calcium channel blocker has been shown to reduce iron-induced toxicity in neuronal and brain endothelial cells. Our current study investigates NGP1-01, a multimodal drug acting as an antagonist at both the NMDA receptor and the L-type calcium channel. Our previous studies support NGP1-01 as a promising neuroprotective agent in diseases involving calcium-related excitotoxicity. We demonstrate here that NGP1-01 (1 and 10μM) pretreatment abrogates the effects of iron overload in brain endothelial cells protecting cellular viability. Both concentrations of NGP1-01 were found to attenuate iron-induced reduction in cellular viability to a similar extent, and were statistically significant. To further verify the mechanism, the L-type calcium channel agonist FPL 64176 was administered to promote iron uptake. Addition of NGP1-01 dose-dependently reduced FPL 64176 stimulated uptake of iron. These data support further evaluation of NGP1-01 as a neuroprotective agent, not only in diseases associated with excitotoxicity, but also in those of iron overload. Copyright © 2012 Elsevier B.V. All rights reserved.

An Improved Mathematical Scheme for LTE-Advanced Coexistence with FM Broadcasting Service

PubMed Central

Al-hetar, Abdulaziz M.

2016-01-01

Power spectral density (PSD) overlapping analysis is considered the surest approach to evaluate feasibility of compatibility between wireless communication systems. In this paper, a new closed-form for the Interference Signal Power Attenuation (ISPA) is mathematically derived to evaluate interference caused from Orthogonal Frequency Division Multiplexing (OFDM)-based Long Term Evolution (LTE)-Advanced into Frequency Modulation (FM) broadcasting service. In this scheme, ISPA loss due to PSD overlapping of both OFDM-based LTE-Advanced and FM broadcasting service is computed. The proposed model can estimate power attenuation loss more precisely than the Advanced Minimum Coupling Loss (A-MCL) and approximate-ISPA methods. Numerical results demonstrate that the interference power is less than that obtained using the A-MCL and approximate ISPA methods by 2.8 and 1.5 dB at the co-channel and by 5.2 and 2.2 dB at the adjacent channel with null guard band, respectively. The outperformance of this scheme over the other methods leads to more diminishing in the required physical distance between the two systems which ultimately supports efficient use of the radio frequency spectrum. PMID:27855216

An Improved Mathematical Scheme for LTE-Advanced Coexistence with FM Broadcasting Service.

PubMed

Shamsan, Zaid Ahmed; Al-Hetar, Abdulaziz M

2016-01-01

Power spectral density (PSD) overlapping analysis is considered the surest approach to evaluate feasibility of compatibility between wireless communication systems. In this paper, a new closed-form for the Interference Signal Power Attenuation (ISPA) is mathematically derived to evaluate interference caused from Orthogonal Frequency Division Multiplexing (OFDM)-based Long Term Evolution (LTE)-Advanced into Frequency Modulation (FM) broadcasting service. In this scheme, ISPA loss due to PSD overlapping of both OFDM-based LTE-Advanced and FM broadcasting service is computed. The proposed model can estimate power attenuation loss more precisely than the Advanced Minimum Coupling Loss (A-MCL) and approximate-ISPA methods. Numerical results demonstrate that the interference power is less than that obtained using the A-MCL and approximate ISPA methods by 2.8 and 1.5 dB at the co-channel and by 5.2 and 2.2 dB at the adjacent channel with null guard band, respectively. The outperformance of this scheme over the other methods leads to more diminishing in the required physical distance between the two systems which ultimately supports efficient use of the radio frequency spectrum.

HiRadProp: High-Frequency Modeling and Prediction of Tropospheric Radiopropagation Parameters from Ground-Based-Multi-Channel Radiometric Measurements between Ka and W Band

DTIC Science & Technology

2016-05-11

new physically -based prediction models for all-weather path attenuation estimation at Ka, V and W band from multi- channel microwave radiometric data...of new physically -based prediction models for all-weather path attenuation estimation at Ka, V and W band from multi- channel microwave radiometric...the medium behavior at these frequency bands from both a physical and a statistical point of view (e.g., [5]-[7]). However, these campaigns are

Shock wave attenuation in a micro-channel

NASA Astrophysics Data System (ADS)

Giordano, J.; Perrier, P.; Meister, L.; Brouillette, M.

2018-05-01

This work presents optical measurements of shock wave attenuation in a glass micro-channel. This transparent facility, with a cross section ranging from 1 mm× 150 μm to 1 mm× 500 μm, allowed for the use of high-speed schlieren videography to visualize the propagation of a shock wave within the entire micro-channel and to quantify velocity attenuation of the wave due to wall effects. In this paper, we present the experimental technique and the relevant data treatment we have used to increase the sensitivity of shock wave detection. Then, we compared our experimental results for different channel widths, lengths, and shock wave velocities with the analytical model for shock attenuation proposed by Russell (J Fluid Mech 27(2):305-314, 1967), which assumes laminar flow, and by Mirels (Attenuation in a shock tube due to unsteady-boundary-layer action, NACA Report 1333, 1957) for turbulent flow. We found that these models are inadequate to predict the observed data, owing to the presence of fully developed flow which violates the basic assumption of these models. The data are also compared with the empirical shock attenuation models proposed by Zeitoun (Phys Fluids 27(1):011701, 2015) and Deshpande and Puranik (Shock Waves 26(4):465-475, 2016), where better agreement is observed. Finally, we presented experimental data for the flow field behind the shock wave from measurements of the Mach wave angle which shows globally decreasing flow Mach numbers due to viscous wall effects.

Disturbed Processing of Contextual Information in HCN3 Channel Deficient Mice

PubMed Central

Stieglitz, Marc S.; Fenske, Stefanie; Hammelmann, Verena; Becirovic, Elvir; Schöttle, Verena; Delorme, James E.; Schöll-Weidinger, Martha; Mader, Robert; Deussing, Jan; Wolfer, David P.; Seeliger, Mathias W.; Albrecht, Urs; Wotjak, Carsten T.; Biel, Martin; Michalakis, Stylianos; Wahl-Schott, Christian

2018-01-01

Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) in the nervous system are implicated in a variety of neuronal functions including learning and memory, regulation of vigilance states and pain. Dysfunctions or genetic loss of these channels have been shown to cause human diseases such as epilepsy, depression, schizophrenia, and Parkinson's disease. The physiological functions of HCN1 and HCN2 channels in the nervous system have been analyzed using genetic knockout mouse models. By contrast, there are no such genetic studies for HCN3 channels so far. Here, we use a HCN3-deficient (HCN3−/−) mouse line, which has been previously generated in our group to examine the expression and function of this channel in the CNS. Specifically, we investigate the role of HCN3 channels for the regulation of circadian rhythm and for the determination of behavior. Contrary to previous suggestions we find that HCN3−/− mice show normal visual, photic, and non-photic circadian function. In addition, HCN3−/− mice are impaired in processing contextual information, which is characterized by attenuated long-term extinction of contextual fear and increased fear to a neutral context upon repeated exposure. PMID:29375299

Transmembrane S1 mutations in CNGA3 from achromatopsia 2 patients cause loss of function and impaired cellular trafficking of the cone CNG channel.

PubMed

Patel, Kirti A; Bartoli, Kristen M; Fandino, Richard A; Ngatchou, Anita N; Woch, Gustaw; Carey, Jannette; Tanaka, Jacqueline C

2005-07-01

Achromatopsia 2, an inherited retinal disorder resulting in attenuation or loss of cone function, is caused by mutations in the alpha subunit of the cone cyclic nucleotide-gated (CNG) channel gene CNGA3. Examination of mutations that cluster in the first transmembrane segment of the protein may provide insight into its role in CNG channel structure, function, biogenesis, and pathophysiology. The human CNGA3 gene was tagged at the C terminus with green fluorescent protein. Four mutations, Y181C, N182Y, L186F, and C191Y, were expressed in human embryonic kidney cells. Protein expression was evaluated with immunoblot analysis and cellular localization was determined by immunocytochemistry. Channel function was evaluated by patch-clamp electrophysiology. All the mutations result in loss of channel function, as determined by the failure of cGMP to activate wild-type currents in excised patches. Full-length mutant proteins were synthesized but retained in the endoplasmic reticulum. Glycerol treatment did not rescue channel function nor did coexpression with CNGB3, a subunit of native hetero-tetrameric cone channels. A control mutant, C191S, exhibited cGMP current activation with significantly reduced cooperativity, suggesting that mutations in the first transmembrane domain alter in inter- or intrasubunit communication. The results implicate the first transmembrane segment in both maturation and function of CNG channels. The defects are not reversed with glycerol, a chemical chaperone that rescues channel function in some channelopathies. Molecular analysis of achromatopsia 2 mutations may be useful in evaluating potential therapeutic approaches for treatment of this channelopathy.

Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice

PubMed Central

Tong, Xiaoping; Ao, Yan; Faas, Guido C.; Nwaobi, Sinifunanya E.; Xu, Ji; Haustein, Martin D.; Anderson, Mark A.; Mody, Istvan; Olsen, Michelle L.; Sofroniew, Michael V.; Khakh, Baljit S.

2014-01-01

Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, which display mutant huntingtin in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models is not associated with classical astrogliosis, but is associated with decreased Kir4.1 K+ channel functional expression, leading to elevated in vivo levels of striatal extracellular K+, which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K+, recovered aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte–mediated K+ homeostasis, revealing astrocytes and Kir4.1 channels as novel therapeutic targets. PMID:24686787

Touch responsiveness in zebrafish requires voltage-gated calcium channel 2.1b

PubMed Central

Low, Sean E.; Woods, Ian G.; Lachance, Mathieu; Ryan, Joel; Saint-Amant, Louis

2012-01-01

The molecular and physiological basis of the touch-unresponsive zebrafish mutant fakir has remained elusive. Here we report that the fakir phenotype is caused by a missense mutation in the gene encoding voltage-gated calcium channel 2.1b (CACNA1Ab). Injection of RNA encoding wild-type CaV2.1 restores touch responsiveness in fakir mutants, whereas knockdown of CACNA1Ab via morpholino oligonucleotides recapitulates the fakir mutant phenotype. Fakir mutants display normal current-evoked synaptic communication at the neuromuscular junction but have attenuated touch-evoked activation of motor neurons. NMDA-evoked fictive swimming is not affected by the loss of CaV2.1b, suggesting that this channel is not required for motor pattern generation. These results, coupled with the expression of CACNA1Ab by sensory neurons, suggest that CaV2.1b channel activity is necessary for touch-evoked activation of the locomotor network in zebrafish. PMID:22490555

Operator-sum representation for bosonic Gaussian channels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ivan, J. Solomon; Sabapathy, Krishna Kumar; Simon, R.

2011-10-15

Operator-sum or Kraus representations for single-mode bosonic Gaussian channels are developed, and several of their consequences explored. The fact that the two-mode metaplectic operators acting as unitary purification of these channels do not, in their canonical form, mix the position and momentum variables is exploited to present a procedure which applies uniformly to all families in the Holevo classification. In this procedure the Kraus operators of every quantum-limited Gaussian channel can be simply read off from the matrix elements of a corresponding metaplectic operator. Kraus operators are employed to bring out, in the Fock basis, the manner in which themore » antilinear, unphysical matrix transposition map when accompanied by injection of a threshold classical noise becomes a physical channel, denoted D({kappa}) in the Holevo classification. The matrix transposition channels D({kappa}), D({kappa}{sup -1}) turn out to be a dual pair in the sense that their Kraus operators are related by the adjoint operation. The amplifier channel with amplification factor {kappa} and the beam-splitter channel with attenuation factor {kappa}{sup -1} turn out to be mutually dual in the same sense. The action of the quantum-limited attenuator and amplifier channels as simply scaling maps on suitable quasiprobabilities in phase space is examined in the Kraus picture. Consideration of cumulants is used to examine the issue of fixed points. The semigroup property of the amplifier and attenuator families leads in both cases to a Zeno-like effect arising as a consequence of interrupted evolution. In the cases of entanglement-breaking channels a description in terms of rank 1 Kraus operators is shown to emerge quite simply. In contradistinction, it is shown that there is not even one finite rank operator in the entire linear span of Kraus operators of the quantum-limited amplifier or attenuator families, an assertion far stronger than the statement that these are not entanglement breaking channels. A characterization of extremality in terms of Kraus operators, originally due to Choi, is employed to show that all quantum-limited Gaussian channels are extremal. The fact that almost every noisy Gaussian channel can be realized as a product of a pair of quantum-limited channels is used to construct a discrete set of linearly independent Kraus operators for these noisy Gaussian channels, including the classical noise channel, and these Kraus operators have a particularly simple structure.« less

Structural model of the SARS coronavirus E channel in LMPG micelles.

PubMed

Surya, Wahyu; Li, Yan; Torres, Jaume

2018-06-01

Coronaviruses (CoV) cause common colds in humans, but are also responsible for the recent Severe Acute, and Middle East, respiratory syndromes (SARS and MERS, respectively). A promising approach for prevention are live attenuated vaccines (LAVs), some of which target the envelope (E) protein, which is a small membrane protein that forms ion channels. Unfortunately, detailed structural information is still limited for SARS-CoV E, and non-existent for other CoV E proteins. Herein, we report a structural model of a SARS-CoV E construct in LMPG micelles with, for the first time, unequivocal intermolecular NOEs. The model corresponding to the detergent-embedded region is consistent with previously obtained orientational restraints obtained in lipid bilayers and in vivo escape mutants. The C-terminal domain is mostly α-helical, and extramembrane intermolecular NOEs suggest interactions that may affect the TM channel conformation. Copyright © 2018 Elsevier B.V. All rights reserved.

Cilnidipine, an L/N-type calcium channel blocker prevents acquisition and expression of ethanol-induced locomotor sensitization in mice.

PubMed

Bhutada, Pravinkumar; Mundhada, Yogita; Patil, Jayshree; Rahigude, Anand; Zambare, Krushna; Deshmukh, Prashant; Tanwar, Dhanshree; Jain, Kishor

2012-04-11

Several evidences indicated the involvement of L- and N-type calcium channels in behavioral effects of drugs of abuse, including ethanol. Calcium channels are implicated in ethanol-induced behaviors and neurochemical responses. Calcium channel antagonists block the psychostimulants induced behavioral sensitization. Recently, it is demonstrated that L-, N- and T-type calcium channel blockers attenuate the acute locomotor stimulant effects of ethanol. However, no evidence indicated the role of calcium channels in ethanol-induced psychomotor sensitization. Therefore, present study evaluated the influence of cilnidipine, an L/N-type calcium channel blocker on acquisition and expression of ethanol-induced locomotor sensitization. The results revealed that cilnidipine (0.1 and 1.0μg/mouse, i.c.v.) attenuates the expression of sensitization to locomotor stimulant effect of ethanol (2.0g/kg, i.p.), whereas pre- treatment of cilnidipine (0.1 and 1.0μg/mouse, i.c.v.) during development of sensitization blocks acquisition and attenuates expression of sensitization to locomotor stimulant effect of ethanol. Cilnidipine per se did not influence locomotor activity in tested doses. Further, cilnidipine had no influence on effect of ethanol on rotarod performance. These results support the hypothesis that neuroadaptive changes in calcium channels participate in the acquisition and the expression of ethanol-induced locomotor sensitization. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The nicorandil-induced vasodilation in humans is inhibited by miconazole.

PubMed

Ueda, Keiko; Goto, Chikara; Jitsuiki, Daisuke; Umemura, Takashi; Nishioka, Kenji; Kimura, Masashi; Noma, Kensuke; Nakagawa, Keigo; Oshima, Tetsuya; Yoshizumi, Masao; Chayama, Kazuaki; Higashi, Yukihito

2005-04-01

Nicorandil, N-(2-hydroxyethyl)-nicotinamide nitrate, exerts its vasodilatory effects by opening ATP-sensitive potassium (K-ATP) channels and by acting as the exogenous nitric oxide (NO). It is not clear, however, whether the actions of other endothelium-dependent vasodilators, such as NO, endothelium-derived hyperpolarizing factor (EDHF), and prostaglandins, contribute to nicorandil-induced vasodilation in the vasculature in humans. We evaluated forearm blood flow (FBF) response to intraarterial infusion of nicorandil alone and in the presence of glibenclamide, a K-ATP channel inhibitor, N(G)-monomethyl-L-arginine, an NO synthase inhibitor, indomethacin, a cyclooxygenase inhibitor, or miconazol, a cytochrome P-450 inhibitor, in 24 healthy male subjects. FBF was measured using strain-gauge plethysmography. Infusion of nicorandil significantly increased the FBF response in a dose-dependent manner. Intraarterial infusion of glibenclamide attenuated nicorandil-induced vasodilation (160.9 +/- 21.2% versus 90.2 +/- 19.4%, P < 0.01), and miconazole also attenuated the FBF response to nicorandil (160.9 +/- 21.2% versus 66.1 +/- 9.2%, P < 0.001). N-monomethyl-L-arginine or indomethacin did not alter the FBF response to nicorandil. These findings suggest that nicorandil causes vasodilation in forearm circulation in humans, at least in part through a pathway that is dependent on K-ATP channels and cytochrome P-450, but not on endogenous NO and prostaglandins. EDHF may contribute to nicorandil-induced vasodilation in humans.

Channel adjustments to historical disturbances along the lower Brazos and Sabine Rivers, south-central USA

NASA Astrophysics Data System (ADS)

Heitmuller, Franklin T.

2014-01-01

Historical channel adjustments are documented and discussed in context with anthropogenic disturbances along two meandering, coastal plain rivers - the lower Brazos and Sabine Rivers in the south-central United States. Hard-copy streamflow-measurement notes of the U.S. Geological Survey were utilized to render historical cross sections (1925-2007) at nine gauging stations, which were complemented with repeat photographs and flood-frequency analysis to assess trajectories of channel change and interpret causative mechanisms. Downstream- and upstream-propagating disturbances caused episodes of channel-bed incision and aggradation at different locations for distinct time periods along both rivers. Incision associated with upstream dams is detected, but channels are compensated downstream with sediment inputs from lateral channel migration and tributaries. In one case, temporary aggradation along the Brazos River at Waco was likely caused by a combination of dam construction and regional soil erosion. Channel-bed incision on the lowermost Brazos River is unrelated to dams, but is associated with instream aggregate extraction, possibly in conjunction with downstream channelization. On the Sabine River, extensive aggradation during the 1930s might be associated with logging activities (1880s-1930s), but whether the cause is pervasive regional-scale hillslope erosion or local-scale mill-site activities is indeterminate. Following passage of this sediment, the river generally recovered to pre-disturbance conditions and has exhibited stability despite a mainstem reservoir. Translation of this sediment slug is attenuated by a transition to a flood-prone, distributary-dominated system downstream of the Holocene-Pleistocene terrace onlap position. Additional findings include cross-channel hingepoints separating thalweg incision from simultaneous point-bar or bank accretion at meander bends, which indicates channel adjustment occurs along non-cohesive beds in preference to cohesive or artificially reinforced banks. Also, flood reduction has resulted in bankfull stages that are higher than levels associated with the post-regulation 2-year return period. Finally, vegetation encroachment along banks since the 1970s coupled with reduced flooding along the lower Brazos River has promoted bank accretion deposits that, when fully developed, serve as morphologic indicators of the post-regulation 1- to 2-year return period stage.

47 CFR 74.794 - Digital emissions.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Stringent mask. In the first 500 kHz from the channel edges, emissions must be attenuated no less than 47 dB... determined by the following formula: A(dB) = 47 + 11.5 (Δf-0.5) (iii) Full service mask: (A) The power level... first 500 kHz from the channel edge the emissions must be attenuated no less than 47 dB. More than 6 MHz...

47 CFR 74.794 - Digital emissions.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Stringent mask. In the first 500 kHz from the channel edges, emissions must be attenuated no less than 47 dB... determined by the following formula: A(dB) = 47 + 11.5 (Δf-0.5) (iii) Full service mask: (A) The power level... first 500 kHz from the channel edge the emissions must be attenuated no less than 47 dB. More than 6 MHz...

47 CFR 74.794 - Digital emissions.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) Stringent mask. In the first 500 kHz from the channel edges, emissions must be attenuated no less than 47 dB... determined by the following formula: A(dB) = 47 + 11.5 (Δf-0.5) (iii) Full service mask: (A) The power level... first 500 kHz from the channel edge the emissions must be attenuated no less than 47 dB. More than 6 MHz...

47 CFR 74.794 - Digital emissions.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) Stringent mask. In the first 500 kHz from the channel edges, emissions must be attenuated no less than 47 dB... determined by the following formula: A(dB) = 47 + 11.5 (Δf-0.5) (iii) Full service mask: (A) The power level... first 500 kHz from the channel edge the emissions must be attenuated no less than 47 dB. More than 6 MHz...

BAX channel activity mediates lysosomal disruption linked to Parkinson disease.

PubMed

Bové, Jordi; Martínez-Vicente, Marta; Dehay, Benjamin; Perier, Celine; Recasens, Ariadna; Bombrun, Agnes; Antonsson, Bruno; Vila, Miquel

2014-05-01

Lysosomal disruption is increasingly regarded as a major pathogenic event in Parkinson disease (PD). A reduced number of intraneuronal lysosomes, decreased levels of lysosomal-associated proteins and accumulation of undegraded autophagosomes (AP) are observed in PD-derived samples, including fibroblasts, induced pluripotent stem cell-derived dopaminergic neurons, and post-mortem brain tissue. Mechanistic studies in toxic and genetic rodent PD models attribute PD-related lysosomal breakdown to abnormal lysosomal membrane permeabilization (LMP). However, the molecular mechanisms underlying PD-linked LMP and subsequent lysosomal defects remain virtually unknown, thereby precluding their potential therapeutic targeting. Here we show that the pro-apoptotic protein BAX (BCL2-associated X protein), which permeabilizes mitochondrial membranes in PD models and is activated in PD patients, translocates and internalizes into lysosomal membranes early following treatment with the parkinsonian neurotoxin MPTP, both in vitro and in vivo, within a time-frame correlating with LMP, lysosomal disruption, and autophagosome accumulation and preceding mitochondrial permeabilization and dopaminergic neurodegeneration. Supporting a direct permeabilizing effect of BAX on lysosomal membranes, recombinant BAX is able to induce LMP in purified mouse brain lysosomes and the latter can be prevented by pharmacological blockade of BAX channel activity. Furthermore, pharmacological BAX channel inhibition is able to prevent LMP, restore lysosomal levels, reverse AP accumulation, and attenuate mitochondrial permeabilization and overall nigrostriatal degeneration caused by MPTP, both in vitro and in vivo. Overall, our results reveal that PD-linked lysosomal impairment relies on BAX-induced LMP, and point to small molecules able to block BAX channel activity as potentially beneficial to attenuate both lysosomal defects and neurodegeneration occurring in PD.

Management of a Complex Open Channel Network During Flood Events

NASA Astrophysics Data System (ADS)

Franchini, M.; Valiani, A.; Schippa, L.; Mascellani, G.

2003-04-01

Most part of the area around Ferrara (Italy) is below the mean sea level and an extensive drainage system combined with several pump stations allows the use of this area for both urban development and industrial and agricultural activities. The three main channels of this hydraulic system constitute the Ferrara Inland Waterway (total length approximately 70 km), which connects the Po river near Ferrara to the sea. Because of the level difference between the upstream and dowstream ends of the waterway, three locks are located along it, each of them combined with a set of gates to control the water levels. During rainfall events, most of the water of the basin flows into the waterway and heavy precipitations sometimes cause flooding in several areas. This is due to the insufficiency of the channel network dimensions and an inadequate manual operation of the gates. This study presents a hydrological-hydraulic model for the entire Ferrara basin and a system of rules in order to operate the gates. In particular, their opening is designed to be regulated in real time by monitoring the water level in several sections along the channels. Besides flood peak attenuation, this operation strategy contributes also to the maintenance of a constant water level for irrigation and fluvial navigation during the dry periods. With reference to the flood event of May 1996, it is shown that this floodgate operation policy, unlike that which was actually adopted during that event, would lead to a significant flood peak attenuation, avoiding flooding in the area upstream of Ferrara.

Urban Infrastructure, Channel-Floodplain Morphology and Flood Flow Patterns

NASA Astrophysics Data System (ADS)

Miller, A. J.; Smith, J. A.; Nelson, C. B.

2006-12-01

The relationship between the channel and the floodplain in urban settings is heavily influenced by (1) altered watershed hydrologic response and frequency distribution of flows, (2) channel enlargement resulting from altered hydrology under conditions of limited sediment supply, (3) direct modification of channels and floodplains for purposes of erosion mitigation, flood protection, commercial development and creation of public amenities, (4) valley constrictions and flow obstructions associated with bridges, culverts, road embankments and other types of floodplain encroachment causing fragmentation or longitudinal segmentation of the riparian corridor. Field observation of inundation patterns associated with recurring floods in the Baltimore metropolitan area is used in combination with 2-dimensional hydraulic modeling to simulate patterns of floodplain inundation and to explore the relationships between magnitude and shape of the flood hydrograph, morphology of the urban channel-floodplain system, and the frequency and extent of floodplain inundation. Case studies include a July 2004 flood associated with a 300-year 2-hour rainfall in a small (14.2 km2) urban watershed, as well as several other events caused by summer thunderstorms with shorter recurrence intervals that generated an extraordinary flood response. The influence of urban infrastructure on flood inundation and flow patterns is expressed in terms of altered (and hysteretic) stage-discharge relationships, stepped flood profiles, rapid longitudinal attenuation of flood waves, and transient flow reversals at confluences and constrictions. Given the current level of interest in restoration measures these patterns merit consideration in planning future development and mitigation efforts.

Presynaptic inhibition of transmitter release from rat sympathetic neurons by bradykinin.

PubMed

Edelbauer, Hannah; Lechner, Stefan G; Mayer, Martina; Scholze, Thomas; Boehm, Stefan

2005-06-01

Bradykinin is known to stimulate neurons in rat sympathetic ganglia and to enhance transmitter release from their axons by interfering with the autoinhibitory feedback, actions that involve protein kinase C. Here, bradykinin caused a transient increase in the release of previously incorporated [3H] noradrenaline from primary cultures of dissociated rat sympathetic neurons. When this effect was abolished by tetrodotoxin, bradykinin caused an inhibition of tritium overflow triggered by depolarizing K+ concentrations. This inhibition was additive to that caused by the alpha2-adrenergic agonist UK 14304, desensitized within 12 min, was insensitive to pertussis toxin, and was enhanced when protein kinase C was inactivated. The effect was half maximal at 4 nm and antagonized competitively by the B2 receptor antagonist Hoe 140. The cyclooxygenase inhibitor indomethacin and the angiotensin converting enzyme inhibitor captopril did not alter the inhibition by bradykinin. The M-type K+ channel opener retigabine attenuated the secretagogue action of bradykinin, but left its inhibitory action unaltered. In whole-cell patch-clamp recordings, bradykinin reduced voltage-activated Ca2+ currents in a pertussis toxin-insensitive manner, and this action was additive to the inhibition by UK 14304. These results demonstrate that bradykinin inhibits noradrenaline release from rat sympathetic neurons via presynaptic B2 receptors. This effect does not involve cyclooxygenase products, M-type K+ channels, or protein kinase C, but rather an inhibition of voltage-gated Ca2+ channels.

Probing free-space quantum channels with laboratory-based experiments

NASA Astrophysics Data System (ADS)

Bohmann, M.; Kruse, R.; Sperling, J.; Silberhorn, C.; Vogel, W.

2017-06-01

Atmospheric channels are a promising candidate to establish secure quantum communication on a global scale. However, due to their turbulent nature, it is crucial to understand the impact of the atmosphere on the quantum properties of light and examine it experimentally. In this paper, we introduce a method to probe atmospheric free-space links with quantum light on a laboratory scale. In contrast to previous works, our method models arbitrary intensity losses caused by turbulence to emulate general atmospheric conditions. This allows us to characterize turbulent quantum channels in a well-controlled manner. To implement this technique, we perform a series of measurements with different constant attenuations and simulate the fluctuating losses by combining the obtained data. We directly test the proposed method with an on-chip source of nonclassical light and a time-bin-multiplexed detection system. With the obtained data, we characterize the nonclassicality of the generated states for different atmospheric noise models and analyze a postselection protocol. This general technique in atmospheric quantum optics allows for studying turbulent quantum channels and predicting their properties for future applications.

Activity-dependent downregulation of M-Type (Kv7) K⁺ channels surface expression requires the activation of iGluRs/Ca²⁺/PKC signaling pathway in hippocampal neuron.

PubMed

Li, Cai; Lu, Qing; Huang, Pengcheng; Fu, Tianli; Li, Changjun; Guo, Lianjun; Xu, Xulin

2015-08-01

M-type (Kv7) K(+) channels, encoded by KCNQ2-KCNQ5 genes, play a pivotal role in controlling neuronal excitability. However, precisely how neuronal activity regulates Kv7 channel translocation has not yet been fully defined. Here we reported activity-dependent changes in Kv7 channel subunits Kv7.2 and Kv7.3 surface expression by glutamate (glu). In the present study, we found that treatment with glutamate rapidly caused a specific decrease in M-current as well as Kv7 channel surface expression in primary cultured hippocampal neurons. The glutamate effects were mimicked by NMDA and AMPA. The glutamate effects on Kv7 channels were partially attenuated by pre-treatment of NMDA receptors antagonist d,l-APV or AMPA-KA receptors antagonist CNQX. The signal required Ca(2+) influx through L-type Ca(2+) channel and intracellular Ca(2+) elevations. PKC activation was involved in the glutamate-induced reduction of Kv7 channel surface expression. Moreover, a significant reduction of Kv7 channel surface expression occurred following glycine-induced "chem"-LTP in vitro and hippocampus-dependent behavioral learning training in vivo. These results demonstrated that activity-dependent reduction of Kv7 channel surface expression through activation of ionotropic glutamate receptors (iGluRs)/Ca(2+)/PKC signaling pathway might be an important molecular mechanism for regulation of neuronal excitability and synaptic plasticity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mitragynine and its potential blocking effects on specific cardiac potassium channels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tay, Yea Lu; Teah, Yi Fan; Chong, Yoong Min

2016-08-15

Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac I{sub Kr} current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, I{sub K1}, a Kir current mediated by Kir2.1 channel and I{sub KACh}, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on themore » current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC{sub 50} value of 1.62 μM and 1.15 μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit I{sub KACh} current with an IC{sub 50} value of 3.32 μM but has no significant effects on I{sub K1}. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks. - Highlights: • The potential cardiac potassium channel blocking properties of mitragynine were investigated. • Mitragynine blocks hERG channel and I{sub Kr} in hERG-transfected HEK293 cells and hERG cRNA-injected Xenopus oocytes. • Mitragynine inhibits the hERG protein but not the mRNA expression. • Mitragynine inhibits GIRK channel. • Simultaneous hERG and GIRK channel blockade may cause additive cardiotoxicity risks.« less

Energy absorber for sodium-heated heat exchanger

DOEpatents

Essebaggers, J.

1975-12-01

A heat exchanger is described in which water-carrying tubes are heated by liquid sodium and in which the results of accidental contact between the water and the sodium caused by failure of one or more of the water tubes is minimized. An energy absorbing chamber contains a compressible gas and is connected to the body of flowing sodium by a channel so that, in the event of a sodium-water reaction, products of the reaction will partially fill the energy absorbing chamber to attenuate the rise in pressure within the heat exchanger.

SPM and XPM crosstalk in WDM systems with DRA: Channel spacing and attenuation effects

NASA Astrophysics Data System (ADS)

Morsy, Emadeldeen; Fayed, Heba A.; Abd El Aziz, Ahmed; Aly, Moustafa H.

2018-06-01

This paper presents a theoretical analysis of a closed formula for nonlinear crosstalk due to self-phase modulation (SPM) and cross phase modulation (XPM) in wavelength division multiplexing (WDM) systems. The influence of channel spacing and attenuation on the system behavior is modeled and investigated. The system under consideration is a standard single-mode fiber (SSMF) with a single-span distributed Raman amplifier (DRA) and is operating at 100 Gbps.

Measurement and analysis of channel attenuation characteristics for an implantable galvanic coupling human-body communication.

PubMed

Zhang, Shuang; Pun, Sio Hang; Mak, Peng Un; Qin, Yu-Ping; Liu, Yi-He; Vai, Mang I

2016-11-14

In this study, an experiment was designed to verify the low power consumption of galvanic coupling human-body communication. A silver electrode (silver content: 99%) is placed in a pig leg and a sine wave signal with the power of 0 dBm is input. Compared with radio frequency communication and antenna transmission communication, attenuation is reduced by approximately 10 to 15 dB, so channel characteristics are highly improved.

A numerical investigation of the impacts of river and floodplain restoration on the process of floodwave attenuation

NASA Astrophysics Data System (ADS)

Stone, M. C.; Byrne, C.; Morrison, R.

2015-12-01

It is widely recognized that past river engineering, flood control, and floodplain development activities have tended to work against nature rather than with it. The consequence in many cases has been severe degradation of our natural ecosystems. This, combined with an increased appreciation for the benefits of properly functioning ecosystems, has prompted efforts to restore rivers to a more natural state. However, most restoration projects currently focus on a narrow set of goals, such as endangered species recovery or channel stabilization. In order to shift the restoration community towards more holistic perspectives and approaches, it is necessary to improve understanding of river and floodplain hydrogeomorphic processes and their role in supporting healthy ecosystems. The goal of this research was to investigate the impacts of river engineering and restoration practices on the process of floodwave attenuation. This goal was addressed through numerical investigations that allowed us to: (1) quantify mass and momentum fluxes between river channels and floodplains; (2) investigate the influence of mass and momentum fluxes on floodwave attenuation processes; and (3) evaluate the impacts of river and floodplain restoration on floodwave attenuation. Two-dimensional hydrodynamic models were applied to the Rio Grande, San Joaquin, and Gila rivers in the Southwestern United States using novel modeling approaches to describe dynamic floodplain roughness, fluxes at channel/floodplain interfaces, and attenuation along river corridors. The results provide important insights into the role of floodplain characteristics on floodwave movement and the potential for enhancing floodwave attenuation through river restoration.

Anatomy of a Flash Flood in the Amargosa Desert, U.S.A.

NASA Astrophysics Data System (ADS)

Stonestrom, D. A.; Prudic, D. E.; Glancy, P. A.; Beck, D. A.

2004-12-01

In August 2004, intense convective rainstorms caused flash flooding throughout the Amargosa River drainage network, temporarily closing Death Valley National Park and causing two fatalities when runoff from Furnace Creek and other channels overtopped roadways in the Park. In 1998, we began installing streambed temperature loggers, pressure transducers, and scour chains in the normally dry channel and selected tributaries of the river in the Amargosa Desert and Oasis Valley. The primary objective of this work is to improve understanding of ground-water recharge from ephemeral streamflows under current climatic conditions. Two weeks after the flash flooding, we visited instrumented sites and estimated peak flows by surveying high-water marks and corresponding channel geometries. Time series of temperatures and stages, together with peak-flow estimates, reveal the routing and evolution of distinct flood pulses in the upper Amargosa River basin. The data also reveal previously undocumented details of individual flash-flood hydrographs, including initial and subsequent flood pulses at two sites. Arid environments are prone to flash flooding not only because vegetation is sparse, but also because the surface-water network is decoupled from underlying ground water by a thick unsaturated zone. Nonlinear interactions between runoff (with energy potentials on the order of a meter of head) and the unsaturated zone (with energy potentials on the order of negative hundreds of meters of head) keep advancing fronts of flood pulses sharp. Profiles of water content beneath the main channel before and after the passage of a flood pulse, together with down-channel attenuation of flow volume within individual pulses, show the leaky nature of dry alluvial channels and the efficiency at which flash floods become potential recharge.

TRPA1 channel mediates organophosphate-induced delayed neuropathy

PubMed Central

Ding, Qiang; Fang, Sui; Chen, Xueqin; Wang, Youxin; Li, Jian; Tian, Fuyun; Xu, Xiang; Attali, Bernard; Xie, Xin; Gao, Zhaobing

2017-01-01

The organophosphate-induced delayed neuropathy (OPIDN), often leads to paresthesias, ataxia and paralysis, occurs in the late-stage of acute poisoning or after repeated exposures to organophosphate (OP) insecticides or nerve agents, and may contribute to the Gulf War Syndrome. The acute phase of OP poisoning is often attributed to acetylcholinesterase inhibition. However, the underlying mechanism for the delayed neuropathy remains unknown and no treatment is available. Here we demonstrate that TRPA1 channel (Transient receptor potential cation channel, member A1) mediates OPIDN. A variety of OPs, exemplified by malathion, activates TRPA1 but not other neuronal TRP channels. Malathion increases the intracellular calcium levels and upregulates the excitability of mouse dorsal root ganglion neurons in vitro. Mice with repeated exposures to malathion also develop local tissue nerve injuries and pain-related behaviors, which resembles OPIDN. Both the neuropathological changes and the nocifensive behaviors can be attenuated by treatment of TRPA1 antagonist HC030031 or abolished by knockout of Trpa1 gene. In the classic hens OPIDN model, malathion causes nerve injuries and ataxia to a similar level as the positive inducer tri-ortho-cresyl phosphate (TOCP), which also activates TRPA1 channel. Treatment with HC030031 reduces the damages caused by malathion or tri-ortho-cresyl phosphate. Duloxetine and Ketotifen, two commercially available drugs exhibiting TRPA1 inhibitory activity, show neuroprotective effects against OPIDN and might be used in emergency situations. The current study suggests TRPA1 is the major mediator of OPIDN and targeting TRPA1 is an effective way for the treatment of OPIDN. PMID:28894590

An improved ultra wideband channel model including the frequency-dependent attenuation for in-body communications.

PubMed

Khaleghi, A; Chávez-Santiago, R; Balasingham, I

2012-01-01

Ultra wideband (UWB) technology has big potential for applications in wireless body area networks (WBANs). The inherent characteristics of UWB signals make them suitable for the wireless interface of medical sensors. In particular, implanted medical wireless sensors for monitoring physiological parameters, automatic drug provision, etc. can benefit greatly from this ultra low power (ULP) interface. As with any other wireless technology, accurate knowledge of the channel is necessary for the proper design of communication systems. Only a few models that describe the radio propagation inside the human body have been published. Moreover, there is no comprehensive UWB in-body propagation model that includes the frequency-dependent attenuation. Hence, this paper extends a statistical model for UWB propagation channels inside the human chest in the 1-6 GHz frequency range by including the frequency-dependent attenuation. This is done by modeling the spectrum shape of distorted pulses at different depths inside the human chest. The distortion of the pulse was obtained through numerical simulations using a voxel representation of the human body. We propose a mathematical expression for the spectrum shape of the distorted pulses that act as a window function to reproduce the effects of frequency-dependent attenuation.

Critical band masking reveals the effects of optical distortions on the channel mediating letter identification.

PubMed

Young, Laura K; Smithson, Hannah E

2014-01-01

There is evidence that letter identification is mediated by only a narrow band of spatial frequencies and that the center frequency of the neural channel thought to underlie this selectivity is related to the size of the letters. When letters are spatially filtered (at a fixed size) the channel tuning characteristics change according to the properties of the spatial filter (Majaj et al., 2002). Optical aberrations in the eye act to spatially filter the image formed on the retina-their effect is generally to attenuate high frequencies more than low frequencies but often in a non-monotonic way. We might expect the change in the spatial frequency spectrum caused by the aberration to predict the shift in channel tuning observed for aberrated letters. We show that this is not the case. We used critical-band masking to estimate channel-tuning in the presence of three types of aberration-defocus, coma and secondary astigmatism. We found that the maximum masking was shifted to lower frequencies in the presence of an aberration and that this result was not simply predicted by the spatial-frequency-dependent degradation in image quality, assessed via metrics that have previously been shown to correlate well with performance loss in the presence of an aberration. We show that if image quality effects are taken into account (using visual Strehl metrics), the neural channel required to model the data is shifted to lower frequencies compared to the control (no-aberration) condition. Additionally, we show that when spurious resolution (caused by π phase shifts in the optical transfer function) in the image is masked, the channel tuning properties for aberrated letters are affected, suggesting that there may be interference between visual channels. Even in the presence of simulated aberrations, whose properties change from trial-to-trial, observers exhibit flexibility in selecting the spatial frequencies that support letter identification.

A Parametric Computational Analysis into Galvanic Coupling Intrabody Communication.

PubMed

Callejon, M Amparo; Del Campo, P; Reina-Tosina, Javier; Roa, Laura M

2017-08-02

Intrabody Communication (IBC) uses the human body tissues as transmission media for electrical signals to interconnect personal health devices in wireless body area networks. The main goal of this work is to conduct a computational analysis covering some bioelectric issues that still have not been fully explained, such as the modeling of the skin-electrode impedance, the differences associated to the use of constant voltage or current excitation modes, or the influence on attenuation of the subject's anthropometrical and bioelectric properties. With this aim, a computational finite element model has been developed, allowing the IBC channel attenuation as well as the electric field and current density through arm tissues to be computed as a function of these parameters. As a conclusion, this parametric analysis has in turn permitted us to disclose some knowledge about the causes and effects of the above-mentioned issues, thus explaining and complementing previous results reported in the literature.

Integrated PET/MR breast cancer imaging: Attenuation correction and implementation of a 16-channel RF coil

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oehmigen, Mark, E-mail: mark.oehmigen@uni-due.de

Purpose: This study aims to develop, implement, and evaluate a 16-channel radiofrequency (RF) coil for integrated positron emission tomography/magnetic resonance (PET/MR) imaging of breast cancer. The RF coil is designed for optimized MR imaging performance and PET transparency and attenuation correction (AC) is applied for accurate PET quantification. Methods: A 16-channel breast array RF coil was designed for integrated PET/MR hybrid imaging of breast cancer lesions. The RF coil features a lightweight rigid design and is positioned with a spacer at a defined position on the patient table of an integrated PET/MR system. Attenuation correction is performed by generating andmore » applying a dedicated 3D CT-based template attenuation map. Reposition accuracy of the RF coil on the system patient table while using the positioning frame was tested in repeated measurements using MR-visible markers. The MR, PET, and PET/MR imaging performances were systematically evaluated using modular breast phantoms. Attenuation correction of the RF coil was evaluated with difference measurements of the active breast phantoms filled with radiotracer in the PET detector with and without the RF coil in place, serving as a standard of reference measurement. The overall PET/MR imaging performance and PET quantification accuracy of the new 16-channel RF coil and its AC were then evaluated in first clinical examinations on ten patients with local breast cancer. Results: The RF breast array coil provides excellent signal-to-noise ratio and signal homogeneity across the volume of the breast phantoms in MR imaging and visualizes small structures in the phantoms down to 0.4 mm in plane. Difference measurements with PET revealed a global loss and thus attenuation of counts by 13% (mean value across the whole phantom volume) when the RF coil is placed in the PET detector. Local attenuation ranging from 0% in the middle of the phantoms up to 24% was detected in the peripheral regions of the phantoms at positions closer to attenuating hardware structures of the RF coil. The position accuracy of the RF coil on the patient table when using the positioning frame was determined well below 1 mm for all three spatial dimensions. This ensures perfect position match between the RF coil and its three-dimensional attenuation template during the PET data reconstruction process. When applying the CT-based AC of the RF coil, the global attenuation bias was mostly compensated to ±0.5% across the entire breast imaging volume. The patient study revealed high quality MR, PET, and combined PET/MR imaging of breast cancer. Quantitative activity measurements in all 11 breast cancer lesions of the ten patients resulted in increased mean difference values of SUV{sub max} 11.8% (minimum 3.2%; maximum 23.2%) between nonAC images and images when AC of the RF breast coil was applied. This supports the quantitative results of the phantom study as well as successful attenuation correction of the RF coil. Conclusions: A 16-channel breast RF coil was designed for optimized MR imaging performance and PET transparency and was successfully integrated with its dedicated attenuation correction template into a whole-body PET/MR system. Systematic PET/MR imaging evaluation with phantoms and an initial study on patients with breast cancer provided excellent MR and PET image quality and accurate PET quantification.« less

Impact of stream restoration on flood waves

NASA Astrophysics Data System (ADS)

Sholtes, J.; Doyle, M.

2008-12-01

Restoration of channelized or incised streams has the potential to reduce downstream flooding via storing and dissipating the energy of flood waves. Restoration design elements such as restoring meanders, reducing slope, restoring floodplain connectivity, re-introducing in-channel woody debris, and re-vegetating banks and the floodplain have the capacity to attenuate flood waves via energy dissipation and channel and floodplain storage. Flood discharge hydrographs measured up and downstream of several restored reaches of varying stream order and located in both urban and rural catchments are coupled with direct measurements of stream roughness at various stages to directly measure changes to peak discharge, flood wave celerity, and dispersion. A one-dimensional unsteady flow routing model, HEC-RAS, is calibrated and used to compare attenuation characteristics between pre and post restoration conditions. Modeled sensitivity results indicate that a restoration project placed on a smaller order stream demonstrates the highest relative reduction in peak discharge of routed flood waves compared to one of equal length on a higher order stream. Reductions in bed slope, extensions in channel length, and increases in channel and floodplain roughness follow restoration placement with the watershed in relative importance. By better understanding how design, scale, and location of restored reaches within a catchment hydraulically impact flood flows, this study contributes both to restoration design and site decision making. It also quantifies the effect of reach scale stream restoration on flood wave attenuation.

Attenuation and bit error rate for four co-propagating spatially multiplexed optical communication channels of exactly same wavelength in step index multimode fibers

NASA Astrophysics Data System (ADS)

Murshid, Syed H.; Chakravarty, Abhijit

2011-06-01

Spatial domain multiplexing (SDM) utilizes co-propagation of exactly the same wavelength in optical fibers to increase the bandwidth by integer multiples. Input signals from multiple independent single mode pigtail laser sources are launched at different input angles into a single multimode carrier fiber. The SDM channels follow helical paths and traverse through the carrier fiber without interfering with each other. The optical energy from the different sources is spatially distributed and takes the form of concentric circular donut shaped rings, where each ring corresponds to an independent laser source. At the output end of the fiber these donut shaped independent channels can be separated either with the help of bulk optics or integrated concentric optical detectors. This presents the experimental setup and results for a four channel SDM system. The attenuation and bit error rate for individual channels of such a system is also presented.

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

PubMed Central

Nesin, Vasyl; Wiley, Graham; Kousi, Maria; Ong, E-Ching; Lehmann, Thomas; Nicholl, David J.; Suri, Mohnish; Shahrizaila, Nortina; Katsanis, Nicholas; Gaffney, Patrick M.; Wierenga, Klaas J.; Tsiokas, Leonidas

2014-01-01

Signaling through the store-operated Ca2+ release-activated Ca2+ (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca2+ homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca2+ sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca2+-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca2+ entry in the treatment of patients with Stormorken syndrome and related pathologic conditions. PMID:24591628

Use of acoustic classification of sidescan sonar data for mapping benthic habitat in the Northern Channel Islands, California

USGS Publications Warehouse

Cochrane, Guy R.; Lafferty, Kevin D.

2002-01-01

Highly reflective seafloor features imaged by sidescan sonar in nearshore waters off the Northern Channel Islands (California, USA) have been observed in subsequent submersible dives to be areas of thin sand covering bedrock. Adjacent areas of rocky seafloor, suitable as habitat for endangered species of abalone and rockfish, and encrusting organisms, cannot be differentiated from the areas of thin sand on the basis of acoustic backscatter (i.e. grey level) alone. We found second-order textural analysis of sidescan sonar data useful to differentiate the bottom types where data is not degraded by near-range distortion (caused by slant-range and ground-range corrections), and where data is not degraded by far-range signal attenuation. Hand editing based on submersible observations is necessary to completely convert the sidescan sonar image to a bottom character classification map suitable for habitat mapping.

Evaluation of an in vitro cell assay to select attenuated bacterial mutants of Aeromonas hydrophila and Edwardsiella tarda to channel catfish

USDA-ARS?s Scientific Manuscript database

To evaluate the feasibility of using an in vitro cell assay to select attenuated bacterial mutants. Using catfish gill cells G1B, the feasibility of using an in vitro assay instead of in vivo virulence assay using live fish to select attenuated bacterial mutants was evaluated in this study. Pearson ...

Animal model for angiotensin II effects in the internal anal sphincter smooth muscle: mechanism of action.

PubMed

Fan, Ya-Ping; Puri, Rajinder N; Rattan, Satish

2002-03-01

Effect of ANG II was investigated in in vitro smooth muscle strips and in isolated smooth muscle cells (SMC). Among different species, rat internal and sphincter (IAS) smooth muscle showed significant and reproducible contraction that remained unmodified by different neurohumoral inhibitors. The AT(1) antagonist losartan but not AT(2) antagonist PD-123319 antagonized ANG II-induced contraction of the IAS smooth muscle and SMC. ANG II-induced contraction of rat IAS smooth muscle and SMC was attenuated by tyrosine kinase inhibitors genistein and tyrphostin, protein kinase C (PKC) inhibitor H-7, Ca(2+) channel blocker nicardipine, Rho kinase inhibitor Y-27632 or p(44/42) mitogen-activating protein kinase (MAPK(44/42)) inhibitor PD-98059. Combinations of nicardipine and H-7, Y-27632, and PD-98059 caused further attenuation of the ANG II effects. Western blot analyses revealed the presence of both AT(1) and AT(2) receptors. We conclude that ANG II causes contraction of rat IAS smooth muscle by the activation of AT(1) receptors at the SMC and involves multiple intracellular pathways, influx of Ca(2+), and activation of PKC, Rho kinase, and MAPK(44/42).

Inward rectifier potassium (Kir2.1) channels as end-stage boosters of endothelium-dependent vasodilators.

PubMed

Sonkusare, Swapnil K; Dalsgaard, Thomas; Bonev, Adrian D; Nelson, Mark T

2016-06-15

Increase in endothelial cell (EC) calcium activates calcium-sensitive intermediate and small conductance potassium (IK and SK) channels, thereby causing hyperpolarization and endothelium-dependent vasodilatation. Endothelial cells express inward rectifier potassium (Kir) channels, but their role in endothelium-dependent vasodilatation is not clear. In the mesenteric arteries, only ECs, but not smooth muscle cells, displayed Kir currents that were predominantly mediated by the Kir2.1 isoform. Endothelium-dependent vasodilatations in response to muscarinic receptor, TRPV4 (transient receptor potential vanilloid 4) channel and IK/SK channel agonists were highly attenuated by Kir channel inhibitors and by Kir2.1 channel knockdown. These results point to EC Kir channels as amplifiers of vasodilatation in response to increases in EC calcium and IK/SK channel activation and suggest that EC Kir channels could be targeted to treat endothelial dysfunction, which is a hallmark of vascular disorders. Endothelium-dependent vasodilators, such as acetylcholine, increase intracellular Ca(2+) through activation of transient receptor potential vanilloid 4 (TRPV4) channels in the plasma membrane and inositol trisphosphate receptors in the endoplasmic reticulum, leading to stimulation of Ca(2+) -sensitive intermediate and small conductance K(+) (IK and SK, respectively) channels. Although strong inward rectifier K(+) (Kir) channels have been reported in the native endothelial cells (ECs) their role in EC-dependent vasodilatation is not clear. Here, we test the idea that Kir channels boost the EC-dependent vasodilatation of resistance-sized arteries. We show that ECs, but not smooth muscle cells, of small mesenteric arteries have Kir currents, which are substantially reduced in EC-specific Kir2.1 knockdown (EC-Kir2.1(-/-) ) mice. Elevation of extracellular K(+) to 14 mm caused vasodilatation of pressurized arteries, which was prevented by endothelial denudation and Kir channel inhibitors (Ba(2+) , ML-133) or in the arteries from EC-Kir2.1(-/-) mice. Potassium-induced dilatations were unaffected by inhibitors of TRPV4, IK and SK channels. The Kir channel blocker, Ba(2+) , did not affect currents through TRPV4, IK or SK channels. Endothelial cell-dependent vasodilatations in response to activation of muscarinic receptors, TRPV4 channels or IK/SK channels were reduced, but not eliminated, by Kir channel inhibitors or EC-Kir2.1(-/-) . In angiotensin II-induced hypertension, the Kir channel function was not altered, although the endothelium-dependent vasodilatation was severely impaired. Our results support the concept that EC Kir2 channels boost vasodilatory signals that are generated by Ca(2+) -dependent activation of IK and SK channels. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Inward rectifier potassium (Kir2.1) channels as end‐stage boosters of endothelium‐dependent vasodilators

PubMed Central

Dalsgaard, Thomas; Bonev, Adrian D.; Nelson, Mark T.

2016-01-01

Key points Increase in endothelial cell (EC) calcium activates calcium‐sensitive intermediate and small conductance potassium (IK and SK) channels, thereby causing hyperpolarization and endothelium‐dependent vasodilatation.Endothelial cells express inward rectifier potassium (Kir) channels, but their role in endothelium‐dependent vasodilatation is not clear.In the mesenteric arteries, only ECs, but not smooth muscle cells, displayed Kir currents that were predominantly mediated by the Kir2.1 isoform.Endothelium‐dependent vasodilatations in response to muscarinic receptor, TRPV4 (transient receptor potential vanilloid 4) channel and IK/SK channel agonists were highly attenuated by Kir channel inhibitors and by Kir2.1 channel knockdown.These results point to EC Kir channels as amplifiers of vasodilatation in response to increases in EC calcium and IK/SK channel activation and suggest that EC Kir channels could be targeted to treat endothelial dysfunction, which is a hallmark of vascular disorders. Abstract Endothelium‐dependent vasodilators, such as acetylcholine, increase intracellular Ca2+ through activation of transient receptor potential vanilloid 4 (TRPV4) channels in the plasma membrane and inositol trisphosphate receptors in the endoplasmic reticulum, leading to stimulation of Ca2+‐sensitive intermediate and small conductance K+ (IK and SK, respectively) channels. Although strong inward rectifier K+ (Kir) channels have been reported in the native endothelial cells (ECs) their role in EC‐dependent vasodilatation is not clear. Here, we test the idea that Kir channels boost the EC‐dependent vasodilatation of resistance‐sized arteries. We show that ECs, but not smooth muscle cells, of small mesenteric arteries have Kir currents, which are substantially reduced in EC‐specific Kir2.1 knockdown (EC‐Kir2.1 −/−) mice. Elevation of extracellular K+ to 14 mm caused vasodilatation of pressurized arteries, which was prevented by endothelial denudation and Kir channel inhibitors (Ba2+, ML‐133) or in the arteries from EC‐Kir2.1 −/− mice. Potassium‐induced dilatations were unaffected by inhibitors of TRPV4, IK and SK channels. The Kir channel blocker, Ba2+, did not affect currents through TRPV4, IK or SK channels. Endothelial cell‐dependent vasodilatations in response to activation of muscarinic receptors, TRPV4 channels or IK/SK channels were reduced, but not eliminated, by Kir channel inhibitors or EC‐Kir2.1 −/−. In angiotensin II‐induced hypertension, the Kir channel function was not altered, although the endothelium‐dependent vasodilatation was severely impaired. Our results support the concept that EC Kir2 channels boost vasodilatory signals that are generated by Ca2+‐dependent activation of IK and SK channels. PMID:26840527

Blockade and knock-out of CALHM1 channels attenuate ischemic brain damage.

PubMed

Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Ruiz, Asier; Chara, Juan C; Pérez-Samartín, Alberto; Marambaud, Philippe; Matute, Carlos

2018-06-01

Overactivation of purinergic receptors during cerebral ischemia results in a massive release of neurotransmitters, including adenosine triphosphate (ATP), to the extracellular space which leads to cell death. Some hypothetical pathways of ATP release are large ion channels, such as calcium homeostasis modulator 1 (CALHM1), a membrane ion channel that can permeate ATP. Since this transmitter contributes to postischemic brain damage, we hypothesized that CALHM1 activation may be a relevant target to attenuate stroke injury. Here, we analyzed the contribution of CALHM1 to postanoxic depolarization after ischemia in cultured neurons and in cortical slices. We observed that the onset of postanoxic currents in neurons in those preparations was delayed after its blockade with ruthenium red or silencing of Calhm1 gene by short hairpin RNA, as well as in slices from CALHM1 knockout mice. Subsequently, we used transient middle cerebral artery occlusion and found that ruthenium red, a blocker of CALHM1, or the lack of CALHM1, substantially attenuated the motor symptoms and reduced significantly the infarct volume. These results show that CALHM1 channels mediate postanoxic depolarization in neurons and brain damage after ischemia. Therefore, targeting CALHM1 may have a high therapeutic potential for treating brain damage after ischemia.

Reach-Scale Channel Adjustments to Channel Network Geometry in Mountain Bedrock Streams

NASA Astrophysics Data System (ADS)

Plitzuweit, S. J.; Springer, G. S.

2008-12-01

Channel network geometry (CNG) is a critical determinant of hydrological response and may significantly affect incision processes within the Appalachian Plateau near Richwood, West Virginia. The Williams, Cherry, and Cranberry Rivers share drainage divides and their lower reaches flow atop resistant, quartz-rich sandstones. The lower two-thirds of the Cranberry and Williams Rivers display linear profiles atop the sandstones; whereas the Cherry is concave upwards atop the sandstones. Because lithologies and geological structures are similar among the watersheds, we tested whether differences in CNGs explain the profile shapes and reach-scale channel properties. Specifically, we quantified CNG by calculating reach- specific area-distance functions using DEMs. The area-distance functions were then converted into synthetic hydrographs to model hydrological responses. The Cherry River exhibits a classic dendritic drainage pattern, producing peaked hydrographs and low interval transit times. The Cranberry River displays a trellis-like drainage pattern, which produces attenuated hydrographs and high interval transit times. The upstream reaches of the Williams River have a dendritic drainage pattern, but the lower two-thirds of the watershed transitions into an elongated basin with trellis-like CNG. Reach gradients are steeper in the lower reaches of the Williams and Cranberry Rivers where hydrographs are attenuated. In contrast, peaked hydrographs within the Cherry River are associated with lower reach gradients despite resistant sandstone channel beds. Trellis-like CNG may restrict the ability of downstream reaches within the Williams and Cranberry Rivers to achieve the critical discharge needed to cause incision during floods (all other things being equal). If so, increased reach gradients may be hydraulic adjustments that compensate for comparatively low discharges. We are now applying the synthetic hydrographs to HEC-RAS flow models generated from field channel surveys in order to analyze whether stream power and shear stress are adjusted to reflect CNG at the reach- scale. These models are compared to those with discharges calculated using drainage area and precipitation totals alone. We conclude that gradients in bedrock mountain streams may reflect basin-scale hydrology (CNG) and not simply local geological or geomorphic factors. This challenges the conclusions of others who ascribe local channel adjustments to: i) lithology and structure alone, or ii) local colluvium grain sizes.

Detectability index of differential phase contrast CT compared with conventional CT: a preliminary channelized Hotelling observer study

NASA Astrophysics Data System (ADS)

Tang, Xiangyang; Yang, Yi; Tang, Shaojie

2013-03-01

Under the framework of model observer with signal and background exactly known (SKE/BKE), we investigate the detectability of differential phase contrast CT compared with that of the conventional attenuation-based CT. Using the channelized Hotelling observer and the radially symmetric difference-of-Gaussians channel template , we investigate the detectability index and its variation over the dimension of object and detector cells. The preliminary data show that the differential phase contrast CT outperforms the conventional attenuation-based CT significantly in the detectability index while both the object to be detected and the cell of detector used for data acquisition are relatively small. However, the differential phase contrast CT's dominance in the detectability index diminishes with increasing dimension of either object or detector cell, and virtually disappears while the dimension of object or detector cell approaches a threshold, respectively. It is hoped that the preliminary data reported in this paper may provide insightful understanding of the differential phase contrast CT's characteristic in the detectability index and its comparison with that of the conventional attenuation-based CT.

[6]-Gingerol induces bone loss in ovary intact adult mice and augments osteoclast function via the transient receptor potential vanilloid 1 channel.

PubMed

Khan, Kainat; Singh, Akanksha; Mittal, Monika; Sharan, Kunal; Singh, Nidhi; Dixit, Preety; Sanyal, Sabyasachi; Maurya, Rakesh; Chattopadhyay, Naibedya

2012-12-01

[6]-Gingerol, a major constituent of ginger, is considered to have several health beneficial effects. The effect of 6-gingerol on bone cells and skeleton of mice was investigated. The effects of 6-gingerol on mouse bone marrow macrophages and osteoblasts were studied. 6-Gingerol-stimulated osteoclast differentiation of bone marrow macrophages but had no effect on osteoblasts. Capsazepine, an inhibitor of TRPV1 (transient receptor potential vanilloid 1) channel, attenuated the pro-osteoclastogenic effect of 6-gingerol or capsaicin (an agonist of TRPV1). Similar to capsaicin, 6-gingerol stimulated Ca(2) + influx in osteoclasts. The effect of daily feeding of 6-gingerol for 5 wk on the skeleton of adult female Balb/cByJ mice was investigated. Mice treated with capsaicin and ovariectomized (OVx) mice served as controls for osteopenia. 6-Gingerol caused increase in trabecular osteoclast number, microarchitectural erosion at all trabecular sites and loss of vertebral stiffness, and these effects were comparable to capsaicin or OVx group. Osteoclast-specific serum and gene markers of 6-gingerol-treated mice were higher than the OVx group. Bone formation was unaffected by 6-gingerol. Daily feeding of 6-gingerol to skeletally mature female mice caused trabecular osteopenia, and the mechanism appeared to be activation of osteoclast formation via the TRPV1 channel. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Basal activity of voltage-gated Ca(2+) channels controls the IP3-mediated contraction by α(1)-adrenoceptor stimulation of mouse aorta segments.

PubMed

Leloup, Arthur J; Van Hove, Cor E; De Meyer, Guido R Y; Schrijvers, Dorien M; Fransen, Paul

2015-08-05

α1-Adrenoceptor stimulation of mouse aorta causes intracellular Ca(2+) release from sarcoplasmic reticulum Ca(2+) stores via stimulation of inositoltriphosphate (IP3) receptors. It is hypothesized that this Ca(2+) release from the contractile and IP3-sensitive Ca(2+) store is under the continuous dynamic control of time-independent basal Ca(2+) influx via L-type voltage-gated Ca(2+) channels (LCC) residing in their window voltage range. Mouse aortic segments were α1-adrenoceptor stimulated with phenylephrine in the absence of external Ca(2+) (0Ca) to measure phasic isometric contractions. They gradually decreased with time in 0Ca, were inhibited with 2-aminoethoxydiphenyl borate, and declined with previous membrane potential hyperpolarization (levcromakalim) or with previous inhibition of LCC (diltiazem). Former basal stimulation of LCC with depolarization (15 mM K(+)) or with BAY K8644 increased the subsequent phasic contractions by phenylephrine in 0Ca. Although exogenous NO (diethylamine NONOate) reduced the phasic contractions by phenylephrine, stimulation of endothelial cells with acetylcholine in 0Ca failed to attenuate these phasic contractions. Finally, inhibition of the basal release of NO with N(Ω)-nitro-L-arginine methyl ester also attenuated the phasic contractions by phenylephrine. Results indicated that α1-adrenoceptor stimulation with phenylephrine causes phasic contractions, which are controlled by basal LCC and endothelial NO synthase activity. Endothelial NO release by acetylcholine was absent in 0Ca. Given the growing interest in the active regulation of arterial compliance, the dependence of contractile SR Ca(2+) store-refilling in basal conditions on the activity of LCC and basal eNOS may contribute to a more thorough understanding of physiological mechanisms leading to arterial stiffness. Copyright © 2015. Published by Elsevier B.V.

Active local control of propeller-aircraft run-up noise.

PubMed

Hodgson, Murray; Guo, Jingnan; Germain, Pierre

2003-12-01

Engine run-ups are part of the regular maintenance schedule at Vancouver International Airport. The noise generated by the run-ups propagates into neighboring communities, disturbing the residents. Active noise control is a potentially cost-effective alternative to passive methods, such as enclosures. Propeller aircraft generate low-frequency tonal noise that is highly compatible with active control. This paper presents a preliminary investigation of the feasibility and effectiveness of controlling run-up noise from propeller aircraft using local active control. Computer simulations for different configurations of multi-channel active-noise-control systems, aimed at reducing run-up noise in adjacent residential areas using a local-control strategy, were performed. These were based on an optimal configuration of a single-channel control system studied previously. The variations of the attenuation and amplification zones with the number of control channels, and with source/control-system geometry, were studied. Here, the aircraft was modeled using one or two sources, with monopole or multipole radiation patterns. Both free-field and half-space conditions were considered: for the configurations studied, results were similar in the two cases. In both cases, large triangular quiet zones, with local attenuations of 10 dB or more, were obtained when nine or more control channels were used. Increases of noise were predicted outside of these areas, but these were minimized as more control channels were employed. By combining predicted attenuations with measured noise spectra, noise levels after implementation of an active control system were estimated.

Role of ATP-sensitive potassium channels in the piracetam induced blockade of opioid effects.

PubMed

Rehni, Ashish K; Singh, Nirmal; Jindal, Seema

2007-12-01

The present study has been designed to investigate the effect of piracetam on morphine/ buprenorphine-induced antinociception in rats and effect of piracetam on morphine or minoxidil induced relaxation in KCl-precontracted isolated rat aortic ring preparation. Nociceptive threshold was measured by the tail flick test in rats. The cumulative dose responses of morphine or minoxidil were recorded in KCl-precontracted isolated rat aortic ring preparation. Piracetam attenuated buprenorphine-induced antinociception in rats. Piracetam significantly reduced the morphine and minoxidil induced relaxation in KCl precontracted isolated rat aortic ring preparation suggesting that piracetam interferes with opioid receptor and ATP-sensitive potassium channel (KATP) opener mediated responses in vitro. Thus, it may be suggested that piracetam attenuates opioid effects by an opioid receptor-KATP channel linked mechanism.

Bladder contractility is modulated by Kv7 channels in pig detrusor.

PubMed

Svalø, Julie; Bille, Michala; Parameswaran Theepakaran, Neeraja; Sheykhzade, Majid; Nordling, Jørgen; Bouchelouche, Pierre

2013-09-05

Kv7 channels are involved in smooth muscle relaxation, and accordingly we believe that they constitute potential targets for the treatment of overactive bladder syndrome. We have therefore used myography to examine the function of Kv7 channels in detrusor, i.e. pig bladder, with a view to determining the effects of the following potassium channel activators: ML213 (Kv7.2/Kv7.4 channels) and retigabine (Kv7.2-7.5 channels). Retigabine produced a concentration-dependent relaxation of carbachol- and electric field-induced contractions. The potency was similar in magnitude to that of ML213-induced relaxation, suggesting that Kv7.2 and/or Kv7.4 channels constitute the subtypes that are relevant to bladder contractility. The effects of retigabine and ML213 were attenuated by pre-incubation with 10µM XE991 (Kv7.1-7.5 channel blocker) (P<0.05), which in turn confirmed Kv7 channel selectivity. Subtype-selective effects were further investigated by incubating the detrusor with 10µM chromanol 293B (Kv7.1 channel blocker). Regardless of the experimental protocol, this did not cause a further increase in the evoked contraction. In contrast, the addition of XE991 potentiated the KCl-induced contractions, but not those induced by carbachol or electric field, indicating the presence of a phosphatidyl-inositol-4,5-biphosphate-dependent mechanism amongst the Kv7 channels in detrusor. qRT-PCR studies of the mRNA transcript level of Kv7.3-7.5 channels displayed a higher level of Kv7.4 transcript in detrusor compared to that present in brain cortex and heart tissues. Thus, we have shown that Kv7.4 channels are expressed and functionally active in pig detrusor, and that the use of selective Kv7.4 channel modulators in the treatment of detrusor overactivity seems promising. © 2013 Elsevier B.V. All rights reserved.

Calculation of in situ acoustic sediment attenuation using off-the-shelf horizontal ADCPs in low concentration settings

USGS Publications Warehouse

Haught, Dan; Venditti, Jeremy G.; Wright, Scott A.

2017-01-01

The use of “off-the-shelf” acoustic Doppler velocity profilers (ADCPs) to estimate suspended sediment concentration and grain-size in rivers requires robust methods to estimate sound attenuation by suspended sediment. Theoretical estimates of sediment attenuation require a priori knowledge of the concentration and grain-size distribution (GSD), making the method impractical to apply in routine monitoring programs. In situ methods use acoustic backscatter profile slope to estimate sediment attenuation, and are a more attractive option. However, the performance of in situ sediment attenuation methods has not been extensively compared to theoretical methods. We used three collocated horizontally mounted ADCPs in the Fraser River at Mission, British Columbia and 298 observations of concentration and GSD along the acoustic beams to calculate theoretical and in situ sediment attenuation. Conversion of acoustic intensity from counts to decibels is influenced by the instrument noise floor, which affects the backscatter profile shape and therefore in situ attenuation. We develop a method that converts counts to decibels to maximize profile length, which is useful in rivers where cross-channel acoustic profile penetration is a fraction of total channel width. Nevertheless, the agreement between theoretical and in situ attenuation is poor at low concentrations because cross-stream gradients in concentration, sediment size or GSD can develop, which affect the backscatter profiles. We establish threshold concentrations below which in situ attenuation is unreliable in Fraser River. Our results call for careful examination of cross-stream changes in suspended sediment characteristics and acoustic profiles across a range of flows before in situ attenuation methods are applied in river monitoring programs.

Signaling mechanisms mediating muscarinic enhancement of GABAergic synaptic transmission in the spinal cord.

PubMed

Zhang, H-M; Chen, S-R; Cai, Y-Q; Richardson, T E; Driver, L C; Lopez-Berestein, G; Pan, H-L

2009-02-18

Activation of muscarinic acetylcholine receptors (mAChRs) inhibits spinal nociceptive transmission by potentiation of GABAergic tone through M(2), M(3), and M(4) subtypes. To study the signaling mechanisms involved in this unique mAChR action, GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) of lamina II neurons were recorded using whole-cell patch clamp techniques in rat spinal cord slices. The mAChR agonist oxotremorine-M caused a profound increase in the frequency of GABAergic sIPSCs, which was abolished in the Ca(2+)-free solution. Inhibition of voltage-gated Ca(2+) channels with Cd(2+) and Ni(2+) largely reduced the effect of oxotremorine-M on sIPSCs. Blocking nonselective cation channels (NSCCs) with SKF96365 or 2-APB also largely attenuated the effect of oxotremorine-M. However, the KCNQ channel blocker XE991 and the adenylyl cyclase inhibitor MDL12330A had no significant effect on oxotremorine-M-induced increases in sIPSCs. Furthermore, the phosphoinositide-3-kinase (PI3K) inhibitor wortmannin or LY294002 significantly reduced the potentiating effect of oxotremorine-M on sIPSCs. In the spinal cord in which the M(3) subtype was specifically knocked down by intrathecal small interfering RNA (siRNA) treatment, SKF96365 and wortmannin still significantly attenuated the effect of oxotremorine-M. In contrast, SKF96365 and wortmannin both failed to alter the effect of oxotremorine-M on sIPSCs when the M(2)/M(4) mAChRs were blocked. Therefore, our study provides new evidence that activation of mAChRs increases synaptic GABA release through Ca(2+) influx and voltage-gated Ca(2+) channels. The PI3K-NSCC signaling cascade is primarily involved in the excitation of GABAergic interneurons by the M(2)/M(4) mAChRs in the spinal dorsal horn.

Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior

PubMed Central

Cannady, Reginald; McGonigal, Justin T.; Newsom, Ryan J.; Woodward, John J.

2017-01-01

Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (KCa2) channels have also been implicated in extinction learning of fear memories, and mGlu5 receptor activation can reduce KCa2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined KCa2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats. This study also explored related neuronal and synaptic mechanisms within the IL-PFC that underlie mGlu5-dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu5 in ex vivo slices significantly reduced KCa2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of KCa2 channel activity by mGlu5 receptors. Additionally, positive modulation of KCa2 channels prevented mGlu5 receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (KCa2 channel allosteric inhibitor) significantly enhanced extinction of alcohol-seeking behavior across multiple extinction sessions, an effect that persisted for 3 weeks, but was not observed after apamin microinfusions into the prelimbic PFC. Positive modulation of IL-PFC KCa2 channels significantly attenuated mGlu5-dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu5-dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of KCa2 channels. Moreover, these findings demonstrate that KCa2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior. SIGNIFICANCE STATEMENT Alcohol use disorder is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles, and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on relapse in alcoholics. PMID:28320841

Amplitude Variation of Bottom Simulating Reflection with Respect to Frequency - Transitional Base or Attenuation?

USGS Publications Warehouse

Lee, Myung W.

2007-01-01

The amplitude of a bottom simulating reflection (BSR), which occurs near the phase boundary between gas hydrate-bearing sediments and underlying gas-filled sediments, strongly depends on the frequency content of a seismic signal, as well as the impedance contrast across the phase boundary. A strong-amplitude BSR, detectable in a conventional seismic profile, is a good indicator of the presence of free gas beneath the phase boundary. However, the BSR as observed in low-frequency multichannel seismic data is generally difficult to identify in high-frequency, single-channel seismic data. To investigate the frequency dependence of BSR amplitudes, single-channel seismic data acquired with an air gun source at Blake Ridge, which is located off the shore of South Carolina, were analyzed in the frequency range of 10-240 Hz. The frequency-dependent impedance contrast caused by the velocity dispersion in partially gas saturated sediments is important to accurately analyze BSR amplitude. Analysis indicates that seismic attenuation of gas hydrate-bearing sediments, velocity dispersion, and a transitional base all contribute to the frequency-dependent BSR amplitude variation in the frequency range of 10-500 Hz. When velocity dispersion is incorporated into the BSR amplitude analysis, the frequency-dependent BSR amplitude at Blake Ridge can be explained with gas hydrate-bearing sediments having a quality factor of about 250 and a transitional base with a thickness of about 1 meter.

Performance analysis of MISO multi-hop FSO links over log-normal channels with fog and beam divergence attenuations

NASA Astrophysics Data System (ADS)

Abaza, Mohamed; Mesleh, Raed; Mansour, Ali; Aggoune, el-Hadi

2015-01-01

The performance analysis of a multi-hop decode and forward relaying free-space optical (FSO) communication system is presented in this paper. The considered FSO system uses intensity modulation and direct detection as means of transmission and reception. Atmospheric turbulence impacts are modeled as a log-normal channel, and different weather attenuation effects and geometric losses are taken into account. It is shown that multi-hop is an efficient technique to mitigate such effects in FSO communication systems. A comparison with direct link and multiple-input single-output (MISO) systems considering correlation effects at the transmitter is provided. Results show that MISO multi-hop FSO systems are superior than their counterparts over links exhibiting high attenuation. Monte Carlo simulation results are provided to validate the bit error rate (BER) analyses and conclusions.

Targeting the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Assembly Domain Attenuates Inflammation-induced Hypersensitivity*

PubMed Central

Flynn, Robyn; Chapman, Kevin; Iftinca, Mircea; Aboushousha, Reem; Varela, Diego; Altier, Christophe

2014-01-01

The transient receptor potential channel vanilloid type 1 (TRPV1) is a non-selective cation channel expressed in sensory neurons of the dorsal root and trigeminal ganglia. TRPV1 is a polymodal channel activated by noxious heat, capsaicin, and protons. As a sensor for noxious stimuli, TRPV1 channel has been described as a key contributor to pain signaling. To form a functional channel, TRPV1 subunits must assemble into tetramers, and several studies have identified the TRPV1 C terminus as an essential element in subunit association. Here we combined biochemical assays with electrophysiology and imaging-based bimolecular fluorescence complementation (BiFC) and bioluminescence resonance energy transfer (BRET) in live cells to identify a short motif in the C-terminal tail of the TRPV1 subunit that governs channel assembly. Removing this region through early truncation or targeted deletion results in loss of subunit association and channel function. Importantly, we found that interfering with TRPV1 subunit association using a plasma membrane-tethered peptide attenuated mechanical and thermal hypersensitivity in two mouse models of inflammatory hyperalgesia. This represents a novel mechanism to disrupt TRPV1 subunit assembly and hence may offer a new analgesic tool for pain relief. PMID:24808184

Targeting the transient receptor potential vanilloid type 1 (TRPV1) assembly domain attenuates inflammation-induced hypersensitivity.

PubMed

Flynn, Robyn; Chapman, Kevin; Iftinca, Mircea; Aboushousha, Reem; Varela, Diego; Altier, Christophe

2014-06-13

The transient receptor potential channel vanilloid type 1 (TRPV1) is a non-selective cation channel expressed in sensory neurons of the dorsal root and trigeminal ganglia. TRPV1 is a polymodal channel activated by noxious heat, capsaicin, and protons. As a sensor for noxious stimuli, TRPV1 channel has been described as a key contributor to pain signaling. To form a functional channel, TRPV1 subunits must assemble into tetramers, and several studies have identified the TRPV1 C terminus as an essential element in subunit association. Here we combined biochemical assays with electrophysiology and imaging-based bimolecular fluorescence complementation (BiFC) and bioluminescence resonance energy transfer (BRET) in live cells to identify a short motif in the C-terminal tail of the TRPV1 subunit that governs channel assembly. Removing this region through early truncation or targeted deletion results in loss of subunit association and channel function. Importantly, we found that interfering with TRPV1 subunit association using a plasma membrane-tethered peptide attenuated mechanical and thermal hypersensitivity in two mouse models of inflammatory hyperalgesia. This represents a novel mechanism to disrupt TRPV1 subunit assembly and hence may offer a new analgesic tool for pain relief. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Modeling small-scale and large-scale flood wave processes as indicators of channel-floodplain connectivity

NASA Astrophysics Data System (ADS)

Byrne, C. F.; Stone, M. C.

2016-12-01

Anthropogenic alterations to rivers and floodplains, either in the context of river engineering or river restoration efforts, have no doubt impacted channel-floodplain connectivity in the majority of developed river systems. River management strategies now often strive to retain or improve ecological integrity of floodplains. Therefore, there is a need to quantify the hydrodynamic processes that have implications for river geomorphology and ecology within the channel-floodplain interface. Because field quantification of these processes is extremely difficult, new methods in hydrodynamic modeling can help to inform river science. This research focused on the assessment of channel-floodplain flow dynamics using two-dimensional hydrodynamic modeling and presents various methods of hydrodynamic process quantification in unsteady flow scenarios. The objectives of this research were to: (1) quantify the small-scale processes of mass and momentum transfer from the main channel to the floodplain; and (2) assess how these processes accrue to meaningful levels to affect the large-scale process of flood wave attenuation. This was achieved by modeling the heavily manipulated Albuquerque Reach of the Rio Grande in New Mexico. Results are presented as mass and momentum fluxes along the channel-floodplain boundaries with a focus on the application of these methods to unsteady flood wave modeling. In addition, quantification of downstream flood wave attenuation is presented as attenuation ratios of discharge and stage, as well as wave celerity. Mass and momentum fluxes during flood waves are shown to be highly variable over spatial and temporal scales and demonstrate the implications of lateral surface connectivity. Results from this research and further application of the methods presented here can help river scientists better understand the dynamics of flood processes especially in the context of process-based river restoration.

Efficacy of a live attenuated Edwardsiella ictaluri oral vaccine in channel and hybrid catfish

USDA-ARS?s Scientific Manuscript database

Intensive fish production systems resort to higher stocking densities and feeding rates in culture conditions to manifest suboptimal conditions to facilitate disease outbreaks leading to production losses. This study was conducted to evaluate the efficacy of an oral live-attenuated Edwardsiella ict...

TRPM8 Channel Activation Induced by Monoterpenoid Rotundifolone Underlies Mesenteric Artery Relaxation.

PubMed

Silva, Darizy Flavia; de Almeida, Monica Moura; Chaves, Cinthia Guedes; Braz, Ana Letícia; Gomes, Maria Aparecida; Pinho-da-Silva, Leidiane; Pesquero, Jorge Luiz; Andrade, Viviane Aguiar; Leite, Maria de Fátima; de Albuquerque, José George Ferreira; Araujo, Islania Giselia Albuquerque; Nunes, Xirley Pereira; Barbosa-Filho, José Maria; Cruz, Jader dos Santos; Correia, Nadja de Azevedo; de Medeiros, Isac Almeida

2015-01-01

In this study, our aims were to investigate transient receptor potential melastatin-8 channels (TRPM8) involvement in rotundifolone induced relaxation in the mesenteric artery and to increase the understanding of the role of these thermosensitive TRP channels in vascular tissue. Thus, message and protein levels of TRPM8 were measured by semi-quantitative PCR and western blotting in superior mesenteric arteries from 12 week-old Spague-Dawley (SD) rats. Isometric tension recordings evaluated the relaxant response in mesenteric rings were also performed. Additionally, the intracellular Ca2+ changes in mesenteric artery myocytes were measured using confocal microscopy. Using PCR and western blotting, both TRPM8 channel mRNA and protein expression was measured in SD rat mesenteric artery. Rotundifolone and menthol induced relaxation in the isolated superior mesenteric artery from SD rats and improved the relaxant response induced by cool temperatures. Also, this monoterpene induced an increase in transient intracellular Ca2+. These responses were significantly attenuated by pretreatment with capsazepine or BCTC, both TRPM8 channels blockers. The response induced by rotundifolone was not significantly attenuated by ruthenium red, a non-selective TRP channels blocker, or following capsaicin-mediated desensitization of TRPV1. Our findings suggest that rotundifolone induces relaxation by activating TRPM8 channels in rat superior mesenteric artery, more selectively than menthol, the classic TRPM8 agonist, and TRPM8 channels participates in vasodilatory pathways in isolated rat mesenteric arteries.

Estimating surface reflectance from Himawari-8/AHI reflectance channels Using 6SV

NASA Astrophysics Data System (ADS)

Lee, Kyeong-sang; Choi, Sungwon; Seo, Minji; Seong, Noh-hun; Han, Kyung-soo

2017-04-01

TOA (Top Of Atmospheric) reflectance observed by satellite is modified by the influence of atmosphere such as absorbing and scattering by molecular and gasses. Removing TOA reflectance attenuation which is caused by the atmospheric is essential. surface reflectance with compensated atmospheric effects used as important input data for land product such as Normalized Difference Vegetation Index (NDVI), Land Surface Albedo (LSA) and etc. In this study, we Second Simulation of a Satellite Signal in the Solar Spectrum Vector (6SV) Radiative Transfer Model (RTM) for atmospheric correction and estimating surface reflectance from Himawari-8/Advanced Himawari Imager (AHI) reflectance channels. 6SV has the advantage that it has high accuracy by performing the atmospheric correction by dividing the width of the satellite channel by 2.5 nm, but it is slow to use in the operation. So, we use LUT approach to reduce the computation time and avoid the intensive calculation required for retrieving surface reflectance. Estimated surface reflectance data were compared with PROBA-V S1 data to evaluate the accuracy. As a result Root Mean Square Error (RMSE) and bias were about 0.05 and -0.02. It is considered that this error is due to the difference of angle component and Spectral Response Function (SRF) of each channel.

Sediment supply versus local hydraulic controls on sediment transport and storage in a river with large sediment loads

USGS Publications Warehouse

Dean, David; Topping, David; Schmidt, John C.; Griffiths, Ronald; Sabol, Thomas

2016-01-01

The Rio Grande in the Big Bend region of Texas, USA, and Chihuahua and Coahuila, Mexico, undergoes rapid geomorphic changes as a result of its large sediment supply and variable hydrology; thus, it is a useful natural laboratory to investigate the relative importance of flow strength and sediment supply in controlling alluvial channel change. We analyzed a suite of sediment transport and geomorphic data to determine the cumulative influence of different flood types on changing channel form. In this study, physically based analyses suggest that channel change in the Rio Grande is controlled by both changes in flow strength and sediment supply over different spatial and temporal scales. Channel narrowing is primarily caused by substantial deposition of sediment supplied to the Rio Grande during tributary-sourced flash floods. Tributary floods have large suspended-sediment concentrations, occur for short durations, and attenuate rapidly downstream in the Rio Grande, depositing much of their sediment in downstream reaches. Long-duration floods on the mainstem have the capacity to enlarge the Rio Grande, and these floods, released from upstream dams, can either erode or deposit sediment in the Rio Grande depending upon the antecedent in-channel sediment supply and the magnitude and duration of the flood. Geomorphic and sediment transport analyses show that the locations and rates of sand erosion and deposition during long-duration floods are most strongly controlled by spatial changes in flow strength, largely through changes in channel slope. However, spatial differences in the in-channel sediment supply regulate sediment evacuation or accumulation over time in long reaches (greater than a kilometer).

Nimodipine, an L-type calcium channel blocker attenuates mitochondrial dysfunctions to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice.

PubMed

Singh, Alpana; Verma, Poonam; Balaji, Gillela; Samantaray, Supriti; Mohanakumar, Kochupurackal P

2016-10-01

Parkinson's disease (PD), the most common progressive neurodegenerative movement disorder, results from loss of dopaminergic neurons of substantia nigra pars compacta. These neurons exhibit Cav1.3 channel-dependent pacemaking activity. Epidemiological studies suggest reduced risk for PD in population under long-term antihypertensive therapy with L-type calcium channel antagonists. These prompted us to investigate nimodipine, an L-type calcium channel blocker for neuroprotective effect in cellular and animal models of PD. Nimodipine (0.1-10 μM) significantly attenuated 1-methyl-4-phenyl pyridinium ion-induced loss in mitochondrial morphology, mitochondrial membrane potential and increases in intracellular calcium levels in SH-SY5Y neuroblastoma cell line as measured respectively employing Mitotracker green staining, TMRM, and Fura-2 fluorescence, but only a feeble neuroprotective effect was observed in MTT assay. Nimodipine dose-dependently reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian syndromes (akinesia and catalepsy) and loss in swimming ability in Balb/c mice. It attenuated MPTP-induced loss of dopaminergic tyrosine hydroxylase positive neurons in substantia nigra, improved mitochondrial oxygen consumption and inhibited reactive oxygen species production in the striatal mitochondria measured using dichlorodihydrofluorescein fluorescence, but failed to block striatal dopamine depletion. These results point to an involvement of L-type calcium channels in MPTP-induced dopaminergic neuronal death in experimental parkinsonism and more importantly provide evidences for nimodipine to improve mitochondrial integrity and function. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lg wave attenuation in southeastern margin of Tibetan Plateau and the Indochina Peninsula and its implications of potential crustal flow

NASA Astrophysics Data System (ADS)

He, X.; Zhao, L. F.; Xie, X. B.; Yao, Z. X.

2017-12-01

Mechanisms that accommodate tectonic deformation in southeastern Tibetan Plateau and the Indochina Peninsula have been under heated debate between two popular end-number models, rigid block extrusion and viscous crustal flow channel, while recent studies suggest that they are not irreconcilable (e.g., Liu et al., 2014). To provide new insights into regional tectonic evolution, we collect 22,242 vertical seismograms and perform the Lg wave attenuation tomography at 58 individual frequencies between 0.05-10.0 Hz to investigate Lg wave attenuation in this region. The resultant broadband Lg wave attenuation model exhibits strong lateral variation that correlates with regional tectonics. A significant low Q belt, originating in the southeast Tibet, striking southeast and connecting to northern South China Sea, is the most conspicuous feature in our Lg Q maps, indicating intense crustal deformation and tectonic activities. For the northwestern part of this belt, two low Q channels joint beneath Songpan-Ganzi block but separate beneath Chuan-Dian block (eastern channel) and northern Sibumasu block (western channel) encountering Chuxiong basin in the central Chuan-Dian. This acute Lg attenuation may be resulted from viscous lower crust, thermal activities, shear heating along strike-slip fault and fractured brittle upper crust. The two channels are also consistent with zones of low seismic velocity and high conductivity between depth of 20 and 40 km (Bai et al., 2010; Bao et al., 2015), indicating possible partial-molten mid and lower crust. Together with evidences from paleo-elevation reconstruction and seismic anisotropy (Li et al., 2015; Wei et al., 2013), gravity-driven flow of viscous partial-molten mid-lower crust, which underlies brittle upper crust, is suggested and the mechanism that ductile flow of thickened lower crust uplifts topography and drags brittle upper crust to move with respect to each other may accommodate regional tectonics. We attribute distinct low Q zones beneath Yinggehai basin to ultra-thick sediment and sever thermal activities, and another obvious low Q zone beneath Sumatra Islands to dozens of volcanos. This work is supported by the Earthquake Experimental Field, CEA (grants 2016 CESE 0203) and the National Natural Science Foundation of China (grants 41374065, 41630210).

TRPV1 inhibition attenuates IL-13 mediated asthma features in mice by reducing airway epithelial injury.

PubMed

Rehman, Rakhshinda; Bhat, Younus Ahmad; Panda, Lipsa; Mabalirajan, Ulaganathan

2013-03-01

Even though neurogenic axis is well known in asthma pathogenesis much attention had not been given on this aspect. Recent studies have reported the importance of TRP channels, calcium-permeable ion channels and key molecules in neurogenic axis, in asthma therapeutics. The role of TRPV1 channels has been underestimated in chronic respiratory diseases as TRPV1 knockout mice of C57BL/6 strains did not attenuate the features of these diseases. However, this could be due to strain differences in the distribution of airway capsaicin receptors. Here, we show that TRPV1 inhibition attenuates IL-13 induced asthma features by reducing airway epithelial injury in BALB/c mice. We found that IL-13 increased not only the lung TRPV1 levels but also TRPV1 expression in bronchial epithelia in BALB/c rather than in C57BL/6 mice. TRPV1 knockdown attenuated airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and subepithelial fibrosis induced by IL-13 in BALB/c mice. Further, TRPV1 siRNA treatment reduced not only the cytosolic calpain and mitochondrial calpain 10 activities in the lung but also bronchial epithelial apoptosis indicating that TRPV1 siRNA might have corrected the intracellular and intramitochondrial calcium overload and its consequent apoptosis. Knockdown of IL-13 in allergen induced asthmatic mice reduced TRPV1, cytochrome c, and activities of calpain and caspase 3 in lung cytosol. Thus, these findings suggest that induction of TRPV1 with IL-13 in bronchial epithelia could lead to epithelial injury in in vivo condition. Since TRPV1 expression is correlated with human asthma severity, TRPV1 inhibition could be beneficial in attenuating airway epithelial injury and asthma features. Copyright © 2013 Elsevier B.V. All rights reserved.

Modulation of Connexin-36 Gap Junction Channels by Intracellular pH and Magnesium Ions

PubMed Central

Rimkute, Lina; Kraujalis, Tadas; Snipas, Mindaugas; Palacios-Prado, Nicolas; Jotautis, Vaidas; Skeberdis, Vytenis A.; Bukauskas, Feliksas F.

2018-01-01

Connexin-36 (Cx36) protein forms gap junction (GJ) channels in pancreatic beta cells and is also the main Cx isoform forming electrical synapses in the adult mammalian brain. Cx36 GJs can be regulated by intracellular pH (pHi) and cytosolic magnesium ion concentration ([Mg2+]i), which can vary significantly under various physiological and pathological conditions. However, the combined effect and relationship of these two factors over Cx36-dependent coupling have not been previously studied in detail. Our experimental results in HeLa cells expressing Cx36 show that changes in both pHi and [Mg2+]i affect junctional conductance (gj) in an interdependent manner; in other words, intracellular acidification cause increase or decay in gj depending on whether [Mg2+]i is high or low, respectively, and intracellular alkalization cause reduction in gj independently of [Mg2+]i. Our experimental and modelling data support the hypothesis that Cx36 GJ channels contain two separate gating mechanisms, and both are differentially sensitive to changes in pHi and [Mg2+]i. Using recombinant Cx36 we found that two glutamate residues in the N-terminus could be partly responsible for the observed interrelated effect of pHi and [Mg2+]i. Mutation of glutamate at position 8 attenuated the stimulatory effect of intracellular acidification at high [Mg2+]i, while mutation at position 12 and double mutation at both positions reversed stimulatory effect to inhibition. Moreover, Cx36*E8Q lost the initial increase of gj at low [Mg2+]i and double mutation lost the sensitivity to high [Mg2+]i. These results suggest that E8 and E12 are involved in regulation of Cx36 GJ channels by Mg2+ and H+ ions. PMID:29706896

Development of multichannel MEG system at IGCAR

NASA Astrophysics Data System (ADS)

Mariyappa, N.; Parasakthi, C.; Gireesan, K.; Sengottuvel, S.; Patel, Rajesh; Janawadkar, M. P.; Radhakrishnan, T. S.; Sundar, C. S.

2013-02-01

We describe some of the challenging aspects in the indigenous development of the whole head multichannel magnetoencephalography (MEG) system at IGCAR, Kalpakkam. These are: i) fabrication and testing of a helmet shaped sensor array holder of a polymeric material experimentally tested to be compatible with liquid helium temperatures, ii) the design and fabrication of the PCB adapter modules, keeping in mind the inter-track cross talk considerations between the electrical leads used to provide connections from SQUID at liquid helium temperature (4.2K) to the electronics at room temperature (300K) and iii) use of high resistance manganin wires for the 86 channels (86×8 leads) essential to reduce the total heat leak which, however, inevitably causes an attenuation of the SQUID output signal due to voltage drop in the leads. We have presently populated 22 of the 86 channels, which include 6 reference channels to reject the common mode noise. The whole head MEG system to cover all the lobes of the brain will be progressively assembled when other three PCB adapter modules, presently under fabrication, become available. The MEG system will be used for a variety of basic and clinical studies including localization of epileptic foci during pre-surgical mapping in collaboration with neurologists.

TRPM8 Channel Activation Induced by Monoterpenoid Rotundifolone Underlies Mesenteric Artery Relaxation

PubMed Central

Silva, Darizy Flavia; de Almeida, Monica Moura; Chaves, Cinthia Guedes; Braz, Ana Letícia; Gomes, Maria Aparecida; Pinho-da-Silva, Leidiane; Pesquero, Jorge Luiz; Andrade, Viviane Aguiar; Leite, Maria de Fátima; de Albuquerque, José George Ferreira; Araujo, Islania Giselia Albuquerque; Nunes, Xirley Pereira; Barbosa-Filho, José Maria; Cruz, Jader dos Santos; Correia, Nadja de Azevedo; de Medeiros, Isac Almeida

2015-01-01

In this study, our aims were to investigate transient receptor potential melastatin-8 channels (TRPM8) involvement in rotundifolone induced relaxation in the mesenteric artery and to increase the understanding of the role of these thermosensitive TRP channels in vascular tissue. Thus, message and protein levels of TRPM8 were measured by semi-quantitative PCR and western blotting in superior mesenteric arteries from 12 week-old Spague-Dawley (SD) rats. Isometric tension recordings evaluated the relaxant response in mesenteric rings were also performed. Additionally, the intracellular Ca2+ changes in mesenteric artery myocytes were measured using confocal microscopy. Using PCR and western blotting, both TRPM8 channel mRNA and protein expression was measured in SD rat mesenteric artery. Rotundifolone and menthol induced relaxation in the isolated superior mesenteric artery from SD rats and improved the relaxant response induced by cool temperatures. Also, this monoterpene induced an increase in transient intracellular Ca2+. These responses were significantly attenuated by pretreatment with capsazepine or BCTC, both TRPM8 channels blockers. The response induced by rotundifolone was not significantly attenuated by ruthenium red, a non-selective TRP channels blocker, or following capsaicin-mediated desensitization of TRPV1. Our findings suggest that rotundifolone induces relaxation by activating TRPM8 channels in rat superior mesenteric artery, more selectively than menthol, the classic TRPM8 agonist, and TRPM8 channels participates in vasodilatory pathways in isolated rat mesenteric arteries. PMID:26599698

Experimental quantum teleportation over a high-loss free-space channel.

PubMed

Ma, Xiao-song; Kropatschek, Sebastian; Naylor, William; Scheidl, Thomas; Kofler, Johannes; Herbst, Thomas; Zeilinger, Anton; Ursin, Rupert

2012-10-08

We present a high-fidelity quantum teleportation experiment over a high-loss free-space channel between two laboratories. We teleported six states of three mutually unbiased bases and obtained an average state fidelity of 0.82(1), well beyond the classical limit of 2/3. With the obtained data, we tomographically reconstructed the process matrices of quantum teleportation. The free-space channel attenuation of 31 dB corresponds to the estimated attenuation regime for a down-link from a low-earth-orbit satellite to a ground station. We also discussed various important technical issues for future experiments, including the dark counts of single-photon detectors, coincidence-window width etc. Our experiment tested the limit of performing quantum teleportation with state-of-the-art resources. It is an important step towards future satellite-based quantum teleportation and paves the way for establishing a worldwide quantum communication network.

Characterising and classifying agricultural drainage channels for sediment and phosphorus management

NASA Astrophysics Data System (ADS)

Shore, Mairead; Jordan, Phil; Mellander, Per-Erik; Quinn, Mary Kelly; Daly, Karen; Sims, James Tom; Melland, Alice

2016-04-01

In agricultural landscapes, surface ditches and streams can significantly influence the attenuation and transfer of sediment and phosphorus (P) from upstream sources to receiving water-bodies. The sediment attenuation and/or transfer capacity of these features depends on channel physical characteristics. This is similar for P, in addition to the sediment physico-chemical characteristics. Therefore, a greater understanding of (i) channel physical characteristics and (ii) the associated sediment physico-chemical characteristics could be used to develop channel-specific management strategies for the reduction of downstream sediment and P transfers. Using a detailed field survey of surface channel networks in a well-drained arable and a poorly-drained grassland catchment (both c.10km2), this study (i) characterised all ditches and streams in both catchments, (ii) investigated the physico-chemical characteristics of sediments in a subset of ditches, (iii) classified all channels into four classes of fine sediment retention and/or transfer likelihood based on a comparison of physical characteristics (slope and drainage area) with observations of fine sediment accumulation and (iv) considered P management strategies that are suited to each class. Mehlich3-Al/P and Mehlich3-Ca/P contents of ditch sediments in the well (non-calcareous) and poorly (calcareous) drained catchments, respectively, indicated potential for soluble P retention (above thresholds of 11.7 and 74, respectively). In general, ditches with low slopes had the greatest potential to retain fine sediment and associated particulate P. As sediments in these catchments are likely to primarily adsorb, rather than release soluble P, these flat ditches are also likely to reduce soluble P loading downstream. Ditches with moderate-high slopes had the greatest potential to mobilise fine sediment and associated P during event flows. Ditch dimensions were not closely related to their indicative flow volumes and were over-engineered, which likely reduces downstream P transfer. Streams had the greatest potential to convey fine sediment and associated P during event flows. Optimising these linear features for eutrophication management in headwaters, periodic removal of fine sediment and maintenance of channel vegetation in net attenuating and transferring channels, respectively, would help to minimise sediment and P transfers from these catchments.

First wide-angle view of channelized turbidity currents links migrating cyclic steps to flow characteristics

PubMed Central

Hughes Clarke, John E.

2016-01-01

Field observations of turbidity currents remain scarce, and thus there is continued debate about their internal structure and how they modify underlying bedforms. Here, I present the results of a new imaging method that examines multiple surge-like turbidity currents within a delta front channel, as they pass over crescent-shaped bedforms. Seven discrete flows over a 2-h period vary in speed from 0.5 to 3.0 ms−1. Only flows that exhibit a distinct acoustically attenuating layer at the base, appear to cause bedform migration. That layer thickens abruptly downstream of the bottom of the lee slope of the bedform, and the upper surface of the layer fluctuates rapidly at that point. The basal layer is inferred to reflect a strong near-bed gradient in density and the thickening is interpreted as a hydraulic jump. These results represent field-scale flow observations in support of a cyclic step origin of crescent-shaped bedforms. PMID:27283503

Frequency-dependent reliability of spike propagation is function of axonal voltage-gated sodium channels in cerebellar Purkinje cells.

PubMed

Yang, Zhilai; Wang, Jin-Hui

2013-12-01

The spike propagation on nerve axons, like synaptic transmission, is essential to ensure neuronal communication. The secure propagation of sequential spikes toward axonal terminals has been challenged in the neurons with a high firing rate, such as cerebellar Purkinje cells. The shortfall of spike propagation makes some digital spikes disappearing at axonal terminals, such that the elucidation of the mechanisms underlying spike propagation reliability is crucial to find the strategy of preventing loss of neuronal codes. As the spike propagation failure is influenced by the membrane potentials, this process is likely caused by altering the functional status of voltage-gated sodium channels (VGSC). We examined this hypothesis in Purkinje cells by using pair-recordings at their somata and axonal blebs in cerebellar slices. The reliability of spike propagation was deteriorated by elevating spike frequency. The frequency-dependent reliability of spike propagation was attenuated by inactivating VGSCs and improved by removing their inactivation. Thus, the functional status of axonal VGSCs influences the reliability of spike propagation.

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain

PubMed Central

Li, Zhe; Tseng, Pang-Yen; Tiwari, Vinod; Xu, Qian; He, Shao-Qiu; Wang, Yan; Zheng, Qin; Han, Liang; Wu, Zhiping; Blobaum, Anna L.; Cui, Yiyuan; Tiwari, Vineeta; Sun, Shuohao; Cheng, Yingying; Huang-Lionnet, Julie H. Y.; Geng, Yixun; Xiao, Bo; Peng, Junmin; Hopkins, Corey; Raja, Srinivasa N.; Guan, Yun; Dong, Xinzhong

2017-01-01

Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse Mrgprs with human MrgprX1. This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8–22 (BAM8–22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8–22 to inhibit high-voltage-activated Ca2+ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8–22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain. PMID:28223516

Characterization of pulsed flow attenuation on a regulated montane river

NASA Astrophysics Data System (ADS)

Fong, C. S.; Yarnell, S. M.; Fleenor, W. E.; Viers, J. H.

2013-12-01

A major benefit of hydropower is its ability to respond quickly to fluctuating electrical loads. However, the sharp changes in discharge caused by this practice have detrimental environmental effects downstream. This study investigated the effects of hydrograph shape on attenuation of regulated pulsed flow events by first categorizing, then modeling the downstream movement of representative pulses on the upper Tuolumne River below Holm Powerhouse in the Sierra Nevada mountains of California. This system was managed by a public utility and produced flow pulses primarily for hydroelectricity generation and/or whitewater recreation. Operations were highly influenced by a system-wide "Water First" policy, which prioritized drinking water supply and quality over other beneficial uses. Pulses were therefore associated with a spectrum of time scales, from predetermined schedules decided far in advance to hydropeaking operations responding to real-time demands. We extracted underlying hydrograph shape patterns using principal component analysis on individual pulsed flow events released from 1988-2012 (n=4439). From principal component loadings, six shape categories were determined: rectangular, front-step, back-step, goalpost, centered tower, and other. The rectangular and stepped shapes were the most frequent, composing 62% and 24% of total events, respectively. The rectangular shape was often produced by 'standard' hydropeaking or recreational releases, while the stepped shapes were often used for water conservation or were recreational flows bordered by periods of electricity generation. The stepped shape increased in occurrence after the "Water First" policy took effect in 1993 and dominated two drier years (2007 and 2009). After categorization by shape, magnitude and durational indices were used to fabricate representative pulsed flow events. Attenuation of these representative pulses was then modeled using a 1D hydraulic model of 42 river km prepared in HEC-RAS. As no operational measures or physical structures existed within the system to counter the adverse effects of pulsed flow events, natural attenuation was the only potential major mitigation agent. However, model results demonstrated a clear durational threshold for representative pulses (~ 3-5 hrs) over which the degree of attenuation of ramping rates and peak discharge approached a limit. These thresholds were unique to the study reach and were dependent upon river morphology, bed characteristics, and flow rates. Increasing baseflows did not necessarily increase attenuation of pulses, most likely due to minimal increases in bed friction forces in this fairly steep and confined channel. Simulations of front and back-step representative pulses showed trade-offs between attenuation of peak magnitudes and steepness of ramping rates. Finally, a range of rising ramping rates were shown to steepen downstream above initial rates due to the study reach's channel morphology. Reshaping pulses to be more ecologically benign at all points downstream was infeasible if the system was required to maintain current electricity production and recreational service levels.

Development and pharmacological characterization of a model of sleep disruption-induced hypersensitivity in the rat.

PubMed

Wodarski, R; Schuh-Hofer, S; Yurek, D A; Wafford, K A; Gilmour, G; Treede, R-D; Kennedy, J D

2015-04-01

Sleep disturbance is a commonly reported co-morbidity in chronic pain patients, and conversely, disruption of sleep can cause acute and long-lasting hypersensitivity to painful stimuli. The underlying mechanisms of sleep disruption-induced pain hypersensitivity are poorly understood. Confounding factors of previous studies have been the sleep disruption protocols, such as the 'pedestal over water' or 'inverted flower pot' methods, that can cause large stress responses and therefore may significantly affect pain outcome measures. Sleep disruption was induced by placing rats for 8 h in a slowly rotating cylindrical cage causing arousal via the righting reflex. Mechanical (Von Frey filaments) and thermal (Hargreaves) nociceptive thresholds were assessed, and plasma corticosterone levels were measured (mass spectroscopy). Sleep disruption-induced hypersensitivity was pharmacologically characterized with drugs relevant for pain treatment, including gabapentin (30 mg/kg and 50 mg/kg), Ica-6p (Kv7.2/7.3 potassium channel opener; 10 mg/kg), ibuprofen (30 mg/kg and 100 mg/kg) and amitriptyline (10 mg/kg). Eight hours of sleep disruption caused robust mechanical and heat hypersensitivity in the absence of a measurable change in plasma corticosterone levels. Gabapentin had no effect on reduced nociceptive thresholds. Ibuprofen attenuated mechanical thresholds, while Ica-6p and amitriptyline attenuated only reduced thermal nociceptive thresholds. These results show that acute and low-stress sleep disruption causes mechanical and heat hypersensitivity in rats. Mechanical and heat hypersensitivity exhibited differential sensitivity to pharmacological agents, thus suggesting dissociable mechanisms for those two modalities. Ultimately, this model could help identify underlying mechanisms linking sleep disruption and hypersensitivity. © 2014 European Pain Federation - EFIC®

Grape seed proanthocyanidin extract attenuates oxidant injury in cardiomyocytes.

PubMed

Shao, Zuo-Hui; Becker, Lance B; Vanden Hoek, Terry L; Schumacker, Paul T; Li, Chang-Qing; Zhao, Danhong; Wojcik, Kim; Anderson, Travis; Qin, Yimin; Dey, Lucy; Yuan, Chun-Su

2003-06-01

This study sought to test whether grape seed proanthocyanidin extract (GSPE) attenuates exogenous and endogenous oxidant stress induced in chick cardiomyocytes and whether this cytoprotection is mediated by PKC activation, mito K(ATP) channel opening, NO production, oxidant scavenging, or iron chelating effects. Cells were exposed to hydrogen peroxide (H(2)O(2)) (exogenous oxidant stress, 0.5mM) or antimycin A (endogenous oxidant stress, 100 micro M) for 2h following pretreatment with GSPE at various concentrations for 2h. Cells were also pretreated with GSPE or with inhibitors of PKC (chelerytherine), mito K(ATP) channel (5-hydroxydecanoate), nitric oxide synthase (nitro-L-arginine methyl ester) for 2h. Oxidant stress was measured by 2',7'-dichlorofluorescin diacetate and cell viability was assessed using propidium iodide. Free radical scavenging and iron chelating ability was tested in vitro. GSPE dose-dependently attenuated oxidant formation and significantly improved cell survival and contractile function. However, inhibitors of PKC, mito K(ATP) channel or NO synthase failed to abolish the protective action of GSPE during H(2)O(2) or antimycin A exposure. In vitro studies suggested that GSPE scavenges H(2)O(2), hydroxyl radical and superoxide, and may chelate iron. These results indicate that GSPE confers cardioprotection against exogenous H(2)O(2)- or antimycin A-induced oxidant injury. Its effect does not require PKC, mito K(ATP) channel, or NO synthase, presumably because it acts by reactive oxygen species scavenging and iron chelating directly.

An Analysis of Responses to Defibrotide in the Pulmonary Vascular Bed of the Cat.

PubMed

Kaye, Alan D; Skonieczny, Brendan D; Kaye, Aaron J; Harris, Zoey I; Luk, Eric J

2016-01-01

Defibrotide is a polydisperse mixture of single-stranded oligonucleotides with many pharmacologic properties and multiple actions on the vascular endothelium. Responses to defibrotide and other vasodepressor agents were evaluated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure. Lobar arterial pressure was increased to a high steady level with the thromboxane A2 analog U-46619. Under increased-tone conditions, defibrotide caused dose-dependent decreases in lobar arterial pressure without altering systemic arterial and left atrial pressures. Responses to defibrotide were significantly attenuated after the administration of the cyclooxygenase inhibitor sodium meclofenamate. Responses to defibrotide were also significantly attenuated after the administration of both the adenosine 1 and 2 receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine and 8-(3-chlorostyryl)caffeine. Responses to defibrotide were not altered after the administration of the vascular selective adenosine triphosphate-sensitive potassium channel blocker U-37883A, or after the administration of the nitric oxide synthase inhibitor L-N-(1-iminoethyl)-ornithine. These data show that defibrotide has significant vasodepressor activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to defibrotide are partially dependent on both the activation of the cyclooxygenase enzyme and adenosine 1 and 2 receptor pathways and independent of the activation of adenosine triphosphate-sensitive potassium channels or the synthesis of nitric oxide in the pulmonary vascular bed of the cat.

Direct Position Determination of Unknown Signals in the Presence of Multipath Propagation

PubMed Central

Yu, Hongyi

2018-01-01

A novel geolocation architecture, termed “Multiple Transponders and Multiple Receivers for Multiple Emitters Positioning System (MTRE)” is proposed in this paper. Existing Direct Position Determination (DPD) methods take advantage of a rather simple channel assumption (line of sight channels with complex path attenuations) and a simplified MUltiple SIgnal Classification (MUSIC) algorithm cost function to avoid the high dimension searching. We point out that the simplified assumption and cost function reduce the positioning accuracy because of the singularity of the array manifold in a multi-path environment. We present a DPD model for unknown signals in the presence of Multi-path Propagation (MP-DPD) in this paper. MP-DPD adds non-negative real path attenuation constraints to avoid the mistake caused by the singularity of the array manifold. The Multi-path Propagation MUSIC (MP-MUSIC) method and the Active Set Algorithm (ASA) are designed to reduce the dimension of searching. A Multi-path Propagation Maximum Likelihood (MP-ML) method is proposed in addition to overcome the limitation of MP-MUSIC in the sense of a time-sensitive application. An iterative algorithm and an approach of initial value setting are given to make the MP-ML time consumption acceptable. Numerical results validate the performances improvement of MP-MUSIC and MP-ML. A closed form of the Cramér–Rao Lower Bound (CRLB) is derived as a benchmark to evaluate the performances of MP-MUSIC and MP-ML. PMID:29562601

Direct Position Determination of Unknown Signals in the Presence of Multipath Propagation.

PubMed

Du, Jianping; Wang, Ding; Yu, Wanting; Yu, Hongyi

2018-03-17

A novel geolocation architecture, termed "Multiple Transponders and Multiple Receivers for Multiple Emitters Positioning System (MTRE)" is proposed in this paper. Existing Direct Position Determination (DPD) methods take advantage of a rather simple channel assumption (line of sight channels with complex path attenuations) and a simplified MUltiple SIgnal Classification (MUSIC) algorithm cost function to avoid the high dimension searching. We point out that the simplified assumption and cost function reduce the positioning accuracy because of the singularity of the array manifold in a multi-path environment. We present a DPD model for unknown signals in the presence of Multi-path Propagation (MP-DPD) in this paper. MP-DPD adds non-negative real path attenuation constraints to avoid the mistake caused by the singularity of the array manifold. The Multi-path Propagation MUSIC (MP-MUSIC) method and the Active Set Algorithm (ASA) are designed to reduce the dimension of searching. A Multi-path Propagation Maximum Likelihood (MP-ML) method is proposed in addition to overcome the limitation of MP-MUSIC in the sense of a time-sensitive application. An iterative algorithm and an approach of initial value setting are given to make the MP-ML time consumption acceptable. Numerical results validate the performances improvement of MP-MUSIC and MP-ML. A closed form of the Cramér-Rao Lower Bound (CRLB) is derived as a benchmark to evaluate the performances of MP-MUSIC and MP-ML.

Melatonin mediates vasodilation through both direct and indirect activation of BKCa channels.

PubMed

Zhao, T; Zhang, H; Jin, C; Qiu, F; Wu, Y; Shi, L

2017-10-01

Melatonin, synthesized primarily by the pineal gland, is a neuroendocrine hormone with high membrane permeability. The vascular effects of melatonin, including vasoconstriction and vasodilation, have been demonstrated in numerous studies. However, the mechanisms underlying these effects are not fully understood. Large-conductance Ca 2+ -activated K + (BK Ca ) channels are expressed broadly on smooth muscle cells and play an important role in vascular tone regulation. This study explored the mechanisms of myocyte BK Ca channels and endothelial factors underlying the action of melatonin on the mesenteric arteries (MAs). Vascular contractility and patch-clamp studies were performed on myocytes of MAs from Wistar rats. Melatonin induced significant vasodilation on MAs. In the presence of N ω -nitro-l-arginine methyl ester (l-NAME), a potent endothelial oxide synthase (eNOS) inhibitor, melatonin elicited concentration-dependent relaxation, with lowered pIC 50 The effect of melatonin was significantly attenuated in the presence of BK Ca channel blocker iberiotoxin or MT1/MT2 receptor antagonist luzindole in both (+) l-NAME and (-) l-NAME groups. In the (+) l-NAME group, iberiotoxin caused a parallel rightward shift of the melatonin concentration-relaxation curve, with pIC 50 lower than that of luzindole. Both inside-out and cell-attached patch-clamp recordings showed that melatonin significantly increased the open probability, mean open time and voltage sensitivity of BK Ca channels. In a cell-attached patch-clamp configuration, the melatonin-induced enhancement of BK Ca channel activity was significantly suppressed by luzindole. These findings indicate that in addition to the activation of eNOS, melatonin-induced vasorelaxation of MAs is partially attributable to its direct (passing through the cell membrane) and indirect (via MT1/MT2 receptors) activation of the BK Ca channels on mesenteric arterial myocytes. © 2017 Society for Endocrinology.

Potassium channels and prostacyclin contribute to vasorelaxant activities of Tridax procumbens crude aqueous leaf extract in rat superior mesenteric arteries.

PubMed

Salahdeen, H M; Adebari, A O; Murtala, B A; Alada, A R A

2015-03-01

Previous studies have shown that aqueous extract of the leaf of Tridax procuinbens is capable of lowering blood pressure through its vasodilatory effects. In the present study attempt was made to examine the biological active components of T procuinbens leaf using GC-MS methods. We further investigated the role of K+ channels in the vasorelaxation effects of Tridax procumbens using rat isolated mesenteric artery. The superior mesenteric artery isolated from healthy, young adult Wistar rats (250-300 g) were precontracted with phenylephrine (PE) (10(-7) M) and potassium chloride (KCl) (60 mM) and were treated with Various concentrations of aqueous extract ofT procumbens (0.9.0 mg/ml). The changes in arterial tension were recorded using a force-displacement transducer (Model 7004; Ugo Basil Varese, Italy) coupled to data capsule acquisition system. The results of GG-MS revealed the presence of linoleic acid. The T. procumbens extract (TPE) ranging from 0.5-9.0 mg/mI significantly (p<0.05) reduced the, contraction induced by (PE) and (KCl) in a concentration-dependent manner. The extract also antagonised the calcium-induced vasoconstriction (1(-9) - 10(-5)) in calcium-free with high concentration of potassium as well as. in calcium- and potassium free physiological solutions. The vasorelaxing effect caused by TPE was significantly (p<0.05) attenuated with preincubation of potassium channels blockers (Barium chloride and apamin), NO synthaseinhibitor (L-NAME), prostacyclin inhibitor (indomethacin), atropine; propranolol, and methylene blue while it was not affected by preincubation with glibenclamide and tetra ethyl ammonium, 4-aminopyridine (4-AP) and oxadiazolo quinoxalin (ODQ). The results of this study demonstrate that T procumbens extract causes vasodilatory effects by blocking calcium channels and the vasodilatory effect of the extract may also be due to stimulation of prostacyclin production and opening of small-conductance Ga2+ activated potassium channels. The observed effect of this extract may be probably due to the presence of linoleic acid in this extract.

Characteristics of III-nitride based laser diode employed for short range underwater wireless optical communications

NASA Astrophysics Data System (ADS)

Xue, Bin; Liu, Zhe; Yang, Jie; Feng, Liangsen; Zhang, Ning; Wang, Junxi; Li, Jinmin

2018-03-01

An off-the-shelf green laser diode (LD) was measured to investigate its temperature dependent characteristics. Performance of the device was severely restricted by rising temperature in terms of increasing threshold current and decreasing modulation bandwidth. The observation reveals that dynamic characteristics of the LD is sensitive to temperature. Influence of light attenuation on the modulation bandwidth of the green LD was also studied. The impact of light attenuation on the modulation bandwidth of the LD in short and low turbid water channel was not obvious while slight difference in modulation bandwidth under same injection level was observed between water channel and free space even at short range.

Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior.

PubMed

Cannady, Reginald; McGonigal, Justin T; Newsom, Ryan J; Woodward, John J; Mulholland, Patrick J; Gass, Justin T

2017-04-19

Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu 5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (K Ca 2) channels have also been implicated in extinction learning of fear memories, and mGlu 5 receptor activation can reduce K Ca 2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined K Ca 2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats. This study also explored related neuronal and synaptic mechanisms within the IL-PFC that underlie mGlu 5 -dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu 5 in ex vivo slices significantly reduced K Ca 2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of K Ca 2 channel activity by mGlu 5 receptors. Additionally, positive modulation of K Ca 2 channels prevented mGlu 5 receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (K Ca 2 channel allosteric inhibitor) significantly enhanced extinction of alcohol-seeking behavior across multiple extinction sessions, an effect that persisted for 3 weeks, but was not observed after apamin microinfusions into the prelimbic PFC. Positive modulation of IL-PFC K Ca 2 channels significantly attenuated mGlu 5 -dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu 5 -dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of K Ca 2 channels. Moreover, these findings demonstrate that K Ca 2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior. SIGNIFICANCE STATEMENT Alcohol use disorder is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles, and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on relapse in alcoholics. Copyright © 2017 the authors 0270-6474/17/374359-11$15.00/0.

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or ‘classical’ congenital myopathy

PubMed Central

Zaharieva, Irina T.; Thor, Michael G.; Oates, Emily C.; van Karnebeek, Clara; Hendson, Glenda; Blom, Eveline; Witting, Nanna; Rasmussen, Magnhild; Gabbett, Michael T.; Ravenscroft, Gianina; Sframeli, Maria; Suetterlin, Karen; Sarkozy, Anna; D’Argenzio, Luigi; Hartley, Louise; Matthews, Emma; Pitt, Matthew; Vissing, John; Ballegaard, Martin; Krarup, Christian; Slørdahl, Andreas; Halvorsen, Hanne; Ye, Xin Cynthia; Zhang, Lin-Hua; Løkken, Nicoline; Werlauff, Ulla; Abdelsayed, Mena; Davis, Mark R.; Feng, Lucy; Phadke, Rahul; Sewry, Caroline A.; Morgan, Jennifer E.; Laing, Nigel G.; Vallance, Hilary; Ruben, Peter; Hanna, Michael G.; Lewis, Suzanne; Kamsteeg, Erik-Jan; Männikkö, Roope

2016-01-01

Abstract See Cannon (doi: 10.1093/brain/awv400 ) for a scientific commentary on this article. Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Na v 1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero - or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Na v 1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Na v 1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy. PMID:26700687

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy.

PubMed

Zaharieva, Irina T; Thor, Michael G; Oates, Emily C; van Karnebeek, Clara; Hendson, Glenda; Blom, Eveline; Witting, Nanna; Rasmussen, Magnhild; Gabbett, Michael T; Ravenscroft, Gianina; Sframeli, Maria; Suetterlin, Karen; Sarkozy, Anna; D'Argenzio, Luigi; Hartley, Louise; Matthews, Emma; Pitt, Matthew; Vissing, John; Ballegaard, Martin; Krarup, Christian; Slørdahl, Andreas; Halvorsen, Hanne; Ye, Xin Cynthia; Zhang, Lin-Hua; Løkken, Nicoline; Werlauff, Ulla; Abdelsayed, Mena; Davis, Mark R; Feng, Lucy; Phadke, Rahul; Sewry, Caroline A; Morgan, Jennifer E; Laing, Nigel G; Vallance, Hilary; Ruben, Peter; Hanna, Michael G; Lewis, Suzanne; Kamsteeg, Erik-Jan; Männikkö, Roope; Muntoni, Francesco

2016-03-01

Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Examination of Single- and Multi-Channel GPR Bridge Deck Condition Assessment Methods with Comparison to Complementary NDE Results

NASA Astrophysics Data System (ADS)

Romero, Francisco A.; Manacorda, Guido; Simi, Alessandro; Gucunski, Nenad; Parvardeh, Hooman

2013-04-01

A sixteen-channel GPR system which houses both longitudinally- and transversely-polarized, 2.0 GHz antenna elements within a single housing was compared with a single-channel GPR system that was separately using both 1.5GHz and 2.6GHz antennas oriented in the transverse polarization, for the purpose of determining effectiveness of bridge deck condition assessment. The multi-channel system has obvious benefits which include closely-spaced GPR antennas (channels) that provide better lateral resolution, as well as combined data sets from co-linear antennas oriented in both the transverse and longitudinal polarizations, which has benefits for imaging within the deck's internal structure. However, the primary objective was to determine whether the multi-channel system would perform in a similar manner to proven single-channel GPR technology during an attenuation-based GPR condition assessment on an older, partially deteriorated deck in northwestern New Jersey that is annually exposed to freeze-thaw conditions as well as de-icing salts. These assessments were made by focusing on identifying the strongest reflections from the upper mat of transversely-oriented rebars within the deck and comparing reflection strength, or conversely, attenuation of the GPR signal, from each of the 'picked' GPR rebar responses. Coordinates for each of the GPR picks, along with amplitude or attenuation measurements, were gridded and contour-plotted for the purpose of identifying areas identified as either relatively deteriorated or sound. Initially, results were compared for data with no applied correction that takes into account GPR signal attenuation with increasing depth within the concrete deck. Final GPR maps were produced incorporating a depth-correction technique similar to what is described by Barnes, et. al., Romero, et. al, and Gucunski, et. al., a process which has been clearly demonstrated to better correlate GPR results with not only ground truth (cores, sounding) but also with other NDE technologies. Not only did all the single- and multi-channel system comparisons generate nearly identical deterioration maps when GPR results were compared and examined, but mapped results obtained from other NDE methods on the same deck were used to identify zones where corrosive environment (electrical resistivity - ER) elastic modulus (ultrasonic surface wave - USW), and identified delaminations (impact-echo - IE) had commonality with the GPR results. A summary of the equipment used, as well as general data collection and analysis procedures is provided for the GPR condition assessments. Brief descriptions of background and references to how the complementary NDT technologies are deployed, and how data are interpreted, are also discussed. Comparative maps for all technologies are used for illustrative purposes.

Non-steroidal Anti-inflammatory Drugs Attenuate Hyperalgesia and Block Upregulation of Trigeminal Ganglionic Sodium Channel 1.7 after Induction of Temporomandibular Joint Inflammation in Rats.

PubMed

Bi, Rui Yun; Ding, Yun; Gan, Ye Hua

2016-03-01

To investigate the association between the analgesic effect of non-steroidal antiinflammatory drugs (NSAIDs) and sodium channel 1.7 (Nav1.7) expression in the trigeminal ganglion (TG). Temporomandibular joint (TMJ) inflammation was induced by complete Freund's adjuvant (CFA) in female rats. Ibuprofen, diclofenac sodium and meloxicam were given intragastrically before induction of TMJ inflammation. Histopathological evaluation and scoring of TMJ inflammation was used to evaluate the level of inflammation. The head withdrawal threshold and food intake were measured to evaluate TMJ nociceptive responses. The mRNA and protein expression of trigeminal ganglionic Nav1.7 was examined using real-time polymerase chain reaction and western blot. Twenty-four hours after the injection of CFA into the TMJs, NSAIDs attenuated hyperalgesia of inflamed TMJ and simultaneously blocked inflammation-induced upregulation of Nav1.7 mRNA and protein expression in the TG. However, ibuprofen and diclofenac sodium slightly attenuated TMJ inflammation and meloxicam did not affect TMJ inflammation. Attenuation of hyperalgesia of inflamed TMJ by NSAIDs might be associated with their role in blocking upregulation of trigeminal ganglionic Nav1.7.

Classical capacity of Gaussian thermal memory channels

NASA Astrophysics Data System (ADS)

De Palma, G.; Mari, A.; Giovannetti, V.

2014-10-01

The classical capacity of phase-invariant Gaussian channels has been recently determined under the assumption that such channels are memoryless. In this work we generalize this result by deriving the classical capacity of a model of quantum memory channel, in which the output states depend on the previous input states. In particular we extend the analysis of Lupo et al. [Phys. Rev. Lett. 104, 030501 (2010), 10.1103/PhysRevLett.104.030501 and Phys. Rev. A 82, 032312 (2010), 10.1103/PhysRevA.82.032312] from quantum limited channels to thermal attenuators and thermal amplifiers. Our result applies in many situations in which the physical communication channel is affected by nonzero memory and by thermal noise.

AMTB, a TRPM8 channel blocker: evidence in rats for activity in overactive bladder and painful bladder syndrome.

PubMed

Lashinger, Erin S R; Steiginga, Matthew S; Hieble, J Paul; Leon, Lisa A; Gardner, Scott D; Nagilla, Rakesh; Davenport, Elizabeth A; Hoffman, Bryan E; Laping, Nicholas J; Su, Xin

2008-09-01

The activation of the TRPM8 channel, a member of the large class of TRP ion channels, has been reported to be involved in overactive bladder and painful bladder syndrome, although an endogenous activator has not been identified. In this study, N-(3-aminopropyl)-2-{[(3-methylphenyl) methyl]oxy}-N-(2-thienylmethyl)benzamide hydrochloride salt (AMTB) was evaluated as a TRPM8 channel blocker and used as a tool to evaluate the effects of this class of ion channel blocker on volume-induced bladder contraction and nociceptive reflex responses to noxious bladder distension in the rat. AMTB inhibits icilin-induced TRPM8 channel activation as measured in a Ca(2+) influx assay, with a pIC(50) of 6.23. In the anesthetized rat, intravenous administration of AMTB (3 mg/kg) decreased the frequency of volume-induced bladder contractions, without reducing the amplitude of contraction. The nociceptive response was measured by analyzing both visceromotor reflex (VMR) and cardiovascular (pressor) responses to urinary bladder distension (UBD) under 1% isoflurane. AMTB (10 mg/kg) significantly attenuated reflex responses to noxious UBD to 5.42 and 56.51% of the maximal VMR response and pressor response, respectively. The ID50 value on VMR response was 2.42 +/- 0.46 mg/kg. These results demonstrate that TRPM8 channel blocker can act on the bladder afferent pathway to attenuate the bladder micturition reflex and nociceptive reflex responses in the rat. Targeting TRPM8 channel may provide a new therapeutic opportunity for overactive bladder and painful bladder syndrome.

Hyperforin attenuates microglia activation and inhibits p65-Ser276 NFκB phosphorylation in the rat piriform cortex following status epilepticus.

PubMed

Lee, Sang-Kyu; Kim, Ji-Eun; Kim, Yeon-Joo; Kim, Min-Ju; Kang, Tae-Cheon

2014-08-01

Hyperforin, a lipophilic constituent of medicinal herb St. John's Wort, has neurobiological effects including antidepressant activity, antibiotic potency, anti-inflammatory activity and anti-tumoral properties. Furthermore, hyperforin activates transient receptor potential conical channel-6 (TRPC6), a nonselective cation channel. To elucidate the roles of hyperforin and TRPC6 in neuroinflammation in vivo, we investigated the effect of hyperforin on neuroinflammatory responses and its related events in the rat piriform cortex (PC) following status epilepticus (SE). Hyperforin attenuated microglial activation, p65-serine 276 NFκB phosphorylation, and suppressed TNF-α expression in the PC following SE. Hyperforin also effectively alleviated SE-induced vasogenic edema formation, neuronal damage, microglial TRPC6 induction and blood-derived monocyte infiltration. Our findings suggest that hyperforin may effectively attenuate microglia-mediated neuroinflammation in the TRPC6-independent manner. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels

PubMed Central

Yin, Shijin; Luo, Jialie; Qian, Aihua; Yu, Weihua; Hu, Hongzhen

2014-01-01

Background and PurposeRetinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARβ, is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels. Experimental ApproachWe performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours. Key ResultsLE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies. Conclusions and ImplicationsThis blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels. PMID:24308840

LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels.

PubMed

Yin, Shijin; Luo, Jialie; Qian, Aihua; Yu, Weihua; Hu, Hongzhen

2014-03-01

Retinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARβ , is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels. We performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours. LE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies. This blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels. © 2013 The British Pharmacological Society.

Store-depletion and hyperforin activate distinct types of Ca(2+)-conducting channels in cortical neurons.

PubMed

Gibon, Julien; Tu, Peng; Bouron, Alexandre

2010-06-01

Cortical neurons embryos (E13) from murine brain have a wide diversity of plasma membrane Ca(2+)-conducting channels. For instance, they express several types of transient receptor potential channels of C-type (TRPC) and hyperforin, a potent TRPC6-channel activator, controls the activity of TRPC6-like channels. In addition, E13 cortical neurons possess plasma membrane channels activated in response to the depletion of internal Ca(2+) pools. Since some TRPC channels seem to be involved in the activity of store-depletion-activated channels, we investigated whether hyperforin and the depletion of the Ca(2+) stores control similar or distinct Ca(2+) routes. Calcium imaging experiments performed with the fluorescent Ca(2+) indicator Fluo-4 showed that the TRPC3 channel blocker Pyr3 potently inhibits with an IC(50) of 0.5microM the entry of Ca(2+) triggered in response to the thapsigargin-dependent depletion of the Ca(2+) stores. On the other hand, Pyr3 does not block the hyperforin-sensitive Ca(2+) entry. In contrast to the hyperforin responses, the Ca(2+) entry through the store-depletion-activated channels is down-regulated by the competitive tyrosine kinase inhibitors genistein and PP2. In addition, the immunosuppressant FK506, known to modulate several classes of Ca(2+)-conducting channels, strongly attenuates the entry of Ca(2+) through the store-depletion-activated channels, leaving the hyperforin-sensitive responses unaffected. Hence, the Zn(2+) chelator TPEN markedly attenuated the hyperforin-sensitive responses without modifying the thapsigargin-dependent Ca(2+) signals. Pyr3-insensitive channels are key components of the hyperforin-sensitive channels, whereas the thapsigargin-dependent depletion of the Ca(2+) stores of the endoplasmic reticulum activates Pyr3-sensitive channels. Altogether, these data support the notion that hyperforin and the depletion of the Ca(2+) pools control distinct plasma membrane Ca(2+)-conducting channels. This report further illustrates that, at the beginning of the corticogenesis, immature cortical neurons express diverse functional Ca(2+) channels. 2010 Elsevier Ltd. All rights reserved.

Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea-pig isolated bronchus.

PubMed

Harrison, S; Reddy, S; Page, C P; Spina, D

1998-12-01

We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. Cyclosporin A (10 microM) failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl)-benzyl and SR48968, respectively. Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was significantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 microM) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. The N-type calcium channel blocker, omega-Conotoxin (omegaCTX: 10 nM), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, omega-CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A. In bronchial preparations desensitized by repeated application of capsaicin (1 microM), the contractile responses to both cyclosporin A (100 microM) and FK506 (100 microM), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 microM) were not altered. Furthermore, repeated application of cyclosporin A (100 microM) significantly inhibited the contractile response to capsaicin (1 microM). The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea-pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels.

Low-Dose Ethanol Preconditioning Protects Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury By Activating Large Conductance, Ca2+-Activated K+ Channels In Vitro.

PubMed

Su, Fang; Guo, An-Chen; Li, Wei-Wei; Zhao, Yi-Long; Qu, Zheng-Yi; Wang, Yong-Jun; Wang, Qun; Zhu, Yu-Lan

2017-02-01

Increasing evidence suggests that low to moderate ethanol ingestion protects against the deleterious effects of subsequent ischemia/reperfusion; however, the underlying mechanism has not been elucidated. In the present study, we showed that expression of the neuronal large-conductance, Ca 2+ -activated K + channel (BK Ca ) α-subunit was upregulated in cultured neurons exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) compared with controls. Preconditioning with low-dose ethanol (10 mmol/L) increased cell survival rate in neurons subjected to OGD/R, attenuated the OGD/R-induced elevation of cytosolic Ca 2+ levels, and reduced the number of apoptotic neurons. Western blots revealed that ethanol preconditioning upregulated expression of the anti-apoptotic protein Bcl-2 and downregulated the pro-apoptotic protein Bax. The protective effect of ethanol preconditioning was antagonized by a BK Ca channel inhibitor, paxilline. Inside-out patches in primary neurons also demonstrated the direct activation of the BK Ca channel by 10 mmol/L ethanol. The above results indicated that low-dose ethanol preconditioning exerts its neuroprotective effects by attenuating the elevation of cytosolic Ca 2+ and preventing neuronal apoptosis, and this is mediated by BK Ca channel activation.

TRPC1 is involved in Ca²⁺ influx and cytotoxicity following Pb²⁺ exposure in human embryonic kidney cells.

PubMed

Zhang, Hongmei; Li, Wenjun; Xue, Yong; Zou, Fei

2014-08-17

Lead (Pb(2+)) is a divalent heavy metal ion which causes severe damage to almost all life forms and is therefore considered a notorious toxicant. Exposure to Pb(2+) is associated with poor cognitive development in children at relatively low levels that previously were thought to be safe. The mechanism through which Pb(2+) enters cells, however, is unclear. Previous studies have showed that Ca(2+) release-activated Ca(2+) protein 1 (Orai1), a component of store-operated Ca(2+) channels (SOCs), contributes to Pb(2+) cellular entry. Canonical transient receptor potential (TRPC1) channel 1 is a transient receptor potential (TRP) channel which is sometimes referred to as a SOC. The present study was designed to investigate the role of TRPC1 in Pb(2+) entry and toxicity in human embryonic kidney cells (HEK293). Additionally, changes in intracellular Ca(2+) concentration were determined through Fluo-4 and Mag-fluo-4 fluorescent Ca(2+) imaging. Following Pb(2+) exposure, there was a dose-dependent decrease in cell viability. Overexpression of TRPC1 increased Pb(2+)-induced cell death, while knockdown of this channel attenuated cell death. There was increased entry of Pb(2+), as measured by inductively coupled plasma mass spectrometry (ICP-MS), following overexpression of TRPC1. Conversely, knockdown of TRPC1 led to a decrease in Pb(2+) influx. Down-regulation of STIM1 by RNA interference attenuated the Pb(2+) influx, and transfection with a mutant STIM1, which could not gate TRPC1, had a similar effect. Co-transfection of mutant STIM1 and mutant TRPC1, which restore the electrostatic interaction between STIM1 and TRPC1, resumed Pb(2+) entry in HEK293 cells. Down-regulation of TRPC1 by RNA interference decreased Ca(2+) influx whilst its overexpression increased Ca(2+) entry in HEK293 cells. These results suggest that TRPC1 is involved in the cytotoxicity and entry of Pb(2+) through molecular interactions with STIM1 and subsequent Ca(2+) influx in HEK293 cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Memory restoring and neuroprotective effects of the proline-containing dipeptide, GVS-111, in a photochemical stroke model.

PubMed

Ostrovskaya, R U; Romanova, G A; Barskov, I V; Shanina, E V; Gudasheva, T A; Victorov, I V; Voronina, T A; Seredenin, S B

1999-09-01

Local thrombosis of the frontal cortex (Fr1 and Fr3 fields), caused by combination of the intravenous photosensitive dye Rose Bengal administration with focused high-intensity illumination of the frontal bone, was shown to provoke a pronounced deficit in step-through passive avoidance performance in rats without concomitant motor disturbances. N-Phenylacetyl-L-prolylglycine ethyl ester (GVS-111) administered intravenously at a dose of 0.5 mg/kg/day, for the first time 1 h after ischaemic lesion and then for 9 post-operative days, with the last administration 15 min before testing, attenuated the deficit. This treatment significantly diminished the volume of the infarcted area. Thus, post-ischaemic injection of GVS-111 demonstrated both cognition-restoring and neuroprotective properties. The cognition-restoring effect is probably based on an increase in neocortical and hippocampal neuronal plasticity. Neuroprotective effects of GVS-111 combine antioxidant activity with the ability to attenuate glutamate-provoked neurotoxicity and block voltage-gated ionic channels, i.e. the compound mitigates the main metabolic shifts involved in pathogenesis of brain ischaemia.

Agmatine attenuates brain edema through reducing the expression of aquaporin-1 after cerebral ischemia

PubMed Central

Kim, Jae Hwan; Lee, Yong Woo; Park, Kyung Ah; Lee, Won Taek; Lee, Jong Eun

2010-01-01

Brain edema is frequently shown after cerebral ischemia. It is an expansion of brain volume because of increasing water content in brain. It causes to increase mortality after stroke. Agmatine, formed by the decarboxylation of -arginine by arginine decarboxylase, has been shown to be neuroprotective in trauma and ischemia models. The purpose of this study was to investigate the effect of agmatine for brain edema in ischemic brain damage and to evaluate the expression of aquaporins (AQPs). Results showed that agmatine significantly reduced brain swelling volume 22 h after 2 h middle cerebral artery occlusion in mice. Water content in brain tissue was clearly decreased 24 h after ischemic injury by agmatine treatment. Blood–brain barrier (BBB) disruption was diminished with agmatine than without. The expressions of AQPs-1 and -9 were well correlated with brain edema as water channels, were significantly decreased by agmatine treatment. It can thus be suggested that agmatine could attenuate brain edema by limitting BBB disruption and blocking the accumulation of brain water content through lessening the expression of AQP-1 after cerebral ischemia. PMID:20029450

Persistence of Episodic Extreme Events: Sustained Colluvial Contributions of Fine Sediment to Vermont Rivers Post-Irene

NASA Astrophysics Data System (ADS)

Dethier, E.; Magilligan, F. J.; Renshaw, C. E.; Sinclair, D.

2014-12-01

Tropical Storm Irene generated devastating floods in New England in 2011, causing more than $500 million of damage. In intervening years, many geomorphic signs of disturbance have attenuated, suggesting that impacts may be ephemeral. Yet persistent impact continues: channel-proximal landslide scars linger as point sources of fine sediment 3 yrs post-Irene. We evaluate the legacy of this major disturbance while also testing conceptual models of hillslope-channel connectivity and subsequent downstream sediment routing. We measure sustained landslide erosion by comparing DEMs generated by a Terrestrial Laser Scanner and trace sediment mobility using in-channel measurements of embeddedness, sediment concentration, and fallout radionuclide activity. We augmented detailed temporal sampling of an 850 m2 landslide along a 2nd-order stream with a spatially robust summer 2014 field campaign, scanning an additional 12 landslides. The initially sampled landslide eroded 250 m3 of sediment between fall 2013 and May 2014, averaging 0.3 m of erosion with nearly all erosion occurring during a two-week spring snowmelt. Landslide sediments had high measured 7Be activity (t1/2=53.4 d), caused by subaerial exposure; sediment collected downstream of the landslide had higher 7Be activity than that collected upstream, suggesting landslide provenance. Channel sediment upstream of the landslide had remained in the channel long enough for 7Be to decay below detectable activity. Embeddedness, a measure of fine sediment on a channel bed, was higher downstream of the landslide than upstream. Remote sensing reveals >50 similar landslides within the White River alone, and hundreds more in Vermont. Thus, landslide scar inputs may continue to influence the regional fine sediment budget. Ongoing successive scans in multiple watersheds show erosion continues in summer, an observation corroborated by elevated suspended sediment concentrations downstream of landslides after rain events. Summertime erosion has generally been low, but one extreme storm triggered >4000 m3 of erosion on a 3500 m2 landslide along the 5th-order Williams River, averaging 1.3 m erosion across the landslide. Understanding the loci of affected reaches and the magnitude of the continued effect is critical in assessing the long-term legacy of extreme events.

TRPV2 channel inhibitors attenuate fibroblast differentiation and contraction mediated by keratinocyte-derived TGF-β1 in an in vitro wound healing model of rats.

PubMed

Ishii, Taro; Uchida, Kunitoshi; Hata, Shozaburo; Hatta, Mitsutoki; Kita, Tomo; Miyake, Yuki; Okamura, Kazuhiko; Tamaoki, Sachio; Ishikawa, Hiroyuki; Yamazaki, Jun

2018-06-01

Keratinocytes release several factors that are involved in wound contracture and scar formation. We previously reported that a three-dimensional reconstruction model derived from rat skin represents a good wound healing model. We characterized the role of transient receptor potential (TRP) channels in the release of transforming growth factor (TGF)-β1 from keratinocytes and the differentiation of fibroblasts to identify possible promising pharmacological approaches to prevent scar formation and contractures. The three-dimensional culture model was made from rat keratinocytes seeded on a collagen gel in which dermal fibroblasts had been embedded. Among the TRP channel inhibitors tested, the TRPV2 inhibitors SKF96365 and tranilast attenuated most potently keratinocyte-dependent and - independent collagen gel contraction due to TGF-β signaling as well as TGF-β1 release from keratinocytes and α-smooth muscle actin production in myofibroblasts. Besides the low amounts detected in normal dermis, TRPV2 mRNA and protein levels were increased after fibroblasts were embedded in the gel. TRPV2 was also expressed in the epidermis and keratinocyte layers of the model. Both inhibitors and TRPV2 siRNA attenuated the intracellular increase of Ca 2+ induced by the TRPV agonist 2-aminoethoxydiphenyl borate in TGF-β1-pretreated fibroblasts. This is the first study to show that compounds targeting TRPV2 channels ameliorate wound contraction through the inhibition of TGF-β1 release and the differentiation of dermal fibroblasts in a culture model. Copyright © 2018. Published by Elsevier B.V.

Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation

PubMed Central

2012-01-01

Background Transient receptor potential cation channel subfamily M member 8 (TRPM8) is activated by cold temperature in vitro and has been demonstrated to act as a ‘cold temperature sensor’ in vivo. Although it is known that agonists of this ‘cold temperature sensor’, such as menthol and icilin, cause a transient increase in body temperature (Tb), it is not known if TRPM8 plays a role in Tb regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in Tb regulation. Results We characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496) as potent and selective antagonists of TRPM8 and tested their effects on Tb in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in Tb (maximum decrease of 0.98°C). Since thermoregulation is a homeostatic process that maintains Tb about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in Tb. Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the Tb decrease Day 2 onwards. Conclusions The data reported here demonstrate that TRPM8 channels play a role in Tb regulation. Further, a reduction of magnitude in Tb decrease after repeated dosing of an antagonist suggests that TRPM8’s role in Tb maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics. PMID:22571355

Modeling, Simulation, and Analysis of a Decoy State Enabled Quantum Key Distribution System

DTIC Science & Technology

2015-03-26

through the fiber , we assume Alice and Bob have correct basis alignment and timing control for reference frame correction and precise photon detection...optical components ( laser , polarization modulator, electronic variable optical attenuator, fixed optical attenuator, fiber channel, beamsplitter...generated by the laser in the CPG propagate through multiple optical components, each with a unique propagation delay before reaching the OPM. Timing

SPECIAL ISSUE ON OPTICAL PROCESSING OF INFORMATION: Circulatory fibre-optic memory loop with a built-in service channel

NASA Astrophysics Data System (ADS)

Pilipovich, V. A.; Esman, A. K.; Goncharenko, I. A.; Posed'ko, V. S.; Solonovich, I. F.

1995-10-01

A method for increasing the information capacity and enhancing the reliability of information storage in a dynamic fibre-optic memory is proposed. An additional built-in channel with counterpropagating circulation of signals is provided for this purpose. This additional channel can be used to transmit both information and service signals, such as address words, clock signals, correcting sequences, etc. The possibility of compensating the attenuation of an information signal by stimulated Raman scattering is considered.

Radio Implementation of a Testbed For Cognitive Radio Source Localization Using USRPS and GNU Radio

DTIC Science & Technology

2014-09-01

average received energy F FFT vector size FS sampling rate g gain h channel attenuation H0 hypothesis 0 H1 hypothesis 1 I in-phase L packet size...Amplitude Modulation (QAM)). The baseband signal is then sent to the USRP in the form of in-phase (I) and quadrature (Q) complex samples to be further... sampling rate defines the bandwidth of the transmitted signal, which must be less than the channel separation to give non- overlapping channels. The FFT

TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shirakawa, Hisashi; Yamaoka, Tomoko; Sanpei, Kazuaki

2008-12-26

Transient receptor potential vanilloid 1 (TRPV1) functions as a polymodal nociceptor and is activated by several vanilloids, including capsaicin, protons and heat. Although TRPV1 channels are widely distributed in the brain, their roles remain unclear. Here, we investigated the roles of TRPV1 in cytotoxic processes using TRPV1-expressing cultured rat cortical neurons. Capsaicin induced severe neuronal death with apoptotic features, which was completely inhibited by the TRPV1 antagonist capsazepine and was dependent on extracellular Ca{sup 2+} influx. Interestingly, nifedipine, a specific L-type Ca{sup 2+} channel blocker, attenuated capsaicin cytotoxicity, even when applied 2-4 h after the capsaicin. ERK inhibitor PD98059 andmore » several antioxidants, but not the JNK and p38 inhibitors, attenuated capsaicin cytotoxicity. Together, these data indicate that TRPV1 activation triggers apoptotic cell death of rat cortical cultures via L-type Ca{sup 2+} channel opening, Ca{sup 2+} influx, ERK phosphorylation, and reactive oxygen species production.« less

Membrane stiffening by STOML3 facilitates mechanosensation in sensory neurons

PubMed Central

Qi, Yanmei; Andolfi, Laura; Frattini, Flavia; Mayer, Florian; Lazzarino, Marco; Hu, Jing

2015-01-01

Sensing force is crucial to maintain the viability of all living cells. Despite its fundamental importance, how force is sensed at the molecular level remains largely unknown. Here we show that stomatin-like protein-3 (STOML3) controls membrane mechanics by binding cholesterol and thus facilitates force transfer and tunes the sensitivity of mechano-gated channels, including Piezo channels. STOML3 is detected in cholesterol-rich lipid rafts. In mouse sensory neurons, depletion of cholesterol and deficiency of STOML3 similarly and interdependently attenuate mechanosensitivity while modulating membrane mechanics. In heterologous systems, intact STOML3 is required to maintain membrane mechanics to sensitize Piezo1 and Piezo2 channels. In C57BL/6N, but not STOML3−/− mice, tactile allodynia is attenuated by cholesterol depletion, suggesting that membrane stiffening by STOML3 is essential for mechanical sensitivity. Targeting the STOML3–cholesterol association might offer an alternative strategy for control of chronic pain. PMID:26443885

Spatio-Temporal Evolution of Sound Speed Channels on the Chukchi Shelf

NASA Astrophysics Data System (ADS)

Eickmeier, J.; Badiey, M.; Wan, L.

2017-12-01

The physics of an acoustic waveguide are influenced by various boundary conditions as well as spatial and temporal fluctuations in temperature and salinity profiles the water column. The shallow water Canadian Basin Acoustic Propagation Experiment (CANAPE) experiment was designed to study the effect of oceanographic variability on the acoustic field. A pilot study was conducted in the summer of 2015, full deployment of acoustic and environmental moorings took place in 2016, and recovery will occur in late 2017. An example of strong oceanographic variability in the SW region is depicted in Figure 1. Over the course of 7 days, warm Bering Sea water arrived on the Chukchi Shelf and sank in the water column to between 25 m and 125 m depth. This warm water spread to a range of 10 km and a potential eddy of warm water formed causing an increase in sound speed between 15 km and 20 km range in Fig. 1(b). Due to the increased sound speed, a strong sound channel evolved between 100 m and 200 m for acoustic waves arriving from off the shelf, deep water sources. In Fig. 1(a), the initial formation of the acoustic channel is only evident in 50 m to 100 m of water out to a range of 5 km. Recorded environmental data will be used to study fluctuations in sound speed channel formation on the Chukchi Shelf. Data collected in 2015 and 2016 have shown sound duct evolution over 7 days and over a one-month period. Analysis is projected to show sound channel formation over a new range of spatio-temporal scales. This analysis will show a cycle of sound channels opening and closing on the shelf, where this cycle strongly influences the propagation path, range and attenuation of acoustic waves.

Prolonged Attenuation of Amygdala-Kindled Seizure Measures in Rats by Convection-Enhanced Delivery of the N-Type Calcium Channel Antagonists ω-Conotoxin GVIA and ω-Conotoxin MVIIA

PubMed Central

Gasior, Maciej; White, Natalie A.; Rogawski, Michael A.

2008-01-01

Convection-enhanced delivery (CED) permits the homogeneous distribution of therapeutic agents throughout localized regions of the brain parenchyma without causing tissue damage as occurs with bolus injection. Here, we examined whether CED infusion of the N-type calcium channel antagonists ω-conotoxin GVIA (ω-CTX-G) and ω-conotoxin MVIIA (ω-CTX-M) can attenuate kindling measures in fully amygdala-kindled rats. Rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received infusions of vehicle, ω-CTX-G (0.005, 0.05, and 0.5 nmol), ω-CTX-M (0.05, 0.15, and 0.5 nmol), proteolytically inactivated ω-CTX-M (0.5 nmol), or carbamazepine (500 nmol) into the stimulation site. CED of ω-CTX-G and ω-CTX-M over a 20-min period resulted in a dose-dependent increase in the afterdischarge threshold and a decrease in the afterdischarge duration and behavioral seizure score and duration during a period of 20 min to 1 week after the infusion, indicating an inhibitory effect on the triggering and expression of kindled seizures. The protective effects of ω-conotoxins reached a maximum at 48 h postinfusion, and then they gradually resolved over the next 5 days. In contrast, carbamazepine was active at 20 min but not at 24 h after the infusion, whereas CED of vehicle or inactivated ω-CTX-M had no effect. Except for transient tremor in some rats receiving the highest toxin doses, no adverse effects were observed. These results indicate that local CED of high-molecular-weight presynaptic N-type calcium channel blockers can produce long-lasting inhibition of brain excitability and that they may provide prolonged seizure protection in focal seizure disorders. PMID:17717191

Information-efficient spectral imaging sensor

DOEpatents

Sweatt, William C.; Gentry, Stephen M.; Boye, Clinton A.; Grotbeck, Carter L.; Stallard, Brian R.; Descour, Michael R.

2003-01-01

A programmable optical filter for use in multispectral and hyperspectral imaging. The filter splits the light collected by an optical telescope into two channels for each of the pixels in a row in a scanned image, one channel to handle the positive elements of a spectral basis filter and one for the negative elements of the spectral basis filter. Each channel for each pixel disperses its light into n spectral bins, with the light in each bin being attenuated in accordance with the value of the associated positive or negative element of the spectral basis vector. The spectral basis vector is constructed so that its positive elements emphasize the presence of a target and its negative elements emphasize the presence of the constituents of the background of the imaged scene. The attenuated light in the channels is re-imaged onto separate detectors for each pixel and then the signals from the detectors are combined to give an indication of the presence or not of the target in each pixel of the scanned scene. This system provides for a very efficient optical determination of the presence of the target, as opposed to the very data intensive data manipulations that are required in conventional hyperspectral imaging systems.

Detection flying aircraft from Landsat 8 OLI data

NASA Astrophysics Data System (ADS)

Zhao, F.; Xia, L.; Kylling, A.; Li, R. Q.; Shang, H.; Xu, Ming

2018-07-01

Monitoring flying aircraft from satellite data is important for evaluating the climate impact caused by the global aviation industry. However, due to the small size of aircraft and the complex surface types, it is almost impossible to identify aircraft from satellite data with moderate resolution, e.g. 30 m. In this study, the 1.38 μm water vapor absorption channel, often used for cirrus cloud or ash detection, is for the first time used to monitor flying aircraft from Landsat 8 data. The basic theory behind the detection of flying aircraft is that in the 1.38 μm channel most of the background reflectance between the ground and the aircraft is masked due to the strong water vapor absorption, while the signal of the flying aircraft will be attenuated less due to the low water vapor content between the satellite and the aircraft. A new composition of the Laplacian and Sobel operators for segmenting aircraft and other features were used to identify the flying aircraft. The Landsat 8 Operational Land Imager (OLI) 2.1 μm channel was used to make the method succeed under low vapor content. The accuracy assessment based on 65 Landsat 8 images indicated that the percentage of leakage is 3.18% and the percentage of false alarm is 0.532%.

Capsaicin-induced reactivation of latent herpes simplex virus type 1 in sensory neurons in culture.

PubMed

Hunsperger, Elizabeth A; Wilcox, Christine L

2003-05-01

Herpes simplex virus type 1 (HSV-1) produces a life-long latent infection in neurons of the peripheral nervous system, primarily in the trigeminal and dorsal root ganglia. Neurons of these ganglia express high levels of the capsaicin receptor, also known as the vanilloid receptor-1 (VR-1). VR-1 is a non-selective ion channel, found on sensory neurons, that primarily fluxes Ca(2+) ions in response to various stimuli, including physiologically acidic conditions, heat greater than 45 degrees C and noxious compounds such as capsaicin. Using an in vitro neuronal model to study HSV-1 latency and reactivation, we found that agonists of the VR-1 channel - capsaicin and heat - resulted in reactivation of latent HSV-1. Capsaicin-induced reactivation of HSV-1 latently infected neurons was dose-dependent. Additionally, activation of VR-1 at its optimal temperature of 46 degrees C caused a significant increase in virus titres, which could be attenuated with the VR-1 antagonist, capsazepine. VR-1 activation that resulted in HSV-1 reactivation was calcium-dependent, since the calcium chelator BAPTA significantly reduced reactivation following treatment with caspsaicin and forskolin. Taken together, these results suggest that activation of the VR-1 channel, often associated with increases in intracellular calcium, results in HSV-1 reactivation in sensory neurons.

Joint channel estimation and multi-user detection for multipath fading channels in DS-CDMA systems

NASA Astrophysics Data System (ADS)

Wu, Sau-Hsuan; Kuo, C.-C. Jay

2002-11-01

The technique of joint blind channel estimation and multiple access interference (MAI) suppression for an asynchronous code-division multiple-access (CDMA) system is investigated in this research. To identify and track dispersive time-varying fading channels and to avoid the phase ambiguity that come with the second-order statistic approaches, a sliding-window scheme using the expectation maximization (EM) algorithm is proposed. The complexity of joint channel equalization and symbol detection for all users increases exponentially with system loading and the channel memory. The situation is exacerbated if strong inter-symbol interference (ISI) exists. To reduce the complexity and the number of samples required for channel estimation, a blind multiuser detector is developed. Together with multi-stage interference cancellation using soft outputs provided by this detector, our algorithm can track fading channels with no phase ambiguity even when channel gains attenuate close to zero.

VEGF attenuated increase of outward delayed-rectifier potassium currents in hippocampal neurons induced by focal ischemia via PI3-K pathway.

PubMed

Wu, K W; Yang, P; Li, S S; Liu, C W; Sun, F Y

2015-07-09

We recently indicated that the vascular endothelial growth factor (VEGF) protects neurons against hypoxic death via enhancement of tyrosine phosphorylation of Kv1.2, an isoform of the delayed-rectifier potassium channels through activation of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway. The present study investigated whether VEGF could attenuate ischemia-induced increase of the potassium currents in the hippocampal pyramidal neurons of rats after ischemic injury. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) to induce brain ischemia. The whole-cell patch-clamp technique was used to record the potassium currents of hippocampal neurons in brain slices from the ischemically injured brains of the rats 24h after MCAO. We detected that transient MCAO caused a significant increase of voltage-gated potassium currents (Kv) and outward delayed-rectifier potassium currents (IK), but not outward transient potassium currents (IA), in the ipsilateral hippocampus compared with the sham. Moreover, we found that VEGF could acutely, reversibly and voltage-dependently inhibit the ischemia-induced IK increase. This inhibitory effect of VEGF could be completely abolished by wortmannin, an inhibitor of PI3-K. Our data indicate that VEGF attenuates the ischemia-induced increase of IK via activation of the PI3-K signaling pathway. Published by Elsevier Ltd.

Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells

PubMed Central

Jehle, J; Ficker, E; Wan, X; Deschenes, I; Kisselbach, J; Wiedmann, F; Staudacher, I; Schmidt, C; Schweizer, PA; Becker, R; Katus, HA; Thomas, D

2013-01-01

Background and Purpose Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene (hERG)/IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K+ channels. Experimental Approach Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration (APD) was assessed in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. Key Results Zolpidem caused acute hERG channel blockade in oocytes (IC50 = 61.5 μM) and in HEK 293 cells (IC50 = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I–V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. Conclusions and Implications Zolpidem inhibits cardiac hERG K+ channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose. PMID:23061993

Impact of Hyperpolarization-activated, Cyclic Nucleotide-gated Cation Channel Type 2 for the Xenon-mediated Anesthetic Effect: Evidence from In Vitro and In Vivo Experiments.

PubMed

Mattusch, Corinna; Kratzer, Stephan; Buerge, Martina; Kreuzer, Matthias; Engel, Tatiana; Kopp, Claudia; Biel, Martin; Hammelmann, Verena; Ying, Shui-Wang; Goldstein, Peter A; Kochs, Eberhard; Haseneder, Rainer; Rammes, Gerhard

2015-05-01

The thalamus is thought to be crucially involved in the anesthetic state. Here, we investigated the effect of the inhaled anesthetic xenon on stimulus-evoked thalamocortical network activity and on excitability of thalamocortical neurons. Because hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are key regulators of neuronal excitability in the thalamus, the effect of xenon on HCN channels was examined. The effects of xenon on thalamocortical network activity were investigated in acutely prepared brain slices from adult wild-type and HCN2 knockout mice by means of voltage-sensitive dye imaging. The influence of xenon on single-cell excitability in brain slices was investigated using the whole-cell patch-clamp technique. Effects of xenon on HCN channels were verified in human embryonic kidney cells expressing HCN2 channels. Xenon concentration-dependently diminished thalamocortical signal propagation. In neurons, xenon reduced HCN channel-mediated Ih current amplitude by 33.4 ± 12.2% (at -133 mV; n = 7; P = 0.041) and caused a left-shift in the voltage of half-maximum activation (V1/2) from -98.8 ± 1.6 to -108.0 ± 4.2 mV (n = 8; P = 0.035). Similar effects were seen in human embryonic kidney cells. The impairment of HCN channel function was negligible when intracellular cyclic adenosine monophosphate level was increased. Using HCN2 mice, we could demonstrate that xenon did neither attenuate in vitro thalamocortical signal propagation nor did it show sedating effects in vivo. Here, we clearly showed that xenon impairs HCN2 channel function, and this impairment is dependent on intracellular cyclic adenosine monophosphate levels. We provide evidence that this effect reduces thalamocortical signal propagation and probably contributes to the hypnotic properties of xenon.

Energy Conservation in Optical Fibers With Distributed Brick-Walls Filters

NASA Astrophysics Data System (ADS)

Garcia, Javier; Ghozlan, Hassan; Kramer, Gerhard

2018-05-01

A band-pass filtering scheme is proposed to mitigate spectral broadening and channel coupling in the Nonlinear Schr\\"odinger (NLS) fiber optic channel. The scheme is modeled by modifying the NLS Equation to include an attenuation profile with multiple brick-wall filters centered at different frequencies. It is shown that this brick-walls profile conserves the total in-band energy of the launch signal. Furthermore, energy fluctuations between the filtered channels are characterized, and conditions on the channel spacings are derived that ensure energy conservation in each channel. The maximum spectral efficiency of such a system is derived, and a constructive rule for achieving it using Sidon sequences is provided.

DOR activation inhibits anoxic/ischemic Na+ influx through Na+ channels via PKC mechanisms in the cortex.

PubMed

Chao, Dongman; He, Xiaozhou; Yang, Yilin; Bazzy-Asaad, Alia; Lazarus, Lawrence H; Balboni, Gianfranco; Kim, Dong H; Xia, Ying

2012-08-01

Activation of delta-opioid receptors (DOR) is neuroprotective against hypoxic/ischemic injury in the cortex, which is at least partially related to its action against hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal injury. Na(+) influx through TTX-sensitive voltage-gated Na(+) channels may be a main mechanism for hypoxia-induced disruption of K(+) homeostasis, with DOR activation attenuating the disruption of ionic homeostasis by targeting voltage-gated Na(+) channels. In the present study we examined the role of DOR in the regulation of Na(+) influx in anoxia and simulated ischemia (oxygen-glucose deprivation) as well as the effect of DOR activation on the Na(+) influx induced by a Na(+) channel opener without anoxic/ischemic stress and explored a potential PKC mechanism underlying the DOR action. We directly measured extracellular Na(+) activity in mouse cortical slices with Na(+) selective electrodes and found that (1) anoxia-induced Na(+) influx occurred mainly through TTX-sensitive Na(+) channels; (2) DOR activation inhibited the anoxia/ischemia-induced Na(+) influx; (3) veratridine, a Na(+) channel opener, enhanced the anoxia-induced Na(+) influx; this could be attenuated by DOR activation; (4) DOR activation did not reduce the anoxia-induced Na(+) influx in the presence of chelerythrine, a broad-spectrum PKC blocker; and (5) DOR effects were blocked by PKCβII peptide inhibitor, and PKCθ pseudosubstrate inhibitor, respectively. We conclude that DOR activation inhibits anoxia-induced Na(+) influx through Na(+) channels via PKC (especially PKCβII and PKCθ isoforms) dependent mechanisms in the cortex. Copyright © 2012 Elsevier Inc. All rights reserved.

Kainate receptor pore‐forming and auxiliary subunits regulate channel block by a novel mechanism

PubMed Central

Brown, Patricia M. G. E.; Aurousseau, Mark R. P.; Musgaard, Maria; Biggin, Philip C.

2016-01-01

Key points Kainate receptor heteromerization and auxiliary subunits, Neto1 and Neto2, attenuate polyamine ion‐channel block by facilitating blocker permeation.Relief of polyamine block in GluK2/GluK5 heteromers results from a key proline residue that produces architectural changes in the channel pore α‐helical region.Auxiliary subunits exert an additive effect to heteromerization, and thus relief of polyamine block is due to a different mechanism.Our findings have broad implications for work on polyamine block of other cation‐selective ion channels. Abstract Channel block and permeation by cytoplasmic polyamines is a common feature of many cation‐selective ion channels. Although the channel block mechanism has been studied extensively, polyamine permeation has been considered less significant as it occurs at extreme positive membrane potentials. Here, we show that kainate receptor (KAR) heteromerization and association with auxiliary proteins, Neto1 and Neto2, attenuate polyamine block by enhancing blocker permeation. Consequently, polyamine permeation and unblock occur at more negative and physiologically relevant membrane potentials. In GluK2/GluK5 heteromers, enhanced permeation is due to a single proline residue in GluK5 that alters the dynamics of the α‐helical region of the selectivity filter. The effect of auxiliary proteins is additive, and therefore the structural basis of polyamine permeation and unblock is through a different mechanism. As native receptors are thought to assemble as heteromers in complex with auxiliary proteins, our data identify an unappreciated impact of polyamine permeation in shaping the signalling properties of neuronal KARs and point to a structural mechanism that may be shared amongst other cation‐selective ion channels. PMID:26682513

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine

PubMed Central

Goodwill, Adam G.; Fu, Lijuan; Noblet, Jillian N.; Casalini, Eli D.; Berwick, Zachary C.; Kassab, Ghassan S.; Tune, Johnathan D.

2016-01-01

Hydrogen peroxide (H2O2) and voltage-dependent K+ (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. PMID:26825518

KV7 channels contribute to paracrine, but not metabolic or ischemic, regulation of coronary vascular reactivity in swine.

PubMed

Goodwill, Adam G; Fu, Lijuan; Noblet, Jillian N; Casalini, Eli D; Sassoon, Daniel; Berwick, Zachary C; Kassab, Ghassan S; Tune, Johnathan D; Dick, Gregory M

2016-03-15

Hydrogen peroxide (H2O2) and voltage-dependent K(+) (KV) channels play key roles in regulating coronary blood flow in response to metabolic, ischemic, and paracrine stimuli. The KV channels responsible have not been identified, but KV7 channels are possible candidates. Existing data regarding KV7 channel function in the coronary circulation (limited to ex vivo assessments) are mixed. Thus we examined the hypothesis that KV7 channels are present in cells of the coronary vascular wall and regulate vasodilation in swine. We performed a variety of molecular, biochemical, and functional (in vivo and ex vivo) studies. Coronary arteries expressed KCNQ genes (quantitative PCR) and KV7.4 protein (Western blot). Immunostaining demonstrated KV7.4 expression in conduit and resistance vessels, perhaps most prominently in the endothelial and adventitial layers. Flupirtine, a KV7 opener, relaxed coronary artery rings, and this was attenuated by linopirdine, a KV7 blocker. Endothelial denudation inhibited the flupirtine-induced and linopirdine-sensitive relaxation of coronary artery rings. Moreover, linopirdine diminished bradykinin-induced endothelial-dependent relaxation of coronary artery rings. There was no effect of intracoronary flupirtine or linopirdine on coronary blood flow at the resting heart rate in vivo. Linopirdine had no effect on coronary vasodilation in vivo elicited by ischemia, H2O2, or tachycardia. However, bradykinin increased coronary blood flow in vivo, and this was attenuated by linopirdine. These data indicate that KV7 channels are expressed in some coronary cell type(s) and influence endothelial function. Other physiological functions of coronary vascular KV7 channels remain unclear, but they do appear to contribute to endothelium-dependent responses to paracrine stimuli. Copyright © 2016 the American Physiological Society.

Analgesic ineffectiveness of lacosamide after spinal nerve ligation and its sodium channel activity in injured neurons.

PubMed

Hagenacker, T; Schäfer, N; Büsselberg, D; Schäfers, M

2013-07-01

Lacosamide is a novel anti-epileptic drug that enhances the slow- and not fast-inactivating state of voltage-gated sodium channels. Lacosamide has demonstrated analgesic efficacy in several animal studies but preclinical studies on neuropathic pain models are rare, and recent clinical trials showed no superior analgesic effects. Here, we examine whether an acute or chronic administration of lacosamide (3-60 mg/kg, i.p.) attenuates pain behaviour induced by spinal nerve ligation (SNL). To validate the inhibitory efficacy of lacosamide on voltage-gated sodium channels, sodium currents in naïve and SNL-injured dorsal root ganglion (DRG) neurons were recorded using whole-cell patch clamping. Lacosamide only marginally attenuated thermal hyperalgesia, but not tactile allodynia when applied once 7 or 14 days after SNL and showed no analgesic effect when applied daily for 19 days. In naïve neurons, 100 μmol/L lacosamide inhibited sodium channel currents by 58% and enhanced the slow inactivation (87% for lacosamide vs. 47% for control). In contrast, lacosamide inhibited sodium currents in injured DRG neurons by only 15%, while the effects on slow inactivation were diminished. Isolated currents from the NaV 1.8 channel subtype were only marginally changed by lacosamide. The reduced effectiveness of lacosamide on voltage-gated sodium channel currents in injured DRG neurons may contribute to the reduced analgesic effect observed for the SNL model. © 2012 European Federation of International Association for the Study of Pain Chapters.

Optimizing catecholaminergic polymorphic ventricular tachycardia therapy in calsequestrin-mutant mice

PubMed Central

Katz, Guy; Khoury, Assad; Kurtzwald, Efrat; Hochhauser, Edith; Porat, Eyal; Shainberg, Asher; Seidman, Jonathan G.; Seidman, Christine E.; Lorber, Abraham; Eldar, Michael; Arad, Michael

2014-01-01

BACKGROUND Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal arrhythmia provoked by physical or emotional stress and mediated by spontaneous Ca2+ release and delayed after-depolarizations. Beta-adrenergic blockers are the therapy of choice but fail to control arrhythmia in up to 50% of patients. OBJECTIVE To optimize antiarrhythmic therapy in recessively inherited CPVT caused by calsequestrin (CASQ2) mutations. METHODS Murine heart rhythm telemetry was obtained at rest, during treadmill exercise, and after injection of epinephrine. The protocol was repeated after injection of different antiarrhythmic drugs. Results were then validated in human patients. RESULTS Adult CASQ2 mutant mice had complex ventricular arrhythmia at rest and developed bidirectional and polymorphic ventricular tachycardia on exertion. Class I antiarrhythmic agents (procainamide, lidocaine, flecainide) were ineffective in controlling arrhythmia. Propranolol and sotalol attenuated arrhythmia at rest but failed to prevent VT during sympathetic stimulation. The calcium channel blocker verapamil showed a dose-dependent protection against CPVT. Verapamil was more effective than the dihydropyridine L-type Ca2+ channel blocker nifedipine, and its activity was markedly enhanced when combined with propranolol. Human patients homozygous for CASQ2D307H mutation, remaining symptomatic despite chronic β-blocker therapy, underwent exercise testing according to the Bruce protocol with continuous electrocardiogram recording. Verapamil was combined with propranolol at maximum tolerated doses. Adding verapamil attenuated ventricular arrhythmia and prolonged exercise duration in five of 11 patients. CONCLUSION Verapamil is highly effective against catecholamine-induced arrhythmia in mice with CASQ2 mutations and may potentiate the antiarrhythmic activity of β-blockers in humans with CPVT2. PMID:20620233

Electroacupuncture Reduces Carrageenan- and CFA-Induced Inflammatory Pain Accompanied by Changing the Expression of Nav1.7 and Nav1.8, rather than Nav1.9, in Mice Dorsal Root Ganglia.

PubMed

Huang, Chun-Ping; Chen, Hsiang-Ni; Su, Hong-Lin; Hsieh, Ching-Liang; Chen, Wei-Hsin; Lai, Zhen-Rung; Lin, Yi-Wen

2013-01-01

Several voltage-gated sodium channels (Navs) from nociceptive nerve fibers have been identified as important effectors in pain signaling. The objective of this study is to investigate the electroacupuncture (EA) analgesia mechanism by changing the expression of Navs in mice dorsal root ganglia (DRG). We injected carrageenan and complete Freund's adjuvant (CFA) into the mice plantar surface of the hind paw to induce inflammation and examined the antinociception effect of EA at the Zusanli (ST36) acupoint at 2 Hz low frequency. Mechanical hyperalgesia was evaluated by using electronic von Frey filaments, and thermal hyperalgesia was assessed using Hargreaves' test. Furthermore, we observed the expression and quality of Navs in DRG neurons. Our results showed that EA reduced mechanical and thermal pain in inflammatory animal model. The expression of Nav1.7 and Nav1.8 was increased after 4 days of carrageenan- and CFA-elicited inflammatory pain and further attenuated by 2 Hz EA stimulation. The attenuation cannot be observed in Nav1.9 sodium channels. We demonstrated that EA at Zusanli (ST36) acupoint at 2 Hz low-frequency stimulation attenuated inflammatory pain accompanied by decreasing the expression of Nav1.7 and 1.8, rather than Nav1.9, sodium channels in peripheral DRG neurons.

Sphingosine 1-phosphate and human ether-a'-go-go-related gene potassium channels modulate migration in human anaplastic thyroid cancer cells.

PubMed

Asghar, Muhammad Yasir; Viitanen, Tero; Kemppainen, Kati; Törnquist, Kid

2012-10-01

Anaplastic thyroid cancer (ATC) is the most aggressive form of human thyroid cancer, lacking any effective treatment. Sphingosine 1-phosphate (S1P) receptors and human ether-a'-go-go-related gene (HERG (KCNH2)) potassium channels are important modulators of cell migration. In this study, we have shown that the S1P(1-3) receptors are expressed in C643 and THJ-16T human ATC cell lines, both at mRNA and protein level. S1P inhibited migration of these cells and of follicular FTC-133 thyroid cancer cells. Using the S1P(1,3) inhibitor VPC-23019, the S1P(2) inhibitor JTE-013, and the S1P(2) receptor siRNA, we showed that the effect was mediated through S1P(2). Treatment of the cells with the Rho inhibitor C3 transferase abolished the effect of S1P on migration. S1P attenuated Rac activity, and inhibiting Rac decreased migration. Sphingosine kinase inhibitor enhanced basal migration of cells, and addition of exogenous S1P inhibited migration. C643 cells expressed a nonconducting HERG protein, and S1P decreased HERG protein expression. The HERG blocker E-4031 decreased migration. Interestingly, downregulating HERG protein with siRNA decreased the basal migration. In experiments using HEK cells overexpressing HERG, we showed that S1P decreased channel protein expression and current and that S1P attenuated migration of the cells. We conclude that S1P attenuates migration of C643 ATC cells by activating S1P(2) and the Rho pathway. The attenuated migration is also, in part, dependent on a S1P-induced decrease of HERG protein.

A Practical Millimeter-Wave Holographic Imaging System with Tunable IF Attenuator

NASA Astrophysics Data System (ADS)

Zhu, Yu-Kun; Yang, Ming-Hui; Wu, Liang; Sun, Yun; Sun, Xiao-Wei

2017-10-01

A practical millimeter-wave (mmw) holographic imaging system with tunable intermediate frequency (IF) attenuator has been developed. It can be used for the detection of concealed weapons at security checkpoints, especially the airport. The system is utilized to scan the passenger and detect the weapons hidden in the clothes. To reconstruct the three dimensions (3-D) image, a holographic mmw imaging algorithm based on aperture synthesis and back scattering is presented. The system is active and works at 28-33 GHz. Tunable IF attenuator is applied to compensate the intensity and phase differences between multi-channels and multi-frequencies.

Summary of oceanographic measurements for characterizing light attenuation and sediment resuspension in the Barnegat Bay-Little Egg Harbor Estuary, New Jersey, 2013

USGS Publications Warehouse

Dickhudt, Patrick J.; Ganju, Neil K.; Montgomery, Ellyn T.

2015-08-28

The U.S. Geological Survey, in cooperation with the New Jersey Department of Environmental Protection, measured suspended-sediment concentrations, currents, waves, light attenuation, and a variety of other water-quality parameters in the summer of 2013 in Barnegat Bay-Little Egg Harbor, New Jersey. These measurements quantified light attenuation and sediment resuspension in three seagrass meadows. Data were acquired sequentially at three paired channel-shoal sites, as the equipment was moved from south to north in the estuary. Data were collected for approximately 3 weeks at each site.

Assessment of potential for natural attenuation of chlorinated ethenes and ethanes in ground water at a petrochemical reclamation site, Harris County, Texas

USGS Publications Warehouse

Huff, Glenn F.; Braun, Christopher L.; Lee, Roger W.

2000-01-01

Redox conditions in the Numerous Sand Channels Zone beneath a petrochemical reclamation site in Harris County, Texas, range from sulfate reducing to methanogenic as indicated by the presence of methane in ground water and the range of molecular hydrogen concentrations. Assessment of the potential for reductive dechlorination using BIOCHLOR as a screening tool indicated conditions favoring anaerobic degradation of chlorinated organic compounds in the Numerous Sand Channels Zone. Evidence supporting reductive dechlorination includes apparently biogenic cis-1,2-dichloroethene; an increased ratio of 1,2-dichloroethane to 1,1,2-trichloroethane downgradient from the assumed contaminant source area; ethene and methane concentrations greater than background concentrations within the area of the contaminant plume; and a positive correlation of the ratio of ethene to vinyl chloride as a function of methane concentrations. The body of evidence presented in this report argues for hydrogenolysis of trichloroethene to cis-1,2-dichloroethene; of 1,1,2-trichloroethane to 1,2-dichloroethane; and of vinyl chloride to ethene within the Numerous Sand Channels Zone. Simulations using BIOCHLOR yielded apparent first-order decay constants for reductive dechlorination in the sequence Tetrachloroethene --> trichloroethene --> cis-1,2-dichloroethene --> vinyl chloride --> ethene within the range of literature values reported for each compound and apparent first-order decay constants for reductive dechlorination in the sequence 1,1,2-trichloroethane --> 1,2-dichloroethane slightly greater than literature values reported for each compound along the upgradient segment of a simulated ground-water flowpath. Except for vinyl chloride, apparent rates of reductive dechlorination for all simulated species show a marked decrease along the downgradient segment of the simulated ground-water flowpath. Evidence for reductive dechlorination of chlorinated ethenes within the Numerous Sand Channels Zone indicates potential for natural attenuation of chlorinated ethenes. Reductive dechlorination of chlorinated ethanes apparently occurs to a lesser extent, indicating relatively less potential for natural attenuation of chlorinated ethanes. Additional data are needed on the concentrations and distribution of chlorinated ethenes and ethanes in individual fine sand intervals of the Numerous Sand Channels Zone. This information, combined with lower minimum reporting levels for future chloroethane analyses, might enable a more complete and quantitative assessment of the potential for natural attenuation at the site.

[A case of migraine presenting with thunderclap headache associated with posterior reversible encephalopathy syndrome].

PubMed

Katoh, Hirotaka; Saito, Yu; Ohwan, Yoshiyuki; Kasai, Hideyo; Fujita, Kazuhisa; Kawamura, Mitsuru

2014-10-01

We report a 47-year-old woman who developed a thunderclap headache. Head axial, fluid-attenuated inversion recovery magnetic resonance imaging (FLAIR MRI) revealed high signal lesions in the left occipital and right parietal lobes. Apparent diffusion coefficient mapping showed a vasogenic edema pattern. Upon admission, the patient's blood pressure was normal and the neurological examination was unremarkable. As thunderclap headaches are associated with a repeated rise in blood pressure, we considered cerebral vasoconstriction and administered a calcium channel blocker. Thereafter, her headache with high blood pressure eased significantly and the high signal lesions on FLAIR MRI disappeared. We diagnosed the condition as posterior reversible encephalopathy syndrome (PRES). In addition, head magnetic resonance angiogram showed vasoconstriction of the right anterior cerebral artery, left middle cerebral artery, and bilateral posterior cerebral artery. Calcium channel blocker use was continued and vasoconstriction improved by day 70. In this case, the presenting symptom was thunderclap headache, which is a characteristic feature of reversible cerebral vasoconstriction syndrome (RCVS). Therefore, PRES may be caused by RCVS.

Experimental comparison of performance degradation from terahertz and infrared wireless links in fog.

PubMed

Su, Ke; Moeller, Lothar; Barat, Robert B; Federici, John F

2012-02-01

We describe a lab setup for analyzing impairments of terahertz (THz) and infrared (IR) free space links caused by local refraction index changes in the signal's propagation paths that could be induced by turbulence, particles, humidity, etc. A THz signal comprising a 2.5 Gb/s data load modulated on a carrier at 625 GHz, is launched through a weather emulating chamber, detected, and its performance analyzed. An IR beam at 1.5 um wavelength carrying the same data load is superposed with the THz beam, propagating through the same weather conditions and also performance analyzed. We modulate the IR channel with a usual non-return-to-zero (NRZ) format but use duobinary coding for driving our THz source, which enables signaling at high data rate and higher output power. As both beams pass through the same channel perturbations and as their degradations are recorded simultaneously we can simultaneously compare the weather impact on both. We investigate scintillation and fog attenuation effects for the THz and IR signals by measuring bit error rates (BER), signal power, and phase front distortions. © 2012 Optical Society of America

Tropical cyclone warm core analyses with FY-3 microwave temperature sounder data

NASA Astrophysics Data System (ADS)

Liu, Zhe; Bai, Jie; Zhang, Wenjun; Yan, Jun; Zhou, Zhuhua

2014-05-01

Space-borne microwave instruments are well suited to analyze Tropical Cyclone (TC) warm core structure, because certain wavelengths of microwave energy are able to penetrate the cirrus above TC. With the vector discrete-ordinate microwave radiative transfer model, the basic atmospheric parameters of Hurricane BOB are used to simulate the upwelling brightness temperatures on each channel of the Microwave Temperature Sounder (MWTS) onboard FY-3A/3B observation. Based on the simulation, the characteristic of 1109 super typhoon "Muifa" warm core structure is analyzed with the MWTS channel 3. Through the radiative and hydrostatic equation, TC warm core brightness temperature anomalies are related to surface pressure anomalies. In order to correct the radiation attenuation caused by MWTS scan geometric features, and improve the capability in capturing the relatively complete warm core radiation, a proposed algorithm is devised to correct the bias from receiving warm core microwave radiation, shows similar time-variant tendency with "Muifa" minimal sea level pressure as described by TC best track data. As the next generation of FY-3 satellite will be launched in 2012, this method will be further verified

Prevention of ventricular arrhythmia and calcium dysregulation in a catecholaminergic polymorphic ventricular tachycardia mouse model carrying calsequestrin-2 mutation.

PubMed

Alcalai, Ronny; Wakimoto, Hiroko; Arad, Michael; Planer, David; Konno, Tetsuo; Wang, Libin; Seidman, Jon G; Seidman, Christine E; Berul, Charles I

2011-03-01

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmic syndrome caused by mutations in genes encoding the calcium-regulation proteins cardiac ryanodine receptor (RyR2) or calsequestrin-2 (CASQ2). Mechanistic studies indicate that CPVT is mediated by diastolic Ca(2+) overload and increased Ca(2+) leak through the RyR2 channel, implying that treatment targeting these defects might be efficacious in CPVT. CPVT mouse models that lack CASQ2 were treated with Ca(2+) -channel inhibitors, β-adrenergic inhibitors, or Mg(2+) . Treatment effects on ventricular arrhythmia, sarcoplasmic reticulum (SR) protein expression and Ca(2+) transients of isolated myocytes were assessed. Each study agent reduced the frequency of stress-induced ventricular arrhythmia in mutant mice. The Ca(2+) channel blocker verapamil was most efficacious and completely prevented arrhythmia in 85% of mice. Verapamil significantly increased the SR Ca(2+) content in mutant myocytes, diminished diastolic Ca(2+) overload, increased systolic Ca(2+) amplitude, and prevented Ca(2+) oscillations in stressed mutant myocytes. Ca(2+) channel inhibition by verapamil rectified abnormal calcium handling in CPVT myocytes and prevented ventricular arrhythmias. Verapamil-induced partial normalization of SR Ca(2+) content in mutant myocytes implicates CASQ2 as modulator of RyR2 activity, rather than or in addition to, Ca(2+) buffer protein. Agents such as verapamil that attenuate cardiomyocyte calcium overload are appropriate for assessing clinical efficacy in human CPVT. © 2010 Wiley Periodicals, Inc.

Prevention of Ventricular Arrhythmia and Calcium Dysregulation in a Catecholaminergic Polymorphic Ventricular Tachycardia Mouse Model Carrying Calsequestrin-2 Mutation

PubMed Central

Alcalai, Ronny; Wakimoto, Hiroko; Arad, Michael; Planer, David; Konno, Tetsuo; Wang, Libin; Seidman, Jon G.; Seidman, Christine E.; Berul, Charles I

2010-01-01

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmic syndrome caused by mutations in genes encoding the calcium-regulation proteins cardiac ryanodine receptor (RyR2) or calsequestrin-2 (CASQ2). Mechanistic studies indicate that CPVT is mediated by diastolic Ca2+ overload and increased Ca2+ leak through the RyR2 channel, implying that treatment targeting these defects might be efficacious in CPVT. Method and results CPVT mouse models that lack CASQ2 were treated with Ca2+-channel inhibitors, β-adrenergic inhibitors, or Mg2+. Treatment effects on ventricular arrhythmia, sarcoplasmic reticulum (SR) protein expression and Ca2+ transients of isolated myocytes were assessed. Each study agent reduced the frequency of stress-induced ventricular arrhythmia in mutant mice. The Ca2+ channel blocker verapamil was most efficacious and completely prevented arrhythmia in 85% of mice. Verapamil significantly increased the SR Ca2+ content in mutant myocytes, diminished diastolic Ca2+ overload, increased systolic Ca2+ amplitude, and prevented Ca2+ oscillations in stressed mutant myocytes. Conclusions Ca2+ channel inhibition by verapamil rectified abnormal calcium handling in CPVT myocytes and prevented ventricular arrhythmias. Verapamil-induced partial normalization of SR Ca2+ content in mutant myocytes implicates CASQ2 as modulator of RyR2 activity, rather than or in addition to, Ca2+ buffer protein. Agents such as verapamil that attenuate cardiomyocyte calcium overload are appropriate for assessing clinical efficacy in human CPVT. PMID:20807279

Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of ASIC1a Channels to Extracellular Acidosis

PubMed Central

Duan, Bo; Wang, Yi-Zhi; Yang, Tao; Chu, Xiang-Ping; Yu, Ye; Huang, Yu; Cao, Hui; Hansen, Jillian; Simon, Roger P.; Zhu, Michael X.; Xiong, Zhi-Gang; Xu, Tian-Le

2011-01-01

Ischemic brain injury is a major problem associated with stroke. It has been increasingly recognized that acid-sensing ion channels (ASICs) contribute significantly to ischemic neuronal damage, but the underlying mechanism has remained elusive. Here, we show that extracellular spermine, one of the endogenous polyamines, exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. Pharmacological blockade of ASIC1a or deletion of the ASIC1 gene greatly reduces the enhancing effect of spermine in ischemic neuronal damage both in cultures of dissociated neurons and in a mouse model of focal ischemia. Mechanistically, spermine profoundly reduces desensitization of ASIC1a by slowing down desensitization in the open state, shifting steady-state desensitization to more acidic pH, and accelerating recovery between repeated periods of acid stimulation. Spermine-mediated potentiation of ASIC1a activity is occluded by PcTX1 (psalmotoxin 1), a specific ASIC1a inhibitor binding to its extracellular domain. Functionally, the enhanced channel activity is accompanied by increased acid-induced neuronal membrane depolarization and cytoplasmic Ca2+ overload, which may partially explain the exacerbated neuronal damage caused by spermine. More importantly, blocking endogenous spermine synthesis significantly attenuates ischemic brain injury mediated by ASIC1a but not that by NMDA receptors. Thus, extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Our data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction. PMID:21307247

The delayed rectifier potassium conductance in the sarcolemma and the transverse tubular system membranes of mammalian skeletal muscle fibers

PubMed Central

DiFranco, Marino; Quinonez, Marbella

2012-01-01

A two-microelectrode voltage clamp and optical measurements of membrane potential changes at the transverse tubular system (TTS) were used to characterize delayed rectifier K currents (IKV) in murine muscle fibers stained with the potentiometric dye di-8-ANEPPS. In intact fibers, IKV displays the canonical hallmarks of KV channels: voltage-dependent delayed activation and decay in time. The voltage dependence of the peak conductance (gKV) was only accounted for by double Boltzmann fits, suggesting at least two channel contributions to IKV. Osmotically treated fibers showed significant disconnection of the TTS and displayed smaller IKV, but with similar voltage dependence and time decays to intact fibers. This suggests that inactivation may be responsible for most of the decay in IKV records. A two-channel model that faithfully simulates IKV records in osmotically treated fibers comprises a low threshold and steeply voltage-dependent channel (channel A), which contributes ∼31% of gKV, and a more abundant high threshold channel (channel B), with shallower voltage dependence. Significant expression of the IKV1.4 and IKV3.4 channels was demonstrated by immunoblotting. Rectangular depolarizing pulses elicited step-like di-8-ANEPPS transients in intact fibers rendered electrically passive. In contrast, activation of IKV resulted in time- and voltage-dependent attenuations in optical transients that coincided in time with the peaks of IKV records. Normalized peak attenuations showed the same voltage dependence as peak IKV plots. A radial cable model including channels A and B and K diffusion in the TTS was used to simulate IKV and average TTS voltage changes. Model predictions and experimental data were compared to determine what fraction of gKV in the TTS accounted simultaneously for the electrical and optical data. Best predictions suggest that KV channels are approximately equally distributed in the sarcolemma and TTS membranes; under these conditions, >70% of IKV arises from the TTS. PMID:22851675

Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain

PubMed Central

Kanju, Patrick; Chen, Yong; Lee, Whasil; Yeo, Michele; Lee, Suk Hee; Romac, Joelle; Shahid, Rafiq; Fan, Ping; Gooden, David M.; Simon, Sidney A.; Spasojevic, Ivan; Mook, Robert A.; Liddle, Rodger A.; Guilak, Farshid; Liedtke, Wolfgang B.

2016-01-01

TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and wide-spread expression. One of the critical functions of TRPV4 in this spectrum is its involvement in pain and inflammation. However, few small-molecule inhibitors of TRPV4 are available. Here we developed TRPV4-inhibitory molecules based on modifications of a known TRPV4-selective tool-compound, GSK205. We not only increased TRPV4-inhibitory potency, but surprisingly also generated two compounds that potently co-inhibit TRPA1, known to function as chemical sensor of noxious and irritant signaling. We demonstrate TRPV4 inhibition by these compounds in primary cells with known TRPV4 expression - articular chondrocytes and astrocytes. Importantly, our novel compounds attenuate pain behavior in a trigeminal irritant pain model that is known to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain-associated behavior in a model of acute pancreatitis – known to also rely on TRPV4 and TRPA1. Our results illustrate proof of a novel concept inherent in our prototype compounds of a drug that targets two functionally-related TRP channels, and thus can be used to combat isoforms of pain and inflammation in-vivo that involve more than one TRP channel. This approach could provide a novel paradigm for treating other relevant health conditions. PMID:27247148

Experimental demonstration of quantum digital signatures over 43 dB channel loss using differential phase shift quantum key distribution.

PubMed

Collins, Robert J; Amiri, Ryan; Fujiwara, Mikio; Honjo, Toshimori; Shimizu, Kaoru; Tamaki, Kiyoshi; Takeoka, Masahiro; Sasaki, Masahide; Andersson, Erika; Buller, Gerald S

2017-06-12

Ensuring the integrity and transferability of digital messages is an important challenge in modern communications. Although purely mathematical approaches exist, they usually rely on the computational complexity of certain functions, in which case there is no guarantee of long-term security. Alternatively, quantum digital signatures offer security guaranteed by the physical laws of quantum mechanics. Prior experimental demonstrations of quantum digital signatures in optical fiber have typically been limited to operation over short distances and/or operated in a laboratory environment. Here we report the experimental transmission of quantum digital signatures over channel losses of up to 42.8 ± 1.2 dB in a link comprised of 90 km of installed fiber with additional optical attenuation introduced to simulate longer distances. The channel loss of 42.8 ± 1.2 dB corresponds to an equivalent distance of 134.2 ± 3.8 km and this represents the longest effective distance and highest channel loss that quantum digital signatures have been shown to operate over to date. Our theoretical model indicates that this represents close to the maximum possible channel attenuation for this quantum digital signature protocol, defined as the loss for which the signal rate is comparable to the dark count rate of the detectors.

Coherent state coding approaches the capacity of non-Gaussian bosonic channels

NASA Astrophysics Data System (ADS)

Huber, Stefan; König, Robert

2018-05-01

The additivity problem asks if the use of entanglement can boost the information-carrying capacity of a given channel beyond what is achievable by coding with simple product states only. This has recently been shown not to be the case for phase-insensitive one-mode Gaussian channels, but remains unresolved in general. Here we consider two general classes of bosonic noise channels, which include phase-insensitive Gaussian channels as special cases: these are attenuators with general, potentially non-Gaussian environment states and classical noise channels with general probabilistic noise. We show that additivity violations, if existent, are rather minor for all these channels: the maximal gain in classical capacity is bounded by a constant independent of the input energy. Our proof shows that coding by simple classical modulation of coherent states is close to optimal.

TRAP binding to the Bacillus subtilis trp leader region RNA causes efficient transcription termination at a weak intrinsic terminator

PubMed Central

Potter, Kristine D.; Merlino, Natalie M.; Jacobs, Timothy; Gollnick, Paul

2011-01-01

The Bacillus subtilis trpEDCFBA operon is regulated by a transcription attenuation mechanism controlled by the trp RNA-binding attenuation protein (TRAP). TRAP binds to 11 (G/U)AG repeats in the trp leader transcript and prevents formation of an antiterminator, which allows formation of an intrinsic terminator (attenuator). Previously, formation of the attenuator RNA structure was believed to be solely responsible for signaling RNA polymerase (RNAP) to halt transcription. However, base substitutions that prevent formation of the antiterminator, and thus allow the attenuator structure to form constitutively, do not result in efficient transcription termination. The observation that the attenuator requires the presence of TRAP bound to the nascent RNA to cause efficient transcription termination suggests TRAP has an additional role in causing termination at the attenuator. We show that the trp attenuator is a weak intrinsic terminator due to low GC content of the hairpin stem and interruptions in the U-stretch following the hairpin. We also provide evidence that termination at the trp attenuator requires forward translocation of RNA polymerase and that TRAP binding to the nascent transcript can induce this activity. PMID:21097886

TRAP binding to the Bacillus subtilis trp leader region RNA causes efficient transcription termination at a weak intrinsic terminator.

PubMed

Potter, Kristine D; Merlino, Natalie M; Jacobs, Timothy; Gollnick, Paul

2011-03-01

The Bacillus subtilis trpEDCFBA operon is regulated by a transcription attenuation mechanism controlled by the trp RNA-binding attenuation protein (TRAP). TRAP binds to 11 (G/U)AG repeats in the trp leader transcript and prevents formation of an antiterminator, which allows formation of an intrinsic terminator (attenuator). Previously, formation of the attenuator RNA structure was believed to be solely responsible for signaling RNA polymerase (RNAP) to halt transcription. However, base substitutions that prevent formation of the antiterminator, and thus allow the attenuator structure to form constitutively, do not result in efficient transcription termination. The observation that the attenuator requires the presence of TRAP bound to the nascent RNA to cause efficient transcription termination suggests TRAP has an additional role in causing termination at the attenuator. We show that the trp attenuator is a weak intrinsic terminator due to low GC content of the hairpin stem and interruptions in the U-stretch following the hairpin. We also provide evidence that termination at the trp attenuator requires forward translocation of RNA polymerase and that TRAP binding to the nascent transcript can induce this activity.

The roles of the Na+/K+-ATPase, NKCC, and K+ channels in regulating local sweating and cutaneous blood flow during exercise in humans in vivo.

PubMed

Louie, Jeffrey C; Fujii, Naoto; Meade, Robert D; Kenny, Glen P

2016-11-01

Na + /K + -ATPase has been shown to regulate the sweating and cutaneous vascular responses during exercise; however, similar studies have not been conducted to assess the roles of the Na-K-2Cl co-transporter (NKCC) and K + channels. Additionally, it remains to be determined if these mechanisms underpinning the heat loss responses differ with exercise intensity. Eleven young (24 ± 4 years) males performed three 30-min semirecumbent cycling bouts at low (30% VO 2peak ), moderate (50% VO 2peak ), and high (70% VO 2peak ) intensity, respectively, each separated by 20-min recovery periods. Using intradermal microdialysis, four forearm skin sites were continuously perfused with either: (1) lactated Ringer solution (Control); (2) 6 mmol·L -1 ouabain (Na + /K + -ATPase inhibitor); (3) 10 mmol·L -1 bumetanide (NKCC inhibitor); or (4) 50 mmol·L -1 BaCl 2 (nonspecific K + channel inhibitor); sites at which we assessed local sweat rate (LSR) and cutaneous vascular conductance (CVC). Inhibition of Na + /K + -ATPase attenuated LSR compared to Control during the moderate and high-intensity exercise bouts (both P ˂ 0.01), whereas attenuations with NKCC and K + channel inhibition were only apparent during the high-intensity exercise bout (both P ≤ 0.05). Na + /K + -ATPase inhibition augmented CVC during all exercise intensities (all P ˂ 0.01), whereas CVC was greater with NKCC inhibition during the low-intensity exercise only (P ˂ 0.01) and attenuated with K + channel inhibition during the moderate and high-intensity exercise conditions (both P ˂ 0.01). We show that Na + /K + -ATPase, NKCC and K +  channels all contribute to the regulation of sweating and cutaneous blood flow but their influence is dependent on the intensity of dynamic exercise. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Studies of Scattering, Reflectivity, and Transmitivity in WBAN Channel: Feasibility of Using UWB

PubMed Central

Kabir, Md. Humaun; Ashrafuzzaman, Kazi; Chowdhury, M. Sanaullah; Kwak, Kyung Sup

2010-01-01

The Wireless Personal Area Network (WPAN) is one of the fledging paradigms that the next generation of wireless systems is sprouting towards. Among them, a more specific category is the Wireless Body Area Network (WBAN) used for health monitoring. On the other hand, Ultra-Wideband (UWB) comes with a number of desirable features at the physical layer for wireless communications. One big challenge in adoption of UWB in WBAN is the fact that signals get attenuated exponentially. Due to the intrinsic structural complexity in human body, electromagnetic waves show a profound variation during propagation through it. The reflection and transmission coefficients of human body are highly dependent upon the dielectric constants as well as upon the frequency. The difference in structural materials such as fat, muscles and blood essentially makes electromagnetic wave attenuation to be different along the way. Thus, a complete characterization of body channel is a challenging task. The connection between attenuation and frequency of the signal makes the investigation of UWB in WBAN an interesting proposition. In this paper, we study analytically the impact of body channels on electromagnetic signal propagation with reference to UWB. In the process, scattering, reflectivity and transmitivity have been addressed with analysis of approximate layer-wise modeling, and with numerical depictions. Pulses with Gaussian profile have been employed in our analysis. It shows that, under reasonable practical approximations, the human body channel can be modeled in layers so as to have the effects of total reflections or total transmissions in certain frequency bands. This could help decide such design issues as antenna characteristics of implant devices for WBAN employing UWB. PMID:22219673

Estrogen attenuates glutamate-induced cell death by inhibiting Ca2+ influx through L-type voltage-gated Ca2+ channels

PubMed Central

Sribnick, Eric A.; Del Re, Angelo M.; Ray, Swapan K.; Woodward, John J.; Banik, Naren L.

2009-01-01

Estrogen-mediated neuroprotection is observed in neurodegenerative disease and neurotrauama models; however, determining a mechanism for these effects has been difficult. We propose that estrogen may limit cell death in the nervous system tissue by inhibiting increases in intracellular free Ca2+. Here, we present data using VSC 4.1 cell line, a ventral spinal motoneuron and neuroblastoma hybrid cell line. Treatment with 1 mM glutamate for 24 h induced apoptosis. When cells were pre-treated with 100 nM 17β-estradiol (estrogen) for 1 h and then co-treated with glutamate, apoptotic death was significantly attenuated. Estrogen also prevented glutamate-mediated changes in resting membrane potential and membrane capacitance. Treatment with either 17α-estradiol or cell impermeable estrogen did not mimic the findings seen with estrogen. Glutamate treatment significantly increased both intracellular free Ca2+ and the activities of downstream proteases such as calpain and caspase-3. Estrogen attenuated both the increases in intracellular free Ca2+ and protease activities. In order to determine the pathway responsible for estrogen-mediated inhibition of these increases in intracellular free Ca2+, cells were treated with several Ca2+ entry inhibitors, but only the L-type Ca2+ channel blocker nifedipine demonstrated cytoprotective effects comparable to estrogen. To expand these findings, cells were treated with the L-type Ca2+ channel agonist FPL 64176, which increased both cell death and intracellular free Ca2+, and estrogen inhibited both effects. From these observations, we conclude that estrogen limits glutamate-induced cell death in VSC 4.1 cells through effects on L-type Ca2+ channels, inhibiting Ca2+ influx as well as activation of the pro-apoptotic proteases calpain and caspase-3. PMID:19389388

Preventive dietary potassium supplementation in young salt-sensitive Dahl rats attenuates development of salt hypertension by decreasing sympathetic vasoconstriction.

PubMed

Zicha, J; Dobešová, Z; Behuliak, M; Kuneš, J; Vaněčková, I

2011-05-01

Increased potassium intake attenuates the development of salt-dependent hypertension, but the detailed mechanisms of blood pressure (BP) reduction are still unclear. The aims of our study were (i) to elucidate these mechanisms, (ii) to compare preventive potassium effects in immature and adult animals and (iii) to evaluate the therapeutic effects of dietary potassium supplementation in rats with established salt hypertension.   Young (4-week-old) and adult (24-week-old) female salt-sensitive Dahl rats were fed a high-salt diet (5% NaCl) or a high-salt diet supplemented with 3% KCl for 5 weeks. The participation of vasoconstrictor (renin-angiotensin and sympathetic nervous systems) and vasodilator systems [prostanoids, Ca(2+) -activated K(+) channels, nitric oxide (NO)] was evaluated using a sequential blockade of these systems. Preventive potassium supplementation attenuated the development of severe salt hypertension in young rats, whereas it had no effects on BP in adult rats with moderate hypertension. Enhanced sympathetic vasoconstriction was responsible for salt hypertension in young rats and its attenuation for potassium-induced BP reduction. Conversely, neither salt hypertension nor its potassium-induced attenuation were associated with significant changes of the vasodilator systems studied. The relative deficiency of vasodilator action of NO and Ca(2+) -activated K(+) channels in salt hypertensive Dahl rats was not improved by potassium supplementation. The attenuation of enhanced sympathetic vasoconstriction is the principal mechanism of antihypertensive action exerted by preventive potassium supplementation in immature Dahl rats. Dietary potassium supplementation has no preventive effects on BP in adult salt-loaded animals or no therapeutic effects on established salt hypertension in young rats. © 2011 The Authors. Acta Physiologica © 2011 Scandinavian Physiological Society.

Modulation of Connexin-36 Gap Junction Channels by Intracellular pH and Magnesium Ions.

PubMed

Rimkute, Lina; Kraujalis, Tadas; Snipas, Mindaugas; Palacios-Prado, Nicolas; Jotautis, Vaidas; Skeberdis, Vytenis A; Bukauskas, Feliksas F

2018-01-01

Connexin-36 (Cx36) protein forms gap junction (GJ) channels in pancreatic beta cells and is also the main Cx isoform forming electrical synapses in the adult mammalian brain. Cx36 GJs can be regulated by intracellular pH (pH i ) and cytosolic magnesium ion concentration ([Mg 2+ ] i ), which can vary significantly under various physiological and pathological conditions. However, the combined effect and relationship of these two factors over Cx36-dependent coupling have not been previously studied in detail. Our experimental results in HeLa cells expressing Cx36 show that changes in both pH i and [Mg 2+ ] i affect junctional conductance (g j ) in an interdependent manner; in other words, intracellular acidification cause increase or decay in g j depending on whether [Mg 2+ ] i is high or low, respectively, and intracellular alkalization cause reduction in g j independently of [Mg 2+ ] i . Our experimental and modelling data support the hypothesis that Cx36 GJ channels contain two separate gating mechanisms, and both are differentially sensitive to changes in pH i and [Mg 2+ ] i . Using recombinant Cx36 we found that two glutamate residues in the N-terminus could be partly responsible for the observed interrelated effect of pH i and [Mg 2+ ] i . Mutation of glutamate at position 8 attenuated the stimulatory effect of intracellular acidification at high [Mg 2+ ] i , while mutation at position 12 and double mutation at both positions reversed stimulatory effect to inhibition. Moreover, Cx36 * E8Q lost the initial increase of g j at low [Mg 2+ ] i and double mutation lost the sensitivity to high [Mg 2+ ] i . These results suggest that E8 and E12 are involved in regulation of Cx36 GJ channels by Mg 2+ and H + ions.

BK Channel-Mediated Relaxation of Urinary Bladder Smooth Muscle: A Novel Paradigm for Phosphodiesterase Type 4 Regulation of Bladder Function

PubMed Central

Xin, Wenkuan; Li, Ning; Cheng, Qiuping

2014-01-01

Elevation of intracellular cAMP and activation of protein kinase A (PKA) lead to activation of large conductance voltage- and Ca2+-activated K+ (BK) channels, thus attenuation of detrusor smooth muscle (DSM) contractility. In this study, we investigated the mechanism by which pharmacological inhibition of cAMP-specific phosphodiesterase 4 (PDE4) with rolipram or Ro-20-1724 (C15H22N2O3) suppresses guinea pig DSM excitability and contractility. We used high-speed line-scanning confocal microscopy, ratiometric fluorescence Ca2+ imaging, and perforated whole-cell patch-clamp techniques on freshly isolated DSM cells, along with isometric tension recordings of DSM isolated strips. Rolipram caused an increase in the frequency of Ca2+ sparks and the spontaneous transient BK currents (TBKCs), hyperpolarized the cell membrane potential (MP), and decreased the intracellular Ca2+ levels. Blocking BK channels with paxilline reversed the hyperpolarizing effect of rolipram and depolarized the MP back to the control levels. In the presence of H-89 [N-[2-[[3-(4-bromophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulfonamide dihydrochloride], a PKA inhibitor, rolipram did not cause MP hyperpolarization. Rolipram or Ro-20-1724 reduced DSM spontaneous and carbachol-induced phasic contraction amplitude, muscle force, duration, and frequency, and electrical field stimulation-induced contraction amplitude, muscle force, and tone. Paxilline recovered DSM contractility, which was suppressed by pretreatment with PDE4 inhibitors. Rolipram had reduced inhibitory effects on DSM contractility in DSM strips pretreated with paxilline. This study revealed a novel cellular mechanism whereby pharmacological inhibition of PDE4 leads to suppression of guinea pig DSM contractility by increasing the frequency of Ca2+ sparks and the functionally coupled TBKCs, consequently hyperpolarizing DSM cell MP. Collectively, this decreases the global intracellular Ca2+ levels and DSM contractility in a BK channel-dependent manner. PMID:24459245

Characterization of a novel 132-bp exon of the human maxi-K channel.

PubMed

Korovkina, V P; Fergus, D J; Holdiman, A J; England, S K

2001-07-01

The large-conductance Ca2+-activated voltage-dependent K+ channel (maxi-K channel) induces a significant repolarizing current that buffers cell excitability. This channel can derive its diversity by alternative splicing of its transcript-producing isoforms that differ in their sensitivity to voltage and intracellular Ca2+. We have identified a novel 132-bp exon of the maxi-K channel from human myometrial cells that encodes 44 amino acids within the first intracellular loop of the channel protein. Distribution analysis reveals that this exon is expressed predominantly in human smooth muscle tissues with the highest abundance in the uterus and aorta and resembles the previously reported distribution of the total maxi-K channel transcript. Single-channel K+ current measurements in fibroblasts transfected with the maxi-K channel containing this novel 132-bp exon demonstrate that the presence of this insert attenuates the sensitivity to voltage and intracellular Ca2+. Alternative splicing to introduce this 132-bp exon into the maxi-K channel may elicit another mode to modulate cell excitability.

The Small Hydrophobic Protein of the Human Respiratory Syncytial Virus Forms Pentameric Ion Channels*

PubMed Central

Gan, Siok-Wan; Tan, Edward; Lin, Xin; Yu, Dejie; Wang, Juejin; Tan, Gregory Ming-Yeong; Vararattanavech, Ardcharaporn; Yeo, Chiew Ying; Soon, Cin Huang; Soong, Tuck Wah; Pervushin, Konstantin; Torres, Jaume

2012-01-01

The small hydrophobic (SH) protein is encoded by the human respiratory syncytial virus. Its absence leads to viral attenuation in the context of whole organisms, and it prevents apoptosis in infected cells. Herein, we have examined the structure of SH protein in detergent micelles and in lipid bilayers, by solution NMR and attenuated total reflection-Fourier transform infrared spectroscopy, respectively. We found that SH protein has a single α-helical transmembrane domain and forms homopentamers in several detergents. In detergent micelles, the transmembrane domain is flanked N-terminally by an α-helix that forms a ring around the lumen of the pore and C-terminally by an extended β-turn. SH protein was found in the plasma membrane of transiently expressing HEK 293 cells, which showed pH-dependent (acid-activated) channel activity. Channel activity was abolished in mutants lacking both native His residues, His22 and His51, but not when either His was present. Herein, we propose that the pentameric model of SH protein presented is a physiologically relevant conformation, albeit probably not the only one, in which SH contributes to RSV infection and replication. Viroporins are short (∼100 amino acids) viral membrane proteins that form oligomers of a defined size, act as proton or ion channels, and in general enhance membrane permeability in the host. However, with some exceptions, their precise biological role of their channel activity is not understood. In general, viroporins resemble poorly specialized proteins but are nevertheless critical for viral fitness. In vivo, viruses lacking viroporins usually exhibit an attenuated or weakened phenotype, altered tropism, and diminished pathological effects. We have chosen to study the SH protein, 64 amino acids long, found in the human respiratory syncytial virus because of the effect of RSV on human health and the lack of adequate antivirals. We show that SH protein forms oligomers that behave as ion channels when activated at low pH. This study adds SH protein to a growing group of viroporins that have been structurally characterized. Although the precise biological role of this pentameric channel is still unknown, this report is nevertheless essential to fill some of the many gaps that exist in the understanding of SH protein function. PMID:22621926

UPLC-DAD/Q-TOF-MS Based Ingredients Identification and Vasorelaxant Effect of Ethanol Extract of Jasmine Flower

PubMed Central

Yin, Yongqiang; Ying, Xuhui; Luan, Hairong; Zhao, Zhenying; Lou, Jianshi; Wang, Deli; Li, Hailin; Wu, Hong

2014-01-01

Chinese people commonly make jasmine tea for recreation and health care. Actually, its medicinal value needs more exploration. In this study, vasorelaxant effect of ethanol extract of jasmine flower (EEJ) on isolated rat thoracic aorta rings was investigated and [Ca2+] was determined in vascular smooth muscle cells by laser scanning confocal microscope (LSCM). The result of aorta rings showed that EEJ could cause concentration-dependent relaxation of endothelium-intact rings precontracted with phenylephrine or KCl which was attenuated after preincubation of the rings with L-NAME and three different K+ channel inhibitors; however, indomethacin and glibenclamide did not affect the vasodilatation of EEJ. In addition, EEJ could inhibit contraction induced by PE on endothelium-denuded rings in Ca2+-free medium as well as by accumulation of Ca2+ in Ca2+-free medium with high K+. LSCM also showed that EEJ could lower the elevated level of [Ca2+] induced by KCl. These indicate that the vasodilation of EEJ is in part related to causing the release of nitric oxide, activation of K+ channels, inhibition of influx of excalcium, and release of calcium from sarcoplasmic reticulum. A total of 20 main ingredients, were identified in EEJ by UPLC-DAD/Q-TOF-MS. The vasodilation activity should be attributed to the high content of flavonoid glycosides and iridoid glycosides found in EEJ. PMID:25628748

H{sub 2}S does not regulate proliferation via T-type Ca{sup 2+} channels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elies, Jacobo; Johnson, Emily; Boyle, John P.

T-type Ca{sup 2+} channels (Cav3.1, 3.2 and 3.3) strongly influence proliferation of various cell types, including vascular smooth muscle cells (VSMCs) and certain cancers. We have recently shown that the gasotransmitter carbon monoxide (CO) inhibits T-type Ca{sup 2+} channels and, in so doing, attenuates proliferation of VSMC. We have also shown that the T-type Ca{sup 2+} channel Cav3.2 is selectively inhibited by hydrogen sulfide (H{sub 2}S) whilst the other channel isoforms (Cav3.1 and Cav3.3) are unaffected. Here, we explored whether inhibition of Cav3.2 by H{sub 2}S could account for the anti-proliferative effects of this gasotransmitter. H{sub 2}S suppressed proliferation inmore » HEK293 cells expressing Cav3.2, as predicted by our previous observations. However, H{sub 2}S was similarly effective in suppressing proliferation in wild type (non-transfected) HEK293 cells and those expressing the H{sub 2}S insensitive channel, Cav3.1. Further studies demonstrated that T-type Ca{sup 2+} channels in the smooth muscle cell line A7r5 and in human coronary VSMCs strongly influenced proliferation. In both cell types, H{sub 2}S caused a concentration-dependent inhibition of proliferation, yet by far the dominant T-type Ca{sup 2+} channel isoform was the H{sub 2}S-insensitive channel, Cav3.1. Our data indicate that inhibition of T-type Ca{sup 2+} channel-mediated proliferation by H{sub 2}S is independent of the channels’ sensitivity to H{sub 2}S. - Highlights: • T-type Ca{sup 2+} channels regulate proliferation and are sensitive to the gasotransmitters CO and H{sub 2}S. • H{sub 2}S reduced proliferation in HEK293 cells expressing the H{sub 2}S sensitive Cav3.2 channel. • H{sub 2}S also inhibited proliferation in non-transfected cells and HEK293 cells expressing Cav3.1. • Native smooth muscle cells primarily express Cav3.1. Their proliferation was also inhibited by H{sub 2}S. • Unlike CO, H{sub 2}S does not regulate smooth muscle proliferation via T-type Ca{sup 2+} channel inhibition.« less

Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1).

PubMed

De Jesús-Pérez, José J; Cruz-Rangel, Silvia; Espino-Saldaña, Ángeles E; Martínez-Torres, Ataúlfo; Qu, Zhiqiang; Hartzell, H Criss; Corral-Fernandez, Nancy E; Pérez-Cornejo, Patricia; Arreola, Jorge

2018-03-01

The TMEM16A-mediated Ca 2+ -activated Cl - current drives several important physiological functions. Membrane lipids regulate ion channels and transporters but their influence on members of the TMEM16 family is poorly understood. Here we have studied the regulation of TMEM16A by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), cholesterol, and fatty acids using patch clamp, biochemistry and fluorescence microscopy. We found that depletion of membrane PI(4,5)P2 causes a decline in TMEM16A current that is independent of cytoskeleton, but is partially prevented by removing intracellular Ca 2+ . On the other hand, supplying PI(4,5)P2 to inside-out patches attenuated channel rundown and/or partially rescued activity after channel rundown. Also, depletion (with methyl-β-cyclodextrin M-βCD) or restoration (with M-βCD+cholesterol) of membrane cholesterol slows down the current decay observed after reduction of PI(4,5)P2. Neither depletion nor restoration of cholesterol change PI(4,5)P2 content. However, M-βCD alone transiently increases TMEM16A activity and dampens rundown whereas M-βCD+cholesterol increases channel rundown. Thus, PI(4,5)P2 is required for TMEM16A function while cholesterol directly and indirectly via a PI(4,5)P2-independent mechanism regulate channel function. Stearic, arachidonic, oleic, docosahexaenoic, and eicosapentaenoic fatty acids as well as methyl stearate inhibit TMEM16A in a dose- and voltage-dependent manner. Phosphatidylserine, a phospholipid whose hydrocarbon tails contain stearic and oleic acids also inhibits TMEM16A. Finally, we show that TMEM16A remains in the plasma membrane after treatment with M-βCD, M-βCD+cholesterol, oleic, or docosahexaenoic acids. Thus, we propose that lipids and fatty acids regulate TMEM16A channels through a membrane-delimited protein-lipid interaction. Copyright © 2017 Elsevier B.V. All rights reserved.

Tides Stabilize Deltas until Humans Interfere

NASA Astrophysics Data System (ADS)

Hoitink, T.; Zheng Bing, W.; Vermeulen, B.; Huismans, Y.; Kastner, K.

2017-12-01

Despite global concerns about river delta degradation caused by extraction of natural resources, sediment retention by reservoirs and sea-level rise, human activity in the world's largest deltas intensifies. In this review, we argue that tides tend to stabilize deltas until humans interfere. Under natural circumstances, delta channels subject to tides are more stable than their fluvial-dominated counterparts. The oscillatory tidal flow counteracts the processes responsible for bank erosion, which explains why unprotected tidal channels migrate only slowly. Peak river discharges attenuate the tides, which creates storage space to accommodate the extra river discharge during extreme events and as a consequence, reduce flood risk. With stronger tides, the river discharge is being distributed more evenly over the various branches in a delta, preventing silting up of smaller channels. Human interference in deltas is massive. Storm surge barriers are constructed, new land is being reclaimed and large-scale sand excavation takes place, to collect building material. Evidence from deltas around the globe shows that in human-controlled deltas the tidal motion often plays a destabilizing role. In channels of the Rhine-Meuse Delta, some 100 scour holes are identified, which relates to the altered tidal motion after completion of a storm surge barrier. Sand mining has led to widespread river bank failures in the tidally-influenced Mekong Delta. The catastrophic flood event in the Gauges-Brahmaputra Delta by Cyclone Aila, which caused the inundation of an embanked polder area for over two years, was preceded by river bank erosion at the mouths of formal tidal channels that were blocked by the embankment. Efforts to predict the developments of degrading deltas are few. Existing delta models are capable of reproducing expanding deltas, which is essentially a matter of simulating the transport of sediment from source in a catchment to the sink in a delta. Processes of soil compaction, mixing of sands and clay, and the influence of peat layers complicate the prediction of delta erosion. Considering sea-level rise, sediment depletion and all the direct human modifications in deltas, there is a need for a new generation delta models using quantified erosion resistance from geological records.

Decoupling Shoreline Behavior Over Variable Time and Space Scales

NASA Astrophysics Data System (ADS)

Hapke, C. J.; Plant, N. G.; Henderson, R.; Schwab, W. C.; Nelson, T. R.

2016-12-01

Despite global concerns about river delta degradation caused by extraction of natural resources, sediment retention by reservoirs and sea-level rise, human activity in the world's largest deltas intensifies. In this review, we argue that tides tend to stabilize deltas until humans interfere. Under natural circumstances, delta channels subject to tides are more stable than their fluvial-dominated counterparts. The oscillatory tidal flow counteracts the processes responsible for bank erosion, which explains why unprotected tidal channels migrate only slowly. Peak river discharges attenuate the tides, which creates storage space to accommodate the extra river discharge during extreme events and as a consequence, reduce flood risk. With stronger tides, the river discharge is being distributed more evenly over the various branches in a delta, preventing silting up of smaller channels. Human interference in deltas is massive. Storm surge barriers are constructed, new land is being reclaimed and large-scale sand excavation takes place, to collect building material. Evidence from deltas around the globe shows that in human-controlled deltas the tidal motion often plays a destabilizing role. In channels of the Rhine-Meuse Delta, some 100 scour holes are identified, which relates to the altered tidal motion after completion of a storm surge barrier. Sand mining has led to widespread river bank failures in the tidally-influenced Mekong Delta. The catastrophic flood event in the Gauges-Brahmaputra Delta by Cyclone Aila, which caused the inundation of an embanked polder area for over two years, was preceded by river bank erosion at the mouths of formal tidal channels that were blocked by the embankment. Efforts to predict the developments of degrading deltas are few. Existing delta models are capable of reproducing expanding deltas, which is essentially a matter of simulating the transport of sediment from source in a catchment to the sink in a delta. Processes of soil compaction, mixing of sands and clay, and the influence of peat layers complicate the prediction of delta erosion. Considering sea-level rise, sediment depletion and all the direct human modifications in deltas, there is a need for a new generation delta models using quantified erosion resistance from geological records.

Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels.

PubMed

Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

2016-08-01

Remote ischemic preconditioning is a well reported therapeutic strategy that induces cardioprotective effects but the underlying intracellular mechanisms have not been widely explored. The current study was designed to investigate the involvement of TRP and especially TRPV channels in remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 alternate cycles of inflation and deflation of 5 min each) was delivered using a blood pressure cuff tied on the hind limb of the anesthetized rat. Using Langendorff's system, the heart was perfused and subjected to 30-min ischemia and 120-min reperfusion. The myocardial injury was assessed by measuring infarct size, lactate dehydrogenase (LDH), creatine kinase (CK), LVDP, +dp/dtmax, -dp/dtmin, heart rate, and coronary flow rate. Gadolinium, TRP blocker, and ruthenium red, TRPV channel blocker, were employed as pharmacological tools. Remote hind limb preconditioning significantly reduced the infarct size, LDH release, CK release and improved coronary flow rate, hemodynamic parameters including LVDP, +dp/dtmax, -dp/dtmin, and heart rate. However, gadolinium (7.5 and 15 mg kg(-1)) and ruthenium red (4 and 8 mg kg(-1)) significantly attenuated the cardioprotective effects suggesting the involvement of TRP especially TRPV channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus possibly activates TRPV channels on the heart or sensory nerve fibers innervating the heart to induce cardioprotective effects. Alternatively, remote hind limb preconditioning stimulus may also activate the mechanosensitive TRP and especially TRPV channels on the sensory nerve fibers innervating the skeletal muscles to trigger cardioprotective neurogenic signaling cascade. The cardioprotective effects of remote hind limb preconditioning may be mediated via activation of mechanosensitive TRP and especially TRPV channels.

Up-Regulatory Effects of Curcumin on Large Conductance Ca2+-Activated K+ Channels

PubMed Central

Hei, Hongya; Li, Fangping; Wang, Yunman; Peng, Wen; Zhang, Xuemei

2015-01-01

Large conductance Ca2+-activated potassium channels (BK) are targets for research that explores therapeutic means to various diseases, owing to the roles of the channels in mediating multiple physiological processes in various cells and tissues. We investigated the pharmacological effects of curcumin, a compound isolated from the herb Curcuma longa, on BK channels. As recorded by whole-cell patch-clamp, curcumin increased BK (α) and BK (α+β1) currents in transfected HEK293 cells as well as the current density of BK in A7r5 smooth muscle cells in a dose-dependent manner. By incubating with curcumin for 24 hours, the current density of exogenous BK (α) in HEK293 cells and the endogenous BK in A7r5 cells were both enhanced notably, though the steady-state activation of the channels did not shift significantly, except for BK (α+β1). Curcumin up-regulated the BK protein expression without changing its mRNA level in A7r5 cells. The surface expression and the half-life of BK channels were also increased by curcumin in HEK293 cells. These effects of curcumin were abolished by MG-132, a proteasome inhibitor. Curcumin also increased ERK 1/2 phosphorylation, while inhibiting ERK by U0126 attenuated the curcumin-induced up-regulation of BK protein expression. We also observed that the curcumin-induced relaxation in the isolated rat aortic rings was significantly attenuated by paxilline, a BK channel specific blocker. These results show that curcumin enhances the activity of the BK channels by interacting with BK directly as well as enhancing BK protein expression through inhibiting proteasomal degradation and activating ERK signaling pathway. The findings suggest that curcumin is a potential BK channel activator and provide novel insight into its complicated pharmacological effects and the underlying mechanisms. PMID:26672753

Determination of channel capacity of the Merced River downstream from Merced Falls Dam, Merced County, California

USGS Publications Warehouse

Blodgett, J.C.; Bertoldi, G.L.

1968-01-01

Peak flows in Dry Creek, as measured 18.7 miles upstream from the mouth of Dry Creek, will be attenuated due to channel storage and will increase the discharge of the Merced River at Cressey by only about 50 per cent of t he Dry Creek peak discharge. Furthermore, Dry Creek seldom carries floodflows during periods of high water on the Merced River.

Minoxidil attenuates ischemia-induced apoptosis in cultured neonatal rat cardiomyocytes.

PubMed

Takatani, Tomoka; Takahashi, Kyoko; Jin, Chengshi; Matsuda, Takahisa; Cheng, Xinyao; Ito, Takashi; Azuma, Junichi

2004-06-01

The effects of minoxidil (a mitochondrial K+(ATP) channel opener) on ischemia-induced necrosis and apoptosis were examined using a cardiomyocyte model of simulated ischemia, since mitochondrial K+(ATP) channel openers have been suggested to be involved in the mechanisms of cardioprotective action against ischemia/reperfusion injury. In the absence of minoxidil, simulated ischemia led to cellular release of creatine phosphokinase (CPK), morphologic degeneration, and beating cessation within 24 to 72 hours. Based on the Hoechst 33258 staining pattern, a significant number of cells placed in sealed flasks underwent apoptosis. Myocytes treated with 5 microM of minoxidil failed to alter the degree of ischemia-induced CPK loss for 48 to 72 hours. However, minoxidil treatment prevented the loss of beating function in many of the ischemic cells, and attenuated the decline in intracellular ATP content after a 48-hour ischemic incubation. The number of nuclear fragmentation was significantly reduced in minoxidil-treated cells after a 72-hour ischemic insult compared with untreated ischemic cells. This effect was blocked by the mitochondrial K+(ATP) channel antagonist 5-HD. The data suggest that minoxidil renders the cell resistant to ischemia-induced necrosis and apoptosis. The beneficial effects of minoxidil appear to be related to the opening of mitochondrial K+(ATP) channels.

Survival of Swiss-Webster mouse cerebellar granule neurons is promoted by a combination of potassium channel blockers.

PubMed

Collins, Anthony; Larson, Maureen K; Pfaff, Jilleen E; Ishmael, Jane E

2007-06-15

Cultured cerebellar granule neurons (CGN) are commonly used to assess neurotoxicity, but are routinely maintained in supraphysiological (25 mM) extracellular K(+) concentrations [K(+)](o). We investigated the effect of potassium channel blockade on survival of CGN derived from Swiss-Webster mice in supraphysiological (25 mM) and physiological (5.6 mM) [K(+)](o). CGN were cultured for 5 days in 25 mM K(+), then in 5.6 mM K(+) or 25 mM K(+) (control). Viability, assayed 24 h later by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) reduction and by lactate dehydrogenase (LDH) release, was approximately 50% in 5.6 mM K(+) versus 25 mM K(+) (p<.001). Potassium channel blockers, 2 mM 4-aminopyridine (4-AP), 2 mM tetraethylammonium (TEA) or 1 mM Ba(2+), individually afforded limited protection in 5.6 mM K(+). However, survival in 5.6 mM K(+) with a combination of 4-AP, TEA and Ba(2+) was similar to survival in 25 mM K(+) without blockers (p<.001 versus 5.6 mM K(+) alone). CGN survival in 25 mM K(+) was attenuated 25% by 2 microM nifedipine (p>.001), but nifedipine did not attenuate neuroprotection by K(+) channel blockers. Together, these results suggest that the survival of CGN depends on the K(+) permeability of the membrane rather than the activity of a particular type of K(+) channel, and that the mechanism of neuroprotection by K(+) channel blockers is different from that of elevated [K(+)](o).

Reduced Sodium Current in the Lateral Ventricular Wall Induces Inferolateral J-Waves.

PubMed

Meijborg, Veronique M F; Potse, Mark; Conrath, Chantal E; Belterman, Charly N W; De Bakker, Jacques M T; Coronel, Ruben

2016-01-01

J-waves in inferolateral leads are associated with a higher risk for idiopathic ventricular fibrillation. We aimed to test potential mechanisms (depolarization or repolarization dependent) responsible for inferolateral J-waves. We hypothesized that inferolateral J-waves can be caused by regional delayed activation of myocardium that is activated late during normal conditions. Computer simulations were performed to evaluate how J-point elevation is influenced by reducing sodium current conductivity (GNa), increasing transient outward current conductivity (Gto), or cellular uncoupling in three predefined ventricular regions (lateral, anterior, or septal). Two pig hearts were Langendorff-perfused with selective perfusion with a sodium channel blocker of lateral or anterior/septal regions. Volume-conducted pseudo-electrocardiograms (ECG) were recorded to detect the presence of J-waves. Epicardial unipolar electrograms were simultaneously recorded to obtain activation times (AT). Simulation data showed that conduction slowing, caused by reduced sodium current, in lateral, but not in other regions induced inferolateral J-waves. An increase in transient outward potassium current or cellular uncoupling in the lateral zone elicited slight J-point elevations which did not meet J-wave criteria. Additional conduction slowing in the entire heart attenuated J-waves and J-point elevations on the ECG, because of masking by the QRS. Experimental data confirmed that conduction slowing attributed to sodium channel blockade in the left lateral but not in the anterior/septal ventricular region induced inferolateral J-waves. J-waves coincided with the delayed activation. Reduced sodium current in the left lateral ventricular myocardium can cause inferolateral J-waves on the ECG.

Mitigation of Flood Hazards Through Modification of Urban Channels and Floodplains

NASA Astrophysics Data System (ADS)

Miller, A. J.; Lee, G.; Bledsoe, B. P.; Stephens, T.

2017-12-01

Small urban watersheds with high percent impervious cover and dense road and storm-drain networks are highly responsive to short-duration high-intensity rainfall events that lead to flash floods. The Baltimore metropolitan area has some of the flashiest urban watersheds in the conterminous U.S., high frequency of channel incision in affected areas, and a large number of watershed restoration projects designed to restore ecosystem services through reconnection of the channel with the floodplain. A question of key importance in these and other urban watersheds is to what extent we can mitigate flood hazards and urban stream syndrome through restoration activities that modify the channel and valley floor. Local and state governments have invested resources in repairing damage caused by extreme events like the July 30, 2016 Ellicott City flood in the Tiber River watershed, as well as more frequent high flows in other local urban streams. Recent reports have investigated how much flood mitigation may be achieved through modification of the channel and floodplain to enhance short-term storage of flood waters on the valley floor or in other subsurface structures, as compared with increasing stormwater management in the headwaters. Ongoing research conducted as part of the UWIN (Urban Water Innovation Network) program utilizes high-resolution topographic point clouds derived by processing of photographs from hand-held cameras or video frames from drone overflights. These are used both to track geomorphic change and to assess flood response with 2d hydraulic modeling tools under alternative mitigation scenarios. Assessment metrics include variations in inundation extent, water depth, hydrograph attenuation, and temporal and spatial characteristics of the 2d depth-averaged velocity field. Examples from diverse urban watersheds are presented to illustrate the range of anticipated outcomes and potential constraints on the effectiveness of downstream vs. headwater mitigation efforts.

Suprachiasmatic nucleus function and circadian entrainment are modulated by G protein-coupled inwardly rectifying (GIRK) channels

PubMed Central

Hablitz, L M; Molzof, H E; Paul, J R; Johnson, R L; Gamble, K L

2014-01-01

Abstract G protein signalling within the central circadian oscillator, the suprachiasmatic nucleus (SCN), is essential for conveying time-of-day information. We sought to determine whether G protein-coupled inwardly rectifying potassium channels (GIRKs) modulate SCN physiology and circadian behaviour. We show that GIRK current and GIRK2 protein expression are greater during the day. Pharmacological inhibition of GIRKs and genetic loss of GIRK2 depolarized the day-time resting membrane potential of SCN neurons compared to controls. Behaviourally, GIRK2 knockout (KO) mice failed to shorten free running period in response to wheel access in constant darkness and entrained more rapidly to a 6 h advance of a 12 h:12 h light–dark (LD) cycle than wild-type (WT) littermate controls. We next examined whether these effects were due to disrupted signalling of neuropeptide Y (NPY), which is known to mediate non-photic phase shifts, attenuate photic phase shifts and activate GIRKs. Indeed, GIRK2 KO SCN slices had significantly fewer silent cells in response to NPY, likely contributing to the absence of NPY-induced phase advances of PER2::LUC rhythms in organotypic SCN cultures from GIRK2 KO mice. Finally, GIRK channel activation is sufficient to cause a non-photic-like phase advance of PER2::LUC rhythms on a Per2Luc+/− background. These results suggest that rhythmic regulation of GIRK2 protein and channel function in the SCN contributes to day-time resting membrane potential, providing a mechanism for the fine tuning responses to non-photic and photic stimuli. Further investigation could provide insight into disorders with circadian disruption comorbidities such as epilepsy and addiction, in which GIRK channels have been implicated. PMID:25217379

The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity.

PubMed

Lund, Trine M; Ploug, Kenneth B; Iversen, Anne; Jensen, Anders A; Jansen-Olesen, Inger

2015-03-01

Glucose is the main energy substrate for neurons, and ketone bodies are known to be alternative substrates. However, the capacity of ketone bodies to support different neuronal functions is still unknown. Thus, a change in energy substrate from glucose alone to a combination of glucose and β-hydroxybutyrate might change neuronal function as there is a known coupling between metabolism and neurotransmission. The purpose of this study was to shed light on the effects of the ketone body β-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown an effect of β-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when β-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of β-hydroxybutyrate, whereas a direct effect of the ketone body on transmitter release was absent. However, the presence of β-hydroxybutyrate augmented transmitter release induced by the KATP channel blocker glibenclamide, thus giving an indirect indication of the involvement of KATP channels in the effects of ketone bodies on transmitter release. Energy metabolism and neurotransmission are linked and involve ATP-sensitive potassium (KATP ) channels. However, it is still unclear how and to what degree available energy substrate affects this link. We investigated the effect of changing energy substrate from only glucose to a combination of glucose and R-β-hydroxybutyrate in cultured neurons. Using the latter combination, glycolysis was diminished, NMDA receptor-induced calcium responses were lower, and the KATP channel blocker glibenclamide caused a higher transmitter release. © 2014 International Society for Neurochemistry.

The attenuation of sound by turbulence in internal flows.

PubMed

Weng, Chenyang; Boij, Susann; Hanifi, Ardeshir

2013-06-01

The attenuation of sound waves due to interaction with low Mach number turbulent boundary layers in internal flows (channel or pipe flow) is examined. Dynamic equations for the turbulent Reynolds stress on the sound wave are derived, and the analytical solution to the equation provides a frequency dependent eddy viscosity model. This model is used to predict the attenuation of sound propagating in fully developed turbulent pipe flow. The predictions are shown to compare well with the experimental data. The proposed dynamic equation shows that the turbulence behaves like a viscoelastic fluid in the interaction process, and that the ratio of turbulent relaxation time near the wall and the sound wave period is the parameter that controls the characteristics of the attenuation induced by the turbulent flow.

Experimental implementation of array-compressed parallel transmission at 7 tesla.

PubMed

Yan, Xinqiang; Cao, Zhipeng; Grissom, William A

2016-06-01

To implement and validate a hardware-based array-compressed parallel transmission (acpTx) system. In array-compressed parallel transmission, a small number of transmit channels drive a larger number of transmit coils, which are connected via an array compression network that implements optimized coil-to-channel combinations. A two channel-to-eight coil array compression network was developed using power splitters, attenuators and phase shifters, and a simulation was performed to investigate the effects of coil coupling on power dissipation in a simplified network. An eight coil transmit array was constructed using induced current elimination decoupling, and the coil and network were validated in benchtop measurements, B1+ mapping scans, and an accelerated spiral excitation experiment. The developed attenuators came within 0.08 dB of the desired attenuations, and reflection coefficients were -22 dB or better. The simulation demonstrated that up to 3× more power was dissipated in the network when coils were poorly isolated (-9.6 dB), versus well-isolated (-31 dB). Compared to split circularly-polarized coil combinations, the additional degrees of freedom provided by the array compression network led to 54% lower squared excitation error in the spiral experiment. Array-compressed parallel transmission was successfully implemented in a hardware system. Further work is needed to develop remote network tuning and to minimize network power dissipation. Magn Reson Med 75:2545-2552, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Changes in IP3 Receptor Expression and Function in Aortic Smooth Muscle of Atherosclerotic Mice

PubMed Central

Ewart, Marie-Ann; Ugusman, Azizah; Vishwanath, Anisha; Almabrouk, Tarek A.M.; Alganga, Husam; Katwan, Omar J.; Hubanova, Pavlina; Currie, Susan; Kennedy, Simon

2017-01-01

Peroxynitrite is an endothelium-independent vasodilator that induces relaxation via membrane hyperpolarization. The activation of IP3 receptors triggers the opening of potassium channels and hyperpolarization. Previously we found that relaxation to peroxynitrite was maintained during the development of atherosclerosis due to changes in the expression of calcium-regulatory proteins. In this study we investigated: (1) the mechanism of peroxynitrite-induced relaxation in the mouse aorta, (2) the effect of atherosclerosis on relaxation to peroxynitrite and other vasodilators, and (3) the effect of atherosclerosis on the expression and function of the IP3 receptor. Aortic function was studied using wire myography, and atherosclerosis was induced by fat-feeding ApoE−/− mice. The expression of IP3 receptors was studied using Western blotting and immunohistochemistry. Relaxation to peroxynitrite was attenuated by the IP3 antagonists 2-APB and xestospongin C and also the Kv channel blocker 4-aminopyridine (4-AP). Atherosclerosis attenuated vasodilation to cromakalim and the AMPK activator A769662 but not peroxynitrite. Relaxation was attenuated to a greater extent by 2-APB in atherosclerotic aortae despite the reduced expression of IP3 receptors. 4-AP was less effective in ApoE−/− mice fat-fed for 4 months. Peroxynitrite relaxation involves an IP3-induced calcium release and KV channel activation. This mechanism becomes less important as atherosclerosis develops, and relaxation to peroxynitrite may be maintained by increased calcium extrusion. PMID:28365690

Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants

PubMed Central

Willis, Daniel N.; Liu, Boyi; Ha, Michael A.; Jordt, Sven-Eric; Morris, John B.

2011-01-01

Menthol, the cooling agent in peppermint, is added to almost all commercially available cigarettes. Menthol stimulates olfactory sensations, and interacts with transient receptor potential melastatin 8 (TRPM8) ion channels in cold-sensitive sensory neurons, and transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing channel. It is highly controversial whether menthol in cigarette smoke exerts pharmacological actions affecting smoking behavior. Using plethysmography, we investigated the effects of menthol on the respiratory sensory irritation response in mice elicited by smoke irritants (acrolein, acetic acid, and cyclohexanone). Menthol, at a concentration (16 ppm) lower than in smoke of mentholated cigarettes, immediately abolished the irritation response to acrolein, an agonist of TRPA1, as did eucalyptol (460 ppm), another TRPM8 agonist. Menthol's effects were reversed by a TRPM8 antagonist, AMTB. Menthol's effects were not specific to acrolein, as menthol also attenuated irritation responses to acetic acid, and cyclohexanone, an agonist of the capsaicin receptor, TRPV1. Menthol was efficiently absorbed in the respiratory tract, reaching local concentrations sufficient for activation of sensory TRP channels. These experiments demonstrate that menthol and eucalyptol, through activation of TRPM8, act as potent counterirritants against a broad spectrum of smoke constituents. Through suppression of respiratory irritation, menthol may facilitate smoke inhalation and promote nicotine addiction and smoking-related morbidities.— Willis, D. N., Liu, B., Ha, M. A., Jordt, S.-E., Morris, J. B. Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants. PMID:21903934

Localisation Microscopy of Breast Epithelial ErbB-2 Receptors and Gap Junctions: Trafficking after γ-Irradiation, Neuregulin-1β, and Trastuzumab Application

PubMed Central

Pilarczyk, Götz; Nesnidal, Ines; Gunkel, Manuel; Bach, Margund; Bestvater, Felix; Hausmann, Michael

2017-01-01

In cancer, vulnerable breast epithelium malignance tendency correlates with number and activation of ErbB receptor tyrosine kinases. In the presented work, we observe ErbB receptors activated by irradiation-induced DNA injury or neuregulin-1β application, or alternatively, attenuated by a therapeutic antibody using high resolution fluorescence localization microscopy. The gap junction turnover coinciding with ErbB receptor activation and co-transport is simultaneously recorded. DNA injury caused by 4 Gray of 6 MeV photon γ-irradiation or alternatively neuregulin-1β application mobilized ErbB receptors in a nucleograde fashion—a process attenuated by trastuzumab antibody application. This was accompanied by increased receptor density, indicating packing into transport units. Factors mobilizing ErbB receptors also mobilized plasma membrane resident gap junction channels. The time course of ErbB receptor activation and gap junction mobilization recapitulates the time course of non-homologous end-joining DNA repair. We explain our findings under terms of DNA injury-induced membrane receptor tyrosine kinase activation and retrograde trafficking. In addition, we interpret the phenomenon of retrograde co-trafficking of gap junction connexons stimulated by ErbB receptor activation. PMID:28208769

Phase-Shifted Based Numerical Method for Modeling Frequency-Dependent Effects on Seismic Reflections

NASA Astrophysics Data System (ADS)

Chen, Xuehua; Qi, Yingkai; He, Xilei; He, Zhenhua; Chen, Hui

2016-08-01

The significant velocity dispersion and attenuation has often been observed when seismic waves propagate in fluid-saturated porous rocks. Both the magnitude and variation features of the velocity dispersion and attenuation are frequency-dependent and related closely to the physical properties of the fluid-saturated porous rocks. To explore the effects of frequency-dependent dispersion and attenuation on the seismic responses, in this work, we present a numerical method for seismic data modeling based on the diffusive and viscous wave equation (DVWE), which introduces the poroelastic theory and takes into account diffusive and viscous attenuation in diffusive-viscous-theory. We derive a phase-shift wave extrapolation algorithm in frequencywavenumber domain for implementing the DVWE-based simulation method that can handle the simultaneous lateral variations in velocity, diffusive coefficient and viscosity. Then, we design a distributary channels model in which a hydrocarbon-saturated sand reservoir is embedded in one of the channels. Next, we calculated the synthetic seismic data to analytically and comparatively illustrate the seismic frequency-dependent behaviors related to the hydrocarbon-saturated reservoir, by employing DVWE-based and conventional acoustic wave equation (AWE) based method, respectively. The results of the synthetic seismic data delineate the intrinsic energy loss, phase delay, lower instantaneous dominant frequency and narrower bandwidth due to the frequency-dependent dispersion and attenuation when seismic wave travels through the hydrocarbon-saturated reservoir. The numerical modeling method is expected to contribute to improve the understanding of the features and mechanism of the seismic frequency-dependent effects resulted from the hydrocarbon-saturated porous rocks.

Design and Development of a Single Channel RSNS Direction Finder

DTIC Science & Technology

2009-03-01

CH2 12VDC 2.5A, and CH3 -12VDC 0.2A Cable 19 Pasternek Cable RG-306 Variable Attenuator 1 Telonic Altair Attenuation Model 8140S Demodulator Board...information is estimated to average 1 hour per response, including the time for reviewing instruction, searching existing data sources, gathering and...Reduction Project (0704-0188) Washington DC 20503. 1 . AGENCY USE ONLY (Leave blank) 2. REPORT DATE March 2009 3. REPORT TYPE AND DATES COVERED

Silicon photonic dynamic optical channel leveler with external feedback loop.

PubMed

Doylend, J K; Jessop, P E; Knights, A P

2010-06-21

We demonstrate a dynamic optical channel leveler composed of a variable optical attenuator (VOA) integrated monolithically with a defect-mediated photodiode in a silicon photonic waveguide device. An external feedback loop mimics an analog circuit such that the photodiode directly controls the VOA to provide blind channel leveling within +/-1 dB across a 7-10 dB dynamic range for wavelengths from 1530 nm to 1570 nm. The device consumes approximately 50 mW electrical power and occupies a 6 mm x 0.1 mm footprint per channel. Dynamic leveling is accomplished without tapping optical power from the output path to the photodiode and thus the loss penalty is minimized.

Fading testbed for free-space optical communications

NASA Astrophysics Data System (ADS)

Shrestha, Amita; Giggenbach, Dirk; Mustafa, Ahmad; Pacheco-Labrador, Jorge; Ramirez, Julio; Rein, Fabian

2016-10-01

Free-space optical (FSO) communication is a very attractive technology offering very high throughput without spectral regulation constraints, yet allowing small antennas (telescopes) and tap-proof communication. However, the transmitted signal has to travel through the atmosphere where it gets influenced by atmospheric turbulence, causing scintillation of the received signal. In addition, climatic effects like fogs, clouds and rain also affect the signal significantly. Moreover, FSO being a line of sight communication requires precise pointing and tracking of the telescopes, which otherwise also causes fading. To achieve error-free transmission, various mitigation techniques like aperture averaging, adaptive optics, transmitter diversity, sophisticated coding and modulation schemes are being investigated and implemented. Evaluating the performance of such systems under controlled conditions is very difficult in field trials since the atmospheric situation constantly changes, and the target scenario (e.g. on aircraft or satellites) is not easily accessible for test purposes. Therefore, with the motivation to be able to test and verify a system under laboratory conditions, DLR has developed a fading testbed that can emulate most realistic channel conditions. The main principle of the fading testbed is to control the input current of a variable optical attenuator such that it attenuates the incoming signal according to the loaded power vector. The sampling frequency and mean power of the vector can be optionally changed according to requirements. This paper provides a brief introduction to software and hardware development of the fading testbed and measurement results showing its accuracy and application scenarios.

Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.

PubMed

Chen, Jun; Joshi, Shailen K; DiDomenico, Stanley; Perner, Richard J; Mikusa, Joe P; Gauvin, Donna M; Segreti, Jason A; Han, Ping; Zhang, Xu-Feng; Niforatos, Wende; Bianchi, Bruce R; Baker, Scott J; Zhong, Chengmin; Simler, Gricelda H; McDonald, Heath A; Schmidt, Robert G; McGaraughty, Steve P; Chu, Katharine L; Faltynek, Connie R; Kort, Michael E; Reilly, Regina M; Kym, Philip R

2011-05-01

Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

On the behavior of return stroke current and the remotely detected electric field change waveform

NASA Astrophysics Data System (ADS)

Shao, Xuan-Min; Lay, Erin; Jacobson, Abram R.

2012-04-01

After accumulating a large number of remotely recorded negative return stroke electric field change waveforms, a subtle but persistent kink was found following the main return stroke peak by several microseconds. To understand the corresponding return stroke current properties behind the kink and the general return stroke radiation waveform, we analyze strokes occurring in triggered lightning flashes for which have been measured both the channel base current and simultaneous remote electric radiation field. In this study, the channel base current is assumed to propagate along the return stroke channel in a dispersive and lossy manner. The measured channel base current is band-pass filtered, and the higher-frequency component is assumed to attenuate faster than the lower-frequency component. The radiation electric field is computed for such a current behavior and is then propagated to distant sensors. It is found that such a return stroke model is capable of very closely reproducing the measured electric waveforms at multiple stations for the triggered return strokes, and such a model is considered applicable to the common behavior of the natural return stroke as well. On the basis of the analysis, a number of other observables are derived. The time-evolving current dispersion and attenuation compare well with previously reported optical observations. The observable speed tends to agree with optical and VHF observations. Line charge density that is removed or deposited by the return stroke is derived, and the implication of the charge density distribution on leader channel decay is discussed.

Comparison of angiotensin II (Ang II) effects in the internal anal sphincter (IAS) and lower esophageal sphincter smooth muscles.

PubMed

Rattan, Satish; Fan, Ya-Ping; Puri, Rajinder N

2002-03-22

Studies were performed to compare the actions of Ang II in the internal anal sphincter (IAS) vs. lower esophageal sphincter (LES) smooth muscles in vitro, in opossum and rabbit. Studies also were carried out in isolated smooth muscle cells. In opossum, Ang II produced no discernible effects in the IAS, but did produce a concentration-dependent contraction in the LES. Conversely, in the rabbit, while Ang II caused a modest response in the LES, it caused a significant contraction in the IAS. The contractile responses of Ang II in the opossum LES were mostly resistant to different neurohumoral antagonists but were antagonized by AT1 antagonist losartan. AT2 antagonist PD 123,319, rather than inhibiting, prolonged the contractile action of Ang II. The contractile actions of Ang II in the opossum LES were not modified by the tyrosine kinase inhibitors (genistein and tyrphostin 1 x 10(-6) M) but were partially attenuated by the PKC inhibitor H-7 (1 x 10(-6) M), Ca2+ channel blocker nicardipine (1 x 10(-5) M), Rho kinase inhibitor HA-1077 (1 x 10(-7) M) or p(44/42) MAP kinase inhibitor PD 98059 (5 x 10(-5) M). The combination of HA-1077 and H-7 did not cause an additive attenuation of Ang II responses. Western blot analyses revealed the presence of both AT1 and AT2 receptors. We conclude that Ang lI-induced contraction of sphincteric smooth muscle occurs primarily by the activation of AT1 receptors at the smooth muscle cells and involves multiple pathways, influx of Ca2+, and PKC, Rho kinase and p(44/42) MAP kinase.

Role of Ca++ Influx via Epidermal TRP Ion Channels

DTIC Science & Technology

2017-12-01

TRPV4, both chemical and by UVB radiation . Both modes of activation were attenuated, almost completely, by TRPV4-selective inhibitor, GSK205 (10µM...to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain-associated behavior in a model of acute ...were effective at significantly diminishing pain behavior in the early phase after formalin whisker-pad injection, which represents an acute chemical

A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats.

PubMed

Scott, Victoria E; Vortherms, Timothy A; Niforatos, Wende; Swensen, Andrew M; Neelands, Torben; Milicic, Ivan; Banfor, Patricia N; King, Andrew; Zhong, Chengmin; Simler, Gricelda; Zhan, Cenchen; Bratcher, Natalie; Boyce-Rustay, Janel M; Zhu, Chang Z; Bhatia, Pramila; Doherty, George; Mack, Helmut; Stewart, Andrew O; Jarvis, Michael F

2012-02-01

Blockade of voltage-gated Ca²⁺ channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²⁺ channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC₅₀=0.8 μM and 1.4 μM, respectively) and T-type (IC₅₀=4.6 μM and 1.2 μM, respectively) Ca²⁺ channels in FLIPR based Ca²⁺ flux assays. A-686085 also potently blocked L-type Ca²⁺ channels (EC₅₀=0.6 μM), however, A-1048400 was much less active in blocking this channel (EC₅₀=28 μM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC₅₀=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²⁺ currents in rat dorsal root ganglion neurons (IC₅₀=3.0 μM and 1.6 μM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²⁺ channels coupled with pharmacological selectivity vs. L-type Ca²⁺ channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function. Copyright © 2011 Elsevier Inc. All rights reserved.

Role of protein kinase A and class II phosphatidylinositol 3-kinase C2β in the downregulation of KCa3.1 channel synthesis and membrane surface expression by lyso-globotriaosylceramide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Ju Yeon; Park, Seonghee, E-mail: sp@ewha.ac.kr

The intermediate conductance calcium-activated potassium channel (KCa3.1) mediates proliferation of many cell types including fibroblasts, and is a molecular target for intervention in various cell proliferative diseases. Our previous study showed that reduction of KCa3.1 channel expression by lyso-globotriaosylceramide (lyso-Gb3) inhibits differentiation into myofibroblasts and collagen synthesis, which might lead to development of ascending thoracic aortic aneurysm secondary to Fabry disease. However, how lyso-Gb3 downregulates KCa3.1 channel expression is unknown. Therefore, we aimed to investigate the underlying mechanisms of lyso-Gb3-mediated KCa3.1 channel downregulation, focusing on the cAMP signaling pathway. We found that lyso-Gb3 increased the intracellular cAMP concentration by upregulationmore » of adenylyl cyclase 6 and inhibited ERK 1/2 phosphorylation through the protein kinase A (PKA) pathway, leading to the inhibition of KCa3.1 channel synthesis, not the exchange protein directly activated by cAMP (Epac) pathway. Moreover, lyso-Gb3 suppressed expression of class II phosphatidylinositol 3-kinase C2β (PI3KC2β) by PKA activation, which reduces the production of phosphatidylinositol 3-phosphate [PI(3)P], and the reduced membrane surface expression of KCa3.1 channel was recovered by increasing the intracellular levels of PI(3)P. Consequently, our findings that lyso-Gb3 inhibited both KCa3.1 channel synthesis and surface expression by increasing intracellular cAMP, and controlled surface expression through changes in PI3KC2β-mediated PI(3)P production, suggest that modulation of PKA and PI3KC2β activity to control of KCa3.1 channel expression can be an alternative important target to attenuate ascending thoracic aortic aneurysms in Fabry disease. - Highlights: • Lyso-Gb3 causes elevation of intracellular cAMP. • Lyso-Gb3 inhibits the ERK 1/2 phosphorylation through PKA, thereby reducing KCa3.1 channel synthesis. • Lyso-Gb3 reduces PI3KC2β-mediated intracellular PI(3)P production. • Lyso-Gb3 reduces both surface and total expression of the KCa3.1 channel. • Increasing intracellular levels of PI(3)P only recovers the reduced surface expression.« less

MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity.

PubMed

Layer, R T; Bland, L R; Skolnick, P

1993-10-15

Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.

Development of a Digital Tracking Array with Single- Channel RSNS and Monopulse Digital Beamforming

DTIC Science & Technology

2010-12-01

Watt CH1 5.05 VDC 4 A, CH2 12 VDC 2.5 A, and CH3 12 VDC 0.2 A Cable 19 Pasternek Cable RG-306 Variable Attenuator 1 Telonic Altair Attenuation Model...for this collection of information is estimated to average 1 hour per response, including the time for reviewing instruction, searching existing data...Management and Budget, Paperwork Reduction Project (0704-0188) Washington DC 20503. 1 . AGENCY USE ONLY (Leave blank) 2. REPORT DATE December 2010 3

Ankle fractures have features of an osteoporotic fracture.

PubMed

Lee, K M; Chung, C Y; Kwon, S S; Won, S H; Lee, S Y; Chung, M K; Park, M S

2013-11-01

We report the bone attenuation of ankle joint measured on computed tomography (CT) and the cause of injury in patients with ankle fractures. The results showed age- and gender-dependent low bone attenuation and low-energy trauma in elderly females, which suggest the osteoporotic features of ankle fractures. This study was performed to investigate the osteoporotic features of ankle fracture in terms of bone attenuation and cause of injury. One hundred ninety-four patients (mean age 51.0 years, standard deviation 15.8 years; 98 males and 96 females) with ankle fracture were included. All patients underwent CT examination, and causes of injury (high/low-energy trauma) were recorded. Mean bone attenuations of the talus, medial malleolus, lateral malleolus, and distal tibial metaphysis were measured on CT images. Patients were divided into younger age (<50 years) and older age (≥50 years) groups, and mean bone attenuation and causes of injury were compared between the two groups in each gender. Proportion of low-energy trauma was higher in the older age group than in the younger age group, but the difference was only significant in female gender (p = 0.011). The older age group showed significantly lower bone attenuation in the talus, medial malleolus, lateral malleolus, and distal tibial metaphysis than the younger age group in both genders. The older age group showed more complex pattern of fractures than the younger age group. With increasing age, bone attenuations tended to decrease and the difference of bone attenuation between the genders tended to increase in the talus, medial malleolus, lateral malleolus, and distal tibial metaphysis. Ankle fracture had features of osteoporotic fracture that is characterized by age- and gender-dependent low bone attenuation. Ankle fracture should not be excluded from the clinical and research interest as well as from the benefit of osteoporosis management.

Sarcoplasmic reticulum buffering of myoplasmic calcium in bovine coronary artery smooth muscle.

PubMed Central

Sturek, M; Kunda, K; Hu, Q

1992-01-01

1. We tested the hypothesis that the sarcoplasmic reticulum (SR) buffers (attenuates) the increase in averaged myoplasmic free [Ca2+] (Ca(im)) resulting from Ca2+ influx. 2. Fura-2 measurements of Ca(im) were obtained in single smooth muscle cells freshly dispersed from bovine coronary artery. 3. Caffeine (5 x 10(-3) M) elicited a transient increase in Ca(im) and depleted the SR Ca2+ store. In the continued presence of caffeine or 10(-5) M-ryanodine SR buffering of Ca(im) was inhibited. Subsequent exposure to high extracellular [K+] (greater than 30 mM, equimolar Na+ removal) elicited a 2-fold more rapid and 2-fold greater peak increase in Ca(im) than high K+ elicited when SR buffering of Ca(im) was normal. The augmented increase in Ca(im) was inhibited 35% by 10(-5) M-diltiazem, 65% by 2 x 10(-4) M-LaCl3, and 87% in Ca(2+)-free external solution. 4. When Ca(im) buffering capacity was increased by partially depleting the SR with a transient (1 min) exposure to caffeine, subsequent exposure to 80 nM-K+ solution increased Ca(im) almost 2-fold more slowly than 80 mM-K+ before depletion of Ca2+ from the SR. However, the influxing Ca2+ was sequestered by the SR and refilled it, as evident by the subsequent caffeine-induced Ca(im) transient being identical to the first. Increasing extracellular [K+] (thus, increasing depolarization and Na+ removal) caused proportional increases in Ca(im) and the subsequent caffeine-induced Ca(im) transients were proportionally larger, indicating a graded filling of the SR by Ca2+ influx. 5. Diltiazem (10(-5) M) inhibited the refilling of the SR achieved by 80 mM-K+, by 26%. Refilling was inhibited 76% by 80 mM-K+, Ca(2+)-free solution, indicating the fraction of refilling dependent on influx of Ca2+ through voltage-gated Ca2+ channels, leak channels, and other influx pathways. Mild depolarization with 35 mM-K+ (no Na+ removal) often caused no increase in Ca(im), but influx through voltage-gated Ca2+ channels occurred because the SR Ca2+ store was refilled. Also, 10(-5) M-diltiazem or 10(-6) M-TA3090 inhibited the refilling to levels attributable only to leak influx of Ca2+. 6. All data support our hypothesis that the SR significantly attenuates the amount of Ca2+ influx that accumulates to increase Ca(im).(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1403813

Functional role for mouse cerebellar NO/cGMP/KATP pathway in ethanol-induced ataxia.

PubMed

Saeed Dar, M

2014-01-01

We have previously shown that brain adenosine A1 receptors and nitric oxide (NO) play an important role in ethanol (EtOH)-induced cerebellar ataxia (EICA) through glutamate/NO/cGMP pathway. I now report possible modulation of EICA by the cerebellar NO/cGMP/K(ATP) pathway. EICA was evaluated by Rotorod in CD-1 male mice. All drugs (K(ATP) activators pinacidil, 0.05, 0.1, 0.5 nmol; minoxidil, 0.01, 0.1, 1.0 pmol; antagonists glipizide/glibenclamide, 0.01, 0.05, 0.1 nmol; NO donor l-arginine, 20 nmol; NOS inhibitors [iNOS] inhibitor L-NAME, 50 nmol; glutamate, 1.5 nmol; adenosine A1 receptor agonist N(6) -cyclohexyladenosine [CHA], 6, 12 pmol; antagonist DPCPX, 0.1 or 0.4 nmol) were given by direct intracerebellar microinfusion via stereotaxically implanted guide cannulas, except EtOH (2 g/kg, i.p.). Pinacidil and minoxidil dose-dependently accentuated, whereas glipizide and glibenclamide markedly attenuated EICA, indicating tonic participation of K(ATP) channels. Glipizide abolished the pinacidil potentiation of EICA, which confirmed both drugs acted via K(ATP) channels. A possible link between K(ATP) channels and glutamate/NO pathway was suggested when (i) CHA (12 pmol) totally abolished l-arginine-induced attenuation of EICA; (ii) L-NAME abolished l-arginine-induced attenuation of EICA associated with further increase in EICA; and (iii) the combined l-arginine and glutamate infusion virtually abolished EICA. Also, whereas CHA abolished glibenclamide-induced attenuation and potentiated pinacidil/minoxidil-induced accentuation of EICA, the effects of DPCPX were just the opposite to those of CHA. The results with CHA therefore suggest a functional link between K(ATP) and A1 receptors and between K(ATP) and glutamate/NO and as an extension may involve participation of NO/cGMP/K(ATP) pathway in EICA. Copyright © 2013 by the Research Society on Alcoholism.

Influence of asymmetric attenuation of single and paired dendritic inputs on summation of synaptic potentials and initiation of action potentials.

PubMed

Fortier, Pierre A; Bray, Chelsea

2013-04-16

Previous studies revealed mechanisms of dendritic inputs leading to action potential initiation at the axon initial segment and backpropagation into the dendritic tree. This interest has recently expanded toward the communication between different parts of the dendritic tree which could preprocess information before reaching the soma. This study tested for effects of asymmetric voltage attenuation between different sites in the dendritic tree on summation of synaptic inputs and action potential initiation using the NEURON simulation environment. Passive responses due to the electrical equivalent circuit of the three-dimensional neuron architecture with leak channels were examined first, followed by the responses after adding voltage-gated channels and finally synaptic noise. Asymmetric attenuation of voltage, which is a function of asymmetric input resistance, was seen between all pairs of dendritic sites but the transfer voltages (voltage recorded at the opposite site from stimulation among a pair of dendritic sites) were equal and also summed linearly with local voltage responses during simultaneous stimulation of both sites. In neurons with voltage-gated channels, we reproduced the observations where a brief stimulus to the proximal ascending dendritic branch of a pyramidal cell triggers a local action potential but a long stimulus triggers a somal action potential. Combined stimulation of a pair of sites in this proximal dendrite did not alter this pattern. The attraction of the action potential onset toward the soma with a long stimulus in the absence of noise was due to the higher density of voltage-gated sodium channels at the axon initial segment. This attraction was, however, negligible at the most remote distal dendritic sites and was replaced by an effect due to high input resistance. Action potential onset occurred at the dendritic site of higher input resistance among a pair of remote dendritic sites, irrespective of which of these two sites received the synaptic input. Exploration of the parameter space showed how the gradient of voltage-gated channel densities and input resistances along a dendrite could draw the action potential onset away from the stimulation site. The attraction of action potential onset toward the higher density of voltage-gated channels in the soma during stimulation of the proximal dendrite was, however, reduced after the addition of synaptic noise. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Endothelin-1 Inhibits the Epithelial Na+ Channel through βPix/14-3-3/Nedd4-2

PubMed Central

Pavlov, Tengis S.; Chahdi, Ahmed; Ilatovskaya, Daria V.; Levchenko, Vladislav; Vandewalle, Alain; Pochynyuk, Oleh

2010-01-01

Epithelial Na+ channels (ENaCs) mediate sodium reabsorption in the cortical collecting duct (CCD), but the regulatory pathways that modulate the activity of these channels are incompletely understood. Here, we observed that endothelin-1 (ET-1) attenuates ENaC activity acutely by reducing the channel's open probability and chronically by decreasing the number of channels in the plasma membrane. To investigate whether β1Pix, a signaling protein activated by ET-1, mediates ENaC activity, we reconstituted ENaC in CHO cells with or without coexpressed β1Pix and found that β1Pix negatively regulates ENaC. Knockdown of βPix in native principal cells abolished the ET-1-induced decrease in ENaC channel number. Furthermore, we found that βPix does not decrease ENaC activity through its guanine nucleotide exchange factor (GEF) activity for Rac1 and Cdc42. Instead, coexpression of β1Pix mutant constructs revealed that β1Pix affects ENaC activity through binding 14-3-3 proteins. Coimmunoprecipitation experiments supported a physical interaction between β1Pix and 14-3-3β in cultured principal cells. Coexpression of 14-3-3β increased ENaC activity in CHO cells, but concomitant expression of β1Pix attenuated this increase. Recruitment of 14-3-3β by β1Pix impaired the interaction of 14-3-3β with the ubiquitin ligase Nedd4-2, thereby promoting ubiquitination and degradation of ENaC. Taken together, these results suggest that the inhibitory effects of chronic ET-1 on ENaC result from βPix interacting with the 14-3-3/Nedd4-2 pathway. PMID:20338996

Testosterone-induced relaxation of coronary arteries: activation of BKCa channels via the cGMP-dependent protein kinase

PubMed Central

Deenadayalu, Viju; Puttabyatappa, Yashoda; Liu, Alexander T.; Stallone, John N.

2012-01-01

Androgens are reported to have both beneficial and detrimental effects on human cardiovascular health. The aim of this study was to characterize nongenomic signaling mechanisms in coronary artery smooth muscle (CASM) and define the ionic basis of testosterone (TES) action. TES-induced relaxation of endothelium-denuded porcine coronary arteries was nearly abolished by 20 nM iberiotoxin, a highly specific inhibitor of large-conductance, calcium-activated potassium (BKCa) channels. Molecular patch-clamp studies confirmed that nanomolar concentrations of TES stimulated BKCa channel activity by ∼100-fold and that inhibition of nitric oxide synthase (NOS) activity by NG-monomethyl-l-arginine nearly abolished this effect. Inhibition of nitric oxide (NO) synthesis or guanylyl cyclase activity also attenuated TES-induced coronary artery relaxation but did not alter relaxation due to 8-bromo-cGMP. Furthermore, we detected TES-stimulated NO production in porcine coronary arteries and in human CASM cells via stimulation of the type 1 neuronal NOS isoform. Inhibition of the cGMP-dependent protein kinase (PKG) attenuated TES-stimulated BKCa channel activity, and direct assay determined that TES increased activity of PKG in a concentration-dependent fashion. Last, the stimulatory effect of TES on BKCa channel activity was mimicked by addition of purified PKG to the cytoplasmic surface of a cell-free membrane patch from CASM myocytes (∼100-fold increase). These findings indicate that TES-induced relaxation of endothelium-denuded coronary arteries is mediated, at least in part, by enhanced NO production, leading to cGMP synthesis and PKG activation, which, in turn, opens BKCa channels. These findings provide a molecular mechanism that could help explain why androgens have been reported to relax coronary arteries and relieve angina pectoris. PMID:22081702

Processing, Characteristics, and Optical Properties of Wet Chemically Derived Planar Dielectric Waveguides.

NASA Astrophysics Data System (ADS)

Weisenbach, Lori Ann

An experimental study of the processing and attenuation characteristics of solution derived, thin film, planar waveguides was made. In this study, the densification and attenuation characteristics of a variety of compositions were compared. To insure that the effects measured reflected compositional differences and not processing artifacts, guidelines for the reproducible fabrication of optical quality layers, irrespective of composition, were established. A broad range of compositions were prepared and an effort was made to keep the various solution syntheses as simple and similar as possible. The densification and attenuation of binary SiO _2-TiO_2 compositions was measured, then compared to the densification and attenuation of SiO_2-TiO_2 -R_{rm x}O _{rm y} (where R = Al or Zn) ternary compositions. Film densification was not strongly dependent upon composition, and was successfully modelled using the Lorentz-Lorenz relation, assuming the open volume in the undensified films were filled with adsorbed water. The attenuation measured at 632.8 nm did not vary with composition, except for the Zn ternary samples. Waveguides with losses of <1dB/cm could be fabricated from all other compositions. Waveguide attenuation was measured for films of different thickness, and compared to modelled predictions. The attenuation increased as layer thickness decreased, suggesting the predominance of the surface scattering contribution. To confirm that absorption losses were negligible, the wavelength dependence of the waveguides was measured. The wavelength dependence varied with composition, suggesting the absorption varied with composition. Possible mechanisms of absorption in the waveguides were discussed; the interaction of the atmosphere with the film structure is proposed as the cause of the deterioration. Film development for the binary SiO_2 -TiO_2 films was also studied as a function of increased firing time at 500^ circC. Multiple firings at 500^ circC increased the film density and the resistance to deterioration, but also increased the surface roughness of the films. Increased surface roughness, increased the scattering losses measured for the guide. The application of solution derived thin films was demonstrated with the successful fabrication of a novel optical device. The fabrication of the Single Leakage -Channel Grating Coupler illustrated specific design tolerances could be met and the resulting device performance near the theoretical maximum.

Turbulence-induced channel crosstalk in an orbital angular momentum-multiplexed free-space optical link

NASA Astrophysics Data System (ADS)

Anguita, Jaime A.; Neifeld, Mark A.; Vasic, Bane V.

2008-05-01

A multichannel free-space optical (FSO) communication system based on orbital angular momentum (OAM)-carrying beams is studied. We numerically analyze the effects of atmospheric turbulence on the system and find that turbulence induces attenuation and crosstalk among channels. Based on a model in which the constituent channels are binary symmetric and crosstalk is a Gaussian noise source, we find optimal sets of OAM states at each turbulence condition studied and determine the aggregate capacity of the multichannel system at those conditions. OAM-multiplexed FSO systems that operate in the weak turbulence regime are found to offer good performance. We verify that the aggregate capacity decreases as the turbulence increases. A per-channel bit-error rate evaluation is presented to show the uneven effects of crosstalk on the constituent channels.

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor.

PubMed

Hinson, Shannon R; Clift, Ian C; Luo, Ningling; Kryzer, Thomas J; Lennon, Vanda A

2017-05-23

Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.

Spider web-structured labyrinthine acoustic metamaterials for low-frequency sound control

NASA Astrophysics Data System (ADS)

Krushynska, A. O.; Bosia, F.; Miniaci, M.; Pugno, N. M.

2017-10-01

Attenuating low-frequency sound remains a challenge, despite many advances in this field. Recently-developed acoustic metamaterials are characterized by unusual wave manipulation abilities that make them ideal candidates for efficient subwavelength sound control. In particular, labyrinthine acoustic metamaterials exhibit extremely high wave reflectivity, conical dispersion, and multiple artificial resonant modes originating from the specifically-designed topological architectures. These features enable broadband sound attenuation, negative refraction, acoustic cloaking and other peculiar effects. However, hybrid and/or tunable metamaterial performance implying enhanced wave reflection and simultaneous presence of conical dispersion at desired frequencies has not been reported so far. In this paper, we propose a new type of labyrinthine acoustic metamaterials (LAMMs) with hybrid dispersion characteristics by exploiting spider web-structured configurations. The developed design approach consists in adding a square surrounding frame to sectorial circular-shaped labyrinthine channels described in previous publications (e.g. (11)). Despite its simplicity, this approach provides tunability in the metamaterial functionality, such as the activation/elimination of subwavelength band gaps and negative group-velocity modes by increasing/decreasing the edge cavity dimensions. Since these cavities can be treated as extensions of variable-width internal channels, it becomes possible to exploit geometrical features, such as channel width, to shift the band gap position and size to desired frequencies. Time transient simulations demonstrate the effectiveness of the proposed metastructures for wave manipulation in terms of transmission or reflection coefficients, amplitude attenuation and time delay at subwavelength frequencies. The obtained results can be important for practical applications of LAMMs such as lightweight acoustic barriers with enhanced broadband wave-reflecting performances.

Potassium channel openers and prostacyclin play a crucial role in mediating the vasorelaxant activity of Gynura procumbens

PubMed Central

2013-01-01

Background Previous studies of Gynura procumbens (G. procumbens) have shown that partially purified fractions of the leaves are capable of lowering the blood pressure of rats by inhibiting angiotensin-converting enzymic activity and causing vasodilatation. The objectives of this study were therefore to further purify the active compounds that exhibited selective effects on blood vessels, determine the mechanism of actions, and to qualitatively analyse the putative compounds present. Methods The butanolic fraction (BU) of the crude ethanolic extract was purified using column chromatography to obtain several sub-fractions of different polarities. The in vitro effects of BU and the sub-fractions on vascular tension were subsequently determined using isolated rat thoracic aortic rings. The most potent sub-fraction (F1) alone was then investigated for its mechanisms of the vasorelaxant activity. In another experiment, thin-layer chromatography was used to qualitatively analyse the active compounds found in F1. Results The BU and the sub-fractions ranging from 10-7 to 10-2 g/ml significantly (p < 0.05) inhibited the sustained tonic contractions induced by phenylephrine and potassium chloride in a concentration-dependent manner with various degree of potency. The most potent sub-fraction (F1) antagonised the calcium-induced vasocontractions (1 x 10-4 – 1 x 10-2 M) in calcium-free with high concentration of potassium as well as in calcium- and potassium-free Krebs-Henseleit solutions. Contractions induced by noradrenaline and caffeine were not affected by F1. The vasorelaxing effect caused by F1 was significantly attenuated with preincubation of potassium channel blockers (glibenclamide and 4-aminopyridine) and prostacyclin inhibitor (indomethacin) while it was not affected by preincubation with tetraethylammonium, l-nitro-arginine methyl esther, propanolol, atropine, oxadiazolo quinoxalin one and methylene blue. The qualitative phytochemical analysis of F1 indicated the presence of flavonoids. Conclusion These results confirm previous findings that G. procumbens causes vasodilatory effects by blocking calcium channels. In addition, the present study further demonstrates that the vasodilatory effect of G. procumbens may also be due to the opening of potassium channels and the stimulation of prostacyclin production. The putative compounds are probably flavonoids in nature. PMID:23879679

A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miyanohara, Jun; Shirakawa, Hisashi, E-mail: shirakaw@pharm.kyoto-u.ac.jp; Sanpei, Kazuaki

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca{sup 2+} permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2more » days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia. - Highlights: • We investigated whether TRPV1 is involved in transient ischemic brain damage in mice. • Neurological deficits and infarct volumes were lower in TRPV1-KO mice than in WT mice. • Injection of a TRPV1 antagonist, capsazepine, attenuated neurological deficits and improved infarct size. • No differences in astrocytic or microglial activation were observed between WT and TRPV1-KO mice.« less

Kcne2 deletion attenuates acute post-ischaemia/reperfusion myocardial infarction

PubMed Central

Hu, Zhaoyang; Crump, Shawn M.; Zhang, Ping; Abbott, Geoffrey W.

2016-01-01

Aims Most cardiac arrhythmia-associated genes encode ion channel subunits and regulatory proteins that are also expressed outside the heart, suggesting that diseases linked to their disruption may be multifactorial. KCNE2 is a ubiquitously expressed potassium channel β subunit associated with cardiac arrhythmia, atherosclerosis, and myocardial infarction (MI) in human populations. Here, we tested the hypothesis that Kcne2 disruption in mice would influence the acute outcome of experimentally induced MI. Methods and results One-year-old male Kcne2+/+ and Kcne2−/− mice were subjected to cardiac ischaemia/reperfusion injury (IRI) by left anterior descending coronary artery ligation. After reperfusion (3 h), infarct size and markers of tissue damage were quantified. Unexpectedly, post-reperfusion, Kcne2−/− mice exhibited 40% lower infarct size, decreased myocardial apoptosis and damage, and more than two-fold lower serum levels of damage markers, lactate dehydrogenase and creatine kinase, than Kcne2+/+ mice. Kcne2 deletion, despite increasing normalized heart weight and prolonging baseline QTc by 70%, helped preserve post-infarct cardiac function (quantified by a Millar catheter), with parameters including left ventricular maximum pressure, max dP/dt (P < 0.01), contractility index, and pressure/time index (P < 0.05) all greater in Kcne2−/− compared with Kcne2+/+ mice. Western blotting indicated two-fold-increased glycogen synthase kinase 3β (GSK-3β) phosphorylation (inactivation) before and after IRI (P < 0.05) in Kcne2−/− mice compared with Kcne2+/+ mice. GSK-3β inhibition by SB216763 mimicked in Kcne2+/+ mice the cardioprotective effects of Kcne2 deletion, but did not further enhance them in Kcne2−/− mice, suggesting that GSK-3β inactivation was a primary cardioprotective mechanism arising from Kcne2 deletion. Conclusions Kcne2 deletion preconditions the heart, attenuating the acute tissue damage caused by an imposed IRI. The findings contribute further evidence that genetic disruption of arrhythmia-associated ion channel genes has cardiac ramifications beyond abnormal electrical activity. PMID:26952045

Role of reactive oxygen species and sulfide-quinone oxoreductase in hydrogen sulfide-induced contraction of rat pulmonary arteries

PubMed Central

Prieto-Lloret, Jesus; Snetkov, Vladimir A.; Shaifta, Yasin; Docio, Inmaculada; Connolly, Michelle J.; MacKay, Charles E.; Knock, Greg A.

2018-01-01

Application of H2S (“sulfide”) elicits a complex contraction in rat pulmonary arteries (PAs) comprising a small transient contraction (phase 1; Ph1) followed by relaxation and then a second, larger, and more sustained contraction (phase 2; Ph2). We investigated the mechanisms causing this response using isometric myography in rat second-order PAs, with Na2S as a sulfide donor. Both phases of contraction to 1,000 μM Na2S were attenuated by the pan-PKC inhibitor Gö6983 (3 μM) and by 50 μM ryanodine; the Ca2+ channel blocker nifedipine (1 μM) was without effect. Ph2 was attenuated by the mitochondrial complex III blocker myxothiazol (1 μM), the NADPH oxidase (NOX) blocker VAS2870 (10 μM), and the antioxidant TEMPOL (3 mM) but was unaffected by the complex I blocker rotenone (1 μM). The bath sulfide concentration, measured using an amperometric sensor, decreased rapidly following Na2S application, and the peak of Ph2 occurred when this had fallen to ~50 μM. Sulfide caused a transient increase in NAD(P)H autofluorescence, the offset of which coincided with development of the Ph2 contraction. Sulfide also caused a brief mitochondrial hyperpolarization (assessed using tetramethylrhodamine ethyl ester), followed immediately by depolarization and then a second more prolonged hyperpolarization, the onset of which was temporally correlated with the Ph2 contraction. Sulfide application to cultured PA smooth muscle cells increased reactive oxygen species (ROS) production (recorded using L012); this was absent when the mitochondrial flavoprotein sulfide-quinone oxoreductase (SQR) was knocked down using small interfering RNA. We propose that the Ph2 contraction is largely caused by SQR-mediated sulfide metabolism, which, by donating electrons to ubiquinone, increases electron production by complex III and thereby ROS production. PMID:29351439

Limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies as a cause of adult-onset mesial temporal lobe epilepsy.

PubMed

Toyota, Tomoko; Akamatsu, Naoki; Tsuji, Sadatoshi; Nishizawa, Shigeru

2014-06-01

Recently, some reports have indicated that limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies (VGKC-Ab) is a cause of adult-onset mesial temporal lobe epilepsy (MTLE). We report a 53-year-old woman who had her first epileptic seizure at the age of 50 years old. Examination by 3-Tesla brain MRI revealed left hippocampal high signal intensity and swelling on fluid-attenuated inversion recovery (FLAIR) and T2-weighted imaging at 2 months after her first seizure. The patient received intravenous methylprednisolone and carbamazepine 300 mg/day. One month later, MRI revealed improvement of her left hippocampal abnormalities. Thereafter, she had no seizures, however, three years after her first seizure, EEG revealed a seizure pattern in the left temporal region. Brain MRI revealed left hippocampal high signal intensity and brain fluorodeoxyglucose positron emission tomography revealed hypermetabolism. Her serum VGKC-Ab levels were 118 pM(normal < 100 pM). Intravenous methylprednisolone therapy was reinitiated. Two months later, her hippocampal abnormalities had improved and 3 months later her VGKC-Ab levels decreased to 4.4 pM. Remission of the epileptic seizures was also observed. This MTLE in the middle age was considered as limbic encephalitis associated with anti- VGKC-Ab. In cases of unexplained adult-onset MTLE, limbic encephalitis associated with anti-VGKC-Ab, which responds well to immunotherapy, should be considered in the differential diagnosis.

Air bubble contact with endothelial cells in vitro induces calcium influx and IP3-dependent release of calcium stores

PubMed Central

Sobolewski, Peter; Kandel, Judith; Klinger, Alexandra L.

2011-01-01

Gas embolism is a serious complication of decompression events and clinical procedures, but the mechanism of resulting injury remains unclear. Previous work has demonstrated that contact between air microbubbles and endothelial cells causes a rapid intracellular calcium transient and can lead to cell death. Here we examined the mechanism responsible for the calcium rise. Single air microbubbles (50–150 μm), trapped at the tip of a micropipette, were micromanipulated into contact with individual human umbilical vein endothelial cells (HUVECs) loaded with Fluo-4 (a fluorescent calcium indicator). Changes in intracellular calcium were then recorded via epifluorescence microscopy. First, we confirmed that HUVECs rapidly respond to air bubble contact with a calcium transient. Next, we examined the involvement of extracellular calcium influx by conducting experiments in low calcium buffer, which markedly attenuated the response, or by pretreating cells with stretch-activated channel blockers (gadolinium chloride or ruthenium red), which abolished the response. Finally, we tested the role of intracellular calcium release by pretreating cells with an inositol 1,4,5-trisphosphate (IP3) receptor blocker (xestospongin C) or phospholipase C inhibitor (neomycin sulfate), which eliminated the response in 64% and 67% of cases, respectively. Collectively, our results lead us to conclude that air bubble contact with endothelial cells causes an influx of calcium through a stretch-activated channel, such as a transient receptor potential vanilloid family member, triggering the release of calcium from intracellular stores via the IP3 pathway. PMID:21633077

Pharmacological evaluation of NSAID-induced gastropathy as a "Translatable" model of referred visceral hypersensitivity.

PubMed

Hummel, Michele; Knappenberger, Terri; Reilly, Meghan; Whiteside, Garth T

2017-09-07

To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity. Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice ( n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential (TRP), sodium and acid-sensing ion channels (ASICs) as well as opioid receptors and guanylate cyclase C (GC-C). Results showed that two opioids and a GC-C agonist, morphine, asimadoline and linaclotide, respectively, the TRP antagonists, AMG9810 and HC-030031 and the sodium channel blocker, carbamazepine, elicited a dose- and/or time-dependent attenuation of referred visceral hypersensitivity, while the ASIC blocker, amiloride, was ineffective at all doses tested. Together, these findings implicate opioid receptors, GC-C, and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly, these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.

Pharmacological evaluation of NSAID-induced gastropathy as a "Translatable" model of referred visceral hypersensitivity

PubMed Central

Hummel, Michele; Knappenberger, Terri; Reilly, Meghan; Whiteside, Garth T

2017-01-01

AIM To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity. METHODS Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice (n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential (TRP), sodium and acid-sensing ion channels (ASICs) as well as opioid receptors and guanylate cyclase C (GC-C). RESULTS Results showed that two opioids and a GC-C agonist, morphine, asimadoline and linaclotide, respectively, the TRP antagonists, AMG9810 and HC-030031 and the sodium channel blocker, carbamazepine, elicited a dose- and/or time-dependent attenuation of referred visceral hypersensitivity, while the ASIC blocker, amiloride, was ineffective at all doses tested. CONCLUSION Together, these findings implicate opioid receptors, GC-C, and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly, these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties. PMID:28970722

Intra-body microwave communication through adipose tissue.

PubMed

Asan, Noor Badariah; Noreland, Daniel; Hassan, Emadeldeen; Redzwan Mohd Shah, Syaiful; Rydberg, Anders; Blokhuis, Taco J; Carlsson, Per-Ola; Voigt, Thiemo; Augustine, Robin

2017-08-01

The human body can act as a medium for the transmission of electromagnetic waves in the wireless body sensor networks context. However, there are transmission losses in biological tissues due to the presence of water and salts. This Letter focuses on lateral intra-body microwave communication through different biological tissue layers and demonstrates the effect of the tissue thicknesses by comparing signal coupling in the channel. For this work, the authors utilise the R-band frequencies since it overlaps the industrial, scientific and medical radio (ISM) band. The channel model in human tissues is proposed based on electromagnetic simulations, validated using equivalent phantom and ex-vivo measurements. The phantom and ex-vivo measurements are compared with simulation modelling. The results show that electromagnetic communication is feasible in the adipose tissue layer with a low attenuation of ∼2 dB per 20 mm for phantom measurements and 4 dB per 20 mm for ex-vivo measurements at 2 GHz. Since the dielectric losses of human adipose tissues are almost half of ex-vivo tissue, an attenuation of around 3 dB per 20 mm is expected. The results show that human adipose tissue can be used as an intra-body communication channel.

Vasodilatory effects of ethanol extract of Radix Paeoniae Rubra and its mechanism of action in the rat aorta.

PubMed

Jin, Song Nan; Wen, Jin Fu; Wang, Ting Ting; Kang, Dae Gill; Lee, Ho Sub; Cho, Kyung Woo

2012-06-26

Radix Paeoniae Rubra (RPR) is an important traditional Chinese medicine (TCM) commonly used in clinic for a long history in China. RPR is the radix of either Paeonia lactiflora Pall. or Paeonia veitchii Lynch. RPR has a wide variety of pharmacological actions such as anti-thrombus, anti-coagulation, and anti-atherosclerotic properties, protecting heart and liver. However, the mechanisms involved are to be defined. The aim of the present study was to define the effect of Paeonia lactiflora Pall. extracts on vascular tension and responsible mechanisms in rat thoracic aortic rings. Ethanol extract of Paeonia lactiflora Pall. (EPL) was examined for their vascular relaxant effects in isolated phenylephrine-precontracted rat thoracic aorta. EPL induced relaxation of the phenylephrine-precontracted aortic rings in a concentration-dependent manner. Vascular relaxation induced by EPL was significantly inhibited by removal of the endothelium or pretreatment of the rings with N(G)-nitro-L-arginine methylester (L-NAME) or 1H-[1,2,4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ). Extracellular Ca²⁺ depletion or diltiazem significantly attenuated EPL-induced vasorelaxation. Modulators of the store-operated Ca²⁺ entry (SOCE), thapsigargin, 2-aminoethyl diphenylborinate and Gd³⁺, and an inhibitor of Akt, wortmannin, markedly attenuated the EPL-induced vasorelaxation. Further, the EPL-induced vasorelaxation was significantly attenuated by pretreatment with tetraethylammonium, a non-selective K(Ca) channels blocker, or glibenclamide, an ATP-sensitive K⁺ channels inhibitor, respectively. Inhibition of cyclooxygenases with indomethacin, and adrenergic and muscarinic receptors blockade had no effects on the EPL-induced vasorelaxation. The present study suggests that EPL relaxes vascular smooth muscle via endothelium-dependent and Akt- and SOCE-eNOS-cGMP-mediated pathways through activation of both K(Ca) and K(ATP) channels and inhibition of L-type Ca²⁺ channels. Copyright © 2012. Published by Elsevier Ireland Ltd.

Backscatter-to-Extinction Ratios in the Top Layers of Tropical Mesoscale Convective Systems and in Isolated Cirrus from LITE Observations

NASA Technical Reports Server (NTRS)

Platt, C. M. R.; Winker, D. M.; Vaughan, M. A.; Miller, S. D.

1999-01-01

Cloud-integrated attenuated backscatter from observations with the Lidar In-Space Technology Experiment (LITE) was studied over a range of cirrus clouds capping some extensive mesoscale convective systems (MCSS) in the Tropical West Pacific. The integrated backscatter when the cloud is completely attenuating, and when corrected for multiple scattering, is a measure of the cloud particle backscatter phase function. Four different cases of MCS were studied. The first was very large, very intense, and fully attenuating, with cloud tops extending to 17 km and a maximum lidar pulse penetration of about 3 km. It also exhibited the highest integrated attenuated isotropic backscatter, with values in the 532-nm channel of up to 2.5 near the center of the system, falling to 0.6 near the edges. The second MCS had cloud tops that extended to 14.8 km. Although MCS2 was almost fully attenuating, the pulse penetration into the cloud was up to 7 km and the MCS2 had a more diffuse appearance than MCS1. The integrated backscatter values were much lower in this system but with some systematic variations between 0.44 and 0.75. The third MCS was Typhoon Melissa. Values of integrated backscatter in tt-ds case varied from 1.64 near the eye of the typhoon to between 0.44 and 1.0 in the areas of typhoon outflow and in the 532-nm channel. Mean pulse penetration through the cloud top was 2-3 km, the lowest penetration of any of the systems. The fourth MCS consisted of a region of outflow from Typhoon Melissa. The cloud was semitransparent for more than half of the image time. During that time, maximum cloud depth was about 7 km. The integrated backscatter varied from about 0.38 to 0.63 in the 532-nm channel when the cloud was fully attenuating. In some isolated cirrus between the main systems, a plot of integrated backscatter against one minus the two-way transmittance gave a linear dependence with a maximum value of 0.35 when the clouds were fully attenuating. The effective backscatter-to-extinction ratios, when allowing for different multiple-scattering factors from space, were often within the range of those observed with ground-based lidar. Exceptions occurred near the centers of the most intense convection, where values were measured that were considerably higher than those in cirrus observed from the surface. In this case, the values were more compatible with theoretical values for perfectly formed hexagonal columns or plates. The large range in theoretically calculated back- scatter-to-extinction ratio and integrated multiple-scattering factor precluded a closer interpretation in terms of cloud microphysics.

Attenuation Compensation of Ultrasonic Wave in Soft Tissue for Acoustic Impedance Measurement of In vivo Bone by Transducer Vibration Method

NASA Astrophysics Data System (ADS)

Yoshizawa, Masasumi; Nakamura, Yuuta; Ishiguro, Masataka; Moriya, Tadashi

2007-07-01

In this paper, we describe a method of compensating the attenuation of the ultrasound caused by soft tissue in the transducer vibration method for the measurement of the acoustic impedance of in vivo bone. In the in vivo measurement, the acoustic impedance of bone is measured through soft tissue; therefore, the amplitude of the ultrasound reflected from the bone is attenuated. This attenuation causes an error of the order of -20 to -30% when the acoustic impedance is determined from the measured signals. To compensate the attenuation, the attenuation coefficient and length of the soft tissue are measured by the transducer vibration method. In the experiment using a phantom, this method allows the measurement of the acoustic impedance typically with an error as small as -8 to 10%.

The Kv7/KCNQ channel blocker XE991 protects nigral dopaminergic neurons in the 6-hydroxydopamine rat model of Parkinson's disease.

PubMed

Liu, Haixia; Jia, Lu; Chen, Xiaoyan; Shi, Limin; Xie, Junxia

2018-03-01

The excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that supply the striatum with dopamine (DA) determines the function of the nigrostriatal system for motor coordination. We previously showed that 4-pyridinylmethyl-9(10H)-anthracenone (XE991), a specific blocker of Kv7/KCNQ channels, enhanced the excitability of nigral DA neurons and resulted in attenuation of haloperidol-induced catalepsy in a Parkinson's disease (PD) rat model. However, whether XE991 exhibits neuroprotective effects towards DA neuron degeneration remains unknown. The aim of this study was to investigate the effects of Kv7/KCNQ channel blocker, XE991, on 6-hydroxydopamine (6-OHDA)-induced nigral DA neuron degeneration and motor dysfunction. Using immunofluorescence staining and western blotting, we showed that intracerebroventricular administration of XE991 prevented the 6-OHDA-induced decrease in tyrosine hydroxylase (TH)-positive neurons and TH protein expression in the SNc. High-performance liquid chromatography with electrochemical detection (HPLC-ECD) also revealed that XE991 partly restored the levels of DA and its metabolites in the striatum. Moreover, XE991 decreased apomorphine (APO)-induced contralateral rotations, enhanced balance and coordination, and attenuated muscle rigidity in 6-OHDA-treated rats. Importantly, all neuroprotective effects by XE991 were abolished by co-application of Kv7/KCNQ channel opener retigabine and XE991. Thus, Kv7/KCNQ channel inhibition by XE991 can exert neuroprotective effects against 6-OHDA-induced degeneration of the nigrostriatal DA system and motor dysfunction. Copyright © 2017. Published by Elsevier Inc.

Aberrant connexin26 hemichannels underlying keratitis-ichthyosis-deafness syndrome are potently inhibited by mefloquine

PubMed Central

Levit, Noah A.; Sellitto, Caterina; Wang, Hong-Zhan; Li, Leping; Srinivas, Miduturu; Brink, Peter R.; White, Thomas W.

2014-01-01

Keratitis-ichthyosis-deafness (KID) syndrome is an ectodermal dysplasia caused by dominant mutations of connexin26 (Cx26). Loss of Cx26 function causes non-syndromic sensorineural deafness, without consequence in the epidermis. Functional analyses have revealed that a majority of KID-causing mutations confer a novel expansion of hemichannel activity, mediated by connexin channels in a non-junctional configuration. Inappropriate Cx26 hemichannel opening is hypothesized to compromise keratinocyte integrity and epidermal homeostasis. Pharmacological modulators of Cx26 are needed to assess the pathomechanistic involvement of hemichannels in the development of hyperkeratosis in KID syndrome. We have used electrophysiological assays to evaluate small molecule analogs of quinine for suppressive effects on aberrant hemichannel currents elicited by KID mutations. Here, we show that mefloquine inhibits several mutant hemichannel forms implicated in KID syndrome when expressed in Xenopus laevis oocytes (IC50≈16µM), using an extracellular divalent cation, zinc (Zn++), as a non-specific positive control for comparison (IC50≈3µM). Furthermore, we used freshly isolated transgenic keratinocytes to show that micromolar concentrations of mefloquine attenuated increased macroscopic membrane currents in primary mouse keratinocytes expressing human Cx26-G45E, a mutation causing a lethal form of KID syndrome. PMID:25229253

Transcriptional Activation of Mucin by Pseudomonas aeruginosa Lipopolysaccharide in the Pathogenesis of Cystic Fibrosis Lung Disease

NASA Astrophysics Data System (ADS)

Li, Jian-Dong; Dohrman, Austin F.; Gallup, Marianne; Miyata, Susumu; Gum, James R.; Kim, Young S.; Nadel, Jay A.; Prince, Alice; Basbaum, Carol B.

1997-02-01

An unresolved question in cystic fibrosis (CF) research is how mutations of the CF transmembrane conductance regulator, a CI ion channel, cause airway mucus obstruction leading to fatal lung disease. Recent evidence has linked the CF transmembrane conductance regulator mutation to the onset and persistence of Pseudomonas aeruginosa infection in the airways, and here we provide evidence directly linking P. aeruginosa infection to mucus overproduction. We show that P. aeruginosa lipopolysaccharide profoundly upregulates transcription of the mucin gene MUC 2 in epithelial cells via inducible enhancer elements and that this effect is blocked by the tyrosine kinase inhibitors genistein and tyrphostin AG 126. These findings improve our understanding of CF pathogenesis and suggest that the attenuation of mucin production by lipopolysaccharide antagonists and tyrosine kinase inhibitors could reduce morbidity and mortality in this disease.

A CMOS merged CDR and continuous-time adaptive equalizer

NASA Astrophysics Data System (ADS)

Sánchez-Azqueta, C.; Aguirre, J.; Gimeno, C.; Aldea, C.; Celma, S.

2015-06-01

We present a low-voltage merged CDR and cntinuous-time adaptive equalizer capable to compensate the attenu- ation of a SI-POF channel while at the same time synchronizing and regenerating the incoming signal in a single stage. The system operates at 1.25 Gbps for NRZ modulation through a 50-m SI-POF channel and it is designed in standard 0.18-μm CMOS fed at 1 V with a power consumption of 43.4 mW.

Evaluation of Potential for Monitored Natural Attenuation of Perchlorate in Groundwater (Indian Head)

DTIC Science & Technology

2010-07-01

United States is through consumption of food (USFDA, 2007). This is a concern because high levels of perchlorate interfere with iodide uptake by the...from more that 50 mg/L to below detection using lactate as a food source; (and) the pH of the aquifer must be buffered to achieve optimal perchlorate...defined by a covering of Nelumbo lutea (American lotus ) which are visible beyond the Subtidal Channel in the photograph Figure 3-14. The main channel

Vertical Ship Motion Study for Ambrose Entrance Channel, New York

DTIC Science & Technology

2014-05-01

channels, PIANC Bulletin 1971, Vol. 1, No. 7, 17-20. Hardy, T. A. 1993. The attenuation of spectral transformation of wind waves on a coral reef ...A80(12): 95 p. Hearn, C. J. 1999. Wave -breaking hydrodynamics within coral reef systems and the effect of changing relative sea level, Journal of...Values of cf applied for coral reefs range from 0.05 to 0.40 (Hardy 1993; Hearn 1999 and Lowe et al. 2005). CMS- Wave uses a default value of cf

Channel analysis for single photon underwater free space quantum key distribution.

PubMed

Shi, Peng; Zhao, Shi-Cheng; Gu, Yong-Jian; Li, Wen-Dong

2015-03-01

We investigate the optical absorption and scattering properties of underwater media pertinent to our underwater free space quantum key distribution (QKD) channel model. With the vector radiative transfer theory and Monte Carlo method, we obtain the attenuation of photons, the fidelity of the scattered photons, the quantum bit error rate, and the sifted key generation rate of underwater quantum communication. It can be observed from our simulations that the most secure single photon underwater free space QKD is feasible in the clearest ocean water.

SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake.

PubMed

Honrath, Birgit; Matschke, Lina; Meyer, Tammo; Magerhans, Lena; Perocchi, Fabiana; Ganjam, Goutham K; Zischka, Hans; Krasel, Cornelius; Gerding, Albert; Bakker, Barbara M; Bünemann, Moritz; Strack, Stefan; Decher, Niels; Culmsee, Carsten; Dolga, Amalia M

2017-05-01

Mitochondrial calcium ([Ca 2+ ] m ) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca 2+ ] m uptake upon SK channel activation as detected by time lapse mitochondrial Ca 2+ measurements with the Ca 2+ -binding mitochondria-targeted aequorin and FRET-based [Ca 2+ ] m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca 2+ ] m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death.

SK2 channels regulate mitochondrial respiration and mitochondrial Ca2+ uptake

PubMed Central

Honrath, Birgit; Matschke, Lina; Meyer, Tammo; Magerhans, Lena; Perocchi, Fabiana; Ganjam, Goutham K; Zischka, Hans; Krasel, Cornelius; Gerding, Albert; Bakker, Barbara M; Bünemann, Moritz; Strack, Stefan; Decher, Niels; Culmsee, Carsten; Dolga, Amalia M

2017-01-01

Mitochondrial calcium ([Ca2+]m) overload and changes in mitochondrial metabolism are key players in neuronal death. Small conductance calcium-activated potassium (SK) channels provide protection in different paradigms of neuronal cell death. Recently, SK channels were identified at the inner mitochondrial membrane, however, their particular role in the observed neuroprotection remains unclear. Here, we show a potential neuroprotective mechanism that involves attenuation of [Ca2+]m uptake upon SK channel activation as detected by time lapse mitochondrial Ca2+ measurements with the Ca2+-binding mitochondria-targeted aequorin and FRET-based [Ca2+]m probes. High-resolution respirometry revealed a reduction in mitochondrial respiration and complex I activity upon pharmacological activation and overexpression of mitochondrial SK2 channels resulting in reduced mitochondrial ROS formation. Overexpression of mitochondria-targeted SK2 channels enhanced mitochondrial resilience against neuronal death, and this effect was inhibited by overexpression of a mitochondria-targeted dominant-negative SK2 channel. These findings suggest that SK channels provide neuroprotection by reducing [Ca2+]m uptake and mitochondrial respiration in conditions, where sustained mitochondrial damage determines progressive neuronal death. PMID:28282037

Drag reduction in a turbulent channel flow using a passivity-based approach

NASA Astrophysics Data System (ADS)

Heins, Peter; Jones, Bryn; Sharma, Atul

2013-11-01

A new active feedback control strategy for attenuating perturbation energy in a turbulent channel flow is presented. Using a passivity-based approach, a controller synthesis procedure has been devised which is capable of making the linear dynamics of a channel flow as close to passive as is possible given the limitations on sensing and actuation. A controller that is capable of making the linearized flow passive is guaranteed to globally stabilize the true flow. The resulting controller is capable of greatly restricting the amount of turbulent energy that the nonlinearity can feed back into the flow. DNS testing of a controller using wall-sensing of streamwise and spanwise shear stress and actuation via wall transpiration acting upon channel flows with Reτ = 100 - 250 showed significant reductions in skin-friction drag.

Acute and chronic hypoxia: implications for cerebral function and exercise tolerance

PubMed Central

Goodall, Stuart; Twomey, Rosie; Amann, Markus

2015-01-01

Purpose To outline how hypoxia profoundly affects neuronal functionality and thus compromise exercise-performance. Methods Investigations using electroencephalography (EEG) and transcranial magnetic stimulation (TMS) detecting neuronal changes at rest and those studying fatiguing effects on whole-body exercise performance in acute (AH) and chronic hypoxia (CH) were evaluated. Results At rest during very early hypoxia (<1-h), slowing of cerebral neuronal activity is evident despite no change in corticospinal excitability. As time in hypoxia progresses (3-h), increased corticospinal excitability becomes evident; however, changes in neuronal activity are unknown. Prolonged exposure (3–5 d) causes a respiratory alkalosis which modulates Na+ channels, potentially explaining reduced neuronal excitability. Locomotor exercise in AH exacerbates the development of peripheral-fatigue; as the severity of hypoxia increases, mechanisms of peripheral-fatigue become less dominant and CNS hypoxia becomes the predominant factor. The greatest central-fatigue in AH occurs when SaO2 is ≤75%, a level that coincides with increasing impairments in neuronal activity. CH does not improve the level of peripheral-fatigue observed in AH; however, it attenuates the development of central-fatigue paralleling increases in cerebral O2 availability and corticospinal excitability. Conclusions The attenuated development of central-fatigue in CH might explain, the improvements in locomotor exercise-performance commonly observed after acclimatisation to high altitude. PMID:25593787

Using seismic coda waves to resolve intrinsic and scattering attenuation

NASA Astrophysics Data System (ADS)

Wang, W.; Shearer, P. M.

2016-12-01

Seismic attenuation is caused by two factors, scattering and intrinsic absorption. Characterizing scattering and absorbing properties and the power spectrum of crustal heterogeneity is a fundamental problem for informing strong ground motion estimates at high frequencies, where scattering and attenuation effects are critical. Determining the relative amount of attenuation caused by scattering and intrinsic absorption has been a long-standing problem in seismology. The wavetrain following the direct body wave phases is called the coda, which is caused by scattered energy. Many studies have analyzed the coda of local events to constrain crustal and upper-mantle scattering strength and intrinsic attenuation. Here we examine two popular attenuation inversion methods, the Multiple Lapse Time Window Method (MLTWM) and the Coda Qc Method. First, based on our previous work on California attenuation structure, we apply an efficient and accurate method, the Monte Carlo Approach, to synthesize seismic envelope functions. We use this code to generate a series of synthetic data based on several complex and realistic forward models. Although the MLTWM assumes a uniform whole space, we use the MLTWM to invert for both scattering and intrinsic attenuation from the synthetic data to test how accurately it can recover the attenuation models. Results for the coda Qc method depend on choices for the length and starting time of the coda-wave time window. Here we explore the relation between the inversion results for Qc, the windowing parameters, and the intrinsic and scattering Q structure of our synthetic model. These results should help assess the practicality and accuracy of the Multiple Lapse Time Window Method and Coda Qc Method when applied to realistic crustal velocity and attenuation models.

Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X).

PubMed

Thomas, Dierk; Hammerling, Bettina C; Wimmer, Anna-Britt; Wu, Kezhong; Ficker, Eckhard; Kuryshev, Yuri A; Scherer, Daniel; Kiehn, Johann; Katus, Hugo A; Schoels, Wolfgang; Karle, Christoph A

2004-12-01

The human ether-a-go-go-related gene (hERG) encodes the rapid component of the cardiac repolarizing delayed rectifier potassium current, I(Kr). The direct interaction of the commonly used protein kinase C (PKC) inhibitor bisindolylmaleimide I (BIM I) with hERG, KvLQT1/minK, and I(Kr) currents was investigated in this study. hERG and KvLQT1/minK channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. In addition, hERG currents in stably transfected human embryonic kidney (HEK 293) cells, native I(Kr) currents and action potentials in isolated guinea pig ventricular cardiomyocytes were recorded using whole-cell patch clamp electrophysiology. Bisindolylmaleimide I blocked hERG currents in HEK 293 cells and Xenopus oocytes in a concentration-dependent manner with IC(50) values of 1.0 and 13.2 muM, respectively. hERG channels were primarily blocked in the open state in a frequency-independent manner. Analysis of the voltage-dependence of block revealed a reduction of inhibition at positive membrane potentials. BIM I caused a shift of -20.3 mV in the voltage-dependence of inactivation. The point mutations tyrosine 652 alanine (Y652A) and phenylalanine 656 alanine (F656A) attenuated hERG current blockade, indicating that BIM I binds to a common drug receptor within the pore region. KvLQT1/minK currents were not significantly altered by BIM I. Finally, 1 muM BIM I reduced native I(Kr) currents by 69.2% and lead to action potential prolongation. In summary, PKC-independent effects have to be carefully considered when using BIM I as PKC inhibitor in experimental models involving hERG channels and I(Kr) currents.

Modeling corona sheath dynamics and effects

NASA Astrophysics Data System (ADS)

Carlson, B.; Lehtinen, N. G.

2016-12-01

The conductive lightning channel is only a centimeter or so in diameter, but charge deposited along such a narrow channel produces a large electric field that drives corona discharge in nearby air, carrying the charge outward several meters. The formation of this "corona sheath" affects a wide range of observable properties of lightning, including the overall charge carried by the channel, the shape, speed, and attenuation of impulsive currents, and the possibility of x-ray production. Simplified electrostatic and electrodynamic models of the formation of the sheath will be discussed, with results given including regions near the tip of a hypothetical channel. These results suggest that the sheath initially expands very rapidly, limiting the lifetime of the intense fields nearest the channel. The expansion gradually slows as the fields decrease, but under certain circumstances a large-scale streamer-like process can lead to enhancement of electric fields displaced from the tip of the channel, possibly suggesting a mechanism for space stem formation and leader stepping.

Ca2+ regulatory mechanisms of exercise protection against coronary artery disease in metabolic syndrome and diabetes.

PubMed

Sturek, Michael

2011-08-01

Chronic exercise attenuates coronary artery disease (CAD) in humans largely independent of reductions in risk factors; thus major protective mechanisms of exercise are directly within the coronary vasculature. Further, tight control of diabetes, e.g., blood glucose, can be detrimental. Accordingly, knowledge of mechanisms by which exercise attenuates diabetic CAD could catalyze development of molecular therapies. Exercise attenuates CAD (atherosclerosis) and restenosis in miniature swine models, which enable precise control of exercise parameters (intensity, duration, and frequency) and characterization of the metabolic syndrome (MetS) and diabetic milieu. Intracellular Ca(2+) is a pivotal second messenger for coronary smooth muscle (CSM) excitation-contraction and excitation-transcription coupling that modulates CSM proliferation, migration, and calcification. CSM of diabetic dyslipidemic Yucatan swine have impaired Ca(2+) extrusion via the plasmalemma Ca(2+) ATPase (PMCA), downregulation of L-type voltage-gated Ca(2+) channels (VGCC), increased Ca(2+) sequestration by the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA), increased nuclear Ca(2+) localization, and greater activation of K channels by Ca(2+) release from the SR. Endurance exercise training prevents Ca(2+) transport changes with virtually no effect on the diabetic milieu (glucose, lipids). In MetS Ossabaw swine transient receptor potential canonical (TRPC) channels are upregulated and exercise training reverses expression and TRPC-mediated Ca(2+) influx with almost no change in the MetS milieu. Overall, exercise effects on Ca(2+) signaling modulate CSM phenotype. Future studies should 1) selectively target key Ca(2+) transporters to determine definitively their causal role in atherosclerosis and 2) combine mechanistic studies with clinical outcomes, e.g., reduction of myocardial infarction.

Correcting infrared satellite estimates of sea surface temperature for atmospheric water vapor attenuation

NASA Technical Reports Server (NTRS)

Emery, William J.; Yu, Yunyue; Wick, Gary A.; Schluessel, Peter; Reynolds, Richard W.

1994-01-01

A new satellite sea surface temperature (SST) algorithm is developed that uses nearly coincident measurements from the microwave special sensor microwave imager (SSM/I) to correct for atmospheric moisture attenuation of the infrared signal from the advanced very high resolution radiometer (AVHRR). This new SST algorithm is applied to AVHRR imagery from the South Pacific and Norwegian seas, which are then compared with simultaneous in situ (ship based) measurements of both skin and bulk SST. In addition, an SST algorithm using a quadratic product of the difference between the two AVHRR thermal infrared channels is compared with the in situ measurements. While the quadratic formulation provides a considerable improvement over the older cross product (CPSST) and multichannel (MCSST) algorithms, the SSM/I corrected SST (called the water vapor or WVSST) shows overall smaller errors when compared to both the skin and bulk in situ SST observations. Applied to individual AVHRR images, the WVSST reveals an SST difference pattern (CPSST-WVSST) similar in shape to the water vapor structure while the CPSST-quadratic SST difference appears unrelated in pattern to the nearly coincident water vapor pattern. An application of the WVSST to week-long composites of global area coverage (GAC) AVHRR data demonstrates again the manner in which the WVSST corrects the AVHRR for atmospheric moisture attenuation. By comparison the quadratic SST method underestimates the SST corrections in the lower latitudes and overestimates the SST in th e higher latitudes. Correlations between the AVHRR thermal channel differences and the SSM/I water vapor demonstrate the inability of the channel difference to represent water vapor in the midlatitude and high latitudes during summer. Compared against drifting buoy data the WVSST and the quadratic SST both exhibit the same general behavior with the relatively small differences with the buoy temperatures.

Possible role of opioids and KATP channels in neuroprotective effect of postconditioning in mice.

PubMed

Pateliya, Bharat Bhai; Singh, Nirmal; Jaggi, Amteshwar Singh

2008-09-01

The present study was designed to investigate the possible role of opioids and K(ATP) channels in ischemic postconditioning-induced reversal of global cerebral ischemia and reperfusion (I/R) induced neuronal injury. Mice were subjected to global ischemia by bilateral carotid artery occlusion for 10 min followed by reperfusion for 24 h, to produce neuronal injury. Ischemic postconditioning was induced by three episodes of carotid artery occlusion and reperfusion of 10 s each, immediately after global ischemia. Morphine postconditioning was induced by administration of morphine (5 mg/kg i.v.), 5 min prior to reperfusion. Naloxone (5 mg/kg i.v.), opioid receptor antagonist, and glibenclamide (5 mg/kg i.v.), K(ATP) channel blocker were administered 10 min before global ischemia. Extent of cerebral injury was assessed by measuring cerebral infarct size using triphenyl tetrazolium chloride (TTC) staining. Short-term memory was evaluated using the elevated plus maze test, while degree of motor incoordination was evaluated using inclined beam-walking, rota-rod and lateral push tests. Bilateral carotid artery occlusion followed by reperfusion resulted in significant increase in infarct size, impairment in short-term memory and motor co-ordination. Ischemic/morphine postconditioning significantly attenuated I/R induced neuronal injury and behavioural alterations. Pretreatments with naloxone and glibenclamide attenuated the neuroprotective effects of ischemic/morphine postconditioning. It may be concluded that ischemic/morphine postconditioning protects I/R induced cerebral injury via activating opioid receptor and K(ATP) channel opening.

Entanglement sensitivity to signal attenuation and amplification

NASA Astrophysics Data System (ADS)

Filippov, Sergey N.; Ziman, Mário

2014-07-01

We analyze general laws of continuous-variable entanglement dynamics during the deterministic attenuation and amplification of the physical signal carrying the entanglement. These processes are inevitably accompanied by noises, so we find fundamental limitations on noise intensities that destroy entanglement of Gaussian and non-Gaussian input states. The phase-insensitive amplification Φ1⊗Φ2⊗⋯ΦN with the power gain κi≥2 (≈3 dB, i =1,...,N) is shown to destroy entanglement of any N-mode Gaussian state even in the case of quantum-limited performance. In contrast, we demonstrate non-Gaussian states with the energy of a few photons such that their entanglement survives within a wide range of noises beyond quantum-limited performance for any degree of attenuation or gain. We detect entanglement preservation properties of the channel Φ1⊗Φ2, where each mode is deterministically attenuated or amplified. Gaussian states of high energy are shown to be robust to very asymmetric attenuations, whereas non-Gaussian states are at an advantage in the case of symmetric attenuation and general amplification. If Φ1=Φ2, the total noise should not exceed 1/2√κ2+1 to guarantee entanglement preservation.

Phase 9 Fiber Optic Cable Microbending and Temperature Cycling Tests

NASA Technical Reports Server (NTRS)

Abushagur, Mustafa A.G.; Huang, Po T.; Hand, Larry

1996-01-01

Optical fibers represent the back bone of the current communications networks. Their performance in the field lacks long term testing data because of the continuous evolution of the manufacturing of fibers and cables. An optical fiber cable that is installed in NASA's KSC has experienced a dramatic increase in attenuation after three years of use from 0.7 dB/km to 7 dB/km in some fibers. A thorough study is presented to assess the causes of such an attenuation increase. Material and chemical decomposition testing showed that there are no changes in the composition of the fiber which might have caused the increase in attenuation. Microbending and heat cycling tests were performed on the cable and individual fibers. It was found that the increase in attenuation is due to microbending caused by excessive stress exerted on the fibers. This was the result of manufacturing and installation irregularities.

Ethanol extract of seeds of Oenothera odorata induces vasorelaxation via endothelium-dependent NO-cGMP signaling through activation of Akt-eNOS-sGC pathway.

PubMed

Kim, Hye Yoom; Oh, Hyuncheol; Li, Xiang; Cho, Kyung Woo; Kang, Dae Gill; Lee, Ho Sub

2011-01-27

The vasorelaxant effect of ethanol extract of seeds of Oenothera odorata (Onagraceae) (one species of evening primroses) (ESOO) and its mechanisms involved were defined. Changes in vascular tension, guanosine 3',5'-cyclic monophosphate (cGMP) levels, and Akt expression were measured in carotid arterial rings from rats. Seeds of Oenothera odorata were extracted with ethanol (94%) and the extract was filtered, concentrated and stored at -70°C. ESOO relaxed endothelium-intact, but not endothelium-denuded, carotid arterial rings in a concentration-dependent manner. Similarly, ESOO increased cGMP levels of the carotid arterial rings. Pretreatment of endothelium-intact arterial rings with L-NAME, an inhibitor of nitric oxide synthase (NOS), or ODQ, an inhibitor of soluble guanylyl cyclase (sGC), blocked the ESOO-induced vasorelaxation and increase in cGMP levels. Nominally Ca(2+)-free but not L-typed Ca(2+) channel inhibition attenuated the ESOO-induced vasorelaxation. Thapsigargin, Gd(3+), and 2-aminoethyl diphenylborinate, modulators of store-operated Ca(2+) entry (SOCE), significantly attenuated the ESOO-induced vasorelaxation and increase in cGMP levels. Further, wortmannin, an inhibitor of Akt, attenuated the ESOO-induced vasorelaxation and increases in cGMP levels and phosphorylated Akt2 expression. K(+) channel blockade with TEA, 4-aminopyridine, and glibenclamide attenuated the ESOO-induced vascular relaxation. Taken together, the present study demonstrates that ESOO relaxes vascular smooth muscle via endothelium-dependent NO-cGMP signaling through activation of the Akt-eNOS-sGC pathway. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

α1- and α2-Adrenergic responsiveness in human skeletal muscle feed arteries: the role of TRPV ion channels in heat-induced sympatholysis

PubMed Central

Gifford, Jayson R.; Ives, Stephen J.; Park, Song-Young; Andtbacka, Robert H. I.; Hyngstrom, John R.; Mueller, Michelle T.; Treiman, Gerald S.; Ward, Christopher; Trinity, Joel D.

2014-01-01

The purpose of this study was to determine if heat inhibits α2-adrenergic vasocontraction, similarly to α1-adrenergic contraction, in isolated human skeletal muscle feed arteries (SMFA) and elucidate the role of the temperature-sensitive vanilloid-type transient receptor potential (TRPV) ion channels in this response. Isolated SMFA from 37 subjects were studied using wire myography. α1 [Phenylephrine (PE)]- and α2 [dexmedetomidine (DEX)]-contractions were induced at 37 and 39°C with and without TRPV family and TRPV4-specific inhibition [ruthenium red (RR) and RN-1734, respectively]. Endothelial function [acetylcholine (ACh)] and smooth muscle function [sodium nitroprusside (SNP) and potassium chloride (KCl)] were also assessed under these conditions. Heat and TRPV inhibition was further examined in endothelium-denuded arteries. Contraction data are reported as a percentage of maximal contraction elicited by 100 mM KCl (LTmax). DEX elicited a small and variable contractile response, one-fifth the magnitude of PE, which was not as clearly attenuated when heated from 37 to 39°C (12 ± 4 to 6 ± 2% LTmax; P = 0.18) as were PE-induced contractions (59 ± 5 to 24 ± 4% LTmax; P < 0.05). Both forms of TRPV inhibition restored PE-induced contraction at 39°C (P < 0.05) implicating these channels, particularly the TRPV4 channels, in the heat-induced attenuation of α1-adrenergic vasocontraction. TRPV inhibition significantly blunted ACh relaxation while denudation prevented heat-induced sympatholysis without having an additive effect when combined with TRPV inhibition. In conclusion, physiological increases in temperature elicit a sympatholysis-like inhibition of α1-adrenergic vasocontraction in human SMFA that appears to be mediated by endothelial TRPV4 ion channels. PMID:25172894

Deep convolutional neural network based antenna selection in multiple-input multiple-output system

NASA Astrophysics Data System (ADS)

Cai, Jiaxin; Li, Yan; Hu, Ying

2018-03-01

Antenna selection of wireless communication system has attracted increasing attention due to the challenge of keeping a balance between communication performance and computational complexity in large-scale Multiple-Input MultipleOutput antenna systems. Recently, deep learning based methods have achieved promising performance for large-scale data processing and analysis in many application fields. This paper is the first attempt to introduce the deep learning technique into the field of Multiple-Input Multiple-Output antenna selection in wireless communications. First, the label of attenuation coefficients channel matrix is generated by minimizing the key performance indicator of training antenna systems. Then, a deep convolutional neural network that explicitly exploits the massive latent cues of attenuation coefficients is learned on the training antenna systems. Finally, we use the adopted deep convolutional neural network to classify the channel matrix labels of test antennas and select the optimal antenna subset. Simulation experimental results demonstrate that our method can achieve better performance than the state-of-the-art baselines for data-driven based wireless antenna selection.

Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction

PubMed Central

Xu, Xiaojuan; Yano, Masafumi; Uchinoumi, Hitoshi; Hino, Akihiro; Suetomi, Takeshi; Ono, Makoto; Tateishi, Hiroki; Oda, Tetsuro; Okuda, Shinichi; Doi, Masahiro; Kobayashi, Shigeki; Yamamoto, Takeshi; Ikeda, Yasuhiro; Ikemoto, Noriaki; Matsuzaki, Masunori

2010-01-01

Calmodulin (CaM), one of the accessory proteins of the cardiac ryanodine receptor (RyR2), is known to play a significant role in the channel regulation of the RyR2. However, the possible involvement of calmodulin in the pathogenic process of catecholaminergic polymorphic ventricular tachycardia (CPVT) has not been investigated. In this study, we investigated the state of RyR2-bound CaM and channel dysfunctions using a knock-in (KI) mouse model with CPVT-linked RyR2 mutation (R2474S). Without added effectors, the affinity of CaM binding to the RyR2 was indistinguishable between KI and WT hearts. In response to cAMP (1 μmol/L), the RyR2 phosphorylation at Ser2808 increased in both WT and KI hearts to the same extent. However, cAMP caused a significant decrease of the CaM binding affinity in KI hearts, but the affinity was unchanged in WT. Dantrolene restored a normal level of CaM-binding affinity in the cAMP-treated KI hearts, suggesting that defective inter-domain interaction between the N-terminal domain and the central domain of the RyR2 (the target of therapeutic effect of dantrolene) is involved in the cAMP-induced reduction of the CaM binding affinity. In saponin-permeabilized cardiomyocytes, the addition of cAMP increased the frequency of spontaneous Ca2+ sparks to a significantly larger extent in KI cardiomyocytes than in WT cardiomyocytes, whereas the addition of a high concentration of CaM attenuated the aberrant increase of Ca2+ sparks. In conclusion, CPVT mutation causes defective inter-domain interaction, significant reduction in the ability of CaM binding to the RyR2, spontaneous Ca2+ leak, and then lethal arrhythmia. PMID:20226167

Bank-derived material dominates fluvial sediment in a suburban Chesapeake Bay watershed

NASA Astrophysics Data System (ADS)

Cashman, M. J.; Gellis, A.; Gorman-Sanisaca, L.; Noe, G. B.; Cogliandro, V.; Baker, A.

2017-12-01

Excess fine sediment is a leading cause of ecological degradation within the Chesapeake Bay watershed. The Piedmont physiographic province, which includes parts of the Washington, D.C. metro area, has the highest sediment yields in the Chesapeake Bay. In order to effectively employ sediment mitigation measures, it is necessary to identify and quantify the contributions of sediments sources within rapidly urbanizing areas in the Piedmont. This sediment fingerprinting study examines the inputs of various sediment sources to Upper Difficult Run (14.2 km2; 22.6% impervious surface), an urbanized watershed in Fairfax County, Virginia. A source sediment library was constructed from collections of stream bank material, forest soils, and road dust from across the watershed. Target fluvial sediments were collected from fine channel margin deposits and from suspended sediment using an autosampler during 16 storm events from 2008 - 2012. Apportionment of the target samples to the source sediments was performed using Sed_SAT, a publically available toolkit for sediment fingerprinting. Bed sediment was found to be dominated by stream bank sources (mean: 96%), with minor contributions from forest (4%) and no detectable contribution from roads (0%). Suspended fine sediments were also found to predominantly originate from stream bank sources (SSC-weighted mean: 91%), with minor contributions from roads (8%), and negligible contributions from forests (1%). Stream bank sources dominated at all discharges, with the greatest contributions from overland sources found only at low discharges. On the rising limb of the hydrograph and at peak flow, sediment concentrations increased due to increasing contributions of bank material rather than surface erosion caused by overland flow. Results demonstrate that stream bank erosion is responsible for the vast majority of fine sediment occurring in this suburban basin of the Chesapeake Bay watershed. This is likely a consequence of storm-water energy characteristics in urbanized watersheds resulting in channel widening and bank failure. Thus, bank stabilization, channel restoration, and/or storm water management to attenuate stream energy may improve the ecological condition of these waterbodies.

A novel inhibitor of active protein kinase G attenuates chronic inflammatory and osteoarthritic pain.

PubMed

Sung, Ying-Ju; Sofoluke, Nelson; Nkamany, Mary; Deng, Shixian; Xie, Yuli; Greenwood, Jeremy; Farid, Ramy; Landry, Donald W; Ambron, Richard T

2017-05-01

Activating PKG-1α induces a long-term hyperexcitability (LTH) in nociceptive neurons. Since the LTH correlates directly with chronic pain in many animal models, we tested the hypothesis that inhibiting PKG-1α would attenuate LTH-mediated pain. We first synthesized and characterized compound N46 (N-((3R,4R)-4-(4-(2-fluoro-3-methoxy-6-propoxybenzoyl)benzamido)pyrrolidin-3-yl)-1H-indazole-5-carboxamide). N46 inhibits PKG-1α with an IC50 of 7.5 nmol, was highly selective when tested against a panel of 274 kinases, and tissue distribution studies indicate that it does not enter the CNS. To evaluate its antinociceptive potential, we used 2 animal models in which the pain involves both activated PKG-1α and LTH. Injecting complete Freund's adjuvant (CFA) into the rat hind paw causes a thermal hyperalgesia that was significantly attenuated 24 hours after a single intravenous injection of N46. Next, we used a rat model of osteoarthritic knee joint pain and found that a single intra-articular injection of N46 alleviated the pain 14 days after the pain was established and the relief lasted for 7 days. Thermal hyperalgesia and osteoarthritic pain are also associated with the activation of the capsaicin-activated transient receptor protein vanilloid-1 (TRPV1) channel. We show that capsaicin activates PKG-1α in nerves and that a subcutaneous delivery of N46 attenuated the mechanical and thermal hypersensitivity elicited by exposure to capsaicin. Thus, PKG-1α appears to be downstream of the transient receptor protein vanilloid-1. Our studies provide proof of concept in animal models that a PKG-1α antagonist has a powerful antinociceptive effect on persistent, already existing inflammatory pain. They further suggest that N46 is a valid chemotype for the further development of such antagonists.

Regulation of inward rectifier potassium current ionic channel remodeling by AT1 -Calcineurin-NFAT signaling pathway in stretch-induced hypertrophic atrial myocytes.

PubMed

He, Jionghong; Xu, Yanan; Yang, Long; Xia, Guiling; Deng, Na; Yang, Yongyao; Tian, Ye; Fu, Zenan; Huang, Yongqi

2018-05-02

Previous studies have shown that the activation of angiotensin II receptor type I (AT 1 ) is attributed to cardiac remodeling stimulated by increased heart load, and that it is followed by the activation of the calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway. Additionally, AT 1 has been found to be a regulator of cardiocyte ionic channel remodeling, and calcineurin-NFAT signals participate in the regulation of cardiocyte ionic channel expression. A hypothesis therefore follows that stretch stimulation may regulate cardiocyte ionic channel remodeling by activating the AT 1 -calcineurin-NFAT pathway. Here, we investigated the role of the AT 1 -calcineurin-NFAT pathway in the remodeling of inward rectifier potassium (I k1 ) channel, in addition to its role in changing action potential, in stretch-induced hypertrophic atrial myocytes of neonatal rats. Our results showed that increased stretch significantly led to atrial myocytes hypertrophy; it also increased the activity of calcineurin enzymatic activity, which was subsequently attenuated by telmisartan or cyclosporine-A. The level of NFAT 3 protein in nuclear extracts, the mRNA and protein expression of Kir2.1 in whole cell extracts, and the density of I k1 were noticeably increased in stretched samples. Stretch stimulation significantly shortened the action potential duration (APD) of repolarization at the 50% and 90% level. Telmisartan, cyclosporine-A, and 11R-VIVIT attenuated stretch-induced alterations in the levels of NFAT 3 , mRNA and protein expression of Kir2.1, the density of I k1 , and the APD. Our findings suggest that the AT 1 -calcineurin-NFAT signaling pathway played an important role in regulating I k1 channel remodeling and APD change in stretch-induced hypertrophic atrial myocytes of neonatal rats. This article is protected by copyright. All rights reserved.

Upgrades to the Closed Bomb Facility and Measurement of Propellant Burning Rate

DTIC Science & Technology

2010-01-01

attenuation ratio myScope.WriteString (":CHAN1:RANGe " + CStr (Me.tbVRange.value)) ‘Sets the vertical voltage range myScope.WriteString (":CHAN1...OFFSet " + CStr (Me.tboffset.value)) ‘Sets the voltage offset myScope.WriteString ":CHAN1:PROB:STYP SING" ‘Sets the signal type...myScope.WriteString (":TRIG:EDGE:SOURce CHAN" + CStr (Int(val(GetRegistry(CollType, cCHANNEL))))) ‘Sets the source channel myScope.WriteString

Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules.

PubMed

Grimm, P Richard; Coleman, Richard; Delpire, Eric; Welling, Paul A

2017-09-01

Aberrant activation of with no lysine (WNK) kinases causes familial hyperkalemic hypertension (FHHt). Thiazide diuretics treat the disease, fostering the view that hyperactivation of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the distal convoluted tubule (DCT) is solely responsible. However, aberrant signaling in the aldosterone-sensitive distal nephron (ASDN) and inhibition of the potassium-excretory renal outer medullary potassium (ROMK) channel have also been implicated. To test these ideas, we introduced kinase-activating mutations after Lox-P sites in the mouse Stk39 gene, which encodes the terminal kinase in the WNK signaling pathway, Ste20-related proline-alanine-rich kinase (SPAK). Renal expression of the constitutively active (CA)-SPAK mutant was specifically targeted to the early DCT using a DCT-driven Cre recombinase. CA-SPAK mice displayed thiazide-treatable hypertension and hyperkalemia, concurrent with NCC hyperphosphorylation. However, thiazide-mediated inhibition of NCC and consequent restoration of sodium excretion did not immediately restore urinary potassium excretion in CA-SPAK mice. Notably, CA-SPAK mice exhibited ASDN remodeling, involving a reduction in connecting tubule mass and attenuation of epithelial sodium channel (ENaC) and ROMK expression and apical localization. Blocking hyperactive NCC in the DCT gradually restored ASDN structure and ENaC and ROMK expression, concurrent with the restoration of urinary potassium excretion. These findings verify that NCC hyperactivity underlies FHHt but also reveal that NCC-dependent changes in the driving force for potassium secretion are not sufficient to explain hyperkalemia. Instead, a DCT-ASDN coupling process controls potassium balance in health and becomes aberrantly activated in FHHt. Copyright © 2017 by the American Society of Nephrology.

More than just antibodies: protective mechanisms of a mucosal vaccine against fish pathogen Flavobacterium columnare

USDA-ARS?s Scientific Manuscript database

A recently developed attenuated vaccine (17-23) for Flavobacterium columnare has been demonstrated to provide superior protection for channel catfish, Ictalurus punctatus, against genetically diverse columnaris isolates. First, we were interested in elucidating the host responses generated by a viru...

Propagation of detonation wave in hydrogen-air mixture in channels with sound-absorbing surfaces

NASA Astrophysics Data System (ADS)

Bivol, G. Yu.; Golovastov, S. V.; Golub, V. V.

2015-12-01

The possibility of using sound-absorbing surfaces for attenuating the intensity of detonation waves propagating in hydrogen-air mixtures has been experimentally studied in a cylindrical detonation tube open at one end, with an explosive initiated by spark discharge at the closed end. Sound-absorbing elements were made of an acoustic-grade foamed rubber with density of 0.035 g/cm3 containing open pores with an average diameter of 0.5 mm. The degree of attenuation of the detonation wave front velocity was determined as dependent on the volume fraction of hydrogen in the gas mixture.

Evaluation of in-channel amperometric detection using a dual-channel microchip electrophoresis device and a two-electrode potentiostat for reverse polarity separations

PubMed Central

Meneses, Diogenes; Gunasekara, Dulan B.; Pichetsurnthorn, Pann; da Silva, José A. F.; de Abreu, Fabiane C.; Lunte, Susan M.

2015-01-01

In-channel amperometric detection combined with dual-channel microchip electrophoresis is evaluated using a two-electrode isolated potentiostat for reverse polarity separations. The device consists of two separate channels with the working and reference electrodes placed at identical positions relative to the end of the channel, enabling noise subtraction. In previous reports of this configuration, normal polarity and a three-electrode detection system were used. In the two-electrode detection system described here, the electrode in the reference channel acts as both the counter and reference. The effect of electrode placement in the channels on noise and detector response was investigated using nitrite, tyrosine, and hydrogen peroxide as model compounds. The effects of electrode material and size and type of reference electrode on noise and the potential shift of hydrodynamic voltammograms for the model compounds were determined. In addition, the performance of two- and three-electrode configurations using Pt and Ag/AgCl reference electrodes was compared. Although the signal was attenuated with the Pt reference, the noise was also significantly reduced. It was found that lower LOD were obtained for all three compounds with the dual-channel configuration compared to single-channel, in-channel detection. The dual-channel method was then used for the detection of nitrite in a dermal microdialysis sample obtained from a sheep following nitroglycerin administration. PMID:25256669

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

PubMed Central

Hinson, Shannon R.; Clift, Ian C.; Luo, Ningling; Kryzer, Thomas J.; Lennon, Vanda A.

2017-01-01

Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR’s gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG–AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO. PMID:28461494

Mechanisms of the palmitoylcarnitine-induced response in vascular endothelial cells.

PubMed

Taki, H; Muraki, K; Imaizumi, Y; Watanabe, M

1999-09-01

The mechanisms of Ca2+ mobilization induced by palmitoylcarnitine (Palcar) in rabbit aortic endothelial cells (ETCs) were examined using electrophysiological techniques. The results obtained were compared with those induced by acetylcholine (ACh). When a rabbit aortic muscle preparation with an intact endothelium was treated with 10 microM Palcar, the ACh-induced relaxation was markedly attenuated, whereas endothelium-independent relaxation caused by sodium nitroprusside was not affected. Under perforated-patch whole-cell-clamp conditions, the application of Palcar over the concentration range 0.3 and 10 microM elicited a slowly activating outward current (IPalcar-out), whereas ACh induced a rapidly activating outward current (IACh). A potassium channel blocker, 4-aminopyridine, significantly inhibited both IPalcar-out and IACh. Removal of external Ca2+ almost abolished IPalcar-out. Under the same conditions, however, IACh remained transient. Addition of cation channel blockers SK&F96365 and La3+ inhibited IPalcar-out more effectively than IACh. Application of staurosporine, an inhibitor of protein kinase C, affected neither IACh nor IPalcar-out. In contrast, treatment of ETCs with pertussis toxin (PTX) reduced IACh and almost abolished IPalcar-out. These findings demonstrate that, in ETCs, Palcar induces Ca2+ influx via the activation of PTX-sensitive GTP-binding protein, leading to the activation of Ca(2+)-dependent K+ current and hyperpolarization of the cell.

Statistical modeling of optical attenuation measurements in continental fog conditions

NASA Astrophysics Data System (ADS)

Khan, Muhammad Saeed; Amin, Muhammad; Awan, Muhammad Saleem; Minhas, Abid Ali; Saleem, Jawad; Khan, Rahimdad

2017-03-01

Free-space optics is an innovative technology that uses atmosphere as a propagation medium to provide higher data rates. These links are heavily affected by atmospheric channel mainly because of fog and clouds that act to scatter and even block the modulated beam of light from reaching the receiver end, hence imposing severe attenuation. A comprehensive statistical study of the fog effects and deep physical understanding of the fog phenomena are very important for suggesting improvements (reliability and efficiency) in such communication systems. In this regard, 6-months real-time measured fog attenuation data are considered and statistically investigated. A detailed statistical analysis related to each fog event for that period is presented; the best probability density functions are selected on the basis of Akaike information criterion, while the estimates of unknown parameters are computed by maximum likelihood estimation technique. The results show that most fog attenuation events follow normal mixture distribution and some follow the Weibull distribution.

Fibroblast growth factor 2 protects against renal ischaemia/reperfusion injury by attenuating mitochondrial damage and proinflammatory signalling.

PubMed

Tan, Xiao-Hua; Zheng, Xiao-Meng; Yu, Li-Xia; He, Jian; Zhu, Hong-Mei; Ge, Xiu-Ping; Ren, Xiao-Li; Ye, Fa-Qing; Bellusci, Saverio; Xiao, Jian; Li, Xiao-Kun; Zhang, Jin-San

2017-11-01

Ischaemia-reperfusion injury (I/RI) is a common cause of acute kidney injury (AKI). The molecular basis underlying I/RI-induced renal pathogenesis and measures to prevent or reverse this pathologic process remains to be resolved. Basic fibroblast growth factor (FGF2) is reported to have protective roles of myocardial infarction as well as in several other I/R related disorders. Herein we present evidence that FGF2 exhibits robust protective effect against renal histological and functional damages in a rat I/RI model. FGF2 treatment greatly alleviated I/R-induced acute renal dysfunction and largely blunted I/R-induced elevation in serum creatinine and blood urea nitrogen, and also the number of TUNEL-positive tubular cells in the kidney. Mechanistically, FGF2 substantially ameliorated renal I/RI by mitigating several mitochondria damaging parameters including pro-apoptotic alteration of Bcl2/Bax expression, caspase-3 activation, loss of mitochondrial membrane potential and K ATP channel integrity. Of note, the protective effect of FGF2 was significantly compromised by the K ATP channel blocker 5-HD. Interestingly, I/RI alone resulted in mild activation of FGFR, whereas FGF2 treatment led to more robust receptor activation. More significantly, post-I/RI administration of FGF2 also exhibited robust protection against I/RI by reducing cell apoptosis, inhibiting the release of damage-associated molecular pattern molecule HMBG1 and activation of its downstream inflammatory cytokines such as IL-1α, IL-6 and TNF α. Taken together, our data suggest that FGF2 offers effective protection against I/RI and improves animal survival by attenuating mitochondrial damage and HMGB1-mediated inflammatory response. Therefore, FGF2 has the potential to be used for the prevention and treatment of I/RI-induced AKI. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Heat Acclimation-Mediated Cross-Tolerance: Origins in within-Life Epigenetics?

PubMed Central

Horowitz, Michal

2017-01-01

The primary outcome of heat acclimation is increased thermotolerance, which stems from enhancement of innate cytoprotective pathways. These pathways produce “ON CALL” molecules that can combat stressors to which the body has never been exposed, via cross-tolerance mechanisms (heat acclimation-mediated cross-tolerance—HACT). The foundation of HACT lies in the sharing of generic stress signaling, combined with tissue/organ- specific protective responses. HACT becomes apparent when acclimatory homeostasis is achieved, lasts for several weeks, and has a memory. HACT differs from other forms of temporal protective mechanisms activated by exposure to lower “doses” of the stressor, which induce adaptation to higher “doses” of the same/different stressor; e.g., preconditioning, hormesis. These terms have been adopted by biochemists, toxicologists, and physiologists to describe the rapid cellular strategies ensuring homeostasis. HACT employs two major protective avenues: constitutive injury attenuation and abrupt post-insult release of help signals enhanced by acclimation. To date, the injury-attenuating features seen in all organs studied include fast-responding, enlarged cytoprotective reserves with HSPs, anti-oxidative, anti-apoptotic molecules, and HIF-1α nuclear and mitochondrial target gene products. Using cardiac ischemia and brain hypoxia models as a guide to the broader framework of phenotypic plasticity, HACT is enabled by a metabolic shift induced by HIF-1α and there are less injuries caused by Ca+2 overload, via channel or complex-protein remodeling, or decreased channel abundance. Epigenetic markers such as post-translational histone modification and altered levels of chromatin modifiers during acclimation and its decline suggest that dynamic epigenetic mechanisms controlling gene expression induce HACT and acclimation memory, to enable the rapid return of the protected phenotype. In this review the link between in vivo physiological evidence and the associated cellular and molecular mechanisms leading to HACT and its difference from short-acting cross-tolerance strategies will be discussed. PMID:28804462

Heat Acclimation-Mediated Cross-Tolerance: Origins in within-Life Epigenetics?

PubMed

Horowitz, Michal

2017-01-01

The primary outcome of heat acclimation is increased thermotolerance, which stems from enhancement of innate cytoprotective pathways. These pathways produce "ON CALL" molecules that can combat stressors to which the body has never been exposed, via cross-tolerance mechanisms (heat acclimation-mediated cross-tolerance-HACT). The foundation of HACT lies in the sharing of generic stress signaling, combined with tissue/organ- specific protective responses. HACT becomes apparent when acclimatory homeostasis is achieved, lasts for several weeks, and has a memory. HACT differs from other forms of temporal protective mechanisms activated by exposure to lower "doses" of the stressor, which induce adaptation to higher "doses" of the same/different stressor; e.g., preconditioning, hormesis. These terms have been adopted by biochemists, toxicologists, and physiologists to describe the rapid cellular strategies ensuring homeostasis. HACT employs two major protective avenues: constitutive injury attenuation and abrupt post-insult release of help signals enhanced by acclimation. To date, the injury-attenuating features seen in all organs studied include fast-responding, enlarged cytoprotective reserves with HSPs, anti-oxidative, anti-apoptotic molecules, and HIF-1α nuclear and mitochondrial target gene products. Using cardiac ischemia and brain hypoxia models as a guide to the broader framework of phenotypic plasticity, HACT is enabled by a metabolic shift induced by HIF-1α and there are less injuries caused by Ca +2 overload, via channel or complex-protein remodeling, or decreased channel abundance. Epigenetic markers such as post-translational histone modification and altered levels of chromatin modifiers during acclimation and its decline suggest that dynamic epigenetic mechanisms controlling gene expression induce HACT and acclimation memory, to enable the rapid return of the protected phenotype. In this review the link between in vivo physiological evidence and the associated cellular and molecular mechanisms leading to HACT and its difference from short-acting cross-tolerance strategies will be discussed.

Retrievals of Profiles of Fine And Coarse Aerosols Using Lidar And Radiometric Space Measurements

NASA Technical Reports Server (NTRS)

Kaufman, Yoram; Tanre, Didier; Leon, Jean-Francois; Pelon, Jacques; Lau, William K. M. (Technical Monitor)

2002-01-01

In couple of years we expect the launch of the CALIPSO lidar spaceborne mission designed to observe aerosols and clouds. CALIPSO will collect profiles of the lidar attenuated backscattering coefficients in two spectral wavelengths (0.53 and 1.06 microns). Observations are provided along the track of the satellite around the globe from pole to pole. The attenuated backscattering coefficients are sensitive to the vertical distribution of aerosol particles, their shape and size. However the information is insufficient to be mapped into unique aerosol physical properties and vertical distribution. Infinite number of physical solutions can reconstruct the same two wavelength backscattered profile measured from space. CALIPSO will fly in formation with the Aqua satellite and the MODIS spectro-radiometer on board. Spectral radiances measured by MODIS in six channels between 0.55 and 2.13 microns simultaneously with the CALIPSO observations can constrain the solutions and resolve this ambiguity, albeit under some assumptions. In this paper we describe the inversion method and apply it to aircraft lidar and MODIS data collected over a dust storm off the coast of West Africa during the SHADE experiment. It is shown that the product of the single scattering albedo, omega, and the phase function, P, for backscattering can be retrieved from the synergism between measurements avoiding a priori hypotheses required for inverting lidar measurements alone. The resultant value of (omega)P(180 deg.) = 0.016/sr are significantly different from what is expected using Mie theory, but are in good agreement with recent results obtained from lidar observations of dust episodes. The inversion is robust in the presence of noise of 10% and 20% in the lidar signal in the 0.53 and 1.06 pm channels respectively. Calibration errors of the lidar of 5 to 10% can cause an error in optical thickness of 20 to 40% respectively in the tested cases. The lidar calibration errors cause degradation in the ability to fit the MODIS data. Therefore the MODIS measurements can be used to identify the calibration problem and correct for it. The CALIPSO-MODIS measurements of the profiles of fine and coarse aerosols, together with CALIPSO measurements of clouds vertical distribution, is expected to be critically important in understanding aerosol transport across continents and political boundaries, and to study aerosol-cloud interaction and its effect on precipitation and global forcing of climate.

Mutation-induced changes of transmembrane pore size revealed by combined ion-channel conductance and single vesicle permeabilization analyses

USDA-ARS?s Scientific Manuscript database

Permeabilization of the endomembrane system by viroporins is instrumental in the progression of host-cell infection by many viral pathogens. Thus, blocking/attenuation of viroporin activity provides a generic methodology for antiviral and vaccine development. We have described that permeabilization ...

More than just antibodies: protective mechanisms of a muscosal vaccine against fish pathogen Flavobacterium columnare

USDA-ARS?s Scientific Manuscript database

A recently developed attenuated vaccine (17-23) for Flavobacterium columnare has been demonstrated to provide superior protection for channel catfish, Ictalurus punctatus, against genetically diverse columnaris isolates (Mohammed et al. 2013). We were interested in examining the mechanisms of this p...

Glyburide is associated with attenuated vasogenic edema in stroke patients

PubMed Central

Kimberly, W. Taylor; Battey, Thomas W. K.; Pham, Ly; Wu, Ona; Yoo, Albert J.; Furie, Karen L.; Singhal, Aneesh B.; Elm, Jordan J.; Stern, Barney J.; Sheth, Kevin N.

2016-01-01

Background and Purpose Brain edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death. Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 (SUR1) and transient receptor potential cation channel subfamily M member 4 (TRPM4). However, the relevance of this pathway to the development of cerebral edema in stroke patients is not known. Methods Using a case control design, we retrospectively assessed neuroimaging and blood markers of cytotoxic and vasogenic edema in subjects who were enrolled in the Glyburide Advantage in Malignant Edema and Stroke-Pilot (GAMES-Pilot) trial. We compared serial brain magnetic resonance images (MRIs) to a cohort with similar large volume infarctions. We also compared matrix metalloproteinase-9 plasma level in large hemispheric stroke. Results We report that IV glyburide was associated with attenuated T2 fluid attenuated inversion recovery (FLAIR) signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood matrix metalloproteinase-9 (MMP-9) level. Conclusions Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke. Verification of these potential imaging and blood biomarkers is warranted in the context of a randomized, placebo-controlled trial. PMID:24072459

Redirection of pyruvate flux toward desired metabolic pathways through substrate channeling between pyruvate kinase and pyruvate-converting enzymes in Saccharomyces cerevisiae.

PubMed

Kim, Sujin; Bae, Sang-Jeong; Hahn, Ji-Sook

2016-04-07

Spatial organization of metabolic enzymes allows substrate channeling, which accelerates processing of intermediates. Here, we investigated the effect of substrate channeling on the flux partitioning at a metabolic branch point, focusing on pyruvate metabolism in Saccharomyces cerevisiae. As a platform strain for the channeling of pyruvate flux, PYK1-Coh-Myc strain was constructed in which PYK1 gene encoding pyruvate kinase is tagged with cohesin domain. By using high-affinity cohesin-dockerin interaction, the pyruvate-forming enzyme Pyk1 was tethered to heterologous pyruvate-converting enzymes, lactate dehydrogenase and α-acetolactate synthase, to produce lactic acid and 2,3-butanediol, respectively. Pyruvate flux was successfully redirected toward desired pathways, with a concomitant decrease in ethanol production even without genetic attenuation of the ethanol-producing pathway. This pyruvate channeling strategy led to an improvement of 2,3-butanediol production by 38%, while showing a limitation in improving lactic acid production due to a reduced activity of lactate dehydrogenase by dockerin tagging.

Substance P Depolarizes Lamprey Spinal Cord Neurons by Inhibiting Background Potassium Channels.

PubMed

Thörn Pérez, Carolina; Hill, Russell H; Grillner, Sten

2015-01-01

Substance P is endogenously released in the adult lamprey spinal cord and accelerates the burst frequency of fictive locomotion. This is achieved by multiple effects on interneurons and motoneurons, including an attenuation of calcium currents, potentiation of NMDA currents and reduction of the reciprocal inhibition. While substance P also depolarizes spinal cord neurons, the underlying mechanism has not been resolved. Here we show that effects of substance P on background K+ channels are the main source for this depolarization. Hyperpolarizing steps induced inward currents during whole-cell voltage clamp that were reduced by substance P. These background K+ channels are pH sensitive and are selectively blocked by anandamide and AVE1231. These blockers counteracted the effect of substance P on these channels and the resting membrane potential depolarization in spinal cord neurons. Thus, we have shown now that substance P inhibits background K+ channels that in turn induce depolarization, which is likely to contribute to the frequency increase observed with substance P during fictive locomotion.

Substance P Depolarizes Lamprey Spinal Cord Neurons by Inhibiting Background Potassium Channels

PubMed Central

Thörn Pérez, Carolina; Hill, Russell H.; Grillner, Sten

2015-01-01

Substance P is endogenously released in the adult lamprey spinal cord and accelerates the burst frequency of fictive locomotion. This is achieved by multiple effects on interneurons and motoneurons, including an attenuation of calcium currents, potentiation of NMDA currents and reduction of the reciprocal inhibition. While substance P also depolarizes spinal cord neurons, the underlying mechanism has not been resolved. Here we show that effects of substance P on background K+ channels are the main source for this depolarization. Hyperpolarizing steps induced inward currents during whole-cell voltage clamp that were reduced by substance P. These background K+ channels are pH sensitive and are selectively blocked by anandamide and AVE1231. These blockers counteracted the effect of substance P on these channels and the resting membrane potential depolarization in spinal cord neurons. Thus, we have shown now that substance P inhibits background K+ channels that in turn induce depolarization, which is likely to contribute to the frequency increase observed with substance P during fictive locomotion. PMID:26197458

Physical and biogeochemical controls on light attenuation in a eutrophic, back-barrier estuary

USGS Publications Warehouse

Ganju, Neil K.; Miselis, Jennifer L.; Aretxabaleta, Alfredo L.

2014-01-01

Light attenuation is a critical parameter governing the ecological function of shallow estuaries. In these systems primary production is often dominated by benthic macroalgae and seagrass; thus light penetration to the bed is of primary importance. We quantified light attenuation in three seagrass meadows in Barnegat Bay, New Jersey, a shallow eutrophic back-barrier estuary; two of the sites were located within designated Ecologically Sensitive Areas (ESAs). We sequentially deployed instrumentation measuring photosynthetically active radiation, chlorophyll-a (chl-a) fluorescence, dissolved organic matter fluorescence (fDOM; a proxy for colored DOM absorbance), turbidity, pressure, and water velocity at 10 min intervals over three week periods at each site. At the southernmost site, where sediment availability was highest, light attenuation was highest and dominated by turbidity and to a lesser extent chl-a and CDOM. At the central site, chl-a dominated followed by turbidity and CDOM, and at the northernmost site turbidity and CDOM contributed equally to light attenuation. At a given site, the temporal variability of light attenuation exceeded the difference in median light attenuation at the three sites, indicating the need for continuous high-temporal resolution measurements. Vessel wakes, anecdotally implicated in increasing sediment resuspension, did not contribute to local resuspension within the seagrass beds, though frequent vessel wakes were observed in the channels. With regards to light attenuation and water clarity, physical and biogeochemical variables appear to outweigh any regulation of boat traffic within the ESAs.

Tadalafil attenuates hypotonicity-induced Ca2+ influx via TRPV2 and TRPV4 in primary rat bladder urothelial cell cultures.

PubMed

Dong, Xiao; Nakagomi, Hiroshi; Miyamoto, Tatsuya; Ihara, Tatsuya; Kira, Satoru; Sawada, Norifumi; Mitsui, Takahiko; Takeda, Masayuki

2018-03-22

To investigate the localization of phosphodiesterase 5 (PDE5) and the molecular mechanism underlying the effect of the PDE5 inhibitor tadalafil in signal transduction in the bladder urothelium. PDE5 expression in rat bladder tissues and cultured primary rat bladder urothelial cells was evaluated using immunochemistry and western blot assays. Ca 2+ influx in cells exposed to isotonic solution, hypotonic solution, a selective transient receptor potential vanilloid 2 (TRPV2) channel agonist (cannabidiol), a selective TRPV4 channel agonist (GSK1016790A), a TRP cation channel melastatin 7 (TRPM7) channel agonist (PIP2), or a purinergic receptor agonist (ATP) in the presence or absence of 10 µM tadalafil was evaluated using calcium imaging techniques. We also evaluated stretch-induced changes in ATP concentration in the mouse bladder in the presence or absence of 100 µM tadalafil. Immunochemistry and western blot analyses demonstrated that PDE5 is abundantly expressed in the bladder urothelium and in primary rat urothelial cells. Ca 2+ influx induced by hypotonic stimulation, GSK1016790A, or cannabidiol was significantly inhibited by tadalafil, whereas ATP-induced Ca 2+ influx was unaffected by tadalafil. PIP2 did not induce Ca2+ influx. ATP release in tadalafil-pretreated bladders significantly decreased compared to control bladders. Tadalafil attenuates Ca 2+ influx via TRPV4 and TRPV2, and inhibits ATP release in the bladder urothelium. These findings indicate that tadalafil functions as an inhibitor of urothelial signal transduction. © 2018 Wiley Periodicals, Inc.

Minoxidil opens mitochondrial KATP channels and confers cardioprotection

PubMed Central

Sato, Toshiaki; Li, Yulong; Saito, Tomoaki; Nakaya, Haruaki

2003-01-01

ATP-sensitive potassium channel in the mitochondrial inner membrane (mitoKATP channel) rather than in the sarcolemma (sarcKATP channel) appears to play an important role in cardioprotection. We examined the effect of minoxidil, a potent antihypertensive agent and hair growth stimulator, on sarcKATP and mitoKATP channels in guinea-pig ventricular myocytes. Minoxidil activated a glybenclamide-sensitive sarcKATP channel current in the whole-cell recording mode with an EC50 of 182.6 μM. Minoxidil reversibly increased the flavoprotein oxidation, an index of mitoKATP channel activity, in a concentration-dependent manner. The EC50 for mitoKATP channel activation was estimated to be 7.3 μM; this value was notably ≈25-fold lower than that for sarcKATP channel activation. Minoxidil (10 μM) significantly attenuated the ouabain-induced increase of mitochondrial Ca2+ concentration, which was measured by loading cells with rhod-2 fluorescence. Furthermore, pretreatment with minoxidil (10 μM) before 20-min no-flow ischaemia significantly improved the recovery of developed tension measured after 60 min of reperfusion in coronary perfused guinea-pig ventricular muscles. These cardioprotective effects of minoxidil were completely abolished by the mitoKATP channel blocker 5-hydroxydecanoate (500 μM). Our results indicate that minoxidil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by the selective activation of mitoKATP channels. PMID:14691056

Minoxidil opens mitochondrial K(ATP) channels and confers cardioprotection.

PubMed

Sato, Toshiaki; Li, Yulong; Saito, Tomoaki; Nakaya, Haruaki

2004-01-01

1. ATP-sensitive potassium channel in the mitochondrial inner membrane (mitoK(ATP) channel) rather than in the sarcolemma (sarcK(ATP) channel) appears to play an important role in cardioprotection. We examined the effect of minoxidil, a potent antihypertensive agent and hair growth stimulator, on sarcK(ATP) and mitoK(ATP) channels in guinea-pig ventricular myocytes. 2. Minoxidil activated a glybenclamide-sensitive sarcK(ATP) channel current in the whole-cell recording mode with an EC(50) of 182.6 microm. Minoxidil reversibly increased the flavoprotein oxidation, an index of mitoK(ATP) channel activity, in a concentration-dependent manner. The EC(50) for mitoK(ATP) channel activation was estimated to be 7.3 microm; this value was notably approximately 25-fold lower than that for sarcK(ATP) channel activation. 3. Minoxidil (10 microm) significantly attenuated the ouabain-induced increase of mitochondrial Ca(2+) concentration, which was measured by loading cells with rhod-2 fluorescence. Furthermore, pretreatment with minoxidil (10 microm) before 20-min no-flow ischaemia significantly improved the recovery of developed tension measured after 60 min of reperfusion in coronary perfused guinea-pig ventricular muscles. These cardioprotective effects of minoxidil were completely abolished by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microm). 4. Our results indicate that minoxidil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by the selective activation of mitoK(ATP) channels.

Characterizing ultraviolet and infrared observational properties for galaxies. II. Features of attenuation law

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mao, Ye-Wei; Kong, Xu; Lin, Lin, E-mail: ywmao@pmo.ac.cn, E-mail: xkong@ustc.edu.cn, E-mail: linlin@shao.ac.cn

Variations in the attenuation law have a significant impact on observed spectral energy distributions for galaxies. As one important observational property for galaxies at ultraviolet and infrared wavelength bands, the correlation between infrared-to-ultraviolet luminosity ratio and ultraviolet color index (or ultraviolet spectral slope), i.e., the IRX-UV relation (or IRX-β relation), offered a widely used formula for correcting dust attenuation in galaxies, but the usability appears to be in doubt now because of considerable dispersion in this relation found by many studies. In this paper, on the basis of spectral synthesis modeling and spatially resolved measurements of four nearby spiral galaxies,more » we provide an interpretation of the deviation in the IRX-UV relation with variations in the attenuation law. From both theoretical and observational viewpoints, two components in the attenuation curve, the linear background and the 2175 Å bump, are suggested to be the parameters in addition to the stellar population age (addressed in the first paper of this series) in the IRX-UV function; different features in the attenuation curve are diagnosed for the galaxies in our sample. Nevertheless, it is often difficult to ascertain the attenuation law for galaxies in actual observations. Possible reasons for preventing the successful detection of the parameters in the attenuation curve are also discussed in this paper, including the degeneracy of the linear background and the 2175 Å bump in observational channels, the requirement for young and dust-rich systems to study, and the difficulty in accurate estimates of dust attenuations at different wavelength bands.« less

Characterizing Ultraviolet and Infrared Observational Properties for Galaxies. II. Features of Attenuation Law

NASA Astrophysics Data System (ADS)

Mao, Ye-Wei; Kong, Xu; Lin, Lin

2014-07-01

Variations in the attenuation law have a significant impact on observed spectral energy distributions for galaxies. As one important observational property for galaxies at ultraviolet and infrared wavelength bands, the correlation between infrared-to-ultraviolet luminosity ratio and ultraviolet color index (or ultraviolet spectral slope), i.e., the IRX-UV relation (or IRX-β relation), offered a widely used formula for correcting dust attenuation in galaxies, but the usability appears to be in doubt now because of considerable dispersion in this relation found by many studies. In this paper, on the basis of spectral synthesis modeling and spatially resolved measurements of four nearby spiral galaxies, we provide an interpretation of the deviation in the IRX-UV relation with variations in the attenuation law. From both theoretical and observational viewpoints, two components in the attenuation curve, the linear background and the 2175 Å bump, are suggested to be the parameters in addition to the stellar population age (addressed in the first paper of this series) in the IRX-UV function; different features in the attenuation curve are diagnosed for the galaxies in our sample. Nevertheless, it is often difficult to ascertain the attenuation law for galaxies in actual observations. Possible reasons for preventing the successful detection of the parameters in the attenuation curve are also discussed in this paper, including the degeneracy of the linear background and the 2175 Å bump in observational channels, the requirement for young and dust-rich systems to study, and the difficulty in accurate estimates of dust attenuations at different wavelength bands.

Tests of peak flow scaling in simulated self-similar river networks

USGS Publications Warehouse

Menabde, M.; Veitzer, S.; Gupta, V.; Sivapalan, M.

2001-01-01

The effect of linear flow routing incorporating attenuation and network topology on peak flow scaling exponent is investigated for an instantaneously applied uniform runoff on simulated deterministic and random self-similar channel networks. The flow routing is modelled by a linear mass conservation equation for a discrete set of channel links connected in parallel and series, and having the same topology as the channel network. A quasi-analytical solution for the unit hydrograph is obtained in terms of recursion relations. The analysis of this solution shows that the peak flow has an asymptotically scaling dependence on the drainage area for deterministic Mandelbrot-Vicsek (MV) and Peano networks, as well as for a subclass of random self-similar channel networks. However, the scaling exponent is shown to be different from that predicted by the scaling properties of the maxima of the width functions. ?? 2001 Elsevier Science Ltd. All rights reserved.

Allosteric Modulation of Ca2+ flux in Ligand-gated Cation Channel (P2X4) by Actions on Lateral Portals*

PubMed Central

Samways, Damien S. K.; Khakh, Baljit S.; Egan, Terrance M.

2012-01-01

Human P2X receptors are a family of seven ATP-gated ion channels that transport Na+, K+, and Ca2+ across cell surface membranes. The P2X4 receptor is unique among family members in its sensitivity to the macrocyclic lactone, ivermectin, which allosterically modulates both ion conduction and channel gating. In this paper we show that removing the fixed negative charge of a single acidic amino acid (Glu51) in the lateral entrance to the transmembrane pore markedly attenuates the effect of ivermectin on Ca2+ current and channel gating. Ca2+ entry through P2X4 receptors is known to trigger downstream signaling pathways in microglia. Our experiments show that the lateral portals could present a novel target for drugs in the treatment of microglia-associated disease including neuropathic pain. PMID:22219189

Gaussian States Minimize the Output Entropy of One-Mode Quantum Gaussian Channels

NASA Astrophysics Data System (ADS)

De Palma, Giacomo; Trevisan, Dario; Giovannetti, Vittorio

2017-04-01

We prove the long-standing conjecture stating that Gaussian thermal input states minimize the output von Neumann entropy of one-mode phase-covariant quantum Gaussian channels among all the input states with a given entropy. Phase-covariant quantum Gaussian channels model the attenuation and the noise that affect any electromagnetic signal in the quantum regime. Our result is crucial to prove the converse theorems for both the triple trade-off region and the capacity region for broadcast communication of the Gaussian quantum-limited amplifier. Our result extends to the quantum regime the entropy power inequality that plays a key role in classical information theory. Our proof exploits a completely new technique based on the recent determination of the p →q norms of the quantum-limited amplifier [De Palma et al., arXiv:1610.09967]. This technique can be applied to any quantum channel.

Gaussian States Minimize the Output Entropy of One-Mode Quantum Gaussian Channels.

PubMed

De Palma, Giacomo; Trevisan, Dario; Giovannetti, Vittorio

2017-04-21

We prove the long-standing conjecture stating that Gaussian thermal input states minimize the output von Neumann entropy of one-mode phase-covariant quantum Gaussian channels among all the input states with a given entropy. Phase-covariant quantum Gaussian channels model the attenuation and the noise that affect any electromagnetic signal in the quantum regime. Our result is crucial to prove the converse theorems for both the triple trade-off region and the capacity region for broadcast communication of the Gaussian quantum-limited amplifier. Our result extends to the quantum regime the entropy power inequality that plays a key role in classical information theory. Our proof exploits a completely new technique based on the recent determination of the p→q norms of the quantum-limited amplifier [De Palma et al., arXiv:1610.09967]. This technique can be applied to any quantum channel.

Comparative effects of valsartan in combination with cilnidipine or amlodipine on cardiac remodeling and diastolic dysfunction in Dahl salt-sensitive rats.

PubMed

Nagasawa, Kai; Takahashi, Keiji; Matsuura, Natsumi; Takatsu, Miwa; Hattori, Takuya; Watanabe, Shogo; Harada, Eri; Niinuma, Kazumi; Murohara, Toyoaki; Nagata, Kohzo

2015-01-01

Angiotensin receptor blockers (ARBs) are often supplemented with calcium channel blockers (CCBs) for treatment of hypertension. We recently showed that the L/N-type CCB cilnidipine has superior cardioprotective effects compared with the L-type CCB amlodipine in Dahl salt-sensitive (DS) rats. We have now compared the effects of the ARB valsartan combined with cilnidipine or amlodipine on cardiac pathophysiology in DS rats. DS rats fed a high-salt diet from 6 weeks of age were treated with vehicle, valsartan alone (10 mg kg(-1) per day), or valsartan combined with either cilnidipine (1 mg kg(-1) per day) or amlodipine (1 mg kg(-1) per day) from 7 to 11 weeks. The salt-induced increase in systolic blood pressure apparent in the vehicle group was attenuated similarly in the three drug treatment groups. Valsartan-cilnidipine attenuated left ventricular (LV) fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation to a greater extent than did valsartan alone or valsartan-amlodipine. In addition, the increases in urinary excretion of dopamine and epinephrine as well as in cardiac renin-angiotensin-aldosterone-system (RAAS) gene expression apparent in vehicle-treated rats were attenuated to a greater extent by valsartan-cilnidipine than by the other two treatments. Valsartan-cilnidipine thus attenuated LV remodeling and diastolic dysfunction more effectively than did valsartan or valsartan-amlodipine in rats with salt-sensitive hypertension, and this superior cardioprotective action of valsartan-cilnidipine compared with valsartan-amlodipine is likely attributable, at least in part, to the greater antioxidant and antiinflammatory effects associated with both greater inhibition of cardiac RAAS gene expression and N-type calcium channel blockade.

Ca(2+)-activated K(+) channel-3.1 blocker TRAM-34 attenuates airway remodeling and eosinophilia in a murine asthma model.

PubMed

Girodet, Pierre-Olivier; Ozier, Annaig; Carvalho, Gabrielle; Ilina, Olga; Ousova, Olga; Gadeau, Alain-Pierre; Begueret, Hugues; Wulff, Heike; Marthan, Roger; Bradding, Peter; Berger, Patrick

2013-02-01

Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K(+) channel K(Ca)3.1 is expressed by many cells implicated in the pathogenesis of asthma, and is involved in both inflammatory and remodeling responses in a number of tissues. The specific K(Ca)3.1 blocker 5-[(2-chlorophenyl)(diphenyl)methyl]-1H-pyrazole (TRAM-34) attenuates BSM cell proliferation, and both mast cell and fibrocyte recruitment in vitro. We aimed to examine the effects of K(Ca)3.1 blockade on BSM remodeling, airway inflammation, and BHR in a murine model of chronic asthma. BALB/c mice were sensitized with intraperitoneal ovalbumin (OVA) on Days 0 and 14, and then challenged with intranasal OVA during Days 14-75. OVA-sensitized/challenged mice received TRAM-34 (120 mg/kg/day, subcutaneous) from Days -7 to 75 (combined treatment), Days -7 to 20 (preventive treatment), or Days 21 to 75 (curative treatment). Untreated mice received daily injections of vehicle (n = 8 per group). Bronchial remodeling was assessed by histological and immunohistochemical analyses. Inflammation was evaluated using bronchoalveolar lavage and flow cytometry. We also determined BHR in both conscious and anesthetized mice via plethysmography. We demonstrated that curative treatment with TRAM-34 abolishes BSM remodeling and subbasement collagen deposition, and attenuates airway eosinophilia. Although curative treatment alone did not significantly reduce BHR, the combined treatment attenuated nonspecific BHR to methacholine. This study indicates that K(Ca)3.1 blockade could provide a new therapeutic strategy in asthma.

Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.

PubMed

Kruse, Martin; Schulze-Bahr, Eric; Corfield, Valerie; Beckmann, Alf; Stallmeyer, Birgit; Kurtbay, Güven; Ohmert, Iris; Schulze-Bahr, Ellen; Brink, Paul; Pongs, Olaf

2009-09-01

Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, we identified the mutation c.19G-->A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. This mutation predicted the amino acid substitution p.E7K in the TRPM4 amino terminus. TRPM4 encodes a Ca2+-activated nonselective cation (CAN) channel that belongs to the transient receptor potential melastatin ion channel family. Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers. Cellular expression studies showed that the c.19G-->A missense mutation attenuated deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface. Our data therefore revealed a gain-of-function mechanism underlying this type of familial heart block.

Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I

PubMed Central

Kruse, Martin; Schulze-Bahr, Eric; Corfield, Valerie; Beckmann, Alf; Stallmeyer, Birgit; Kurtbay, Güven; Ohmert, Iris; Schulze-Bahr, Ellen; Brink, Paul; Pongs, Olaf

2009-01-01

Progressive familial heart block type I (PFHBI) is a progressive cardiac bundle branch disease in the His-Purkinje system that exhibits autosomal-dominant inheritance. In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of PFHBI, we identified the mutation c.19G→A in the transient receptor potential cation channel, subfamily M, member 4 gene (TRPM4) at chromosomal locus 19q13.3. This mutation predicted the amino acid substitution p.E7K in the TRPM4 amino terminus. TRPM4 encodes a Ca2+-activated nonselective cation (CAN) channel that belongs to the transient receptor potential melastatin ion channel family. Quantitative analysis of TRPM4 mRNA content in human cardiac tissue showed the highest expression level in Purkinje fibers. Cellular expression studies showed that the c.19G→A missense mutation attenuated deSUMOylation of the TRPM4 channel. The resulting constitutive SUMOylation of the mutant TRPM4 channel impaired endocytosis and led to elevated TRPM4 channel density at the cell surface. Our data therefore revealed a gain-of-function mechanism underlying this type of familial heart block. PMID:19726882

Design and expected performance of a fast neutron attenuation probe for light element density measurements

DOE PAGES

Sweany, M.; Marleau, P.

2016-07-08

In this paper, we present the design and expected performance of a proof-of-concept 32 channel material identification system. Our system is based on the energy-dependent attenuation of fast neutrons for four elements: hydrogen, carbon, nitrogen and oxygen. We describe a new approach to obtaining a broad range of neutron energies to probe a sample, as well as our technique for reconstructing the molar densities within a sample. The system's performance as a function of time-of-flight energy resolution is explored using a Geant4-based Monte Carlo. Our results indicate that, with the expected detector response of our system, we will be ablemore » to determine the molar density of all four elements to within a 20–30% accuracy in a two hour scan time. In many cases this error is systematically low, thus the ratio between elements is more accurate. This degree of accuracy is enough to distinguish, for example, a sample of water from a sample of pure hydrogen peroxide: the ratio of oxygen to hydrogen is reconstructed to within 8±0.5% of the true value. Lastly, with future algorithm development that accounts for backgrounds caused by scattering within the sample itself, the accuracy of molar densities, not ratios, may improve to the 5–10% level for a two hour scan time.« less

Prevention of Phenytoin-Induced Gingival Overgrowth by Lovastatin in Mice

PubMed Central

Assaggaf, Mohammad A.; Kantarci, Alpdogan; Sume, Siddika S.; Trackman, Philip C.

2016-01-01

Drug-induced gingival overgrowth is caused by the antiseizure medication phenytoin, calcium channel blockers, and ciclosporin. Characteristics of these drug-induced gingival overgrowth lesions differ. We evaluate the ability of a mouse model to mimic human phenytoin-induced gingival overgrowth and assess the ability of a drug to prevent its development. Lovastatin was chosen based on previous analyses of tissue-specific regulation of CCN2 production in human gingival fibroblasts and the known roles of CCN2 in promoting fibrosis and epithelial to mesenchymal transition. Data indicate that anterior gingival tissue overgrowth occurred in phenytoin-treated mice based on gross tissue observations and histomorphometry of tissue sections. Molecular markers of epithelial plasticity and fibrosis were regulated by phenytoin in gingival epithelial tissues and in connective tissues similar to that seen in humans. Lovastatin attenuated epithelial gingival tissue growth in phenytoin-treated mice and altered the expressions of markers for epithelial to mesenchymal transition. Data indicate that phenytoin-induced gingival overgrowth in mice mimics molecular aspects of human gingival overgrowth and that lovastatin normalizes the tissue morphology and the expression of the molecular markers studied. Data are consistent with characterization of phenytoin-induced human gingival overgrowth in vivo and in vitro characteristics of cultured human gingival epithelial and connective tissue cells. Findings suggest that statins may serve to prevent or attenuate phenytoin-induced human gingival overgrowth, although specific human studies are required. PMID:25843680

Quantitative cardiac SPECT reconstruction with reduced image degradation due to patient anatomy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsui, B.M.W.; Zhao, X.D.; Gregoriou, G.K.

1994-12-01

Patient anatomy has complicated effects on cardiac SPECT images. The authors investigated reconstruction methods which substantially reduced these effects for improved image quality. A 3D mathematical cardiac-torso (MCAT) phantom which models the anatomical structures in the thorax region were used in the study. The phantom was modified to simulate variations in patient anatomy including regions of natural thinning along the myocardium, body size, diaphragmatic shape, gender, and size and shape of breasts for female patients. Distributions of attenuation coefficients and Tl-201 uptake in different organs in a normal patient were also simulated. Emission projection data were generated from the phantomsmore » including effects of attenuation and detector response. The authors have observed the attenuation-induced artifacts caused by patient anatomy in the conventional FBP reconstructed images. Accurate attenuation compensation using iterative reconstruction algorithms and attenuation maps substantially reduced the image artifacts and improved quantitative accuracy. They conclude that reconstruction methods which accurately compensate for non-uniform attenuation can substantially reduce image degradation caused by variations in patient anatomy in cardiac SPECT.« less

Strain sensing using optical fibers

NASA Technical Reports Server (NTRS)

Houghton, Richard; Hiles, Steven

1994-01-01

The main source of attenuation which will be studied is the optical fiber's sensitivity to bending at radii that are much larger than the radius of the fiber. This type of environmental attenuation causes losses that are a function of the severity of the bend. The average attenuation caused by bending varies exponentially with the bend radius. There are many different fibers, sources, and testing equipment available. This thesis describes tests that were performed to evaluate the variables that effect bending related attenuation and will discuss the consistency of the results. Descriptions and comparisons will be made between single mode and multimode fibers as well as instrumentation comparisons between detection equipment. Detailed analysis of the effects of the whispering gallery mode will be performed along with theorized methods for characterization of these modes.

Quantum hacking: Saturation attack on practical continuous-variable quantum key distribution

NASA Astrophysics Data System (ADS)

Qin, Hao; Kumar, Rupesh; Alléaume, Romain

2016-07-01

We identify and study a security loophole in continuous-variable quantum key distribution (CVQKD) implementations, related to the imperfect linearity of the homodyne detector. By exploiting this loophole, we propose an active side-channel attack on the Gaussian-modulated coherent-state CVQKD protocol combining an intercept-resend attack with an induced saturation of the homodyne detection on the receiver side (Bob). We show that an attacker can bias the excess noise estimation by displacing the quadratures of the coherent states received by Bob. We propose a saturation model that matches experimental measurements on the homodyne detection and use this model to study the impact of the saturation attack on parameter estimation in CVQKD. We demonstrate that this attack can bias the excess noise estimation beyond the null key threshold for any system parameter, thus leading to a full security break. If we consider an additional criterion imposing that the channel transmission estimation should not be affected by the attack, then the saturation attack can only be launched if the attenuation on the quantum channel is sufficient, corresponding to attenuations larger than approximately 6 dB. We moreover discuss the possible countermeasures against the saturation attack and propose a countermeasure based on Gaussian postselection that can be implemented by classical postprocessing and may allow one to distill the secret key when the raw measurement data are partly saturated.

Origin of the Strain Sensitivity for an Organic Heptazole Thin-Film and Its Strain Gauge Application

NASA Astrophysics Data System (ADS)

Bae, Heesun; Jeon, Pyo Jin; Park, Ji Hoon; Lee, Kimoon

2018-04-01

The authors report on the origin of the strain sensitivity for an organic C26H16N2 (heptazole) thinfilm and its application for the detection of tensile strain. From the electrical characterization on the thin-film transistor adopting a heptazole channel, heptazole film exhibits p-channel conduction with a relatively low value of field-effect mobility (0.05 cm2/Vs), suggesting a hopping conduction behavior via hole carriers. By analyzing the strain and temperature dependences of the electrical conductivity, we reveal that the electrical conduction for a heptazole thin-film is dominated by the variable range hopping process with quite a large energy separation (224.9 meV) between the localized states under a relatively long attenuation length (10.46 Å). This indicates that a change in the inter-grain spacing that is much larger than the attenuation length is responsible for the reversible modification of electrical conductivity depending on strain for the heptazole film. By utilizing our heptazole thin-film both as a strain sensitive passive resistor and an active semiconducting channel layer, we can achieve a strain gauge device exhibiting reversible endurance for tensile strains up to 2.12%. Consequently, this study advances the understanding of the fundamental strain sensing mechanism in a heptazole thin-film toward finding a promise material with a strain gauge for applications as potential flexible devices and/or wearable electronics.

Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation.

PubMed

Lin, Yun; Zhang, Jian-Cheng; Fu, Jun; Chen, Fang; Wang, Jie; Wu, Zhi-Lin; Yuan, Shi-Ying

2013-02-01

Hyperforin, a lipophilic constituent of medicinal herb St John's wort, has been identified as the main active ingredient of St John's wort extract for antidepressant action by experimental and clinical studies. Hyperforin is currently known to activate transient receptor potential canonical (subtype) 6 (TRPC6) channel, increase the phosphorylated CREB (p-CREB), and has N-methyl-D-aspartate receptor-antagonistic effect that convert potential neuroprotective effects in vitro. However, the protective effects of hyperforin on ischemic stroke in vivo remain controversial and its neuroprotective mechanisms are still unclear. This study was designed to examine the effects of intracerebroventricular (i.c.v.) injection of hyperforin on transient focal cerebral ischemia in rats. Hyperforin, when applied immediately after middle cerebral artery occlusion (MCAO) onset, significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores at 24 hours after reperfusion accompanied by elevated TRPC6 and p-CREB activity and decreased SBDP145 activity. When MEK or CaMKIV activity was specifically inhibited, the neuroprotective effect of hyperforin was attenuated, and we observed a correlated decrease in CREB activity. In conclusion, our results clearly showed that i.c.v. injection of hyperforin immediately after MCAO onset blocked calpain-mediated TRPC6 channels degradation, and then to stimulate the Ras/MEK/ERK and CaMKIV pathways that converge on CREB activation, contributed to neuroprotection.

Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation

PubMed Central

Lin, Yun; Zhang, Jian-Cheng; Fu, Jun; Chen, Fang; Wang, Jie; Wu, Zhi-Lin; Yuan, Shi-Ying

2013-01-01

Hyperforin, a lipophilic constituent of medicinal herb St John's wort, has been identified as the main active ingredient of St John's wort extract for antidepressant action by experimental and clinical studies. Hyperforin is currently known to activate transient receptor potential canonical (subtype) 6 (TRPC6) channel, increase the phosphorylated CREB (p-CREB), and has N-methyl-𝒟-aspartate receptor-antagonistic effect that convert potential neuroprotective effects in vitro. However, the protective effects of hyperforin on ischemic stroke in vivo remain controversial and its neuroprotective mechanisms are still unclear. This study was designed to examine the effects of intracerebroventricular (ICV) injection of hyperforin on transient focal cerebral ischemia in rats. Hyperforin, when applied immediately after middle cerebral artery occlusion (MCAO) onset, significantly reduced infarct volumes and apoptotic cells, and also increased neurologic scores at 24 hours after reperfusion accompanied by elevated TRPC6 and p-CREB activity and decreased SBDP145 activity. When MEK or CaMKIV activity was specifically inhibited, the neuroprotective effect of hyperforin was attenuated, and we observed a correlated decrease in CREB activity. In conclusion, our results clearly showed that ICV injection of hyperforin immediately after MCAO onset blocked calpain-mediated TRPC6 channels degradation, and then to stimulate the Ras/MEK/ERK and CaMKIV pathways that converge on CREB activation, contributed to neuroprotection. PMID:23149561

TRPC5-eNOS Axis Negatively Regulates ATP-Induced Cardiomyocyte Hypertrophy.

PubMed

Sunggip, Caroline; Shimoda, Kakeru; Oda, Sayaka; Tanaka, Tomohiro; Nishiyama, Kazuhiro; Mangmool, Supachoke; Nishimura, Akiyuki; Numaga-Tomita, Takuro; Nishida, Motohiro

2018-01-01

Cardiac hypertrophy, induced by neurohumoral factors, including angiotensin II and endothelin-1, is a major predisposing factor for heart failure. These ligands can induce hypertrophic growth of neonatal rat cardiomyocytes (NRCMs) mainly through Ca 2+ -dependent calcineurin/nuclear factor of activated T cell (NFAT) signaling pathways activated by diacylglycerol-activated transient receptor potential canonical 3 and 6 (TRPC3/6) heteromultimer channels. Although extracellular nucleotide, adenosine 5'-triphosphate (ATP), is also known as most potent Ca 2+ -mobilizing ligand that acts on purinergic receptors, ATP never induces cardiomyocyte hypertrophy. Here we show that ATP-induced production of nitric oxide (NO) negatively regulates hypertrophic signaling mediated by TRPC3/6 channels in NRCMs. Pharmacological inhibition of NO synthase (NOS) potentiated ATP-induced increases in NFAT activity, protein synthesis, and transcriptional activity of brain natriuretic peptide. ATP significantly increased NO production and protein kinase G (PKG) activity compared to angiotensin II and endothelin-1. We found that ATP-induced Ca 2+ signaling requires inositol 1,4,5-trisphosphate (IP 3 ) receptor activation. Interestingly, inhibition of TRPC5, but not TRPC6 attenuated ATP-induced activation of Ca 2+ /NFAT-dependent signaling. As inhibition of TRPC5 attenuates ATP-stimulated NOS activation, these results suggest that NO-cGMP-PKG axis activated by IP 3 -mediated TRPC5 channels underlies negative regulation of TRPC3/6-dependent hypertrophic signaling induced by ATP stimulation.

Calculation Of Pneumatic Attenuation In Pressure Sensors

NASA Technical Reports Server (NTRS)

Whitmore, Stephen A.

1991-01-01

Errors caused by attenuation of air-pressure waves in narrow tubes calculated by method based on fundamental equations of flow. Changes in ambient pressure transmitted along narrow tube to sensor. Attenuation of high-frequency components of pressure wave calculated from wave equation derived from Navier-Stokes equations of viscous flow in tube. Developed to understand and compensate for frictional attenuation in narrow tubes used to connect aircraft pressure sensors with pressure taps on affected surfaces.

Initial results from the VPI&SU SIRIO diversity experiment

NASA Technical Reports Server (NTRS)

Towner, G. C.; Marshall, R. E.; Stutzman, W. L.; Bostian, C. W.; Pratt, T.; Manus, E. A.; Wiley, P. H.

1982-01-01

The first year of observations of the precipitation effects on the 11.6-GHz beacon signal from the SIRIO satellite are reported. This experiment is unique in that it uses dual-polarized receivers in a diversity configuration and a low path elevation angle. Rain rate, attenuation, and isolation statistics are presented for both sites. In addition, attenuation diversity gain is plotted and compared to current models. Isolation diversity gain is also discussed. It was found that little improvement in dual-channel isolation is obtained with site diversity at this low elevation angle. The influence of ice clouds was noted in the months of October and November.

Assessing the influence of artificially constructed channels in the growth of afforested black mangrove (Avicennia germinans) within an arid coastal region.

PubMed

Flores-Verdugo, F; Zebadua-Penagos, F; Flores-de-Santiago, F

2015-09-01

Hypersaline conditions are common in sub-tropical latitudes where freshwater availability is seasonal. Hence, hydroperiod plays a crucial role in providing a suitable area for the establishment of new mangrove seedlings. The purpose of this study was to assess the function of hydrological change and irradiance in the growth of afforested black mangrove (Avicennia germinans) along the upper saltpan area by creating six channels of 1 m wide by 0.3 deep and 30 m length. All channels were constructed perpendicular to the main coastline of the Urias lagoon, Pacific coast of Mexico. Seedlings of black mangrove were planted along four of the channels. After ten months, the pore-water salinity concentration within the six channels was reduced by half. Results indicate that there were no significant differences (P > 0.05) in mangrove survival among the channels. However, the optimal growth of black mangroves was near the channels edge. The growth of mangrove seedlings planted under 50% of solar attenuation was 10 times higher as compared to mangroves under direct sunlight. This study shows the feasibility of using channels to enhance tidal flow and decrease hypersaline conditions for future afforestation endeavors in arid coastlines. Copyright © 2015 Elsevier Ltd. All rights reserved.

Role of Ca++ Influx via Epidermal TRP Ion Channels

DTIC Science & Technology

2015-10-01

increase that could be attenuated with TRPv4 selective inhibitor, GSK205 (10µM). Stimulation with camphor (TRPV3), olvanil and capsaicin (TRPV1) did not...writing. When activating TRPV3 with camphor , and TRPV1 with capsaicin and olvanil, there was no significant increase in capacitance. In view of this

Measurement-device-independent quantum key distribution with correlated source-light-intensity errors

NASA Astrophysics Data System (ADS)

Jiang, Cong; Yu, Zong-Wen; Wang, Xiang-Bin

2018-04-01

We present an analysis for measurement-device-independent quantum key distribution with correlated source-light-intensity errors. Numerical results show that the results here can greatly improve the key rate especially with large intensity fluctuations and channel attenuation compared with prior results if the intensity fluctuations of different sources are correlated.

47 CFR 74.750 - Transmission system facilities.

Code of Federal Regulations, 2011 CFR

2011-10-01

... assigned channel. (2) Radio frequency harmonics of the visual and aural carriers, measured at the output terminals of the transmitter, shall be attenuated no less than 60 dB below the peak visual output power...: (i) 0.02 percent of its rated frequency for transmitters rated at no more than 100 watts peak visual...

Velocities and Attenuations of Gas Hydrate-Bearing Sediments

USGS Publications Warehouse

Lee, Myung W.

2007-01-01

Monopole and dipole logging data at the Mallik 5L-38, Mackenzie Delta, Canada, provide a challenge for sonic velocity and attenuation models used to remotely estimate pore-space gas hydrate content. Velocity and attenuation are linked, with velocity dispersion causing increased attenuation. Sonic waveforms for Mallik 5L-38, however, show no velocity dispersion in gas hydrate-bearing layers, yet are highly attenuated. Attenuation models applied to Mallik 5L-38 data are shown to be inconsistent with the observed velocity measurements, and therefore are suspect in their ability to predict gas hydrate content. A model explicitly linking velocity and attenuation data is presented, accurately predicting gas hydrate content from velocity data alone while demonstrating that the attenuation mechanisms at the Mallik 5L-38 site have not yet been identified.

Mutations within ICP4 acquired during in vitro attenuation do not alter virulence of recombinant Marek’s disease viruses in vivo

USDA-ARS?s Scientific Manuscript database

Marek's disease (MD) is a T-cell lymphoma of chickens caused by the oncogenic Marek's disease virus (MDV). MD is primarily controlled by live-attenuated vaccines generated by repeated in vitro serial passage. Previous efforts to characterize attenuated MDVs identified numerous mutations, particularl...

Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons

PubMed Central

Zemel, Benjamin M.; Brown, Eric V.; Urban, Mark W.; Tymanskyj, Stephen R.; Lepore, Angelo C.

2017-01-01

Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI. SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K+ channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1). PMID:28751455

Stratospheric mountain wave attenuation in positive and negative ambient wind shear

NASA Astrophysics Data System (ADS)

Kruse, C. G.; Smith, R. B.

2016-12-01

Recently, much has been learned about the vertical propagation and attenuation of mountain waves launched by the Southern Alps of New Zealand (NZ) from the Deep Propagating Gravity Wave Experiment (DEEPWAVE) field campaign. Over NZ, approximately half of mountain wave events are strongly attenuated in a lower-stratospheric "valve layer," defined as a layer of reduced wind with no critical levels. Within a valve layer, negative wind shear causes mountain waves steepen and attenuate, with the amount of transmitted momentum flux controlled by the minimum wind speed within the layer. The other half of wave events are deep (propagating to 35+ km), usually with positive wind shear. Within these deep events, increasing amplitude with decreasing density causes mountain waves to attenuate gradually (after spatial/temporal averaging). Global reanalyses indicate that this valve layer is a climatological feature in the wintertime mid-latitudes above the subtropical jet, while deep events and gradual attenuation occur over higher latitudes below the polar stratospheric jet. The local physics of mountain wave attenuation in positive and negative ambient wind shear are investigated using realistic winter-long (JJA) 6-km resolution Weather Research and Forecasting (WRF) model simulations over the Andes. Attention is given to the spatiotemporal variability of wave attenuation and the various factors driving this variability (e.g. variability in wave generation, ambient conditions at attenuation level, inherent wave-induced instabilities). Mesoscale potential vorticity generation is used as an indicator of wave attenuation. Additionally, regionally integrated wave momentum flux and gravity wave drag (GWD) within WRF are quantified and compared with parameterized quantities in the MERRA1 and 2 reanalyses.

Statistical Modelling and Characterization of Experimental mm-Wave Indoor Channels for Future 5G Wireless Communication Networks

PubMed Central

Al-Samman, A. M.; Rahman, T. A.; Azmi, M. H.; Hindia, M. N.; Khan, I.; Hanafi, E.

2016-01-01

This paper presents an experimental characterization of millimeter-wave (mm-wave) channels in the 6.5 GHz, 10.5 GHz, 15 GHz, 19 GHz, 28 GHz and 38 GHz frequency bands in an indoor corridor environment. More than 4,000 power delay profiles were measured across the bands using an omnidirectional transmitter antenna and a highly directional horn receiver antenna for both co- and cross-polarized antenna configurations. This paper develops a new path-loss model to account for the frequency attenuation with distance, which we term the frequency attenuation (FA) path-loss model and introduce a frequency-dependent attenuation factor. The large-scale path loss was characterized based on both new and well-known path-loss models. A general and less complex method is also proposed to estimate the cross-polarization discrimination (XPD) factor of close-in reference distance with the XPD (CIX) and ABG with the XPD (ABGX) path-loss models to avoid the computational complexity of minimum mean square error (MMSE) approach. Moreover, small-scale parameters such as root mean square (RMS) delay spread, mean excess (MN-EX) delay, dispersion factors and maximum excess (MAX-EX) delay parameters were used to characterize the multipath channel dispersion. Multiple statistical distributions for RMS delay spread were also investigated. The results show that our proposed models are simpler and more physically-based than other well-known models. The path-loss exponents for all studied models are smaller than that of the free-space model by values in the range of 0.1 to 1.4 for all measured frequencies. The RMS delay spread values varied between 0.2 ns and 13.8 ns, and the dispersion factor values were less than 1 for all measured frequencies. The exponential and Weibull probability distribution models best fit the RMS delay spread empirical distribution for all of the measured frequencies in all scenarios. PMID:27654703

Glucose-6-phosphate dehydrogenase and NADPH redox regulates cardiac myocyte L-type calcium channel activity and myocardial contractile function.

PubMed

Rawat, Dhwajbahadur K; Hecker, Peter; Watanabe, Makino; Chettimada, Sukrutha; Levy, Richard J; Okada, Takao; Edwards, John G; Gupte, Sachin A

2012-01-01

We recently demonstrated that a 17-ketosteroid, epiandrosterone, attenuates L-type Ca(2+) currents (I(Ca-L)) in cardiac myocytes and inhibits myocardial contractility. Because 17-ketosteroids are known to inhibit glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, and to reduce intracellular NADPH levels, we hypothesized that inhibition of G6PD could be a novel signaling mechanism which inhibit I(Ca-L) and, therefore, cardiac contractile function. We tested this idea by examining myocardial function in isolated hearts and Ca(2+) channel activity in isolated cardiac myocytes. Myocardial function was tested in Langendorff perfused hearts and I(Ca-L) were recorded in the whole-cell patch configuration by applying double pulses from a holding potential of -80 mV and then normalized to the peak amplitudes of control currents. 6-Aminonicotinamide, a competitive inhibitor of G6PD, increased pCO(2) and decreased pH. Additionally, 6-aminonicotinamide inhibited G6PD activity, reduced NADPH levels, attenuated peak I(Ca-L) amplitudes, and decreased left ventricular developed pressure and ±dp/dt. Finally, dialyzing NADPH into cells from the patch pipette solution attenuated the suppression of I(Ca-L) by 6-aminonicotinamide. Likewise, in G6PD-deficient mice, G6PD insufficiency in the heart decreased GSH-to-GSSG ratio, superoxide, cholesterol and acetyl CoA. In these mice, M-mode echocardiographic findings showed increased diastolic volume and end-diastolic diameter without changes in the fraction shortening. Taken together, these findings suggest that inhibiting G6PD activity and reducing NADPH levels alters metabolism and leads to inhibition of L-type Ca(2+) channel activity. Notably, this pathway may be involved in modulating myocardial contractility under physiological and pathophysiological conditions during which the pentose phosphate pathway-derived NADPH redox is modulated (e.g., ischemia-reperfusion and heart failure).

Lidocaine attenuation testing: An in vivo investigation of putative LQT3-associated variants in the SCN5A-encoded sodium channel.

PubMed

Anderson, Heather N; Bos, J Martijn; Kapplinger, Jamie D; Meskill, Jana M; Ye, Dan; Ackerman, Michael J

2017-08-01

Long QT syndrome type 3 (LQT3) accounts for 5%-10% of long QT syndrome and results from gain-of-function mutations in the SCN5A-encoded sodium channel. Approximately 2% of healthy individuals host rare SCN5A variants of uncertain significance (VUS). Distinction of true LQT3-causative mutations from background genetic noise is essential. The purpose of this study was to assess the use of the lidocaine attenuation test (LAT) in evaluating patients with possible LQT3. We reviewed the LAT results and medical records for 25 patients with a possible LQT3-associated SCN5A variant. The LAT involved a loading dose of 1 mg/kg of intravenous lidocaine followed by continuous infusion at 50 μg/(kg⋅min) for 20 minutes. If the corrected QT interval shortened by ≥30 ms, the LAT was defined as positive. Sixteen patients (64%) had a positive LAT, 6 of which demonstrated the E1784K variant. A positive LAT correlated in 86% of cases with abnormal in vitro channel function (mean corrected QT interval attenuation 43 ± 3 ms vs 25 ± 5 ms for wild-type variants; P = .03). Four of 5 patients (80%) with a VUS had a positive LAT (T1304M [2 patients], L1786P, and R800L). The T1304M variant demonstrated abnormal in vitro function and a positive LAT, opening the door for a potential variant promotion from VUS to likely pathogenic. The LAT may help distinguish true LQT3-causative mutations from an otherwise noncontributory VUS. Given that lidocaine acts as a late sodium current blocker, a positive LAT may enable the early identification of a pathological accentuation of the late sodium current that could be targeted therapeutically. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Statistical Modelling and Characterization of Experimental mm-Wave Indoor Channels for Future 5G Wireless Communication Networks.

PubMed

Al-Samman, A M; Rahman, T A; Azmi, M H; Hindia, M N; Khan, I; Hanafi, E

This paper presents an experimental characterization of millimeter-wave (mm-wave) channels in the 6.5 GHz, 10.5 GHz, 15 GHz, 19 GHz, 28 GHz and 38 GHz frequency bands in an indoor corridor environment. More than 4,000 power delay profiles were measured across the bands using an omnidirectional transmitter antenna and a highly directional horn receiver antenna for both co- and cross-polarized antenna configurations. This paper develops a new path-loss model to account for the frequency attenuation with distance, which we term the frequency attenuation (FA) path-loss model and introduce a frequency-dependent attenuation factor. The large-scale path loss was characterized based on both new and well-known path-loss models. A general and less complex method is also proposed to estimate the cross-polarization discrimination (XPD) factor of close-in reference distance with the XPD (CIX) and ABG with the XPD (ABGX) path-loss models to avoid the computational complexity of minimum mean square error (MMSE) approach. Moreover, small-scale parameters such as root mean square (RMS) delay spread, mean excess (MN-EX) delay, dispersion factors and maximum excess (MAX-EX) delay parameters were used to characterize the multipath channel dispersion. Multiple statistical distributions for RMS delay spread were also investigated. The results show that our proposed models are simpler and more physically-based than other well-known models. The path-loss exponents for all studied models are smaller than that of the free-space model by values in the range of 0.1 to 1.4 for all measured frequencies. The RMS delay spread values varied between 0.2 ns and 13.8 ns, and the dispersion factor values were less than 1 for all measured frequencies. The exponential and Weibull probability distribution models best fit the RMS delay spread empirical distribution for all of the measured frequencies in all scenarios.

Tectonic Inversion Along the Algerian and Ligurian Margins: On the Insight Provided By Latest Seismic Processing Techniques Applied to Recent and Vintage 2D Offshore Multichannel Seismic Data

NASA Astrophysics Data System (ADS)

Schenini, L.; Beslier, M. O.; Sage, F.; Badji, R.; Galibert, P. Y.; Lepretre, A.; Dessa, J. X.; Aidi, C.; Watremez, L.

2014-12-01

Recent studies on the Algerian and the North-Ligurian margins in the Western Mediterranean have evidenced inversion-related superficial structures, such as folds and asymmetric sedimentary perched basins whose geometry hints at deep compressive structures dipping towards the continent. Deep seismic imaging of these margins is difficult due to steep slope and superficial multiples, and, in the Mediterranean context, to the highly diffractive Messinian evaporitic series in the basin. During the Algerian-French SPIRAL survey (2009, R/V Atalante), 2D marine multi-channel seismic (MCS) reflection data were collected along the Algerian Margin using a 4.5 km, 360 channel digital streamer and a 3040 cu. in. air-gun array. An advanced processing workflow has been laid out using Geocluster CGG software, which includes noise attenuation, 2D SRME multiple attenuation, surface consistent deconvolution, Kirchhoff pre-stack time migration. This processing produces satisfactory seismic images of the whole sedimentary cover, and of southward dipping reflectors in the acoustic basement along the central part of the margin offshore Great Kabylia, that are interpreted as inversion-related blind thrusts as part of flat-ramp systems. We applied this successful processing workflow to old 2D marine MCS data acquired on the North-Ligurian Margin (Malis survey, 1995, R/V Le Nadir), using a 2.5 km, 96 channel streamer and a 1140 cu. in. air-gun array. Particular attention was paid to multiple attenuation in adapting our workflow. The resulting reprocessed seismic images, interpreted with a coincident velocity model obtained by wide-angle data tomography, provide (1) enhanced imaging of the sedimentary cover down to the top of the acoustic basement, including the base of the Messinian evaporites and the sub-salt Miocene series, which appear to be tectonized as far as in the mid-basin, and (2) new evidence of deep crustal structures in the margin which the initial processing had failed to reveal.

Comparison of Instantaneous Frequency Scaling from Rain Attenuation and Optical Disdrometer Measurements at K/Q bands

NASA Technical Reports Server (NTRS)

Nessel, James; Zemba, Michael; Luini, Lorenzo; Riva, Carlo

2015-01-01

Rain attenuation is strongly dependent on the rain rate, but also on the rain drop size distribution (DSD). Typically, models utilize an average drop size distribution, such as those developed by Laws and Parsons, or Marshall and Palmer. However, individual rain events may possess drop size distributions which could be significantly different from the average and will impact, for example, fade mitigation techniques which utilize channel performance estimates from a signal at a different frequency. Therefore, a good understanding of the characteristics and variability of the raindrop size distribution is extremely important in predicting rain attenuation and instantaneous frequency scaling parameters on an event-toevent basis. Since June 2014, NASA Glenn Research Center (GRC) and the Politecnico di Milano (POLIMI) have measured the attenuation due to rain in Milan, Italy, on the 20/40 GHz beacon signal broadcast from the Alphasat TDP#5 Aldo Paraboni Q/V-band Payload. Concomitant with these measurements are the measurements of drop size distribution and rain rate utilizing a Thies Clima laser precipitation monitor (disdrometer). In this paper, we discuss the comparison of the predicted rain attenuation at 20 and 40 GHz derived from the drop size distribution data with the measured rain attenuation. The results are compared on statistical and real-time bases. We will investigate the performance of the rain attenuation model, instantaneous frequency scaling, and the distribution of the scaling factor. Further, seasonal rain characteristics will be analysed.

Managing runoff and flow pathways in a small rural catchment to reduce flood risk with other multi-purpose benefits

NASA Astrophysics Data System (ADS)

Wilkinson, Mark; Welton, Phil; Kerr, Peter; Quinn, Paul; Jonczyk, Jennine

2010-05-01

From 2000 to 2009 there have been a high number of flood events throughout Northern Europe. Meanwhile, there is a demand for land in which to construct homes and businesses on, which is encroaching on land which is prone to flooding. Nevertheless, flood defences usually protect us from this hazard. However, the severity of floods and this demand for land has increased the number of homes which have been flooded in the past ten years. Public spending on flood defences can only go so far which targets the large populations first. Small villages and communities, where in many cases normal flood defences are not cost effective, tend to wait longer for flood mitigation strategies. The Belford Burn (Northumberland, UK) catchment is a small rural catchment that drains an area of 6 km2. It flows through the village of Belford. There is a history of flooding in Belford, with records of flood events dating back to 1877. Normal flood defences are not suitable for this catchment as it failed the Environment Agency (EA) cost benefit criteria for support. There was a desire by the local EA Flood Levy Team and the Northumbria Regional Flood Defence Committee at the Environment Agency to deliver an alternative catchment-based solution to the problem. The EA North East Flood Levy team and Newcastle University have created a partnership to address the flood problem using soft engineered runoff management features. Farm Integrated Runoff Management (FIRM) plans manage flow paths directly by storing slowing and filtering runoff at source on farms. The features are multipurpose addressing water quality, trapping sediment, creating new habitats and storing and attenuating flood flow. Background rainfall and stream stage data have been collected since November 2007. Work on the first mitigation features commenced in July 2008. Since that date five flood events have occurred in the catchment. Two of these flood events caused widespread damage in other areas of the county. However, in Belford only two houses were flooded. Data from the catchment and mitigation features showed that the defence measures resulted in an increase in travel time of the peak and attenuated high flows which would have usually travelled quickly down the channel to the village. For example, the pilot feature appears to have increased the travel time of a flood peak at the top of the catchment from 20 minutes to 35 minutes over a 1 km stretch of channel. There are currently ten active mitigation features present in the catchment. More features are planned for construction this year. Early data from the catchment indicates that the runoff attenuation features are having an impact on reducing flood flows in the channel and also slowing down the flood peak. At the same time the multi-purpose aspects of the features are apparent.

Enhancement of proton transfer in ion channels by membrane phosphate headgroups.

PubMed

Wyatt, Debra L; de Godoy, Carlos Marcelo G; Cukierman, Samuel

2009-05-14

The transfer of protons (H+) in gramicidin (gA) channels is markedly distinct in monoglyceride and phospholipid membranes. In this study, the molecular groups that account for those differences were investigated using a new methodology. The rates of H+ transfer were measured in single gA channels reconstituted in membranes made of plain ceramides or sphingomyelins and compared to those in monoglyceride and phospholipid bilayers. Single-channel conductances to protons (gH) were significantly larger in sphingomyelin than in ceramide membranes. A novel and unsuspected finding was that H+ transfer was heavily attenuated or completely blocked in ceramide (but not in sphingomyelin) membranes in low-ionic-strength solutions. It is reasoned that H-bond dynamics at low ionic strengths between membrane ceramides and gA makes channels dysfunctional. The rate of H+ transfer in gA channels in ceramide membranes is significantly higher than that in monoglyceride bilayers. This suggests that solvation of the hydrophobic surface of gA channels by two acyl chains in ceramides stabilizes the gA channels and the water wire inside the pore, leading to an enhancement of H+ transfer in relation to that occurring in monoglyceride membranes. gH values in gA channels are similar in ceramide and monoglyceride bilayers and in sphingomyelin and phospholipid membranes. It is concluded that phospho headgroups in membranes have significant effects on the rate of H+ transfer at the membrane gA channel/solution interfaces, enhancing the entry and exit rates of protons in channels.

Dietary salt blunts vasodilation by stimulating epithelial sodium channels in endothelial cells from salt-sensitive Dahl rats.

PubMed

Wang, Zi-Rui; Liu, Hui-Bin; Sun, Ying-Ying; Hu, Qing-Qing; Li, Yu-Xia; Zheng, Wei-Wan; Yu, Chang-Jiang; Li, Xin-Yuan; Wu, Ming-Ming; Song, Bin-Lin; Mu, Jian-Jun; Yuan, Zu-Yi; Zhang, Zhi-Ren; Ma, He-Ping

2018-04-01

Our recent studies show that the reduced activity of epithelial sodium channels (ENaC) in endothelial cells accounts for the adaptation of vasculature to salt in Sprague-Dawley rats. The present study examines a hypothesis that enhanced ENaC activity mediates the loss of vasorelaxation in Dahl salt-sensitive (SS) rats. We used the cell-attached patch-clamp technique to record ENaC activity in split-open mesenteric arteries. Western blot and immunofluorescence staining were used to evaluate the levels of aldosterone, ENaC, eNOS and NO. Blood pressure was measured with the tail-cuff method and the artery relaxation was measured with the wire myograph assay. High-salt (HS) diet significantly increased plasma aldosterone and ENaC activity in the endothelial cells of Dahl SS rats. The endothelium-dependent artery relaxation was blunted by HS challenge in these rats. Amiloride, a potent blocker of ENaC, increased both phosphorylated eNOS and NO and therefore prevented the HS-induced loss of vasorelaxation. As, in SS rats, endogenous aldosterone was already elevated by HS challenge, exogenous aldosterone did not further elevate ENaC activity in the rats fed with HS. Eplerenone, a mineralocorticoid receptor antagonist, attenuated the effects of HS on both ENaC activity and artery relaxation. These data suggest that HS diet blunts artery relaxation and causes hypertension via a pathway associated with aldosterone-dependent activation of ENaC in endothelial cells. This pathway provides one of the mechanisms by which HS causes hypertension in Dahl SS rats. This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. © 2017 The British Pharmacological Society.

Ca{sup 2+} influx and ATP release mediated by mechanical stretch in human lung fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murata, Naohiko; Ito, Satoru, E-mail: itori@med.nagoya-u.ac.jp; Furuya, Kishio

Highlights: • Uniaxial stretching activates Ca{sup 2+} signaling in human lung fibroblasts. • Stretch-induced intracellular Ca{sup 2+} elevation is mainly via Ca{sup 2+} influx. • Mechanical strain enhances ATP release from fibroblasts. • Stretch-induced Ca{sup 2+} influx is not mediated by released ATP or actin cytoskeleton. - Abstract: One cause of progressive pulmonary fibrosis is dysregulated wound healing after lung inflammation or damage in patients with idiopathic pulmonary fibrosis and severe acute respiratory distress syndrome. The mechanical forces are considered to regulate pulmonary fibrosis via activation of lung fibroblasts. In this study, the effects of mechanical stretch on the intracellularmore » Ca{sup 2+} concentration ([Ca{sup 2+}]{sub i}) and ATP release were investigated in primary human lung fibroblasts. Uniaxial stretch (10–30% in strain) was applied to fibroblasts cultured in a silicone chamber coated with type I collagen using a stretching apparatus. Following stretching and subsequent unloading, [Ca{sup 2+}]{sub i} transiently increased in a strain-dependent manner. Hypotonic stress, which causes plasma membrane stretching, also transiently increased the [Ca{sup 2+}]{sub i}. The stretch-induced [Ca{sup 2+}]{sub i} elevation was attenuated in Ca{sup 2+}-free solution. In contrast, the increase of [Ca{sup 2+}]{sub i} by a 20% stretch was not inhibited by the inhibitor of stretch-activated channels GsMTx-4, Gd{sup 3+}, ruthenium red, or cytochalasin D. Cyclic stretching induced significant ATP releases from fibroblasts. However, the stretch-induced [Ca{sup 2+}]{sub i} elevation was not inhibited by ATP diphosphohydrolase apyrase or a purinergic receptor antagonist suramin. Taken together, mechanical stretch induces Ca{sup 2+} influx independently of conventional stretch-sensitive ion channels, the actin cytoskeleton, and released ATP.« less

Activation of intestinal Cl- secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator.

PubMed

Bijvelds, Marcel J C; Bot, Alice G M; Escher, Johanna C; De Jonge, Hugo R

2009-09-01

Lubiprostone alleviates constipation by stimulating intestinal fluid secretion, purportedly through activation of ClC-2-type Cl(-) channels. Intestinal obstruction is also a recurrent cause of distress in cystic fibrosis (CF) patients, caused by loss of CF transmembrane conductance regulator (CFTR) Cl(-) channel activity. Because ClC-2 recruitment might be beneficial to CF patients, we investigated lubiprostone's mode of action. Cl(-) transport was measured in an Ussing chamber, in 3 model systems: (1) T84 colonocytes, (2) intestinal epithelium of wild-type and CF mice, and (3) intestinal epithelium of CF patients and controls. In T84 monolayers, lubiprostone induced a robust secretory response. Selective permeabilization of the basolateral plasma membrane revealed that lubiprostone activated an apical Cl(-) conductance. The lubiprostone response was attenuated by H89, an inhibitor of the cAMP-dependent protein kinase, and lubiprostone precluded responsiveness to the cAMP agonist forskolin. CFTR blockage by CFTRinh172, but not ClC-2 blockage by CdCl(2), inhibited the lubiprostone response. Lubiprostone induced a CdCl(2)-insensitive secretory response in mouse intestine, but failed to induce intestinal Cl(-) secretion in Cftr-null mice. Correspondingly, lubiprostone induced a secretory response in human intestinal epithelium, but not in tissue of CF patients. The EP(4)-type prostanoid receptor antagonist L-161,982 blocked the lubiprostone response in all 3 models studied. In T84 cells, lubiprostone induced a rise in cAMP levels that was sensitive to EP(4)-receptor blockage. Lubiprostone enhances intestinal Cl(-) and fluid secretion via prostanoid receptor signaling, triggering activation of CFTR. Therefore, it is of limited use for treatment of CF-related intestinal disease.

Marked synergism between mutant SOD1 and glutamate transport inhibition in the induction of motor neuronal degeneration in spinal cord slice cultures.

PubMed

Yin, Hong Z; Weiss, John H

2012-04-11

Loss of astrocytic glutamate transport capacity in ALS spinal cord supports an excitotoxic contribution to motor neuron (MN) damage in the disease, and dominant gain of function mutations in Cu/Zn superoxide dismutase (SOD1) cause certain familial forms of ALS. We have used organotypic slice cultures from wild type and G93A SOD1 mutant rat spinal cords to examine interactions between excitotoxicity and the presence of mutant SOD1 in the induction of MN degeneration. Slice cultures were prepared from 1 week old pups, and after an additional week in vitro, some were exposed to either a low level (30 μM) of the glutamate uptake inhibitor, trans-pyrrolidine-2,4-dicarboxylic acid (PDC) for 3 weeks, or a higher level (50 μM) for 48 h, followed by histochemical labeling to assess MN injury. In wild type animals these exposures caused relatively little MN degeneration. Similarly, little MN degeneration was seen in slices from SOD1 mutant animals that were not exposed to PDC. However, addition of PDC to SOD1 mutant slices resulted in substantial MN injury, which was markedly attenuated by a Ca2+ permeable AMPA-type (Ca-AMPA) glutamate channel blocker, or by a nitric oxide synthase antagonist. These observations illustrate the utility of the organotypic culture model for the investigation of intracellular interactions underlying MN degeneration in ALS, and support the hypothesis that activation of Ca-AMPA channels on MNs provides a metabolic burden that synergizes with deleterious effects of mutant SOD1 in the induction of MN injury. Copyright © 2012 Elsevier B.V. All rights reserved.

Glial cell-expressed mechanosensitive channel TRPV4 mediates infrasound-induced neuronal impairment.

PubMed

Shi, Ming; Du, Fang; Liu, Yang; Li, Li; Cai, Jing; Zhang, Guo-Feng; Xu, Xiao-Fei; Lin, Tian; Cheng, Hao-Ran; Liu, Xue-Dong; Xiong, Li-Ze; Zhao, Gang

2013-11-01

Vibroacoustic disease, a progressive and systemic disease, mainly involving the central nervous system, is caused by excessive exposure to low-frequency but high-intensity noise generated by various heavy transportations and machineries. Infrasound is a type of low-frequency noise. Our previous studies demonstrated that infrasound at a certain intensity caused neuronal injury in rats but the underlying mechanism(s) is still largely unknown. Here, we showed that glial cell-expressed TRPV4, a Ca(2+)-permeable mechanosensitive channel, mediated infrasound-induced neuronal injury. Among different frequencies and intensities, infrasound at 16 Hz and 130 dB impaired rat learning and memory abilities most severely after 7-14 days exposure, a time during which a prominent loss of hippocampal CA1 neurons was evident. Infrasound also induced significant astrocytic and microglial activation in hippocampal regions following 1- to 7-day exposure, prior to neuronal apoptosis. Moreover, pharmacological inhibition of glial activation in vivo protected against neuronal apoptosis. In vitro, activated glial cell-released proinflammatory cytokines IL-1β and TNF-α were found to be key factors for this neuronal apoptosis. Importantly, infrasound induced an increase in the expression level of TRPV4 both in vivo and in vitro. Knockdown of TRPV4 expression by siRNA or pharmacological inhibition of TRPV4 in cultured glial cells decreased the levels of IL-1β and TNF-α, attenuated neuronal apoptosis, and reduced TRPV4-mediated Ca(2+) influx and NF-κB nuclear translocation. Finally, using various antagonists we revealed that calmodulin and protein kinase C signaling pathways were involved in TRPV4-triggered NF-κB activation. Thus, our results provide the first evidence that glial cell-expressed TRPV4 is a potential key factor responsible for infrasound-induced neuronal impairment.

Dopamine D3 receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: Role of hyperthermia

PubMed Central

Baladi, Michelle G.; Newman, Amy H.; Nielsen, Shannon M.; Hanson, Glen R.; Fleckenstein, Annette E.

2014-01-01

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. PMID:24685638

Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia.

PubMed

Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M; Hanson, Glen R; Fleckenstein, Annette E

2014-06-05

Methamphetamine administration causes long-term deficits to dopaminergic systems that, in humans, are thought to be associated with motor slowing and memory impairment. Methamphetamine interacts with the dopamine transporter (DAT) and increases extracellular concentrations of dopamine that, in turn, binds to a number of dopamine receptor subtypes. Although the relative contribution of each receptor subtype to the effects of methamphetamine is not fully known, non-selective dopamine D2/D3 receptor antagonists can attenuate methamphetamine-induced changes to dopamine systems. The present study extended these findings by testing the role of the dopamine D3 receptor subtype in mediating the long-term dopaminergic, and for comparison serotonergic, deficits caused by methamphetamine. Results indicate that the dopamine D3 receptor selective antagonist, PG01037, attenuated methamphetamine-induced decreases in striatal DAT, but not hippocampal serotonin (5HT) transporter (SERT), function, as assessed 7 days after treatment. However, PG01037 also attenuated methamphetamine-induced hyperthermia. When methamphetamine-induced hyperthermia was maintained by treating rats in a warm ambient environment, PG01037 failed to attenuate the effects of methamphetamine on DAT uptake. Furthermore, PG01037 did not attenuate methamphetamine-induced decreases in dopamine and 5HT content. Taken together, the present study demonstrates that dopamine D3 receptors mediate, in part, the long-term deficits in DAT function caused by methamphetamine, and that this effect likely involves an attenuation of methamphetamine-induced hyperthermia. Copyright © 2014 Elsevier B.V. All rights reserved.

Hypoxia Induces an Increase in Intracellular Magnesium via Transient Receptor Potential Melastatin 7 (TRPM7) Channels in Rat Hippocampal Neurons in Vitro*

PubMed Central

Zhang, Jing; Zhao, Fengbo; Zhao, Yin; Wang, Jing; Pei, Lei; Sun, Ning; Shi, Jing

2011-01-01

TRPM7, a divalent cation channel, plays an important role in neurons damaged from cerebral ischemia due to permitting intracellular calcium overload. This study aimed to explore whether magnesium was transported via a TRPM7 channel into the intracellular space of rat hippocampal neurons after 1 h of oxygen-glucose deprivation (OGD) and acute chemical ischemia (CI) by using methods of the Mg2+ fluorescent probe Mag-Fura-2 to detect intracellular magnesium concentration ([Mg2+]i) and flame atomic absorption spectrometry to measure extracellular magnesium concentration ([Mg2+]o). The results showed that the neuronal [Mg2+]i was 1.51-fold higher after 1 h of OGD at a basal level, and the increase of neuronal [Mg2+]i reached a peak after 1 h of OGD and was kept for 60 min with re-oxygenation. Meanwhile, the [Mg2+]o decreased after 1 h of OGD and recovered to the pre-ischemic level within 15 min after re-oxygenation. In the case of CI, the [Mg2+]i peak immediately appeared in hippocampal neurons. This increase of [Mg2+]i declined by removing extracellular magnesium in OGD or CI. Furthermore, by using Gd3+ or 2-aminoethoxydiphenyl borate to inhibit TRPM7 channels, the [Mg2+]i increase, which was induced by OGD or CI, was attenuated without altering the basal level of [Mg2+]i. By silencing TRPM7 with shRNA in hippocampal neurons, it was found that not only was the increase of [Mg2+]i induced by OGD or CI but also the basal levels of [Mg2+]i were attenuated. In contrast, overexpression of TRPM7 in HEK293 cells exaggerated both the basal levels and increased [Mg2+]i after 1 h of OGD/CI. These results suggest that anoxia induced the increase of [Mg2+]i via TRPM7 channels in rat hippocampal neurons. PMID:21487014

Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine.

PubMed

Thomas, David M; Kuhn, Donald M

2005-02-01

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.

Cardiac Overexpression of Antioxidant Catalase Attenuates Aging-Induced Cardiomyocyte Relaxation Dysfunction

PubMed Central

Ren, Jun; Li, Qun; Wu, Shan; Li, Shi-Yan; Babcock, Sara A.

2007-01-01

Catalase, an enzyme which detoxifies H2O2, may interfere with cardiac aging. To test this hypothesis, contractile and intracellular Ca2+ properties were evaluated in cardiomyocytes from young (3–4 mo) and old (26–28 mo) FVB and transgenic mice with cardiac overexpression of catalase. Contractile indices analyzed included peak shortening (PS), time-to-90% PS (TPS90), time-to-90% relengthening (TR90), half-width duration (HWD), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ levels or decay rate. Levels of advanced glycation endproduct (AGE), Na+/Ca2+ exchanger (NCX), sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a), phospholamban (PLB), myosin heavy chain (MHC), membrane Ca2+ and K+ channels were measured by western blot. Catalase transgene prolonged survival while did not alter myocyte function by itself. Aging depressed ± dL/dt, prolonged HWD, TR90 and intracellular Ca2+ decay without affecting other indices in FVB myocytes. Aged FVB myocytes exhibited a stepper decline in PS in response to elevated stimulus or a dampened rise in PS in response to elevated extracellular Ca2+ levels. Interestingly, aging-induced defects were nullified or significantly attenuated by catalase. AGE level was elevated by 5-fold in aged FVB compared with young FVB mice, which was reduced by catalase. Expression of SERCA2a, NCX and Kv1.2 K+ channel was significantly reduced although levels of PLB, L-type Ca2+ channel dihydropyridine receptor and β-MHC isozyme remained unchanged in aged FVB hearts. Catalase restored NCX and Kv1.2 K+ channel but not SERCA2a level in aged mice. In summary, our data suggested that catalase protects cardiomyocytes from aging-induced contractile defect possibly via improved intracellular Ca2+ handling. PMID:17250874

Intractable hyperkalemia due to nicorandil induced potassium channel syndrome.

PubMed

Chowdhry, Vivek; Mohanty, B B

2015-01-01

Nicorandil is a commonly used antianginal agent, which has both nitrate-like and ATP-sensitive potassium (K ATP ) channel activator properties. Activation of potassium channels by nicorandil causes expulsion of potassium ions into the extracellular space leading to membrane hyperpolarization, closure of voltage-gated calcium channels and finally vasodilatation. However, on the other hand, being an activator of K ATP channel, it can expel K + ions out of the cells and can cause hyperkalemia. Here, we report a case of nicorandil induced hyperkalemia unresponsive to medical treatment in a patient with diabetic nephropathy.

Regulation of voltage-gated potassium channels attenuates resistance of side-population cells to gefitinib in the human lung cancer cell line NCI-H460.

PubMed

Choi, Seon Young; Kim, Hang-Rae; Ryu, Pan Dong; Lee, So Yeong

2017-02-21

Side-population (SP) cells that exclude anti-cancer drugs have been found in various tumor cell lines. Moreover, SP cells have a higher proliferative potential and drug resistance than main population cells (Non-SP cells). Also, several ion channels are responsible for the drug resistance and proliferation of SP cells in cancer. To confirm the expression and function of voltage-gated potassium (Kv) channels of SP cells, these cells, as well as highly expressed ATP-binding cassette (ABC) transporters and stemness genes, were isolated from a gefitinib-resistant human lung adenocarcinoma cell line (NCI-H460), using Hoechst 33342 efflux. In the present study, we found that mRNA expression of Kv channels in SP cells was different compared to Non-SP cells, and the resistance of SP cells to gefitinib was weakened with a combination treatment of gefitinib and Kv channel blockers or a Kv7 opener, compared to single-treatment gefitinib, through inhibition of the Ras-Raf signaling pathway. The findings indicate that Kv channels in SP cells could be new targets for reducing the resistance to gefitinib.

Research on the laser transmission characteristics simulation and comprehensive test in complex channel environment

NASA Astrophysics Data System (ADS)

Fu, Qiang; Liu, Jianhua; Wang, Xiaoman; Jiang, Huilin; Liu, Zhi

2014-12-01

The laser transmission characteristics affected in the complex channel environment, which limits the performance of laser equipment and engineering application severely. The article aim at the influence of laser transmission in atmospheric and seawater channels, summarizes the foreign researching work of the simulation and comprehensive test regarding to the laser transmission characteristics in complex environment. And researched the theory of atmospheric turbulence effect, water attenuation features, and put forward the corresponding theoretical model. And researched the simulate technology of atmospheric channel and sea water channel, put forward the analog device plan, adopt the similar theory of flowing to simulate the atmosphere turbulence .When the flowing has the same condition of geometric limits including the same Reynolds, they must be similar to each other in the motivation despite of the difference in the size, speed, and intrinsic quality. On this basis, set up a device for complex channel simulation and comprehensive testing, the overall design of the structure of the device, Hot and Cold Air Convection Simulation of Atmospheric Turbulence, mainly consists of cell body, heating systems, cooling systems, automatic control system. he simulator provides platform and method for the basic research of laser transmission characteristics in the domestic.

Open- and closed-state fast inactivation in sodium channels

PubMed Central

Lehmann-Horn, Frank; Holzherr, Boris D

2011-01-01

The role of sodium channel closed-state fast inactivation in membrane excitability is not well understood. We compared open- and closed-state fast inactivation, and the gating charge immobilized during these transitions, in skeletal muscle channel hNaV1.4. A significant fraction of total charge movement and its immobilization occurred in the absence of channel opening. Simulated action potentials in skeletal muscle fibers were attenuated when pre-conditioned by subthreshold depolarization. Anthopleurin A, a site-3 toxin that inhibits gating charge associated with the movement of DIVS4, was used to assess the role of this voltage sensor in closed-state fast inactivation. Anthopleurin elicited opposing effects on the gating mode, kinetics and charge immobilized during open- versus closed-state fast inactivation. This same toxin produced identical effects on recovery of channel availability and remobilization of gating charge, irrespective of route of entry into fast inactivation. Our findings suggest that depolarization promoting entry into fast inactivation from open versus closed states provides access to the IFMT receptor via different rate-limiting conformational translocations of DIVS4. PMID:21099342

BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival

PubMed Central

Lisak, D; Schacht, T; Gawlitza, A; Albrecht, P; Aktas, O; Koop, B; Gliem, M; Hofstetter, H H; Zanger, K; Bultynck, G; Parys, J B; De Smedt, H; Kindler, T; Adams-Quack, P; Hahn, M; Waisman, A; Reed, J C; Hövelmeyer, N; Methner, A

2016-01-01

The endoplasmic reticulum (ER) serves as the major intracellular Ca2+ store and has a role in the synthesis and folding of proteins. BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is a Ca2+ leak channel also implicated in the response against protein misfolding, thereby connecting the Ca2+ store and protein-folding functions of the ER. We found that BI-1-deficient mice suffer from leukopenia and erythrocytosis, have an increased number of splenic marginal zone B cells and higher abundance and nuclear translocation of NF-κB (nuclear factor-κ light-chain enhancer of activated B cells) proteins, correlating with increased cytosolic and ER Ca2+ levels. When put into culture, purified knockout T cells and even more so B cells die spontaneously. This is preceded by increased activity of the mitochondrial initiator caspase-9 and correlated with a significant surge in mitochondrial Ca2+ levels, suggesting an exhausted mitochondrial Ca2+ buffer capacity as the underlying cause for cell death in vitro. In vivo, T-cell-dependent experimental autoimmune encephalomyelitis and B-cell-dependent antibody production are attenuated, corroborating the ex vivo results. These results suggest that BI-1 has a major role in the functioning of the adaptive immune system by regulating intracellular Ca2+ homeostasis in lymphocytes. PMID:26470731

Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers.

PubMed

Samak, Geetha; Gangwar, Ruchika; Meena, Avtar S; Rao, Roshan G; Shukla, Pradeep K; Manda, Bhargavi; Narayanan, Damodaran; Jaggar, Jonathan H; Rao, RadhaKrishna

2016-12-13

Ethanol is metabolized into acetaldehyde in most tissues. In this study, we investigated the synergistic effect of ethanol and acetaldehyde on the tight junction integrity in Caco-2 cell monolayers. Expression of alcohol dehydrogenase sensitized Caco-2 cells to ethanol-induced tight junction disruption and barrier dysfunction, whereas aldehyde dehydrogenase attenuated acetaldehyde-induced tight junction disruption. Ethanol up to 150 mM did not affect tight junction integrity or barrier function, but it dose-dependently increased acetaldehyde-mediated tight junction disruption and barrier dysfunction. Src kinase and MLCK inhibitors blocked this synergistic effect of ethanol and acetaldehyde on tight junction. Ethanol and acetaldehyde caused a rapid and synergistic elevation of intracellular calcium. Calcium depletion by BAPTA or Ca 2+ -free medium blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. Diltiazem and selective knockdown of TRPV6 or Ca V 1.3 channels, by shRNA blocked ethanol and acetaldehyde-induced tight junction disruption and barrier dysfunction. Ethanol and acetaldehyde induced a rapid and synergistic increase in reactive oxygen species by a calcium-dependent mechanism. N-acetyl-L-cysteine and cyclosporine A, blocked ethanol and acetaldehyde-induced barrier dysfunction and tight junction disruption. These results demonstrate that ethanol and acetaldehyde synergistically disrupt tight junctions by a mechanism involving calcium, oxidative stress, Src kinase and MLCK.

Surface Electrochemistry of Metals

DTIC Science & Technology

1993-04-30

maxima along the 12 directions of open channels .vhich are also the interatomic directions). Elastic scattering angular distributions always contain... scatterer geometric relationships for such samples. Distributions from ordered atomic bilayers reveal that the Auger signal from the underlayer is attenuated...are developing a theoretical model and computational code which include both elastic scattering and inhomogeneous inelastic scattering . We seek

External Barium Affects the Gating of KCNQ1 Potassium Channels and Produces a Pore Block via Two Discrete Sites

PubMed Central

Gibor, Gilad; Yakubovich, Daniel; Peretz, Asher; Attali, Bernard

2004-01-01

The pore properties and the reciprocal interactions between permeant ions and the gating of KCNQ channels are poorly understood. Here we used external barium to investigate the permeation characteristics of homomeric KCNQ1 channels. We assessed the Ba2+ binding kinetics and the concentration and voltage dependence of Ba2+ steady-state block. Our results indicate that extracellular Ba2+ exerts a series of complex effects, including a voltage-dependent pore blockade as well as unique gating alterations. External barium interacts with the permeation pathway of KCNQ1 at two discrete and nonsequential sites. (a) A slow deep Ba2+ site that occludes the channel pore and could be simulated by a model of voltage-dependent block. (b) A fast superficial Ba2+ site that barely contributes to channel block and mostly affects channel gating by shifting rightward the voltage dependence of activation, slowing activation, speeding up deactivation kinetics, and inhibiting channel inactivation. A model of voltage-dependent block cannot predict the complex impact of Ba2+ on channel gating in low external K+ solutions. Ba2+ binding to this superficial site likely modifies the gating transitions states of KCNQ1. Both sites appear to reside in the permeation pathway as high external K+ attenuates Ba2+ inhibition of channel conductance and abolishes its impact on channel gating. Our data suggest that despite the high degree of homology of the pore region among the various K+ channels, KCNQ1 channels display significant structural and functional uniqueness. PMID:15226366

Therapeutic targeting of two-pore-domain potassium (K(2P)) channels in the cardiovascular system.

PubMed

Wiedmann, Felix; Schmidt, Constanze; Lugenbiel, Patrick; Staudacher, Ingo; Rahm, Ann-Kathrin; Seyler, Claudia; Schweizer, Patrick A; Katus, Hugo A; Thomas, Dierk

2016-05-01

The improvement of treatment strategies in cardiovascular medicine is an ongoing process that requires constant optimization. The ability of a therapeutic intervention to prevent cardiovascular pathology largely depends on its capacity to suppress the underlying mechanisms. Attenuation or reversal of disease-specific pathways has emerged as a promising paradigm, providing a mechanistic rationale for patient-tailored therapy. Two-pore-domain K(+) (K(2P)) channels conduct outward K(+) currents that stabilize the resting membrane potential and facilitate action potential repolarization. K(2P) expression in the cardiovascular system and polymodal K2P current regulation suggest functional significance and potential therapeutic roles of the channels. Recent work has focused primarily on K(2P)1.1 [tandem of pore domains in a weak inwardly rectifying K(+) channel (TWIK)-1], K(2P)2.1 [TWIK-related K(+) channel (TREK)-1], and K(2P)3.1 [TWIK-related acid-sensitive K(+) channel (TASK)-1] channels and their role in heart and vessels. K(2P) currents have been implicated in atrial and ventricular arrhythmogenesis and in setting the vascular tone. Furthermore, the association of genetic alterations in K(2P)3.1 channels with atrial fibrillation, cardiac conduction disorders and pulmonary arterial hypertension demonstrates the relevance of the channels in cardiovascular disease. The function, regulation and clinical significance of cardiovascular K(2P) channels are summarized in the present review, and therapeutic options are emphasized. © 2016 Authors; published by Portland Press Limited.

Enhanced heat sink with geometry induced wall-jet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hossain, Md. Mahamudul, E-mail: sohel0991@gmail.com; Tikadar, Amitav; Bari, Fazlul

Mini-channels embedded in solid matrix have already proven to be a very efficient way of electronic cooling. Traditional mini-channel heat sinks consist of single layer of parallel channels. Although mini-channel heat sink can achieve very high heat flux, its pumping requirement for circulating liquid through the channel increase very sharply as the flow velocity increases. The pumping requirements of the heat sink can be reduced by increasing its performance. In this paper a novel approach to increase the thermal performance of the mini-channel heat sink is proposed through geometry induced wall jet which is a passive technique. Geometric irregularities alongmore » the channel length causes abrupt pressure change between the channels which causes cross flow through the interconnections thus one channel faces suction and other channel jet action. This suction and jet action disrupts boundary layer causing enhanced heat transfer performance. A CFD model has been developed using commercially available software package FLUENT to evaluate the technique. A parametric study of the velocities and the effect of the position of the wall-jets have been performed. Significant reduction in thermal resistance has been observed for wall-jets, it is also observed that this reduction in thermal resistance is dependent on the position and shape of the wall jet.« less

Loperamide: A positive modulator for store-operated calcium channels?

PubMed Central

Harper, Jacquie L.; Shin, Yangmee; Daly, John W.

1997-01-01

The depletion of inositol trisphosphate-sensitive intracellular pools of calcium causes activation of store-operated calcium (SOC) channels. Loperamide at 10–30 μM has no effect on intracellular calcium levels alone, but augments calcium levels in cultured cells when SOC channels have been activated. In HL-60 leukemic cells, the apparent positive modulatory effect of loperamide on SOC channels occurs when these channels have been activated after ATP, thapsigargin, or ionomycin-elicited depletion of calcium from intracellular storage sites. Loperamide has no effect when levels of intracellular calcium are elevated through a mechanism not involving SOC channels by using sphingosine. Loperamide caused augmentation of intracellular calcium levels after activation of SOC channels in NIH 3T3 fibroblasts, astrocytoma 1321N cells, smooth muscle DDT-MF2 cells, RBL-2H3 mast cells, and pituitary GH4C1 cells. Only in astrocytoma cells did loperamide cause an elevation in intracellular calcium in the absence of activation of SOC channels. The augmentation of intracellular calcium elicited by loperamide in cultured cells was dependent on extracellular calcium and was somewhat resistant to agents (SKF 96365, miconazole, clotrimazole, nitrendipine, and trifluoperazine) that in the absence of loperamide effectively blocked SOC channels. It appears that loperamide augments influx of calcium through activated SOC channels. PMID:9405713

Cooperative effect of the attenuation determinants derived from poliovirus sabin 1 strain is essential for attenuation of enterovirus 71 in the NOD/SCID mouse infection model.

PubMed

Arita, Minetaro; Ami, Yasushi; Wakita, Takaji; Shimizu, Hiroyuki

2008-02-01

Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and is also associated with serious neurological disorders. An attenuated EV71 strain [EV71(S1-3')] has been established in the cynomolgus monkey infection model; this strain contains the attenuation determinants derived from the type 1 poliovirus vaccine strain, Sabin 1 [PV1(Sabin)], in the 5' nontranslated region (NTR), 3D polymerase, and 3' NTR. In this study, we analyzed the effect of the attenuation determinants of PV1(Sabin) on EV71 infection in a NOD/SCID mouse infection model. We isolated a mouse-adapted EV71 strain [EV71(NOD/SCID)] that causes paralysis of the hind limbs in 3- to 4-week-old NOD/SCID mice by adaptation of the virulent EV71(Nagoya) strain in the brains of NOD/SCID mice. A single mutation at nucleotide 2876 that caused an amino acid change in capsid protein VP1 (change of the glycine at position 145 to glutamic acid) was essential for the mouse-adapted phenotype in NOD/SCID mice. Next, we introduced attenuation determinants derived from PV1(Sabin) along with the mouse adaptation mutation into the EV71(Nagoya) genome. In 4-week-old mice, the determinants in the 3D polymerase and 3' NTR, which are the major temperature-sensitive determinants, had a strong effect on attenuation. In contrast, the effect of individual determinants was weak in 3-week-old NOD/SCID mice, and all the determinants were required for substantial attenuation. These results suggest that a cooperative effect of the attenuation determinants of PV1(Sabin) is essential for attenuated neurovirulence of EV71.

Mechanosensitive channels are activated by stress in the actin stress fibres, and could be involved in gravity sensing in plants.

PubMed

Tatsumi, H; Furuichi, T; Nakano, M; Toyota, M; Hayakawa, K; Sokabe, M; Iida, H

2014-01-01

Mechanosensitive (MS) channels are expressed in a variety of cells. The molecular and biophysical mechanism involved in the regulation of MS channel activities is a central interest in basic biology. MS channels are thought to play crucial roles in gravity sensing in plant cells. To date, two mechanisms have been proposed for MS channel activation. One is that tension development in the lipid bilayer directly activates MS channels. The second mechanism proposes that the cytoskeleton is involved in the channel activation, because MS channel activities are modulated by pharmacological treatments that affect the cytoskeleton. We tested whether tension in the cytoskeleton activates MS channels. Mammalian endothelial cells were microinjected with phalloidin-conjugated beads, which bound to stress fibres, and a traction force to the actin cytoskeleton was applied by dragging the beads with optical tweezers. MS channels were activated when the force was applied, demonstrating that a sub-pN force to the actin filaments activates a single MS channel. Plants may use a similar molecular mechanism in gravity sensing, since the cytoplasmic Ca(2+) concentration increase induced by changes in the gravity vector was attenuated by potential MS channel inhibitors, and by actin-disrupting drugs. These results support the idea that the tension increase in actin filaments by gravity-dependent sedimentation of amyloplasts activates MS Ca(2+) -permeable channels, which can be the molecular mechanism of a Ca(2+) concentration increase through gravistimulation. We review recent progress in the study of tension sensing by actin filaments and MS channels using advanced biophysical methods, and discuss their possible roles in gravisensing. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

Ferulic acid relaxed rat aortic, small mesenteric and coronary arteries by blocking voltage-gated calcium channel and calcium desensitization via dephosphorylation of ERK1/2 and MYPT1.

PubMed

Zhou, Zhong-Yan; Xu, Jia-Qi; Zhao, Wai-Rong; Chen, Xin-Lin; Jin, Yu; Tang, Nuo; Tang, Jing-Yi

2017-11-15

Ferulic acid, a natural ingredient presents in several Chinese Materia Medica such as Radix Angelicae Sinensis, has been identified as an important multifunctional and physiologically active small molecule. However, its pharmacological activity in different blood vessel types and underlying mechanisms are unclear. The present study was to investigate the vascular reactivity and the possible action mechanism of FA on aorta, small mesenteric arteries and coronary arteries isolated from Wistar rats. We found FA dose-dependently relieved the contraction of aorta, small mesenteric arteries and coronary arteries induced by different contractors, U46619, phenylephrine (Phe) and KCl. The relaxant effect of FA was not affected by L-NAME (eNOS inhibitor), ODQ (soluble guanylate cyclase inhibitor), and mechanical removal of endothelium in thoracic aortas. The contraction caused by 60mM KCl (60K) was concentration-dependently hindered by FA pretreatment in all three types of arteries. In Ca 2+ -free 60K solution, FA weakened Ca 2+ -related contraction in a concentration dependent manner. And FA relaxed both fluoride and phorbol ester which were PKC, ERK and Rho-kinase activators induced contraction in aortic rings with or without Ca 2+ in krebs solution. Western blotting experiments in A7r5 cells revealed that FA inhibited calcium sensitization via dephosphorylation of ERK1/2 and MYPT1. Furthermore, the relaxation effect of FA was attenuated by verapamil (calcium channel blocker), ERK inhibitor, and fasudil (ROCK inhibitor). These results provide evidence that FA exhibits endothelium-independent vascular relaxant effect in different types of arteries. The molecular mechanism of vasorelaxation activity of FA probably involved calcium channel inhibition and calcium desensitization. Copyright © 2017. Published by Elsevier B.V.

Impaired natriuretic response to high-NaCl diet plus aldosterone infusion in mice overexpressing human CD39, an ectonucleotidase (NTPDase1).

PubMed

Zhang, Yue; Robson, Simon C; Morris, Kaiya L; Heiney, Kristina M; Dwyer, Karen M; Kishore, Bellamkonda K; Ecelbarger, Carolyn M

2015-06-15

Extracellular nucleotides acting through P2 receptors facilitate natriuresis. To define how purinergic mechanisms are involved in sodium homeostasis, we used transgenic (TG) mice that globally overexpress human CD39 (hCD39, NTPDase1), an ectonucleotidase that hydrolyzes extracellular ATP/ADP to AMP, resulting in an altered extracellular purine profile. On a high-sodium diet (HSD, 3.5% Na(+)), urine volume and serum sodium were significantly higher in TG mice but sodium excretion was unaltered. Furthermore, TG mice showed an attenuated fall in urine aldosterone with HSD. Western blot analysis revealed significantly lower densities (∼40%) of the β-subunit of the epithelial sodium channel (ENaC) in medulla, and the major band (85-kDa) of γ-ENaC in TG mice cortex. To evaluate aldosterone-independent differences, in a second experiment, aldosterone was clamped by osmotic minipump at 20 μg/day, and mice were fed either an HSD or a low-sodium diet (LSD, 0.03% Na(+)). Here, no differences in urine volume or osmolality, or serum aldosterone were found, but TG mice showed a modest, yet significant impairment in late natriuresis (days 3 and 4). Several major sodium transporters or channel subunits were differentially expressed between the genotypes. HSD caused a downregulation of Na-Cl cotransporter (NCC) in both genotypes; and had higher cortical levels of NCC, Na-K-ATPase (α-1 subunit), and α- and γ-ENaC. The Na-K-2Cl cotransporter (NKCC2) was downregulated by HSD in wild-type mice, but it increased in TG mice. In summary, our data support the concept that extracellular nucleotides facilitate natriuresis; they also reveal an aldosterone-independent downregulation of major renal sodium transporters and channel subunits by purinergic signaling.

STRETCH-DEPENDENT SENSITIZATION OF POST-JUNCTIONAL NEURAL EFFECTORS IN COLONIC MUSCLES

PubMed Central

Won, Kyung-Jong; Sanders, Kenton M.; Ward, Sean M.

2012-01-01

Background The colon undergoes distension-induced changes in motor activity as luminal contents or feces increases wall pressure. Input from enteric motor neurons regulates motility. Here we examined stretch-dependent responses in circular muscle strips of murine colon. Methods Length-ramps (6–31μm s−1) were applied in the axis of the circular muscle layer in a controlled manner until 5 mN isometric force was reached. Key Results Length-ramps produced transient membrane potential hyperpolarizations and attenuation of action potential (AP) complexes. Responses were reproducible when ramps were applied every 30s. Stretch-dependent hyperpolarization was blocked by TTX, suggesting AP-dependent release of inhibitory neurotransmitter(s). Atropine did not potentiate stretch-induced hyperpolarizations, but increased compliance of the circular layer. L-NNA inhibited stretch-dependent hyperpolarization and decreased muscle compliance, suggesting release of NO mediates stretch-dependent inhibition. Control membrane potential was restored by the NO donor SNP. Stretch-dependent hyperpolarizations were blocked by L-methionine, an inhibitor of stretch-dependent K+ (SDK) channels in colonic muscles. Loss of ICC, elicited by Kit neutralizing antibody, also inhibited responses to stretch. In presence of L-NNA and apamin, stretch responses became excitatory and were characterized by membrane depolarization and increased AP firing. A neurokinin-1 receptor antagonist inhibited this stretch-dependent increase in excitability. Conclusions & Inferences Our data show that stretch-dependent responses in colonic muscles require tonic firing of enteric inhibitory neurons, but reflex activation of neurons does not appear to be necessary. NO causes activation of SDK channels, and stretch of muscles further activates these channels, explaining the inhibitory response to stretch in colonic muscle strips. PMID:23279087

Water transport across biological membranes: Overton, water channels, and peritoneal dialysis.

PubMed

Devuyst, O

2010-01-01

Peritoneal dialysis involves diffusive and convective transports and osmosis through the highly vascularized peritoneal membrane. Several lines of evidence have demonstrated that the water channel aquaporin-1 (AQP1) corresponds to the ultrasmall pore predicted by the modelization of peritoneal transport. Proof-of-principle studies have shown that upregulation of the expression of AQP1 in peritoneal capillaries is reflected by increased water permeability and ultrafiltration, without affecting the osmotic gradient and the permeability for small solutes. Inversely, studies in Aqp1 mice have shown that haplo-insufficiency in AQP1 is reflected by significant attenuation of water transport. Recent studies have identified lead compounds that could act as agonists of aquaporins, as well as putative binding sites and potential mechanisms of gating the water channel. By modulating water transport, these pharmacological agents could have clinically relevant effects in targeting specific tissues or disease states. These studies on the peritoneal membrane also provide an experimental framework to investigate the role of water channels in the endothelium and various cell types.

Comparison of excitation wavelengths for in vivo deep imaging of mouse brain

NASA Astrophysics Data System (ADS)

Wang, Mengran; Wu, Chunyan; Li, Bo; Xia, Fei; Sinefeld, David; Xu, Chris

2018-02-01

The attenuation of excitation power reaching the focus is the main issue that limits the depth penetration of highresolution imaging of biological tissue. The attenuation is caused by a combination of tissue scattering and absorption. Theoretical model of the effective attenuation length for in vivo mouse brain imaging has been built based on the data of the absorption of water and blood and the Mie scattering of a tissue-like phantom. Such a theoretical model has been corroborated at a number of excitation wavelengths, such as 800 nm, 1300 nm , and 1700 nm ; however, the attenuation caused by absorption is negligible when compared to tissue scattering at all these wavelength windows. Here we performed in vivo three-photon imaging of Texas Red-stained vasculature in the same mouse brain with different excitation wavelengths, 1700 nm, 1550 nm, 1500 nm and 1450 nm. In particular, our studies include the wavelength regime where strong water absorption is present (i.e., 1450 nm), and the attenuation by water absorption is predicted to be the dominant contribution in the excitation attenuation. Based on the experimental results, we found that the effective attenuation length at 1450 nm is significantly shorter than those at 1700 nm and 1300 nm. Our results confirm that the theoretical model based on tissue scattering and water absorption is accurate in predicting the effective attenuation lengths for in vivo imaging. The optimum excitation wavelength windows for in vivo mouse brain imaging are at 1300 nm and 1700 nm.

Action-related auditory ERP attenuation: Paradigms and hypotheses.

PubMed

Horváth, János

2015-11-11

A number studies have shown that the auditory N1 event-related potential (ERP) is attenuated when elicited by self-induced or self-generated sounds. Because N1 is a correlate of auditory feature- and event-detection, it was generally assumed that N1-attenuation reflected the cancellation of auditory re-afference, enabled by the internal forward modeling of the predictable sensory consequences of the given action. Focusing on paradigms utilizing non-speech actions, the present review summarizes recent progress on action-related auditory attenuation. Following a critical analysis of the most widely used, contingent paradigm, two further hypotheses on the possible causes of action-related auditory ERP attenuation are presented. The attention hypotheses suggest that auditory ERP attenuation is brought about by a temporary division of attention between the action and the auditory stimulation. The pre-activation hypothesis suggests that the attenuation is caused by the activation of a sensory template during the initiation of the action, which interferes with the incoming stimulation. Although each hypothesis can account for a number of findings, none of them can accommodate the whole spectrum of results. It is suggested that a better understanding of auditory ERP attenuation phenomena could be achieved by systematic investigations of the types of actions, the degree of action-effect contingency, and the temporal characteristics of action-effect contingency representation-buildup and -deactivation. This article is part of a Special Issue entitled SI: Prediction and Attention. Copyright © 2015. Published by Elsevier B.V.

Geomorphic changes caused by the 2011 flood at selected sites along the lower Missouri River and comparison to historical floods: Chapter H in 2011 floods of the central United States

USGS Publications Warehouse

Juracek, Kyle E.

2014-01-01

An analysis of recent and historical U.S. Geological Survey streamgage information was used to assess geomorphic changes caused by the 2011 flood, in comparison to selected historical floods, at three streamgage sites along the lower Missouri River—Sioux City, Iowa; Omaha, Nebraska; and Kansas City, Missouri. Channel-width change was not evident at the three streamgage sites following the 2011 flood and likely was inhibited by bank stabilization. Pronounced changes in channel-bed elevation were indicated. At Sioux City and Omaha, the geomorphic effects of the 2011 flood were similar in terms of the magnitude of channelbed scour and recovery. At both sites, the 2011 flood caused pronounced scour (about 3 feet) of the channel bed; however, at Omaha, most of the channel-bed scour occurred after the flood had receded. More than 1 year after the flood, the channel bed had only partially recovered (about 1 foot) at both sites. Pronounced scour (about 3 feet at Sioux City and about 1.5 feet at Omaha) also was caused by the 1952 flood, which had a substantially larger peak discharge but was much shorter in duration at both sites. Again, at Omaha, most of the channel- bed scour occurred after the flood had receded. At Sioux City, substantial recovery of the channel bed (about 2.5 feet) was documented 1 year after the 1952 flood. Recovery to the pre-flood elevation was complete by April 1954. The greater recovery following the 1952 flood, compared to the 2011 flood, likely was related to a more abundant sediment supply because the flood predated the completion of most of the main-stem dam, channelization, and bank stabilization projects. At Omaha, following the 1952 flood, the channel bed never fully recovered to its pre-flood elevation. The geomorphic effect of the 2011 flood at Kansas City was fill (about 1 foot) on the channel bed followed by relative stability. The 1952 flood, which had a substantially larger peak discharge but was much shorter in duration, caused modest fill (about 0.5 foot) on the channel bed. The 1993 flood, which also had a substantially larger peak discharge but was much shorter in duration, caused pronounced scour of the channel bed (possibly as much as 4 feet). Similar to the floods at Omaha, much of the channel-bed scour at Kansas City occurred after the 1993 flood had receded. More than 1 year after the 1993 flood, following partial recovery (about 1 foot), the channel bed had stabilized, at least temporarily. Following the 1993 flood, the channel bed never fully recovered to its pre-flood elevation. For each flood in the post-dam era that resulted in substantial channel-bed scour (Sioux City in 2011, Omaha in 2011, Kansas City in 1993), recovery of the channel bed to its pre-flood elevation had not occurred more than 1 year after the flood (20 years after the 1993 flood at Kansas City). Thus, the possibility exists that channel-bed scour caused by large floods may have a cumulative effect along the lower Missouri River. The persistence of the flood-related decreases in channel-bed elevation may be indicative of the constrained ability of the channel to recover given a limited sediment supply caused by one or more of the following factors: upstream storage of sediment in reservoirs, bank stabilization, commercial sand dredging, depletion of readily available sediment by the flood, and a lack of post-flood sediment contributions from tributaries.

Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain.

PubMed

Schuelert, N; Zhang, C; Mogg, A J; Broad, L M; Hepburn, D L; Nisenbaum, E S; Johnson, M P; McDougall, J J

2010-11-01

The present study examined whether local administration of the cannabinoid-2 (CB(2)) receptor agonist GW405833 could modulate joint nociception in control rat knee joints and in an animal model of osteoarthritis (OA). OA was induced in male Wistar rats by intra-articular injection of sodium monoiodo-acetate with a recovery period of 14 days. Immunohistochemistry was used to evaluate the expression of CB(2) and transient receptor potential vanilloid channel-1 (TRPV1) receptors in the dorsal root ganglion (DRG) and synovial membrane of sham- and sodium mono-iodoacetate (MIA)-treated animals. Electrophysiological recordings were made from knee joint primary afferents in response to rotation of the joint both before and following close intra-arterial injection of different doses of GW405833. The effect of intra-articular GW405833 on joint pain perception was determined by hindlimb incapacitance. An in vitro neuronal release assay was used to see if GW405833 caused release of an inflammatory neuropeptide (calcitonin gene-related peptide - CGRP). CB(2) and TRPV1 receptors were co-localized in DRG neurons and synoviocytes in both sham- and MIA-treated animals. Local application of the GW405833 significantly reduced joint afferent firing rate by up to 31% in control knees. In OA knee joints, however, GW405833 had a pronounced sensitising effect on joint mechanoreceptors. Co-administration of GW405833 with the CB(2) receptor antagonist AM630 or pre-administration of the TRPV1 ion channel antagonist SB366791 attenuated the sensitising effect of GW405833. In the pain studies, intra-articular injection of GW405833 into OA knees augmented hindlimb incapacitance, but had no effect on pain behaviour in saline-injected control joints. GW405833 evoked increased CGRP release via a TRPV1 channel-dependent mechanism. These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors. Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Anti-stress effects of cilnidipine and nimodipine in immobilization subjected mice.

PubMed

Kumar, Naresh; Singh, Nirmal; Jaggi, Amteshwar Singh

2012-03-20

The present study was designed to investigate the ameliorative role of cilnidipine and nimodipine in immobilization stress-induced behavioral alterations and memory defects in the mice. Acute stress was induced by immobilizing the mice for 150 min and stress-induced behavioral changes were assessed using actophotometer, hole board, open field and social interaction tests. The learning and memory was evaluated using elevated plus maze tests and biochemically, the corticosterone levels were measured in the blood serum. Acute immobilization stress resulted in decrease in locomotor activity, frequency of head dips and rearings in hole board; line crossing and rearing in the open field; increase in avoidance in social behavior along with development of memory deficits assessed by an increased transfer latency time and elevation of the corticosterone levels. Administration of cilnidipine (10 mg/kg), an L and N-type dual calcium channel blocker, and nimodipine (10 mg/kg), an L-type calcium channel blocker, significantly attenuated the immobilized stress-induced behavioral changes and restored memory deficits along with normalization of the corticosterone levels. Cilnidipine and nimodipine produced comparable beneficial effects in restoring immobilization stress subjected mice. It may be concluded that cilnidipine and nimodipine mediated attenuation of corticosterone release by blockage of calcium channels (both L and N-type) on the HPA-axis is responsible for beneficial effects in restoration of behavioral alterations and memory deficits in immobilization-induced acute stress in mice. Copyright © 2011 Elsevier Inc. All rights reserved.

Estimating the beam attenuation coefficient in coastal waters from AVHRR imagery

NASA Astrophysics Data System (ADS)

Gould, Richard W.; Arnone, Robert A.

1997-09-01

This paper presents an algorithm to estimate particle beam attenuation at 660 nm ( cp660) in coastal areas using the red and near-infrared channels of the NOAA AVHRR satellite sensor. In situ reflectance spectra and cp660 measurements were collected at 23 stations in Case I and II waters during an April 1993 cruise in the northern Gulf of Mexico. The reflectance spectra were weighted by the spectral response of the AVHRR sensor and integrated over the channel 1 waveband to estimate the atmospherically corrected signal recorded by the satellite. An empirical relationship between integrated reflectance and cp660 values was derived with a linear correlation coefficient of 0.88. Because the AVHRR sensor requires a strong channel 1 signal, the algorithm is applicable in highly turbid areas ( cp660 > 1.5 m -1) where scattering from suspended sediment strongly controls the shape and magnitude of the red (550-650 nm) reflectance spectrum. The algorithm was tested on a data set collected 2 years later in different coastal waters in the northern Gulf of Mexico and satellite estimates of cp660 averaged within 37% of measured values. Application of the algorithm provides daily images of nearshore regions at 1 km resolution for evaluating processes affecting ocean color distribution patterns (tides, winds, currents, river discharge). Further validation and refinement of the algorithm are in progress to permit quantitative application in other coastal areas. Published by Elsevier Science Ltd

Performance Analysis of Hybrid WDM-FSO System under Various Weather Conditions

NASA Astrophysics Data System (ADS)

Robinson, S.; Jasmine, S.

2016-09-01

Free Space Optical (FSO) communication is being realized as an effective solution for future accessing networks, offering light passed through air. The performance of FSO system can be primarily degraded by various atmospheric attenuations such as rain, fog, haze and snow. At present, hybridization of Dense Wavelength Division Multiplexing (DWDM) with Coarse Wavelength Division Multiplexing (CWDM) becomes necessary to scale the speed and high bandwidth of the services. In this paper, primarily the attenuation values for different weather conditions are calculated. Then the hybrid WDM-FSO system is proposed, designed and the network parameters such as Bit Error Rate (BER), Quality factor (Q factor) and receiver sensitivity are analyzed with respect to link distance for various weather conditions. For investigation, four CWDM (1,510 nm, 1,530 nm, 1,570 nm and 1,570 nm) channel and eight DWDM channels (1,537.4 nm, 1,538.2 nm, 1,539 nm, 1,539.8 nm, 1,540.6 nm, 1,541.4 nm, 1,542.2 nm and 1,543 nm) are considered whose corresponding channel spacing is 20 nm and 0.8 nm, respectively. In addition, the Erbium Doped Fiber Amplifier (EDFA) is inserted at the receiver end in order to enhance the link distance. The proposed hybrid WDM-FSO system is designed to handle the quality of transmission for 12 users, each at a data rate of 2.5 Gbps along an FSO link distance of about 960 km.

Crucial importance of the endothelial K+ channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction.

PubMed

Milkau, Malte; Köhler, Ralf; de Wit, Cor

2010-09-01

Skeletal muscle activity requires substantial increases in blood flow, and the underlying vasodilation involves endothelial activity, but the contribution of the endothelium-dependent hyperpolarizing factor (EDHF) is only poorly defined. In EDHF signaling, endothelial hyperpolarization mediated by the Ca(2+)-activated K(+) channels SK3 and IK1 is a key step and also initiates gap junction-dependent conducted dilations. We assessed the role of SK3, IK1, and connexin40 (Cx40) in muscular contraction-induced dilations in the microcirculation in vivo. Hitherto, arterioles were observed in the electrically stimulated cremaster skeletal muscle of anesthetized mice lacking SK3, IK1, or Cx40 using intravital microscopy. Genetic deficiency of SK3, but not of IK1, strongly attenuated dilations to muscular contraction. Similarly, pharmacologic blockade of SK3 by the specific blocker UCL1684 impaired such dilations in wild-type and IK1-deficient mice. In contrast, IK1 was required for acetylcholine-induced dilations. Genetic deficiency of Cx40 also attenuated dilations induced by muscular contraction but not by acetylcholine. These data support the concept that endothelial hyperpolarization through activation of SK3 contributes to exercise hyperemia and the hyperpolarization ascends the vascular tree through gap junctions formed by Cx40 to orchestrate dilation. The differential impact of SK3- and IK1-deficiency on dilations to distinct stimuli suggests stimulus-dependent activation of these endothelial channels.

Attempt to develop live attenuated bacterial vaccines by selecting resistance to gossypol, proflavine hemisulfate, novobiocin, or ciprofloxacin.

PubMed

Pridgeon, Julia W; Klesius, Phillip H; Yildirim-Aksoy, Mediha

2013-04-26

In an attempt to develop attenuated bacteria as potential live vaccines, four chemicals (gossypol, proflavine hemisulfate, novobiocin, and ciprofloxacin) were used to modify the following four genera of bacteria through chemical-resistance strategy: (1) Aeromonas hydrophila (9 isolates); (2) Edwardsiella tarda (9 isolates); (3) Streptococcus iniae (9 isolates); and (4) S. agalactiae (11 isolates). All bacteria used in this study were able to develop high resistance to gossypol. However, only some bacteria were able to develop resistance to proflavine hemisulfate, novobiocin, or ciprofloxacin. When the virulence of resistant bacteria was tested in tilapia or catfish, none of the gossypol-resistant isolate was attenuated, whereas majority of the proflavine hemisulfate-resistant isolates were attenuated. However, all proflavine hemisulfate-attenuated bacteria failed to provide significant protection to fish. Eight novobiocin- or ciprofloxacin-resistant Gram-positive bacteria (S. agalactiae and S. inaie) were found to be attenuated. However, none of them offered protection higher than 70%. Of seven attenuated novobiocin- or ciprofloxacin-resistant Gram-negative isolates (A. hydrophila and E. tarda), only one (novobiocin-resistant E. tarda 30305) was found to safe and highly efficacious. When E. tarda 30305-novo vaccinated Nile tilapia were challenged by its virulent E. tarda 30305, relative percent of survival of vaccinated fish at 14- and 28-days post vaccination (dpv) was 100% and 92%, respectively. Similarly, E. tarda 30305-novo offered 100% protection to channel catfish against challenges with virulent parent isolate E. tarda 30305 at both 14- and 28-dpv. Our results suggest that the development of live attenuated bacterial vaccines that are safe and efficacious is challenging, although it is feasible. Published by Elsevier Ltd.

Thin-Layering Effect On Estimating Seismic Attenuation In Methane Hydrate-Bearing Sediments

NASA Astrophysics Data System (ADS)

Lee, K.; Matsushima, J.

2012-12-01

Seismic attenuation is one of the important parameters that provide information concerning both the detection and quantitative assessment of gas-hydrates. We estimated seismic attenuation (1/Q) from surface seismic data acquired at Nankai Trough in Japan. We adapt the Q-versus offset (QVO) method to calculate robust and continuous interval attenuations from CMP gathers. We could observe high attenuation in methane hydrate bearing sediments over the BSR region. However some negative 1/Q values are also shown. This means that the amplitude of high frequency components is increasing with depth. Such results may be due to tuning effect. Here, we carried out numerical test to see how thin-layering effect influences on seismic attenuation results. The results showed that tuning considerably influences the attenuation results, and causes the lower 1/Q values (lower attenuation) and negative 1/Q values.

Matrix metalloproteinase-9 and -2 enhance the ligand sensitivity of photoreceptor cyclic nucleotide-gated channels.

PubMed

Meighan, Peter C; Meighan, Starla E; Rich, Elizabeth D; Brown, R Lane; Varnum, Michael D

2012-01-01

Photoreceptor cyclic nucleotide-gated (CNG) channels are the principal ion channels responsible for transduction of the light-induced change in cGMP concentration into an electrical signal. The ligand sensitivity of photoreceptor CNG channels is subject to regulation by intracellular signaling effectors, including calcium-calmodulin, tyrosine kinases and phosphoinositides. Little is known, however, about regulation of channel activity by modification to extracellular regions of CNG channel subunits. Extracellular proteases MMP9 and -2 are present in the interphotoreceptor matrix adjacent to photoreceptor outer segments. Given that MMPs have been implicated in retinal dysfunction and degeneration, we hypothesized that MMP activity may alter the functional properties of photoreceptor CNG channels. For heterologously expressed rod and cone CNG channels, extracellular exposure to MMPs dramatically increased the apparent affinity for cGMP and the efficacy of cAMP. These changes to ligand sensitivity were not prevented by destabilization of the actin cytoskeleton or by disruption of integrin mediated cell adhesion, but could be attenuated by inhibition of MMP catalytic activity. MMP-mediated gating changes exhibited saturable kinetic properties consistent with enzymatic processing of the CNG channels. In addition, exposure to MMPs decreased the abundance of full-length expressed CNGA3 subunits, with a concomitant increase in putative degradation products. Similar gating effects and apparent proteolysis were observed also for native rod photoreceptor CNG channels. Furthermore, constitutive apparent proteolysis of retinal CNGA1 and retinal MMP9 levels were both elevated in aged mice compared with young mice. Together, these results provide evidence that MMP-mediated proteolysis can regulate the ligand sensitivity of CNG channels.

Matrix metalloproteinase-9 and -2 enhance the ligand sensitivity of photoreceptor cyclic nucleotide-gated channels

PubMed Central

Meighan, Peter C.; Meighan, Starla E.; Rich, Elizabeth D.; Brown, R. Lane; Varnum, Michael D.

2012-01-01

Photoreceptor cyclic nucleotide-gated (CNG) channels are the principal ion channels responsible for transduction of the light-induced change in cGMP concentration into an electrical signal. The ligand sensitivity of photoreceptor CNG channels is subject to regulation by intracellular signaling effectors, including calcium-calmodulin, tyrosine kinases and phosphoinositides. Little is known, however, about regulation of channel activity by modification to extracellular regions of CNG channel subunits. Extracellular proteases MMP9 and -2 are present in the interphotoreceptor matrix adjacent to photoreceptor outer segments. Given that MMPs have been implicated in retinal dysfunction and degeneration, we hypothesized that MMP activity may alter the functional properties of photoreceptor CNG channels. For heterologously expressed rod and cone CNG channels, extracellular exposure to MMPs dramatically increased the apparent affinity for cGMP and the efficacy of cAMP. These changes to ligand sensitivity were not prevented by destabilization of the actin cytoskeleton or by disruption of integrin mediated cell adhesion, but could be attenuated by inhibition of MMP catalytic activity. MMP-mediated gating changes exhibited saturable kinetic properties consistent with enzymatic processing of the CNG channels. In addition, exposure to MMPs decreased the abundance of full-length expressed CNGA3 subunits, with a concomitant increase in putative degradation products. Similar gating effects and apparent proteolysis were observed also for native rod photoreceptor CNG channels. Furthermore, constitutive apparent proteolysis of retinal CNGA1 and retinal MMP9 levels were both elevated in aged mice compared with young mice. Together, these results provide evidence that MMP-mediated proteolysis can regulate the ligand sensitivity of CNG channels. PMID:22699690

Theoretical and experimental studies of turbo product code with time diversity in free space optical communication.

PubMed

Han, Yaoqiang; Dang, Anhong; Ren, Yongxiong; Tang, Junxiong; Guo, Hong

2010-12-20

In free space optical communication (FSOC) systems, channel fading caused by atmospheric turbulence degrades the system performance seriously. However, channel coding combined with diversity techniques can be exploited to mitigate channel fading. In this paper, based on the experimental study of the channel fading effects, we propose to use turbo product code (TPC) as the channel coding scheme, which features good resistance to burst errors and no error floor. However, only channel coding cannot cope with burst errors caused by channel fading, interleaving is also used. We investigate the efficiency of interleaving for different interleaving depths, and then the optimum interleaving depth for TPC is also determined. Finally, an experimental study of TPC with interleaving is demonstrated, and we show that TPC with interleaving can significantly mitigate channel fading in FSOC systems.

Computerized tomography of the otic capsule and otoliths in the oyster toadfish, Opsanus tau.

PubMed

Edds-Walton, Peggy L; Arruda, Julie; Fay, Richard R; Ketten, Darlene R

2015-02-01

The neurocranium of the toadfish (Opsanus tau) exhibits a distinct translucent region in the otic capsule (OC) that may have functional significance for the auditory pathway. This study used ultrahigh resolution computerized tomography (100 µm voxels) to compare the relative density of three sites along the OC (dorsolateral, midlateral, and ventromedial) and two reference sites (dorsal: supraoccipital crest; ventral: parasphenoid bone) in the neurocranium. Higher attenuation occurs where structural density is greater; thus, we compared the X-ray attenuations measured, which provided a measure of relative density. The maximum attenuation value was recorded for each of the five sites (x and y) on consecutive sections throughout the OC and for each of the three calcareous otoliths associated with the sensory maculae (lagena, saccule, and utricle) in the OC. All three otoliths had higher attenuations than any sites in the neurocranium. Both dorsal and ventral reference sites (supraoccipital crest and parasphenoid bone, respectively) had attenuation levels consistent with calcified bone and had relatively small, irregular variations along the length of the OC in all individuals. The lowest relative attenuations (lowest densities) occurred consistently at the three sites along the OC. In addition, the lowest attenuations measured along the OC occurred at the ventromedial site around the saccular otolith for all seven fish. The decrease in bone density along the OC is consistent with the hypothesis that there is a low-density channel in the skull to facilitate transmission of acoustic stimuli to the auditory endorgans of the ear. © 2014 Wiley Periodicals, Inc.

Sediment and channel-geometry investigations for the Kansas River bank stabilization study, Kansas, Nebraska, and Colorado

USGS Publications Warehouse

Osterkamp, W.R.; Curtis, R.E.; Crowther, H.G.

1982-01-01

Analysis of hydrologic data from the Kansas River basin suggests that the channels of the lower Solomon, Saline, and Smoky Hill Rivers have narrowed and stabilized as a result of construction of upstream reservoirs. The Kansas River channel, however, remains relatively unstable and locally active. Streamflow regulation and sediment trapping by reservoirs are possible causes of changes occurring at various Kansas River sites. An inferred deficiency of the suspended-sediment load, however, is likely to cause continuing instability. Suspended sediment in the Kansas River apparently is too sparse to form and maintain stable alluvial banks. The deficiency probably results in an increase of bed material movement, general channel widening, and local braiding. Significant channel degradation is lacking at most sites, but may occur in response to long-term (decades-to-centuries) regulation. Recent degradation near Bonner Springs, Kans., may be the result of sand and gravel removal. Any imposed changes that shorten the channel or reduce the suspended-sediment discharge of the Kansas River are expected to cause additional channel instability. (USGS)

Redox Signaling via Oxidative Inactivation of PTEN Modulates Pressure-Dependent Myogenic Tone in Rat Middle Cerebral Arteries

PubMed Central

Gebremedhin, Debebe; Terashvili, Maia; Wickramasekera, Nadi; Zhang, David X.; Rau, Nicole; Miura, Hiroto; Harder, David R.

2013-01-01

The present study examined the level of generation of reactive oxygen species (ROS) and roles of inactivation of the phosphatase PTEN and the PI3K/Akt signaling pathway in response to an increase in intramural pressure-induced myogenic cerebral arterial constriction. Step increases in intraluminal pressure of cannulated cerebral arteries induced myogenic constriction and concomitant formation of superoxide (O2 .−) and its dismutation product hydrogen peroxide (H2O2) as determined by fluorescent HPLC analysis, microscopic analysis of intensity of dihydroethidium fluorescence and attenuation of pressure-induced myogenic constriction by pretreatment with the ROS scavenger 4,hydroxyl-2,2,6,6-tetramethylpiperidine1-oxyl (tempol) or Mito-tempol or MitoQ in the presence or absence of PEG-catalase. An increase in intraluminal pressure induced oxidation of PTEN and activation of Akt. Pharmacological inhibition of endogenous PTEN activity potentiated pressure-dependent myogenic constriction and caused a reduction in NPo of a 238 pS arterial KCa channel current and an increase in [Ca2+]i level in freshly isolated cerebral arterial muscle cells (CAMCs), responses that were attenuated by Inhibition of the PI3K/Akt pathway. These findings demonstrate an increase in intraluminal pressure induced increase in ROS production triggered redox-sensitive signaling mechanism emanating from the cross-talk between oxidative inactivation of PTEN and activation of the PI3K/Akt signaling pathway that involves in the regulation of pressure-dependent myogenic cerebral arterial constriction. PMID:23861911

Redox signaling via oxidative inactivation of PTEN modulates pressure-dependent myogenic tone in rat middle cerebral arteries.

PubMed

Gebremedhin, Debebe; Terashvili, Maia; Wickramasekera, Nadi; Zhang, David X; Rau, Nicole; Miura, Hiroto; Harder, David R

2013-01-01

The present study examined the level of generation of reactive oxygen species (ROS) and roles of inactivation of the phosphatase PTEN and the PI3K/Akt signaling pathway in response to an increase in intramural pressure-induced myogenic cerebral arterial constriction. Step increases in intraluminal pressure of cannulated cerebral arteries induced myogenic constriction and concomitant formation of superoxide (O2 (.-)) and its dismutation product hydrogen peroxide (H2O2) as determined by fluorescent HPLC analysis, microscopic analysis of intensity of dihydroethidium fluorescence and attenuation of pressure-induced myogenic constriction by pretreatment with the ROS scavenger 4,hydroxyl-2,2,6,6-tetramethylpiperidine1-oxyl (tempol) or Mito-tempol or MitoQ in the presence or absence of PEG-catalase. An increase in intraluminal pressure induced oxidation of PTEN and activation of Akt. Pharmacological inhibition of endogenous PTEN activity potentiated pressure-dependent myogenic constriction and caused a reduction in NPo of a 238 pS arterial KCa channel current and an increase in [Ca(2+)]i level in freshly isolated cerebral arterial muscle cells (CAMCs), responses that were attenuated by Inhibition of the PI3K/Akt pathway. These findings demonstrate an increase in intraluminal pressure induced increase in ROS production triggered redox-sensitive signaling mechanism emanating from the cross-talk between oxidative inactivation of PTEN and activation of the PI3K/Akt signaling pathway that involves in the regulation of pressure-dependent myogenic cerebral arterial constriction.

Reconfigurable high-speed optical fibre networks: Optical wavelength conversion and switching using VCSELs to eliminate channel collisions

NASA Astrophysics Data System (ADS)

Boiyo, Duncan Kiboi; Chabata, T. V.; Kipnoo, E. K. Rotich; Gamatham, R. R. G.; Leitch, A. W. R.; Gibbon, T. B.

2017-01-01

We experimentally provide an alternative solution to channel collisions through up-wavelength conversion and switching by using vertical cavity surface-emitting lasers (VCSELs). This has been achieved by utilizing purely optical wavelength conversion on VCSELs at the low attenuation, 1550 nm transmission window. The corresponding transmission and bit error-rate (BER) performance evaluation is also presented. In this paper, two 1550 nm VCSELs with 50-150 GHz channel spacing are modulated with a 10 Gb/s NRZ PRBS 27-1 data and their interferences investigated. A channel interference penalty range of 0.15-1.63 dB is incurred for 150-50 GHz channel spacing without transmission. To avoid channel collisions and to minimize high interference penalties, the transmitting VCSEL with data is injected into the side-mode of a slave VCSEL to obtain a new up converted wavelength. A 16 dB extinction ratio of the incoming wavelength is achieved when a 15 dBm transmitting beam is injected into the side-mode of a -4.5 dBm slave VCSEL. At 8.5 Gb/s, a 1.1 dB conversion and a 0.5 dB transmission penalties are realized when the converted wavelength is transmitted over a 24.7 km G.655 fibre. This work offers a low-cost, effective wavelength conversion and channel switching to reduce channel collision probability by reconfiguring channels at the node of networks.

Understanding Charge Collection Mechanisms in InGaAs FinFETs Using High-Speed Pulsed-Laser Transient Testing With Tunable Wavelength

NASA Astrophysics Data System (ADS)

Ni, Kai; Sternberg, Andrew L.; Zhang, En Xia; Kozub, John A.; Jiang, Rong; Schrimpf, Ronald D.; Reed, Robert A.; Fleetwood, Daniel M.; Alles, Michael L.; McMorrow, Dale; Lin, Jianqiang; Vardi, Alon; del Alamo, Jesús

2017-08-01

A tunable wavelength laser system and high-resolution transient capture system are introduced to characterize transients in high-mobility MOSFETs. The experimental configuration enables resolution of fast transient signals and new understanding of charge collection mechanisms. The channel layer is critical in the charge collection process for the InGaAs FinFETs examined here. The transient current mainly comes from the channel current, due to shunt effects and parasitic bipolar effects, instead of the junction collection. The charge amplification factor is found to be as high as 14, which makes this technology relatively sensitive to transient radiation. The peak current is inversely proportional to the device gate length. Simulations show that the parasitic bipolar effect is due to source-to-channel barrier lowering caused by hole accumulation in the source and channel. Charge deposited in the channel causes prompt current, while charge deposited below the channel causes delayed and slow current.

Habitat conditions of montane meadows associated with restored and unrestored stream channels of California

Treesearch

K. L. Pope; D. S. Montoya; J. N. Brownlee; J. Dierks; T. E. Lisle

2015-01-01

Mountain meadow habitats are valued for their ecological importance. They attenuate floods, improve water quality, and support high biodiversity. Many meadow habitats in the western US are degraded, and efforts are increasing to restore these montane meadow ecosystems. Rewatering projects such as pond-and-plug quickly raise the water table by blocking the existing...

Novel experimental technique for 3D investigation of high-speed cavitating diesel fuel flows by X-ray micro computed tomography

NASA Astrophysics Data System (ADS)

Lorenzi, M.; Mitroglou, N.; Santini, M.; Gavaises, M.

2017-03-01

An experimental technique for the estimation of the temporal-averaged vapour volume fraction within high-speed cavitating flow orifices is presented. The scientific instrument is designed to employ X-ray micro computed tomography (microCT) as a quantitative 3D measuring technique applied to custom designed, large-scale, orifice-type flow channels made from Polyether-ether-ketone (PEEK). The attenuation of the ionising electromagnetic radiation by the fluid under examination depends on its local density; the transmitted radiation through the cavitation volume is compared to the incident radiation, and combination of radiographies from sufficient number of angles leads to the reconstruction of attenuation coefficients versus the spatial position. This results to a 3D volume fraction distribution measurement of the developing multiphase flow. The experimental results obtained are compared against the high speed shadowgraph visualisation images obtained in an optically transparent nozzle with identical injection geometry; comparison between the temporal mean image and the microCT reconstruction shows excellent agreement. At the same time, the real 3D internal channel geometry (possibly eroded) has been measured and compared to the nominal manufacturing CAD drawing of the test nozzle.

Novel experimental technique for 3D investigation of high-speed cavitating diesel fuel flows by X-ray micro computed tomography.

PubMed

Lorenzi, M; Mitroglou, N; Santini, M; Gavaises, M

2017-03-01

An experimental technique for the estimation of the temporal-averaged vapour volume fraction within high-speed cavitating flow orifices is presented. The scientific instrument is designed to employ X-ray micro computed tomography (microCT) as a quantitative 3D measuring technique applied to custom designed, large-scale, orifice-type flow channels made from Polyether-ether-ketone (PEEK). The attenuation of the ionising electromagnetic radiation by the fluid under examination depends on its local density; the transmitted radiation through the cavitation volume is compared to the incident radiation, and combination of radiographies from sufficient number of angles leads to the reconstruction of attenuation coefficients versus the spatial position. This results to a 3D volume fraction distribution measurement of the developing multiphase flow. The experimental results obtained are compared against the high speed shadowgraph visualisation images obtained in an optically transparent nozzle with identical injection geometry; comparison between the temporal mean image and the microCT reconstruction shows excellent agreement. At the same time, the real 3D internal channel geometry (possibly eroded) has been measured and compared to the nominal manufacturing CAD drawing of the test nozzle.

Measurement of breast-tissue x-ray attenuation by spectral mammography: solid lesions

NASA Astrophysics Data System (ADS)

Fredenberg, Erik; Kilburn-Toppin, Fleur; Willsher, Paula; Moa, Elin; Danielsson, Mats; Dance, David R.; Young, Kenneth C.; Wallis, Matthew G.

2016-04-01

Knowledge of x-ray attenuation is essential for developing and evaluating x-ray imaging technologies. For instance, techniques to distinguish between cysts and solid tumours at mammography screening would be highly desirable to reduce recalls, but the development requires knowledge of the x-ray attenuation for cysts and tumours. We have previously measured the attenuation of cyst fluid using photon-counting spectral mammography. Data on x-ray attenuation for solid breast lesions are available in the literature, but cover a relatively wide range, likely caused by natural spread between samples, random measurement errors, and different experimental conditions. In this study, we have adapted a previously developed spectral method to measure the linear attenuation of solid breast lesions. A total of 56 malignant and 5 benign lesions were included in the study. The samples were placed in a holder that allowed for thickness measurement. Spectral (energy-resolved) images of the samples were acquired and the image signal was mapped to equivalent thicknesses of two known reference materials, which can be used to derive the x-ray attenuation as a function of energy. The spread in equivalent material thicknesses was relatively large between samples, which is likely to be caused mainly by natural variation and only to a minor extent by random measurement errors and sample inhomogeneity. No significant difference in attenuation was found between benign and malignant solid lesions. The separation between cyst-fluid and tumour attenuation was, however, significant, which suggests it may be possible to distinguish cystic from solid breast lesions, and the results lay the groundwork for a clinical trial. In addition, the study adds a relatively large sample set to the published data and may contribute to a reduction in the overall uncertainty in the literature.

Attenuation of tumor necrosis factor-induced endothelial cell cytotoxicity and neutrophil chemiluminescence

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zheng, H.; Crowley, J.J.; Chan, J.C.

Our laboratory has previously shown that the administration of tumor necrosis factor (TNF), a cytokine produced by activated mononuclear cells, to guinea pigs produces a syndrome similar to gram-negative sepsis or ARDS. Pentoxifylline (PTX), a methylxanthine, protects against TNF-induced and sepsis-induced acute lung injury in vivo. We now report on in vitro cellular studies of PMN-mediated cellular injury and its attenuation. We studied TNF-induced bovine pulmonary artery endothelial cell (EC) cytotoxicity both with and without PMN. A 51Cr release assay was used to measure EC damage. Further, we investigated PMN function in response to TNF by measuring chemiluminescence. Agents thatmore » attenuate EC damage and PMN activation were evaluated in the above assays. Results revealed that TNF causes EC injury (p less than 0.05) and PMN increase TNF-induced EC injury. Furthermore, PTX, aminophylline (AMPH), caffeine, and forskolin attenuate TNF-induced EC cytotoxicity only in the presence of PMN (p less than 0.05). Of interest, dibutyryl cAMP (DBcAMP) protects EC from TNF-induced injury both with and without PMN. Agents that may increase cAMP levels in PMN (PTX, DBcAMP, forskolin, isobutyl methylxanthine, and terbutaline) significantly attenuate TNF-induced PMN chemiluminescence (p less than 0.05). We conclude that TNF causes EC damage and PMN increase this damage. Furthermore, PTX, AMPH, caffeine, and forskolin can attenuate TNF-induced EC injury in the presence of PMN, whereas DBcAMP attenuates TNF-induced EC injury with and without PMN. In addition, agents that may increase intracellular cAMP levels in PMN can attenuate TNF-induced PMN chemiluminescence. Thus, these agents likely attenuate TNF-induced PMN-mediated EC injury through their inhibitory effects on PMN.« less

Constraints on mantle melt geometries from body wave attenuation in the Salton Trough and Snake River Plain

NASA Astrophysics Data System (ADS)

Byrnes, J. S.; Bezada, M.

2017-12-01

Melt can be retained in the mantle at triple junctions between grain boundaries, be spread in thin films along two-grain boundaries, or be organized by shear into elongate melt-rich bands. Which of these geometries is most prevalent is unknown. This ambiguity makes the interpretation of anomalous seismic velocities and quality factors difficult, since different geometries would result in different mechanical effects. Here, we compare observations of seismic attenuation beneath the Salton Trough and the Snake River Plain; two regions where the presence of melt has been inferred. The results suggest that seismic attenuation is diagnostic of melt geometry. We measure the relative attenuation of P waves from deep focus earthquakes using a time-domain method. Even though the two regions are underlain by comparably strong low-velocity anomalies, their attenuation signature is very different. The upper mantle beneath the Salton Trough is sufficiently attenuating that the presence of melt must lower Qp, while attenuation beneath the Snake River Plain is not anomalous with respect to surrounding regions. These seemingly contradictory results can be reconciled if different melt geometries characterize each region. SKS splitting from the Salton Trough suggests that melt is organized into melt-rich bands, while this is not the case for the Snake River Plain. We infer that beneath the Snake River Plain melt is retained at triple junctions between grain boundaries, a geometry that is not predicted to cause seismic attenuation. More elongate geometries beneath the Salton Trough may cause seismic attenuation via the melt-squirt mechanism. In light of these results, we conclude that prior observations of low seismic velocities with somewhat high quality factors beneath the East Pacific Rise and Southern California suggest that melt does not organize into elongate bands across much of the asthenosphere.

Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons.

PubMed

Battefeld, Arne; Tran, Baouyen T; Gavrilis, Jason; Cooper, Edward C; Kole, Maarten H P

2014-03-05

Rapid energy-efficient signaling along vertebrate axons is achieved through intricate subcellular arrangements of voltage-gated ion channels and myelination. One recently appreciated example is the tight colocalization of K(v)7 potassium channels and voltage-gated sodium (Na(v)) channels in the axonal initial segment and nodes of Ranvier. The local biophysical properties of these K(v)7 channels and the functional impact of colocalization with Na(v) channels remain poorly understood. Here, we quantitatively examined K(v)7 channels in myelinated axons of rat neocortical pyramidal neurons using high-resolution confocal imaging and patch-clamp recording. K(v)7.2 and 7.3 immunoreactivity steeply increased within the distal two-thirds of the axon initial segment and was mirrored by the conductance density estimates, which increased from ~12 (proximal) to 150 pS μm(-2) (distal). The axonal initial segment and nodal M-currents were similar in voltage dependence and kinetics, carried by K(v)7.2/7.3 heterotetramers, 4% activated at the resting membrane potential and rapidly activated with single-exponential time constants (~15 ms at 28 mV). Experiments and computational modeling showed that while somatodendritic K(v)7 channels are strongly activated by the backpropagating action potential to attenuate the afterdepolarization and repetitive firing, axonal K(v)7 channels are minimally recruited by the forward-propagating action potential. Instead, in nodal domains K(v)7.2/7.3 channels were found to increase Na(v) channel availability and action potential amplitude by stabilizing the resting membrane potential. Thus, K(v)7 clustering near axonal Na(v) channels serves specific and context-dependent roles, both restraining initiation and enhancing conduction of the action potential.

Heteromeric Kv7.2/7.3 Channels Differentially Regulate Action Potential Initiation and Conduction in Neocortical Myelinated Axons

PubMed Central

Battefeld, Arne; Tran, Baouyen T.; Gavrilis, Jason; Cooper, Edward C.

2014-01-01

Rapid energy-efficient signaling along vertebrate axons is achieved through intricate subcellular arrangements of voltage-gated ion channels and myelination. One recently appreciated example is the tight colocalization of Kv7 potassium channels and voltage-gated sodium (Nav) channels in the axonal initial segment and nodes of Ranvier. The local biophysical properties of these Kv7 channels and the functional impact of colocalization with Nav channels remain poorly understood. Here, we quantitatively examined Kv7 channels in myelinated axons of rat neocortical pyramidal neurons using high-resolution confocal imaging and patch-clamp recording. Kv7.2 and 7.3 immunoreactivity steeply increased within the distal two-thirds of the axon initial segment and was mirrored by the conductance density estimates, which increased from ∼12 (proximal) to 150 pS μm−2 (distal). The axonal initial segment and nodal M-currents were similar in voltage dependence and kinetics, carried by Kv7.2/7.3 heterotetramers, 4% activated at the resting membrane potential and rapidly activated with single-exponential time constants (∼15 ms at 28 mV). Experiments and computational modeling showed that while somatodendritic Kv7 channels are strongly activated by the backpropagating action potential to attenuate the afterdepolarization and repetitive firing, axonal Kv7 channels are minimally recruited by the forward-propagating action potential. Instead, in nodal domains Kv7.2/7.3 channels were found to increase Nav channel availability and action potential amplitude by stabilizing the resting membrane potential. Thus, Kv7 clustering near axonal Nav channels serves specific and context-dependent roles, both restraining initiation and enhancing conduction of the action potential. PMID:24599470

Involvement of atrial natriuretic peptide in abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart.

PubMed

Vishwakarma, V K; Goyal, A; Gupta, J K; Upadhyay, P K; Yadav, H N

2018-07-01

Nitric oxide (NO) is an effective mediator of ischemic preconditioning (IPC)-induced cardioprotection. Atrial natriuretic peptide (ANP) is downregulated after ovariectomy, which results in reduction in the level of NO. The present study deals with the investigation of the role of ANP in abrogated cardioprotective effect of IPC in the ovariectomized rat heart. Heart was isolated from ovariectomized rat and mounted on Langendorff's apparatus, subjected to 30 min of ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Krebs-Henseleit solution. The myocardial infract size was estimated employing triphenyltetrazolium chloride stain, and coronary effluent was analyzed for creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release to consider the degree of myocardial injury. The cardiac release of NO was estimated by measuring the level of nitrite in coronary effluent. IPC-mediated cardioprotection was significantly attenuated in ovariectomized rat as compared to normal rat, which was restored by perfusion with ANP. However, this observed cardioprotection was significantly attenuated by perfusion with L-NAME, an endothelial nitric oxide synthase inhibitor, and Glibenclamide, a K ATP channel blocker, alone or in combination noted in terms of increase in myocardial infract size, release of CK-MB and LDH, and also decrease in release of NO. Thus, it is suggested that ANP restores the attenuated cardioprotective effect of IPC in the ovariectomized rat heart which may be due to increase in the availability of NO and consequent increase activation of mitochondrial K ATP channels.

The effect of an L/N-type calcium channel blocker on intradialytic blood pressure in intradialytic hypertensive patients.

PubMed

Ito, Takayasu; Fujimoto, Naoki; Ishikawa, Eiji; Dohi, Kaoru; Fujimoto, Mika; Murata, Tomohiro; Kiyohara, Michiyo; Takeuchi, Hideyuki; Koyabu, Sukenari; Nishimura, Hiroyuki; Takeuchi, Toshiaki; Ito, Masaaki

2018-03-27

Intradialytic hypertension (HTN), which is one of the poor prognostic markers in patients undergoing hemodialysis, may be associated with sympathetic overactivity. The L/N-type calcium channel blocker, cilnidipine, has been reported to suppress sympathetic nerves activity in vivo. Therefore, we hypothesized that cilnidipine could attenuate intradialytic systolic blood pressure (SBP) elevation. Fifty-one patients on chronic hemodialysis who had intradialytic-HTN (SBP elevation ≥10 mmHg during hemodialysis) and no fluid overload were prospectively randomized into two groups: control and cilnidipine groups. Cilnidipine group patients took cilnidipine (10 mg/day) for 12 weeks. The primary endpoint was the change in the intradialytic SBP elevation before and after the 12-week intervention. Before the intervention, no differences were observed in age, sex or pre-dialytic SBP (148.5 ± 12.9 vs. 148.3 ± 19.3 mmHg) between the two groups. Intradialytic SBP elevation was unchanged in the control group. Cilnidipine significantly lowered the post-dialytic SBP with an attenuation of the intradialytic SBP elevation from 12.0 ± 15.4 mmHg to 4.8 ± 10.1 mmHg. However, the observed difference in the intradialytic SBP elevation by cilnidipine did not reach statistical significance (group×time interaction effect p = 0.25). Cathecolamine levels were unaffected by the intervention in both groups. Cilnidipine lowers both the pre- and post-dialytic SBP and might attenuate intradialytic SBP elevation. Therefore, cilnidipine may be effective in lowering SBP during HD in patients with intradialytic-HTN.

Angiotensin II Inhibits the ROMK-like Small Conductance K Channel in Renal Cortical Collecting Duct during Dietary Potassium Restriction*

PubMed Central

Wei, Yuan; Zavilowitz, Beth; Satlin, Lisa M.; Wang, Wen-Hui

2010-01-01

Base-line urinary potassium secretion in the distal nephron is mediated by small conductance rat outer medullary K (ROMK)-like channels. We used the patch clamp technique applied to split-open cortical collecting ducts (CCDs) isolated from rats fed a normal potassium (NK) or low potassium (LK) diet to test the hypothesis that AngII directly inhibits ROMK channel activity. We found that AngII inhibited ROMK channel activity in LK but not NK rats in a dose-dependent manner. The AngII-induced reduction in channel activity was mediated by AT1 receptor (AT1R) binding, because pretreatment of CCDs with losartan but not PD123319 AT1 and AT2 receptor antagonists, respectively, blocked the response. Pretreatment of CCDs with U73122 and calphostin C, inhibitors of phospholipase C (PLC) and protein kinase C (PKC), respectively, abolished the AngII-induced decrease in ROMK channel activity, confirming a role of the PLC-PKC pathway in this response. Studies by others suggest that AngII stimulates an Src family protein-tyrosine kinase (PTK) via PKC-NADPH oxidase. PTK has been shown to regulate the ROMK channel. Inhibition of NADPH oxidase with diphenyliodonium abolished the inhibitory effect of AngII or the PKC activator phorbol 12-myristate 13-acetate on ROMK channels. Suppression of PTK by herbimycin A significantly attenuated the inhibitory effect of AngII on ROMK channel activity. We conclude that AngII inhibits ROMK channel activity through PKC-, NADPH oxidase-, and PTK-dependent pathways under conditions of dietary potassium restriction. PMID:17194699

Angiotensin II inhibits the ROMK-like small conductance K channel in renal cortical collecting duct during dietary potassium restriction.

PubMed

Wei, Yuan; Zavilowitz, Beth; Satlin, Lisa M; Wang, Wen-Hui

2007-03-02

Base-line urinary potassium secretion in the distal nephron is mediated by small conductance rat outer medullary K (ROMK)-like channels. We used the patch clamp technique applied to split-open cortical collecting ducts (CCDs) isolated from rats fed a normal potassium (NK) or low potassium (LK) diet to test the hypothesis that AngII directly inhibits ROMK channel activity. We found that AngII inhibited ROMK channel activity in LK but not NK rats in a dose-dependent manner. The AngII-induced reduction in channel activity was mediated by AT1 receptor (AT1R) binding, because pretreatment of CCDs with losartan but not PD123319 AT1 and AT2 receptor antagonists, respectively, blocked the response. Pretreatment of CCDs with U73122 and calphostin C, inhibitors of phospholipase C (PLC) and protein kinase C (PKC), respectively, abolished the AngII-induced decrease in ROMK channel activity, confirming a role of the PLC-PKC pathway in this response. Studies by others suggest that AngII stimulates an Src family protein-tyrosine kinase (PTK) via PKC-NADPH oxidase. PTK has been shown to regulate the ROMK channel. Inhibition of NADPH oxidase with diphenyliodonium abolished the inhibitory effect of AngII or the PKC activator phorbol 12-myristate 13-acetate on ROMK channels. Suppression of PTK by herbimycin A significantly attenuated the inhibitory effect of AngII on ROMK channel activity. We conclude that AngII inhibits ROMK channel activity through PKC-, NADPH oxidase-, and PTK-dependent pathways under conditions of dietary potassium restriction.

Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons.

PubMed

Zemel, Benjamin M; Muqeem, Tanziyah; Brown, Eric V; Goulão, Miguel; Urban, Mark W; Tymanskyj, Stephen R; Lepore, Angelo C; Covarrubias, Manuel

2017-08-23

Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI. SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have received significant attention, recent studies have identified peripheral nerve hyperexcitability as a driver of persistent pain signaling after SCI. However, the ion channels and signaling molecules responsible for this change in primary sensory neuron excitability are still not well defined. To address this problem, this study used complementary electrophysiological and molecular methods to determine how Kv3.4, a voltage-gated K + channel robustly expressed in dorsal root ganglion neurons, becomes dysfunctional upon calcineurin (CaN) inhibition. The results strongly suggest that CaN inhibition underlies SCI-induced dysfunction of Kv3.4 and the associated excitability changes through upregulation of the native regulator of CaN 1 (RCAN1). Copyright © 2017 the authors 0270-6474/17/378257-17$15.00/0.

Patient position alters attenuation effects in multipinhole cardiac SPECT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Timmins, Rachel; Ruddy, Terrence D.; Wells, R. Glenn, E-mail: gwells@ottawaheart.ca

2015-03-15

Purpose: Dedicated cardiac cameras offer improved sensitivity over conventional SPECT cameras. Sensitivity gains are obtained by large numbers of detectors and novel collimator arrangements such as an array of multiple pinholes that focus on the heart. Pinholes lead to variable amounts of attenuation as a source is moved within the camera field of view. This study evaluated the effects of this variable attenuation on myocardial SPECT images. Methods: Computer simulations were performed for a set of nine point sources distributed in the left ventricular wall (LV). Sources were placed at the location of the heart in both an anthropomorphic andmore » a water-cylinder computer phantom. Sources were translated in x, y, and z by up to 5 cm from the center. Projections were simulated with and without attenuation and the changes in attenuation were compared. A LV with an inferior wall defect was also simulated in both phantoms over the same range of positions. Real camera data were acquired on a Discovery NM530c camera (GE Healthcare, Haifa, Israel) for five min in list-mode using an anthropomorphic phantom (DataSpectrum, Durham, NC) with 100 MBq of Tc-99m in the LV. Images were taken over the same range of positions as the simulations and were compared based on the summed perfusion score (SPS), defect width, and apparent defect uptake for each position. Results: Point sources in the water phantom showed absolute changes in attenuation of ≤8% over the range of positions and relative changes of ≤5% compared to the apex. In the anthropomorphic computer simulations, absolute change increased to 20%. The changes in relative attenuation caused a change in SPS of <1.5 for the water phantom but up to 4.2 in the anthropomorphic phantom. Changes were larger for axial than for transverse translations. These results were supported by SPS changes of up to six seen in the physical anthropomorphic phantom for axial translations. Defect width was also seen to significantly increase. The position-dependent changes were removed with attenuation correction. Conclusions: Translation of a source relative to a multipinhole camera caused only small changes in homogeneous phantoms with SPS changing <1.5. Inhomogeneous attenuating media cause much larger changes to occur when the source is translated. Changes in SPS of up to six were seen in an anthropomorphic phantom for axial translations. Attenuation correction removes the position-dependent changes in attenuation.« less

Modified polarized geometrical attenuation model for bidirectional reflection distribution function based on random surface microfacet theory.

PubMed

Liu, Hong; Zhu, Jingping; Wang, Kai

2015-08-24

The geometrical attenuation model given by Blinn was widely used in the geometrical optics bidirectional reflectance distribution function (BRDF) models. Blinn's geometrical attenuation model based on symmetrical V-groove assumption and ray scalar theory causes obvious inaccuracies in BRDF curves and negatives the effects of polarization. Aiming at these questions, a modified polarized geometrical attenuation model based on random surface microfacet theory is presented by combining of masking and shadowing effects and polarized effect. The p-polarized, s-polarized and unpolarized geometrical attenuation functions are given in their separate expressions and are validated with experimental data of two samples. It shows that the modified polarized geometrical attenuation function reaches better physical rationality, improves the precision of BRDF model, and widens the applications for different polarization.

Pulsed magnetic stimulation modifies amplitude of action potentials in vitro via ionic channels-dependent mechanism.

PubMed

Ahmed, Zaghloul; Wieraszko, Andrzej

2015-07-01

This paper investigates the influence of pulsed magnetic fields (PMFs) on amplitude of evoked, compound action potential (CAP) recorded from the segments of sciatic nerve in vitro. PMFs were applied for 30 min at frequency of 0.16 Hz and intensity of 15 mT. In confirmation of our previous reports, PMF exposure enhanced amplitude of CAPs. The effect persisted beyond PMF activation period. As expected, CAP amplitude was attenuated by antagonists of sodium channel, lidocaine, and tetrodotoxin. Depression of the potential by sodium channels antagonists was reversed by subsequent exposure to PMFs. The effect of elevated potassium concentration and veratridine on the action potential was modified by exposure to PMFs as well. Neither inhibitors of protein kinase C and protein kinase A, nor known free radicals scavengers had any effects on PMF action. Possible mechanisms of PMF action are discussed. © 2015 Wiley Periodicals, Inc.

Tunable high-channel-count bandstop graphene plasmonic filters based on plasmon induced transparency

NASA Astrophysics Data System (ADS)

Zhang, Zhengren; Long, Yang; Ma, Pengyu; Li, Hongqiang

2017-11-01

A high-channel-count bandstop graphene plasmonic filter based on ultracompact plasmonic structure is proposed in this paper. It consists of graphene waveguide side-coupled with a series of graphene filtering units. The study shows that the waveguide-resonator system performs a multiple plasmon induced transparency (PIT) phenomenon. By carefully adjusting the Fermi level of the filtering units, any two adjacent transmitted dips which belong to different PIT units can produce coherent coupling superposition enhancement. This property prevents the attenuation of the high-frequency transmission dips of multiple PIT and leads to an excellent bandstop filter with multiple channels. Specifically, the bandwidth and modulation depth of the filters can be flexibly adjusted by tuning the Fermi energy of the graphene waveguide. This ultracompact plasmonic structure contributes to the achievement of frequency division multiplexing systems for optical computing and communications in highly integrated optical circuits.

TRPC5 channels participate in pressure-sensing in aortic baroreceptors

PubMed Central

Lau, On-Chai; Shen, Bing; Wong, Ching-On; Tjong, Yung-Wui; Lo, Chun-Yin; Wang, Hui-Chuan; Huang, Yu; Yung, Wing-Ho; Chen, Yang-Chao; Fung, Man-Lung; Rudd, John Anthony; Yao, Xiaoqiang

2016-01-01

Blood pressure is maintained within a normal physiological range by a sophisticated regulatory mechanism. Baroreceptors serve as a frontline sensor to detect the change in blood pressure. Nerve signals are then sent to the cardiovascular control centre in the brain in order to stimulate baroreflex responses. Here, we identify TRPC5 channels as a mechanical sensor in aortic baroreceptors. In Trpc5 knockout mice, the pressure-induced action potential firings in the afferent nerve and the baroreflex-mediated heart rate reduction are attenuated. Telemetric measurements of blood pressure demonstrate that Trpc5 knockout mice display severe daily blood pressure fluctuation. Our results suggest that TRPC5 channels represent a key pressure transducer in the baroreceptors and play an important role in maintaining blood pressure stability. Because baroreceptor dysfunction contributes to a variety of cardiovascular diseases including hypertension, heart failure and myocardial infarction, our findings may have important future clinical implications. PMID:27411851

Distillation of mixed-state continuous-variable entanglement by photon subtraction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Shengli; Loock, Peter van

2010-12-15

We present a detailed theoretical analysis for the distillation of one copy of a mixed two-mode continuous-variable entangled state using beam splitters and coherent photon-detection techniques, including conventional on-off detectors and photon-number-resolving detectors. The initial Gaussian mixed-entangled states are generated by transmitting a two-mode squeezed state through a lossy bosonic channel, corresponding to the primary source of errors in current approaches to optical quantum communication. We provide explicit formulas to calculate the entanglement in terms of logarithmic negativity before and after distillation, including losses in the channel and the photon detection, and show that one-copy distillation is still possible evenmore » for losses near the typical fiber channel attenuation length. A lower bound for the transmission coefficient of the photon-subtraction beam splitter is derived, representing the minimal value that still allows to enhance the entanglement.« less

Helicity, membrane incorporation, orientation and thermal stability of the large conductance mechanosensitive ion channel from E. coli

NASA Technical Reports Server (NTRS)

Arkin, I. T.; Sukharev, S. I.; Blount, P.; Kung, C.; Brunger, A. T.

1998-01-01

In this report, we present structural studies on the large conductance mechanosensitive ion channel (MscL) from E. coli in detergent micelles and lipid vesicles. Both transmission Fourier transform infrared spectroscopy and circular dichroism (CD) spectra indicate that the protein is highly helical in detergents as well as liposomes. The secondary structure of the proteins was shown to be highly resistant towards denaturation (25-95 degrees C) based on an ellipticity thermal profile. Amide H+/D+ exchange was shown to be extensive (ca. 66%), implying that two thirds of the protein are water accessible. MscL, reconstituted in oriented lipid bilayers, was shown to possess a net bilayer orientation using dichroic ratios measured by attenuated total-reflection Fourier transform infrared spectroscopy. Here, we present and discuss this initial set of structural data on this new family of ion-channel proteins.

Seismic-wave attenuation associated with crustal faults in the New Madrid seismic zone

USGS Publications Warehouse

Hamilton, R.M.; Mooney, W.D.

1990-01-01

The attenuation of upper crustal seismic waves that are refracted with a velocity of about 6 kilometers per second varies greatly among profiles in the area of the New Madrid seismic zone in the central Mississippi Valley. The waves that have the strongest attenuation pass through the seismic trend along the axis of the Reelfoot rift in the area of the Blytheville arch. Defocusing of the waves in a low-velocity zone and/ or seismic scattering and absorption could cause the attenuation; these effects are most likely associated with the highly deformed rocks along the arch. Consequently, strong seismic-wave attenuation may be a useful criterion for identifying seismogenic fault zones.

Automated Filtering of Common Mode Artifacts in Multi-Channel Physiological Recordings

PubMed Central

Kelly, John W.; Siewiorek, Daniel P.; Smailagic, Asim; Wang, Wei

2014-01-01

The removal of spatially correlated noise is an important step in processing multi-channel recordings. Here, a technique termed the adaptive common average reference (ACAR) is presented as an effective and simple method for removing this noise. The ACAR is based on a combination of the well-known common average reference (CAR) and an adaptive noise canceling (ANC) filter. In a convergent process, the CAR provides a reference to an ANC filter, which in turn provides feedback to enhance the CAR. This method was effective on both simulated and real data, outperforming the standard CAR when the amplitude or polarity of the noise changes across channels. In many cases the ACAR even outperformed independent component analysis (ICA). On 16 channels of simulated data the ACAR was able to attenuate up to approximately 290 dB of noise and could improve signal quality if the original SNR was as high as 5 dB. With an original SNR of 0 dB, the ACAR improved signal quality with only two data channels and performance improved as the number of channels increased. It also performed well under many different conditions for the structure of the noise and signals. Analysis of contaminated electrocorticographic (ECoG) recordings further showed the effectiveness of the ACAR. PMID:23708770

Performance Investigation of FSO-OFDM Communication Systems under the Heavy Rain Weather

NASA Astrophysics Data System (ADS)

Rashidi, Florence; He, Jing; Chen, Lin

2017-12-01

The challenge in the free-space optical (FSO) communication is the propagation of optical signal through different atmospheric conditions such as rain, snow and fog. In this paper, an orthogonal frequency-division multiplexing technique (OFDM) is proposed in the FSO communication system. Meanwhile, considering the rain attenuation models based on Marshal & Palmer and Carbonneau models, the performance of FSO communication system based on the OFDM is evaluated under the heavy-rain condition in Changsha, China. The simulation results show that, under a heavy-rainfall condition of 106.18 mm/h, with an attenuation factor of 7 dB/km based on the Marshal & Palmer model, the bit rate of 2.5 and 4.0 Gbps data can be transmitted over the FSO channels of 1.6 and 1.3 km, respectively, and the bit error rate of less than 1E - 4 can be achieved. In addition, the effect on rain attenuation over the FSO communication system based on the Marshal & Palmer model is less than that of the Carbonneau model.

Calibration of an M L scale for South Africa using tectonic earthquake data recorded by the South African National Seismograph Network: 2006 to 2009

NASA Astrophysics Data System (ADS)

Saunders, Ian; Ottemöller, Lars; Brandt, Martin B. C.; Fourie, Christoffel J. S.

2013-04-01

A relation to determine local magnitude ( M L) based on the original Richter definition is empirically derived from synthetic Wood-Anderson seismograms recorded by the South African National Seismograph Network. In total, 263 earthquakes in the distance range 10 to 1,000 km, representing 1,681 trace amplitudes measured in nanometers from synthesized Wood-Anderson records on the vertical channel were considered to derive an attenuation relation appropriate for South Africa through multiple regression analysis. Additionally, station corrections were determined for 26 stations during the regression analysis resulting in values ranging between -0.31 and 0.50. The most appropriate M L scale for South Africa from this study satisfies the equation: {M_{{{L}}}} = {{lo}}{{{g}}_{{10}}}(A) + 1.149{{lo}}{{{g}}_{{10}}}(R) + 0.00063R + 2.04 - S The anelastic attenuation term derived from this study indicates that ground motion attenuation is significantly different from Southern California but comparable with stable continental regions.

Reconstruction method for fluorescent X-ray computed tomography by least-squares method using singular value decomposition

NASA Astrophysics Data System (ADS)

Yuasa, T.; Akiba, M.; Takeda, T.; Kazama, M.; Hoshino, A.; Watanabe, Y.; Hyodo, K.; Dilmanian, F. A.; Akatsuka, T.; Itai, Y.

1997-02-01

We describe a new attenuation correction method for fluorescent X-ray computed tomography (FXCT) applied to image nonradioactive contrast materials in vivo. The principle of the FXCT imaging is that of computed tomography of the first generation. Using monochromatized synchrotron radiation from the BLNE-5A bending-magnet beam line of Tristan Accumulation Ring in KEK, Japan, we studied phantoms with the FXCT method, and we succeeded in delineating a 4-mm-diameter channel filled with a 500 /spl mu/g I/ml iodine solution in a 20-mm-diameter acrylic cylindrical phantom. However, to detect smaller iodine concentrations, attenuation correction is needed. We present a correction method based on the equation representing the measurement process. The discretized equation system is solved by the least-squares method using the singular value decomposition. The attenuation correction method is applied to the projections by the Monte Carlo simulation and the experiment to confirm its effectiveness.

Brightness temperature and attenuation diversity statistics at 20.6 and 31.65 GHz for the Colorado Research Network

NASA Technical Reports Server (NTRS)

Westwater, Ed R.; Falls, M. J.; Fionda, E.

1992-01-01

A limited network of four dual-channel microwave radiometers, with frequencies of 20.6 and 31.65 GHz, was operated in the front range of eastern Colorado from 1985 to 1988. Data, from November 1987 through October 1988 are analyzed to determine both single-station and joint-station brightness temperature and attenuation statistics. Only zenith observations were made. The spatial separations of the stations varied from 50 km to 190 km. Before the statistics were developed, the data were screened by rigorous quality control methods. One such method, that of 20.6 vs. 31.65 GHz scatter plots, is analyzed in detail, and comparisons are made of measured vs calculated data. At 20.6 and 31.65 GHz, vertical attenuations of 5 and 8 dB are exceeded 0.01 percent of the time. For these four stations and at the same 0.01 percent level, diversity gains from 6 to 8 dB are possible with the 50 to 190 km separations.

The imperatorin derivative OW1, a new vasoactive compound, inhibits VSMC proliferation and extracellular matrix hyperplasia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Nan; Zhang, Yu; Wang, Tao

Chronic hypertension induces vascular remodeling. The most important factor for hypertension treatment is reducing the risk of cardiovascular disease. OW1 is a novel imperatorin derivative that exhibits vasodilative activity and antihypertensive effects in two-kidney one-clip (2K1C) renovascular hypertensive rats. It also inhibited vascular remodeling of the thoracic aorta in a previous study. Here, the inhibitory effects and mechanisms of OW1 on arterial vascular remodeling were investigated in vitro and in 2K1C hypertensive rats in vivo. OW1 (20 μM, 10 μM, 5 μM) inhibited Ang II-induced vascular smooth muscle cells (VSMCs) proliferation and ROS generation in vitro. OW1 also reversed themore » Ang II-mediated inhibition of α-SMA levels and stimulation of OPN levels. Histology results showed that treatment of 2K1C hypertensive rats with OW1 (20, 40, and 80 mg/kg per day, respectively for 5 weeks) in vivo significantly decreased the number of VSMCs, the aortic cross-sectional area (CSA), the media to lumen (M/L) ratio, and the content of collagen I and III in the mesenteric artery. Western blot results also revealed that OW1 stimulated the expression of α-SMA and inhibited the expression of collagen I and III on the thoracic aorta of 2K1C hypertensive rats. In mechanistic studies, OW1 acted as an ACE inhibitor and affected calcium channels. The suppression of MMP expression and the MAPK pathway may account for the effects of OW1 on vascular remodeling. OW1 attenuated vascular remodeling in vitro and in vivo. It could be a novel candidate for hypertension intervention. - Highlights: • OW1, an imperatorin derivative, attenuates vascular remodeling caused by hypertension. • OW1 inhibits VSMC proliferation and media layer hypertrophy. • OW1 acts as an ACE inhibitor and affects calcium channels. • Suppression of MMPs expression and MAPK pathway may account for the effects of OW1 on vascular remodeling.« less

Engineering Hyporheic Zones to Attenuate Heavy Metals in Constructed Urban Streams: Performance Data from Constructed Stream Flumes

NASA Astrophysics Data System (ADS)

Halpin, B. N.; Portmann, A. C.; Herzog, S.; Higgins, C.; McCray, J. E.

2017-12-01

Urban stormwater runoff is a major cause of water quality impairment along ocean shorelines and in rivers, lakes and estuaries across the United States. In addition to pathogens, nutrients, and organic contaminants, a variety of heavy metals are commonly found at elevated concentrations in urban runoff. Although such metals occur in both dissolved and particulate-bound phases, conventional stormwater controls are typically designed to remove suspended solids, while dissolved phase contaminants remain largely untreated. To address this gap in available stormwater controls, a novel technology, termed Biohydrochemical Enhancements for Streamwater Treatment (BEST), has been developed based on inspiration from the natural hyporheic zone (HZ). BEST utilizes a series of alternating streambed permeabilities to drive efficient surface water-HZ exchange. This is combined with reactive and/or sorptive streambed geomedia designed to remove dissolved phase contaminants from constructed urban drainage channels. Previous research at the Colorado School of Mines has shown that a 15-meter flume modified with BEST exhibits greater hyporheic exchange than an all-sand control flume, though both flumes provided greater contaminant attenuation than a selection of actual urban streams. This study again utilized the 15-meter flumes at Colorado School of Mines to evaluate two configurations of BEST for removal of heavy metals commonly found in stormwater runoff, including cadmium, copper, nickel, lead and zinc. In both BEST configurations, the geomedia consisted of a 30/70 (v/v) mix of woodchips and sand, with one configuration using coarse sand (K=0.48 cm/s) and the other using finer sand (K=0.16 cm/s). Both configurations were compared to an all-sand control. To evaluate metals removal, a suite of aqueous metals solution was spiked into each flume, and aqueous concentrations of the five metals of interest were monitored in both the surface and pore water over 24 hours. Differences in hyporheic exchange and residence times, as well as redox conditions, between the BEST configurations and the control impacted heavy metals retention in the engineered streambeds. Overall, engineered hyporheic zones in small urban drainage channels may be a promising option for retaining heavy metals collected by urban stormwater runoff.

Early metabolic responses to lithium/pilocarpine-induced status epilepticus in rat brain.

PubMed

Imran, Imran; Hillert, Markus H; Klein, Jochen

2015-12-01

The lithium-pilocarpine model of status epilepticus is a well-known animal model of temporal lobe epilepsy. We combined this model with in vivo microdialysis to investigate energy metabolites and acute cellular membrane damage during seizure development. Rats were implanted with dialysis probes and pretreated with lithium chloride (127 mg/kg i.p.). Twenty-four hours later, they received pilocarpine (30 mg/kg s.c.) which initiated seizures within 30 min. In the dialysate from rat hippocampus, we observed a transient increase in glucose and a prominent, five-fold increase in lactate during seizures. Lactate release was because of neuronal activation as it was strongly reduced by infusion of tetrodotoxin, administration of atropine or when seizures were terminated by diazepam or ketamine. In ex vivo assays, mitochondrial function as measured by respirometry was not affected by 90 min of seizures. Extracellular levels of choline, however, increased two-fold and glycerol levels 10-fold, which indicate cellular phospholipid breakdown during seizures. Within 60 min of pilocarpine administration, hydroxylation of salicylate increased two-fold and formation of isoprostanes 20-fold, revealing significant oxidative stress in hippocampal tissue. Increases in lactate, glycerol and isoprostanes were abrogated, and increases in choline were completely prevented, when hippocampal probes were perfused with calcium-free solution. Similarly, administration of pregabalin (100 mg/kg i.p.), a calcium channel ligand, 15 min prior to pilocarpine strongly attenuated parameters of membrane damage and oxidative stress. We conclude that seizure development in a rat model of status epilepticus is accompanied by increases in extracellular lactate, choline and glycerol, and by oxidative stress, while mitochondrial function remains intact for at least 90 min. Membrane damage depends on calcium influx and can be prevented by treatment with pregabalin. Status epilepticus (SE) was induced in rats by lithium-pilocarpine ('Pilo') administration, and extracellular metabolites were measured by microdialysis. Seizures caused several-fold increases in lactate levels which were attenuated by diazepam ('Diaz'), ketamine, atropine and tetrodotoxin (TTX). Indicators of oxidative stress and membrane damage were also increased during seizures. Omission of calcium and pregabalin, a calcium channel blocker, reduced cellular damage induced by SE. © 2015 International Society for Neurochemistry.

Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling.

PubMed

Geha, Paul; Yang, Yang; Estacion, Mark; Schulman, Betsy R; Tokuno, Hajime; Apkarian, A Vania; Dib-Hajj, Sulayman D; Waxman, Stephen G

2016-06-01

There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel NaV1.7 make dorsal root ganglion (DRG) neurons hyperexcitable. To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic analysis and functional profiling. Pain in 2 patients with IEM due to the NaV1.7 S241T mutation, predicted by structural modeling and functional analysis to be responsive to carbamazepine, was assessed in a double-blind, placebo-controlled study conducted from September 2014 to April 21, 2015. Functional magnetic resonance imaging assessed patterns of brain activity associated with pain during treatment with placebo or carbamazepine. Multielectrode array technology was used to assess the effect of carbamazepine on firing of DRG neurons carrying S241T mutant channels. Behavioral assessment of pain; functional magnetic resonance imaging; and assessment of firing in DRG neurons carrying S241T mutant channels. This study included 2 patients from the same family with IEM and the S241T NaV1.7 mutation. We showed that, as predicted by molecular modeling, thermodynamic analysis, and functional profiling, carbamazepine attenuated pain in patients with IEM due to the S241T NaV1.7 mutation. Patient 1 reported a reduction in mean time in pain (TIP) per day during the 15-day maintenance period, from 424 minutes while taking placebo to 231.9 minutes while taking carbamazepine (400 mg/day), and a reduction in total TIP over the 15-day maintenance period, from 6360 minutes while taking placebo to 3015 minutes while taking carbamazepine. Patient 2 reported a reduction in mean TIP per day during the maintenance period, from 61 minutes while taking placebo to 9.1 minutes while taking carbamazepine (400 mg then 200 mg/day), and a reduction in total TIP, from 915 minutes while taking placebo over the 15-day maintenance period to 136 minutes while taking carbamazepine. Patient 1 reported a reduction of mean episode duration, from 615 minutes while taking placebo to 274.1 minutes while taking carbamazepine, while patient 2 reported a reduction of the mean episode duration from 91.5 minutes while taking placebo to 45.3 minutes while taking carbamazepine. Patient 1, who had a history of night awakenings from pain, reported 101 awakenings owing to pain while taking placebo during the maintenance period and 32 awakenings while taking carbamazepine. Attenuation of pain was paralleled by a shift in brain activity from valuation and pain areas to primary and secondary somatosensory, motor, and parietal attention areas. Firing of DRG neurons expressing the S241T NaV1.7 mutant channel in response to physiologically relevant thermal stimuli was reduced by carbamazepine. Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neuropathic pain in patients carrying the S241T mutation.

Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments

PubMed Central

Hill, Terence E.; Smith, Jennifer K.; Zhang, Lihong; Juelich, Terry L.; Gong, Bin; Slack, Olga A. L.; Ly, Hoai J.; Lokugamage, Nandadeva; Freiberg, Alexander N.

2015-01-01

ABSTRACT Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and characterized by a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. RVF is caused by Rift Valley fever virus (RVFV; family Bunyaviridae, genus Phlebovirus), which has a tripartite negative-stranded RNA genome (consisting of the S, M, and L segments). Further spread of RVF into countries where the disease is not endemic may affect the economy and public health, and vaccination is an effective approach to prevent the spread of RVFV. A live-attenuated MP-12 vaccine is one of the best-characterized RVF vaccines for safety and efficacy and is currently conditionally licensed for use for veterinary purposes in the United States. Meanwhile, as of 2015, no other RVF vaccine has been conditionally or fully licensed for use in the United States. The MP-12 strain is derived from wild-type pathogenic strain ZH548, and its genome encodes 23 mutations in the three genome segments. However, the mechanism of MP-12 attenuation remains unknown. We characterized the attenuation of wild-type pathogenic strain ZH501 carrying a mutation(s) of the MP-12 S, M, or L segment in a mouse model. Our results indicated that MP-12 is attenuated by the mutations in the S, M, and L segments, while the mutations in the M and L segments confer stronger attenuation than those in the S segment. We identified a combination of 3 amino acid changes, Y259H (Gn), R1182G (Gc), and R1029K (L), that was sufficient to attenuate ZH501. However, strain MP-12 with reversion mutations at those 3 sites was still highly attenuated. Our results indicate that MP-12 attenuation is supported by a combination of multiple partial attenuation mutations and a single reversion mutation is less likely to cause a reversion to virulence of the MP-12 vaccine. IMPORTANCE Rift Valley fever (RVF) is a mosquito-transmitted viral disease that is endemic to Africa and that has the potential to spread into other countries. Vaccination is considered an effective way to prevent the disease, and the only available veterinary RVF vaccine in the United States is a live-attenuated MP-12 vaccine, which is conditionally licensed. Strain MP-12 is different from its parental pathogenic RVFV strain, strain ZH548, because of the presence of 23 mutations. This study determined the role of individual mutations in the attenuation of the MP-12 strain. We found that full attenuation of MP-12 occurs by a combination of multiple mutations. Our findings indicate that a single reversion mutation will less likely cause a major reversion to virulence of the MP-12 vaccine. PMID:25948740

Rift Valley Fever Virus MP-12 Vaccine Is Fully Attenuated by a Combination of Partial Attenuations in the S, M, and L Segments.

PubMed

Ikegami, Tetsuro; Hill, Terence E; Smith, Jennifer K; Zhang, Lihong; Juelich, Terry L; Gong, Bin; Slack, Olga A L; Ly, Hoai J; Lokugamage, Nandadeva; Freiberg, Alexander N

2015-07-01

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and characterized by a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. RVF is caused by Rift Valley fever virus (RVFV; family Bunyaviridae, genus Phlebovirus), which has a tripartite negative-stranded RNA genome (consisting of the S, M, and L segments). Further spread of RVF into countries where the disease is not endemic may affect the economy and public health, and vaccination is an effective approach to prevent the spread of RVFV. A live-attenuated MP-12 vaccine is one of the best-characterized RVF vaccines for safety and efficacy and is currently conditionally licensed for use for veterinary purposes in the United States. Meanwhile, as of 2015, no other RVF vaccine has been conditionally or fully licensed for use in the United States. The MP-12 strain is derived from wild-type pathogenic strain ZH548, and its genome encodes 23 mutations in the three genome segments. However, the mechanism of MP-12 attenuation remains unknown. We characterized the attenuation of wild-type pathogenic strain ZH501 carrying a mutation(s) of the MP-12 S, M, or L segment in a mouse model. Our results indicated that MP-12 is attenuated by the mutations in the S, M, and L segments, while the mutations in the M and L segments confer stronger attenuation than those in the S segment. We identified a combination of 3 amino acid changes, Y259H (Gn), R1182G (Gc), and R1029K (L), that was sufficient to attenuate ZH501. However, strain MP-12 with reversion mutations at those 3 sites was still highly attenuated. Our results indicate that MP-12 attenuation is supported by a combination of multiple partial attenuation mutations and a single reversion mutation is less likely to cause a reversion to virulence of the MP-12 vaccine. Rift Valley fever (RVF) is a mosquito-transmitted viral disease that is endemic to Africa and that has the potential to spread into other countries. Vaccination is considered an effective way to prevent the disease, and the only available veterinary RVF vaccine in the United States is a live-attenuated MP-12 vaccine, which is conditionally licensed. Strain MP-12 is different from its parental pathogenic RVFV strain, strain ZH548, because of the presence of 23 mutations. This study determined the role of individual mutations in the attenuation of the MP-12 strain. We found that full attenuation of MP-12 occurs by a combination of multiple mutations. Our findings indicate that a single reversion mutation will less likely cause a major reversion to virulence of the MP-12 vaccine. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Anoctamin Calcium-Activated Chloride Channels May Modulate Inhibitory Transmission in the Cerebellar Cortex

PubMed Central

Parthier, Daniel; Frings, Stephan; Möhrlen, Frank

2015-01-01

Calcium-activated chloride channels of the anoctamin (alias TMEM16) protein family fulfill critical functions in epithelial fluid transport, smooth muscle contraction and sensory signal processing. Little is known, however, about their contribution to information processing in the central nervous system. Here we examined the recent finding that a calcium-dependent chloride conductance impacts on GABAergic synaptic inhibition in Purkinje cells of the cerebellum. We asked whether anoctamin channels may underlie this chloride conductance. We identified two anoctamin channel proteins, ANO1 and ANO2, in the cerebellar cortex. ANO1 was expressed in inhibitory interneurons of the molecular layer and the granule cell layer. Both channels were expressed in Purkinje cells but, while ANO1 appeared to be retained in the cell body, ANO2 was targeted to the dendritic tree. Functional studies confirmed that ANO2 was involved in a calcium-dependent mode of ionic plasticity that reduces the efficacy of GABAergic synapses. ANO2 channels attenuated GABAergic transmission by increasing the postsynaptic chloride concentration, hence reducing the driving force for chloride influx. Our data suggest that ANO2 channels are involved in a Ca2+-dependent regulation of synaptic weight in GABAergic inhibition. Thus, in balance with the chloride extrusion mechanism via the co-transporter KCC2, ANO2 appears to regulate ionic plasticity in the cerebellum. PMID:26558388

TNF-{alpha} promotes cell survival through stimulation of K{sup +} channel and NF{kappa}B activity in corneal epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Ling; Reinach, Peter; Lu, Luo

2005-11-15

Tumor necrosis factor (TNF-{alpha}) in various cell types induces either cell death or mitogenesis through different signaling pathways. In the present study, we determined in human corneal epithelial cells how TNF-{alpha} also promotes cell survival. Human corneal epithelial (HCE) cells were cultured in DMEM/F-12 medium containing 10% FBS. TNF-{alpha} stimulation induced activation of a voltage-gated K{sup +} channel detected by measuring single channel activity using patch clamp techniques. The effect of TNF-{alpha} on downstream events included NF{kappa}B nuclear translocation and increases in DNA binding activities, but did not elicit ERK, JNK, or p38 limb signaling activation. TNF-{alpha} induced increases inmore » p21 expression resulting in partial cell cycle attenuation in the G{sub 1} phase. Cell cycle progression was also mapped by flow cytometer analysis. Blockade of TNF-{alpha}-induced K{sup +} channel activity effectively prevented NF{kappa}B nuclear translocation and binding to DNA, diminishing the cell-survival protective effect of TNF-{alpha}. In conclusion, TNF-{alpha} promotes survival of HCE cells through sequential stimulation of K{sup +} channel and NF{kappa}B activities. This response to TNF-{alpha} is dependent on stimulating K{sup +} channel activity because following suppression of K{sup +} channel activity TNF-{alpha} failed to activate NF{kappa}B nuclear translocation and binding to nuclear DNA.« less

Podocyte Purinergic P2X4 Channels Are Mechanotransducers That Mediate Cytoskeletal Disorganization.

PubMed

Forst, Anna-Lena; Olteanu, Vlad Sorin; Mollet, Géraldine; Wlodkowski, Tanja; Schaefer, Franz; Dietrich, Alexander; Reiser, Jochen; Gudermann, Thomas; Mederos y Schnitzler, Michael; Storch, Ursula

2016-03-01

Podocytes are specialized, highly differentiated epithelial cells in the kidney glomerulus that are exposed to glomerular capillary pressure and possible increases in mechanical load. The proteins sensing mechanical forces in podocytes are unconfirmed, but the classic transient receptor potential channel 6 (TRPC6) interacting with the MEC-2 homolog podocin may form a mechanosensitive ion channel complex in podocytes. Here, we observed that podocytes respond to mechanical stimulation with increased intracellular calcium concentrations and increased inward cation currents. However, TRPC6-deficient podocytes responded in a manner similar to that of control podocytes, and mechanically induced currents were unaffected by genetic inactivation of TRPC1/3/6 or administration of the broad-range TRPC blocker SKF-96365. Instead, mechanically induced currents were significantly decreased by the specific P2X purinoceptor 4 (P2X4) blocker 5-BDBD. Moreover, mechanical P2X4 channel activation depended on cholesterol and podocin and was inhibited by stabilization of the actin cytoskeleton. Because P2X4 channels are not intrinsically mechanosensitive, we investigated whether podocytes release ATP upon mechanical stimulation using a fluorometric approach. Indeed, mechanically induced ATP release from podocytes was observed. Furthermore, 5-BDBD attenuated mechanically induced reorganization of the actin cytoskeleton. Altogether, our findings reveal a TRPC channel-independent role of P2X4 channels as mechanotransducers in podocytes. Copyright © 2016 by the American Society of Nephrology.

Algorithm for Simulating Atmospheric Turbulence and Aeroelastic Effects on Simulator Motion Systems

NASA Technical Reports Server (NTRS)

Ercole, Anthony V.; Cardullo, Frank M.; Kelly, Lon C.; Houck, Jacob A.

2012-01-01

Atmospheric turbulence produces high frequency accelerations in aircraft, typically greater than the response to pilot input. Motion system equipped flight simulators must present cues representative of the aircraft response to turbulence in order to maintain the integrity of the simulation. Currently, turbulence motion cueing produced by flight simulator motion systems has been less than satisfactory because the turbulence profiles have been attenuated by the motion cueing algorithms. This report presents a new turbulence motion cueing algorithm, referred to as the augmented turbulence channel. Like the previous turbulence algorithms, the output of the channel only augments the vertical degree of freedom of motion. This algorithm employs a parallel aircraft model and an optional high bandwidth cueing filter. Simulation of aeroelastic effects is also an area where frequency content must be preserved by the cueing algorithm. The current aeroelastic implementation uses a similar secondary channel that supplements the primary motion cue. Two studies were conducted using the NASA Langley Visual Motion Simulator and Cockpit Motion Facility to evaluate the effect of the turbulence channel and aeroelastic model on pilot control input. Results indicate that the pilot is better correlated with the aircraft response, when the augmented channel is in place.

Propofol inhibits carbachol-induced chloride secretion by directly targeting the basolateral K+ channel in rat ileum epithelium.

PubMed

Tang, S-H; Wang, H-Y; Sun, H; An, N; Xiao, L; Sun, Q; Zhao, D-B

2017-02-01

Propofol is a widely used intravenous general anesthetic. Acetylcholine (ACh) is critical in controlling epithelial ion transport. This study was to investigate the effects of propofol on ACh-evoked secretion in rat ileum epithelium. The Ussing chamber technique was used to investigate the effects of propofol on carbachol (CCh)-evoked short-circuit currents (Isc). Propofol (10 -2 -10 -6  mol/L) attenuated CCh-evoked Isc of rat ileum mucosa in a dose-dependent manner. The inhibitory effect of propofol was only evident after application to the serosal side. Pretreatment with tetrodotoxin (TTX, 0.3 μmol/L, n=5) had no effect on propofol-induced inhibitory effect, whereas serosal application of K + channel inhibitor, glibenclamide, but not, an ATP-sensitive K + channel inhibitor, largely reduced the inhibitory effect of propofol. In addition, pretreatment with either hexamethonium bromide (HB, nicotinic nACh receptor antagonist) or Cl - channel blockers niflumic acid and cystic fibrosis transmembrane conductance regulator (inh)-172 did not produce any effect on the propofol-induced inhibitory effect. Propofol inhibits CCh-induced intestinal secretion by directly targeting basolateral K + channels. © 2016 John Wiley & Sons Ltd.

Infrared cloud imaging in support of Earth-space optical communication.

PubMed

Nugent, Paul W; Shaw, Joseph A; Piazzolla, Sabino

2009-05-11

The increasing need for high data return from near-Earth and deep-space missions is driving a demand for the establishment of Earth-space optical communication links. These links will require a nearly obstruction-free path to the communication platform, so there is a need to measure spatial and temporal statistics of clouds at potential ground-station sites. A technique is described that uses a ground-based thermal infrared imager to provide continuous day-night cloud detection and classification according to the cloud optical depth and potential communication channel attenuation. The benefit of retrieving cloud optical depth and corresponding attenuation is illustrated through measurements that identify cloudy times when optical communication may still be possible through thin clouds.

Analytical performance study of solar blind non-line-of-sight ultraviolet short-range communication links.

PubMed

Xu, Zhengyuan; Ding, Haipeng; Sadler, Brian M; Chen, Gang

2008-08-15

Motivated by recent advances in solid-state incoherent ultraviolet sources and solar blind detectors, we study communication link performance over a range of less than 1 km with a bit error rate (BER) below 10(-3) in solar blind non-line-of-sight situation. The widely adopted yet complex single scattering channel model is significantly simplified by means of a closed-form expression for tractable analysis. Path loss is given as a function of transceiver geometry as well as atmospheric scattering and attenuation and is compared with experimental data for model validation. The BER performance of a shot-noise-limited receiver under this channel model is demonstrated.

Optimization of training sequence for DFT-spread DMT signal in optical access network with direct detection utilizing DML.

PubMed

Li, Fan; Li, Xinying; Yu, Jianjun; Chen, Lin

2014-09-22

We experimentally demonstrated the transmission of 79.86-Gb/s discrete-Fourier-transform spread 32 QAM discrete multi-tone (DFT-spread 32 QAM-DMT) signal over 20-km standard single-mode fiber (SSMF) utilizing directly modulated laser (DML). The experimental results show DFT-spread effectively reduces Peak-to-Average Power Ratio (PAPR) of DMT signal, and also well overcomes narrowband interference and high frequencies power attenuation. We compared different types of training sequence (TS) symbols and found that the optimized TS for channel estimation is the symbol with digital BPSK/QPSK modulation format due to its best performance against optical link noise during channel estimation.

Time‐lapse imaging of saline‐tracer transport in fractured rock using difference‐attenuation radar tomography

USGS Publications Warehouse

Day-Lewis, Frederick D.; Lane, John W.; Harris, Jerry M.; Gorelick, Steven M.

2003-01-01

Accurate characterization of fractured‐rock aquifer heterogeneity remains one of the most challenging and important problems in groundwater hydrology. We demonstrate a promising strategy to identify preferential flow paths in fractured rock using a combination of geophysical monitoring and conventional hydrogeologic tests. Cross‐well difference‐attenuation ground‐penetrating radar was used to monitor saline‐tracer migration in an experiment at the U.S. Geological Survey Fractured Rock Hydrology Research Site in Grafton County, New Hampshire. Radar data sets were collected every 10 min in three adjoining planes for 5 hours during each of 12 tracer tests. An innovative inversion method accounts for data acquisition times and temporal changes in attenuation during data collection. The inverse algorithm minimizes a combination of two functions. The first is the sum of weighted squared data residuals. Second is a measure of solution complexity based on an a priori space‐time covariance function, subject to constraints that limit radar‐attenuation changes to regions of the tomograms traversed by high difference‐attenuation ray paths. The time series of tomograms indicate relative tracer concentrations and tracer arrival times in the image planes; from these we infer the presence and location of a preferential flow path within a previously identified zone of transmissive fractures. These results provide new insights into solute channeling and the nature of aquifer heterogeneity at the site.

Penetrating injury to the chest by an attenuated energy projectile: a case report and literature review of thoracic injuries caused by "less-lethal" munitions

PubMed Central

Rezende-Neto, Joao; Silva, Fabriccio DF; Porto, Leonardo BO; Teixeira, Luiz C; Tien, Homer; Rizoli, Sandro B

2009-01-01

We present the case of a patient who sustained a penetrating injury to the chest caused by an attenuated energy rubber bullet and review the literature on thoracic injuries caused by plastic and rubber "less-lethal" munitions. The patient of this report underwent a right thoracotomy to extract the projectile as well as a wedge resection of the injured lung parenchyma. This case demonstrates that even supposedly safe riot control munition fired at close range, at the torso, can provoke serious injury. Therefore a thorough investigation and close clinical supervision are justified. PMID:19555511

Penetrating injury to the chest by an attenuated energy projectile: a case report and literature review of thoracic injuries caused by "less-lethal" munitions.

PubMed

Rezende-Neto, Joao; Silva, Fabriccio Df; Porto, Leonardo Bo; Teixeira, Luiz C; Tien, Homer; Rizoli, Sandro B

2009-06-26

We present the case of a patient who sustained a penetrating injury to the chest caused by an attenuated energy rubber bullet and review the literature on thoracic injuries caused by plastic and rubber "less-lethal" munitions. The patient of this report underwent a right thoracotomy to extract the projectile as well as a wedge resection of the injured lung parenchyma. This case demonstrates that even supposedly safe riot control munition fired at close range, at the torso, can provoke serious injury. Therefore a thorough investigation and close clinical supervision are justified.

Reducing endoglin activity limits calcineurin and TRPC-6 expression and improves survival in a mouse model of right ventricular pressure overload.

PubMed

Kapur, Navin K; Qiao, Xiaoying; Paruchuri, Vikram; Mackey, Emily E; Daly, Gerard H; Ughreja, Kishan; Ughreja, Keshan; Morine, Kevin J; Levine, Jonathan; Aronovitz, Mark J; Hill, Nicholas S; Jaffe, Iris Z; Letarte, Michelle; Karas, Richard H

2014-07-11

Right ventricular (RV) failure is a major cause of mortality worldwide and is often a consequence of RV pressure overload (RVPO). Endoglin is a coreceptor for the profibrogenic cytokine, transforming growth factor beta 1 (TGF-β1). TGF-β1 signaling by the canonical transient receptor protein channel 6 (TRPC-6) was recently reported to stimulate calcineurin-mediated myofibroblast transformation, a critical component of cardiac fibrosis. We hypothesized that reduced activity of the TGF-β1 coreceptor, endoglin, limits RV calcineurin expression and improves survival in RVPO. We first demonstrate that endoglin is required for TGF-β1-mediated calcineurin/TRPC-6 expression and up-regulation of alpha-smooth muscle antigen (α-SMA), a marker of myofibroblast transformation, in human RV fibroblasts. Using endoglin haploinsufficient mice (Eng(+/-)) we show that reduced endoglin activity preserves RV function, limits RV fibrosis, and attenuates activation of the calcineurin/TRPC-6/α-SMA pathway in a model of angio-obliterative pulmonary hypertension. Next, using Eng(+/-) mice or a neutralizing antibody (Ab) against endoglin (N-Eng) in wild-type mice, we show that reduced endoglin activity improves survival and attenuates RV fibrosis in models of RVPO induced by pulmonary artery constriction. To explore the utility of targeting endoglin, we observed a reversal of RV fibrosis and calcineurin levels in wild-type mice treated with a N-Eng Ab, compared to an immunoglobulin G control. These data establish endoglin as a regulator of TGF-β1 signaling by calcineurin and TRPC-6 in the RV and identify it as a potential therapeutic target to limit RV fibrosis and improve survival in RVPO, a common cause of death in cardiac and pulmonary disease. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Attenuation of Slab determined from T-wave generation by deep earthquakes

NASA Astrophysics Data System (ADS)

Huang, J.; Ni, S.

2006-05-01

T-wave are seismically generated acoustic waves that propagate over great distance in the ocean sound channel (SOFAR). Because of the high attenuation in both the upper mantle and the ocean crust, T wave is rarely observed for earthquakes deeper than 80 km. However some deep earthquakes deeper than 80km indeed generate apparent T-waves if the subducted slab is continuous Okal et al. (1997) . We studied the deep earthquakes in the Fiji/Tonga region, where the subducted lithosphere is old and thus with small attenuation. After analyzing 33 earthquakes with the depth from 10 Km to 650 Km in Fiji/Tonga, we observed and modeled obvious T-phases from these earthquakes observed at station RAR. We used the T-wave generated by deep earthquakes to compute the quality factor of the Fiji/Tonga slab. The method used in this study is followed the equation (1) by [Groot-Hedlin et al,2001][1]. A=A0/(1+(Ω0/Ω)2)×exp(-LΩ/Qv)×Ωn where the A is the amplitude computed by the practicable data, amplitude depending on the earthquakes, and A0 is the inherent frequency related with the earthquake's half duration, L is the length of ray path that P wave or S travel in the slab, and the V is the velocity of P-wave. In this study, we fix the n=2, by assuming the T- wave scattering points in the Fiji/Tonga island arc having the same attribution as the continental shelf. After some computing and careful analysis, we determined the quality factor of the Fiji/Tonga to be around 1000, Such result is consistent with results from the traditional P,S-wave data[Roth & Wiens,1999][2] . Okal et al. (1997) pointed out that the slab in the part of central South America was also a continuous slab, by modeling apparent T-waves from the great 1994 Bolivian deep earthquake in relation to channeling of S wave energy propagating upward through the slab[3]. [1]Catherine D. de Groot-Hedlin, John A. Orcutt, excitation of T-phases by seafloor scattering, J. Acoust. Soc, 109,1944-1954,2001. [2]Erich G.Roth and Douglas A.Wiens, Leroy M.Dorman, Seismic attenuation tomography of the Tonga-Fiji region using phase pair methods, Geophys. Res.,104,4795-4809,1999. [3]Emile A.Okal and Jacques Talandier, T waves from the great 1994 Bolivian deep earthquake in relation to channeling of S wave energy up the slab, J.Geophys. Res.,102(12):27421-27437,1997.

Compensatory vapor loss and biogeochemical attenuation along flowpaths mute the water resources impacts of insect-induced forest mortality

NASA Astrophysics Data System (ADS)

Biederman, J. A.; Brooks, P. D.; Harpold, A. A.; Gochis, D. J.; Ewers, B. E.; Reed, D. E.; Gutmann, E. D.

2013-12-01

Forested montane catchments are critical to the amount and quality of downstream water resources. In western North America more than 60 million people rely on mountain precipitation, and water managers face uncertain response to an unprecedented forest die-off from mountain pine beetle (MPB) infestation. Reduced snow interception and transpiration are expected to increase streamflow, while increased organic matter decay is expected to increase biogeochemical stream fluxes. Tree- to plot-scale observations have documented some of the expected changes, but there has been little significant change to streamflow or water quality at the larger scales relevant to water resources. A critical gap exists in our understanding of why tree-scale process changes have not led to the expected, large-scale increases in streamflow and biogeochemical fluxes. We address this knowledge gap with observations of water and biogeochemical fluxes at nested spatial scales including tree, hillslope, and catchments from 3 to 700 ha with more than 75% mortality. Catchment discharge showed reduced water yield consistent with co-located eddy covariance observations showing increased vapor losses following MPB. Stable water isotopes showed progressive kinetic fractionation (i.e. unsaturated transition layer above the evaporating surface) in snowpack, soil water and streams indicating greater abiotic evaporation from multiple water sources offsetting decreased interception and transpiration. In the 3rd to 5th years following MPB forest mortality, soil water DOC and DON were similar beneath killed and healthy trees, but concentrations were elevated 2-10 times in groundwater of MPB-impacted sites as compared to unimpacted. Stream water DOC and DON were about 3 times as large during snowmelt runoff in ephemeral zero-order channels of MPB-impacted sites compared to unimpacted. Processing in the headwater streams of MPB-impacted forests rapidly attenuated dissolved organic matter. From the MPB-impacted zero-order channel, DOC and DON were reduced by ~50 % within 5 km downstream in a 700-ha catchment with similar MPB forest mortality. Soil water NO3 up to 500 μeq l-1 during the snowmelt flush was attenuated by an order of magnitude in the riparian groundwater and was usually below detection limit in the adjacent zero-order channel. These observations demonstrate that water resources impacts of insect-induced forest mortality may be muted because 1) compensatory vapor loss can offset expected water yield increases and 2) processing of carbon and nitrogen along both hillslope flowpaths and within headwater streams can rapidly attenuate biogeochemical fluxes.

Molecular mechanism of a COOH-terminal gating determinant in the ROMK channel revealed by a Bartter's disease mutation

PubMed Central

Flagg, Thomas P; Yoo, Dana; Sciortino, Christopher M; Tate, Margaret; Romero, Michael F; Welling, Paul A

2002-01-01

The ROMK subtypes of inward-rectifier K+ channels mediate potassium secretion and regulate NaCl reabsorption in the kidney. Loss-of-function mutations in this pH-sensitive K+ channel cause Bartter's disease, a familial salt wasting nephropathy. One disease-causing mutation truncates the extreme COOH-terminus and induces a closed gating conformation. Here we identify a region within the deleted domain that plays an important role in pH-dependent gating. The domain contains a structural element that functionally interacts with the pH sensor in the cytoplasmic NH2-terminus to set a physiological range of pH sensitivity. Removal of the domain shifts the pKa towards alkaline pH values, causing channel inactivation under physiological conditions. Suppressor mutations within the pH sensor rescued channel gating and trans addition of the cognate peptide restored pH sensitivity. A specific interdomain interaction was revealed in an in vitro protein-protein binding assay between the NH2- and COOH-terminal cytoplasmic domains expressed as bacterial fusion proteins. These results provide new insights into the molecular mechanisms underlying Kir channel regulation and channel gating defects that are associated with Bartter's disease. PMID:12381810

Utilisation of ISA Reverse Genetics and Large-Scale Random Codon Re-Encoding to Produce Attenuated Strains of Tick-Borne Encephalitis Virus within Days.

PubMed

de Fabritus, Lauriane; Nougairède, Antoine; Aubry, Fabien; Gould, Ernest A; de Lamballerie, Xavier

2016-01-01

Large-scale codon re-encoding is a new method of attenuating RNA viruses. However, the use of infectious clones to generate attenuated viruses has inherent technical problems. We previously developed a bacterium-free reverse genetics protocol, designated ISA, and now combined it with large-scale random codon-re-encoding method to produce attenuated tick-borne encephalitis virus (TBEV), a pathogenic flavivirus which causes febrile illness and encephalitis in humans. We produced wild-type (WT) and two re-encoded TBEVs, containing 273 or 273+284 synonymous mutations in the NS5 and NS5+NS3 coding regions respectively. Both re-encoded viruses were attenuated when compared with WT virus using a laboratory mouse model and the relative level of attenuation increased with the degree of re-encoding. Moreover, all infected animals produced neutralizing antibodies. This novel, rapid and efficient approach to engineering attenuated viruses could potentially expedite the development of safe and effective new-generation live attenuated vaccines.

Geomorphic and vegetative recovery processes along modified stream channels of West Tennessee

USGS Publications Warehouse

Simon, Andrew; Hupp, C.R. Tennessee

1992-01-01

Hundreds of miles of streams in West Tennessee have been channelized or otherwise modt@ed since the turn of century. After all or parts of a stream are straightened, dredged, or cleared, systematic hydrologic, geomorphic, and ecologic processes collectively begin to reduce energy conditions towards the premodified state. One hundred and five sites along 15 streams were studied in the Obion, Forked Deer, Hatchie, and Wolf River basins. All studied streams, except the Hatchie River, have had major channel modi@cation along all or parts of their courses. Bank material shear-strength properties were determined through drained borehole-shear testing (168 tests) and used to interpret present critical bank conditions and factors of safety, and to estimate future channel-bank stability. Mean values of cohesive strength and angle of internal friction were 1.26 pounds per square inch and 30.1 degrees, respectively. Dendrogeomorphic analyses were made using botanical evidence of channel-bank failures to determine rates of channel widening; buried riparian stems were analyzed to determine rates of bank accretion. Channel bed-level changes through time and space were represented by a power equation. Plant ecological analyses were ma& to infer relative bank stability, to identify indicator species of the stage of bank recovery, and to determine patterns of vegetation development through the course of channel evolution. Quantitative data on morphologic changes were used with previously developed six-stage models of channel evolution and bank-slope development to estimate trends of geomorphic and ecologic processes and forms through time. Immediately after channel modr@cations, a 10- to 1%yearperiod of channel-bed degradation ensues at and upstream from the most recent modifications (area of maximum disturbance). Channel-bed lowering by &gradation was as much as 20 feet along some stream reaches. Downstream from the area of maximum disturbance, the bed was aggraded by the deposition of sediment supplied by knickpoint migration upstream; aggradation also occurred in initially degraded sites with time. Additionally, if degradation caused an increase in bank height beyond the critical limits of the bank material, a period of channel widening by mass wasting followed. Degradation knickpoints migrated upstream at rates greater than 1 mile per year; the rates attenuated with distance above the area of maximum disturbance. Channel widening rates of up to 16 feet per year were documented along some severely degraded reaches. Planar failures were generally more frequent but rotational failures dominated the most rapidly widening reaches. Total volumes of bank erosion may represent 75percent or more of the total material eroded from the channel, but this material generally exits the drainage basin. Mean factors of safety vary with the stage of channel evolution with the lowest values for planar and rotational failures occurring during the threshold stage (stage IV) 1.00 and 1.15, respectively. As channel gradients decrease, degradation ceases and then a period of ?secondary aggradation ? (at lesser rates than degradation) and bank accretion begins that may fill the channel to near floodplain level. This shift@ in process represents an oscillation in channel bed-level adjustment. Streams in basins underlain by loess may require an order of magnitude more time than sand-bed streams to stabilize due to a lack of coarse-grained material (sand) for aggradation. A systematic progression of riparian species that reflects the six-stage model of channel evolution has been identified. This progression can be used to infer ambient channel stability and hydrogeomorphic conditions. Woody vegetation establishes on low- and mid-bank surfaces (the slough line, initially) at about the same time that bank accretion begins. This slough line forms at a mean temporary stability angle of 24 degrees and expands upslope with time by the accretion of sediments. Species involve

Voltage-gated K+ channel modulators as neuroprotective agents.

PubMed

Leung, Yuk-Man

2010-05-22

A manifestation in neurodegeneration is apoptosis of neurons. Neurons undergoing apoptosis may lose a substantial amount of cytosolic K+ through a number of pathways including K+ efflux via voltage-gated K+ (Kv) channels. The consequent drop in cytosolic [K+] relieves inhibition of an array of pro-apoptotic enzymes such as caspases and nucleases. Blocking Kv channels has been known to prevent neuronal apoptosis by preventing K+ efflux. Some neural diseases such as epilepsy are caused by neuronal hyperexcitability, which eventually may lead to neuronal apoptosis. Reduction in activities of A-type Kv channels and Kv7 subfamily members is amongst the etiological causes of neuronal hyperexcitation; enhancing the opening of these channels may offer opportunities of remedy. This review discusses the potential uses of Kv channel modulators as neuroprotective drugs.

Key Technologies and Applications of Gas Drainage in Underground Coal Mine

NASA Astrophysics Data System (ADS)

Zhou, Bo; Xue, Sheng; Cheng, Jiansheng; Li, Wenquan; Xiao, Jiaping

2018-02-01

It is the basis for the long-drilling directional drilling, precise control of the drilling trajectory and ensuring the effective extension of the drilling trajectory in the target layer. The technology can be used to complete the multi-branch hole construction and increase the effective extraction distance of the coal seam. The gas drainage and the bottom grouting reinforcement in the advanced area are realized, and the geological structure of the coal seam can be proved accurately. It is the main technical scheme for the efficient drainage of gas at home and abroad, and it is applied to the field of geological structure exploration and water exploration and other areas. At present, the data transmission method is relatively mature in the technology and application, including the mud pulse and the electromagnetic wave. Compared with the mud pulse transmission mode, the electromagnetic wave transmission mode has obvious potential in the data transmission rate and drilling fluid, and it is suitable for the coal mine. In this paper, the key technologies of the electromagnetic wave transmission mode are analyzed, including the attenuation characteristics of the electromagnetic transmission channel, the digital modulation scheme, the channel coding method and the weak signal processing technology. A coal mine under the electromagnetic wave drilling prototype is developed, and the ground transmission experiments and down hole transmission test are carried out. The main work includes the following aspects. First, the equivalent transmission line method is used to establish the electromagnetic transmission channel model of coal mine drilling while drilling, and the attenuation of the electromagnetic signal is measured when the electromagnetic channel measured. Second, the coal mine EM-MWD digital modulation method is developed. Third, the optimal linear block code which suitable for EM-MWD communication channel in coal mine is proposed. Fourth, the noise characteristics of well near horizontal directional drilling are analyzed, and the multi-stage filter method is proposed to suppress the natural potential and strong frequency interference signal. And the weak electromagnetic communication signal is extracted from the received signal. Finally, the detailed design of the electromagnetic wave while drilling is given.

Basis material decomposition method for material discrimination with a new spectrometric X-ray imaging detector

NASA Astrophysics Data System (ADS)

Brambilla, A.; Gorecki, A.; Potop, A.; Paulus, C.; Verger, L.

2017-08-01

Energy sensitive photon counting X-ray detectors provide energy dependent information which can be exploited for material identification. The attenuation of an X-ray beam as a function of energy depends on the effective atomic number Zeff and the density. However, the measured attenuation is degraded by the imperfections of the detector response such as charge sharing or pile-up. These imperfections lead to non-linearities that limit the benefits of energy resolved imaging. This work aims to implement a basis material decomposition method which overcomes these problems. Basis material decomposition is based on the fact that the attenuation of any material or complex object can be accurately reproduced by a combination of equivalent thicknesses of basis materials. Our method is based on a calibration phase to learn the response of the detector for different combinations of thicknesses of the basis materials. The decomposition algorithm finds the thicknesses of basis material whose spectrum is closest to the measurement, using a maximum likelihood criterion assuming a Poisson law distribution of photon counts for each energy bin. The method was used with a ME100 linear array spectrometric X-ray imager to decompose different plastic materials on a Polyethylene and Polyvinyl Chloride base. The resulting equivalent thicknesses were used to estimate the effective atomic number Zeff. The results are in good agreement with the theoretical Zeff, regardless of the plastic sample thickness. The linear behaviour of the equivalent lengths makes it possible to process overlapped materials. Moreover, the method was tested with a 3 materials base by adding gadolinium, whose K-edge is not taken into account by the other two materials. The proposed method has the advantage that it can be used with any number of energy channels, taking full advantage of the high energy resolution of the ME100 detector. Although in principle two channels are sufficient, experimental measurements show that the use of a high number of channels significantly improves the accuracy of decomposition by reducing noise and systematic bias.

Aerosol Correction for Remotely Sensed Sea Surface Temperatures From the NOAA AVHRR: Phase II

NASA Astrophysics Data System (ADS)

Nalli, N. R.; Ignatov, A.

2002-05-01

For over two decades, the National Oceanic and Atmospheric Administration (NOAA) has produced global retrievals of sea surface temperature (SST) using infrared (IR) data from the Advanced Very High Resolution Radiometer (AVHRR). The standard multichannel retrieval algorithms are derived from regression analyses of AVHRR window channel brightness temperatures against in situ buoy measurements under non-cloudy conditions thus providing a correction for IR attenuation due to molecular water vapor absorption. However, for atmospheric conditions with elevated aerosol levels (e.g., arising from dust, biomass burning and volcanic eruptions), such algorithms lead to significant negative biases in SST because of IR attenuation arising from aerosol absorption and scattering. This research presents the development of a 2nd-phase aerosol correction algorithm for daytime AVHRR SST. To accomplish this, a long-term (1990-1998), global AVHRR-buoy matchup database was created by merging the Pathfinder Atmospheres (PATMOS) and Oceans (PFMDB) data sets. The merged data are unique in that they include multi-year, global daytime estimates of aerosol optical depth (AOD) derived from AVHRR channels 1 and 2 (0.63 and 0.83 μ m, respectively), along with an effective Angstrom exponent derived from the AOD retrievals (Ignatov and Nalli, 2002). Recent enhancements in the aerosol data constitute an improvement over the Phase I algorithm (Nalli and Stowe, 2002) which relied only on channel 1 AOD and the ratio of normalized reflectance from channels 1 and 2. The Angstrom exponent and channel 2 AOD provide important statistical information about the particle size distribution of the aerosol. The SST bias can be parametrically expressed as a function of observed AVHRR channels 1 and 2 slant-path AOD, normalized reflectance ratio and the Angstrom exponent. Based upon these empirical relationships, aerosol correction equations are then derived for the daytime multichannel and nonlinear SST (MCSST and NLSST) algorithms. Separate sets of coefficients are utilized for two aerosol modes, these being stratospheric/tropospheric (e.g., volcanic aerosol) and tropospheric (e.g., dust, smoke). The algorithms are subsequently applied to retrospective PATMOS data to demonstrate the potential for climate applications. The minimization of cold biases in the AVHRR SST, as demonstrated in this work, should improve its overall utility for the general user community.

Satellite passive microwave rain rate measurement over croplands during spring, summer and fall

NASA Technical Reports Server (NTRS)

Spencer, R. W.

1984-01-01

Rain-rate algorithms for spring, summer and fall that have been developed from comparisons between the brightness temperatures measured by the Nimbus-7 Scanning Multichannel Microwave Radiometer (SMMR) and rain rates derived from operational WSR-57 radars over land are described. Data were utilized from a total of 25 SMMR passes and 234 radars, resulting in about 12,000 observations of about 1600 sq/km areas. Multiple correlation coefficients of 0.63, 0.80 and 0.75 are achieved for the spring, summer and fall algorithms, respectively. Most of this information is in the form of multifrequency contrast in brightness temperature, which is interpreted as a measurement of the degree to which the land-emitted radiation is attenuated by the rain systems. The SMMR 37-GHz channel has more information on rain rate than any other channel. By combining the lower frequency channels with the 37-GHz observations, variations in land and precipitation thermometric temperatures can be removed, leaving rain attenuation as the major effect on brightness temperature. Polarization screening at 37 GHz is found to be sufficient to screen out cases of wet ground, which is only important when the ground is relatively vegetation free. Heavy rain cases are found to be significant part of the algorithms' success, because of the strong microwve signatures (low-brightness temperatures) that result from the presence of precipitation-sized ice in the upper portions of heavily precipitating storms. If IR data are combined with the summer microwave data, an improved (0.85) correlation with radar rain rates is achieved.

Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons

PubMed Central

Guo, Yuan; Zhang, Zhiyong; Wu, Hsiang-en; Luo, Z. David; Hogan, Quinn H.; Pan, Bin

2017-01-01

Painful nerve injury disrupts Ca2+ signaling in primary sensory neurons by elevating plasma membrane Ca2+-ATPase (PMCA) function and depressing sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) function, which decreases endoplasmic reticulum (ER) Ca2+ stores and stimulates store-operated Ca2+ entry (SOCE). The extracellular matrix glycoprotein thrombospondin-4 (TSP4), which is increased after painful nerve injury, decreases Ca2+ current (ICa) through high-voltage–activated Ca2+ channels and increases ICa through low-voltage–activated Ca2+ channels in dorsal root ganglion neurons, which are events similar to the effect of nerve injury. We therefore examined whether TSP4 plays a critical role in injury-induced disruption of intracellular Ca2+ signaling. We found that TSP4 increases PMCA activity, inhibits SERCA, depletes ER Ca2+ stores, and enhances store-operated Ca2+ influx. Injury-induced changes of SERCA and PMCA function are attenuated in TSP4 knock-out mice. Effects of TSP4 on intracellular Ca2+ signaling are attenuated in voltage-gated Ca2+ channel α2δ1 subunit (Cavα2δ1) conditional knock-out mice and are also Protein Kinase C (PKC) signaling dependent. These findings suggest that TSP4 elevation may contribute to the pathogenesis of chronic pain following nerve injury by disrupting intracellular Ca2+ signaling via interacting with the Cavα2δ1 and the subsequent PKC signaling pathway. Controlling TSP4 mediated intracellular Ca2+ signaling in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain. PMID:28232180

Diabetes attenuates urothelial modulation of detrusor contractility and spontaneous activity.

PubMed

Wang, Yi; Tar, Moses T; Fu, Shibo; Melman, Arnold; Davies, Kelvin P

2014-10-01

To investigate the effect of diabetes on urothelial modulation of bladder contractility. Bladder strips (urothelium intact or denuded) were prepared from 8-week-old streptozotocin-induced diabetic (n = 19) and non-diabetic control rats (n = 10). The effect of modulators of MaxiK (iberiotoxin and tetraethylammonium) and Kv7 (XE991 and retigabine) potassium channel activity were investigated for their effects on both carbachol-induced force generation and spontaneous contractile activity. In bladder strips from non-diabetic animals, the presence of the urothelium resulted in marked sensitivity to carbachol-induced force generation by modulators of MaxiK and Kv7 channel activity, whereas in the diabetic animal urothelial sensitivity to these agents was significantly diminished. Urothelial-intact bladder strips from non-diabetic animals were more sensitive to modulators of Kv7 activity in reducing the amplitude of spontaneous phasic contractions than urothelial-denuded bladder strips, whereas in diabetic animals the presence or absence of the urothelium did not alter the sensitivity to modulators of Kv7 activity. Spontaneous activity in the presence of tetraethylammonium was not affected by the urothelium in bladder strips from either diabetic or non-diabetic animals. The presence of the urothelium in bladders from non-diabetic animals modulates the activity of potassium blockers to affect bladder contractility, whereas in the diabetic bladder this effect is attenuated. These findings could help to explain the lack of success of pharmaceutical treatments targeting potassium channels to treat bladder pathology in patients with diseases imparing urothelial function. © 2014 The Japanese Urological Association.

Hv1 proton channel facilitates production of ROS and pro-inflammatory cytokines in microglia and enhances oligodendrocyte progenitor cells damage from oxygen-glucose deprivation in vitro.

PubMed

Yu, Ying; Yu, Zhiyuan; Xie, Minjie; Wang, Wei; Luo, Xiang

2018-03-25

The contribution of microglial activation to oligodendrocyte precursor cell (OPC) damage in the brain is considered to be a principal pathophysiological feature of periventricular leukomalacia (PVL). Nicotinamide adenine dinucleotide phosphate oxidase (NOX)-dependent reactive oxygen species (ROS) produced in microglia has been shown to be significantly toxic to OPCs. The voltage-gated proton channel Hv1 is selectively expressed in microglia and is essential for NOX-dependent ROS production in the central nervous system. This study aimed to investigate the effects of microglial Hv1 deficiency on the protection of OPCs from oxygen-glucose deprivation (OGD)-induced injury in vitro. In the present study, the levels of OGD-induced ROS and pro-inflammatory cytokine production were dramatically lower in Hv1-deficient microglia (Hv1 -/- ) than in wild-type (WT) microglia. Following OGD, OPCs co-cultured with WT microglia had increased apoptosis and decreased proliferation and maturation, while those co-cultured with Hv1 -/- microglia had attenuated apoptosis and greater proliferation and differentiation. Furthermore, the attenuated damage and enhanced regeneration of OPCs were associated with decreases in extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase phosphorylation. These results indicate that the protective effects of Hv1 deficiency on OPCs are due to the suppression of ROS and pro-inflammatory cytokine production in microglia. We thus suggest that the microglial proton channel Hv1 may be a potential therapeutic target in PVL. Copyright © 2017 Elsevier Inc. All rights reserved.

Active zone protein Bassoon co-localizes with presynaptic calcium channel, modifies channel function, and recovers from aging related loss by exercise.

PubMed

Nishimune, Hiroshi; Numata, Tomohiro; Chen, Jie; Aoki, Yudai; Wang, Yonghong; Starr, Miranda P; Mori, Yasuo; Stanford, John A

2012-01-01

The P/Q-type voltage-dependent calcium channels (VDCCs) are essential for synaptic transmission at adult mammalian neuromuscular junctions (NMJs); however, the subsynaptic location of VDCCs relative to active zones in rodent NMJs, and the functional modification of VDCCs by the interaction with active zone protein Bassoon remain unknown. Here, we show that P/Q-type VDCCs distribute in a punctate pattern within the NMJ presynaptic terminals and align in three dimensions with Bassoon. This distribution pattern of P/Q-type VDCCs and Bassoon in NMJs is consistent with our previous study demonstrating the binding of VDCCs and Bassoon. In addition, we now show that the interaction between P/Q-type VDCCs and Bassoon significantly suppressed the inactivation property of P/Q-type VDCCs, suggesting that the Ca(2+) influx may be augmented by Bassoon for efficient synaptic transmission at NMJs. However, presynaptic Bassoon level was significantly attenuated in aged rat NMJs, which suggests an attenuation of VDCC function due to a lack of this interaction between VDCC and Bassoon. Importantly, the decreased Bassoon level in aged NMJs was ameliorated by isometric strength training of muscles for two months. The training increased Bassoon immunoreactivity in NMJs without affecting synapse size. These results demonstrated that the P/Q-type VDCCs preferentially accumulate at NMJ active zones and play essential role in synaptic transmission in conjunction with the active zone protein Bassoon. This molecular mechanism becomes impaired by aging, which suggests altered synaptic function in aged NMJs. However, Bassoon level in aged NMJs can be improved by muscle exercise.

Channelopathies of skeletal muscle excitability

PubMed Central

Cannon, Stephen C.

2016-01-01

Familial disorders of skeletal muscle excitability were initially described early in the last century and are now known to be caused by mutations of voltage-gated ion channels. The clinical manifestations are often striking, with an inability to relax after voluntary contraction (myotonia) or transient attacks of severe weakness (periodic paralysis). An essential feature of these disorders is fluctuation of symptoms that are strongly impacted by environmental triggers such as exercise, temperature, or serum K+ levels. These phenomena have intrigued physiologists for decades, and in the past 25 years the molecular lesions underlying these disorders have been identified and mechanistic studies are providing insights for therapeutic strategies of disease modification. These familial disorders of muscle fiber excitability are “channelopathies” caused by mutations of a chloride channel (ClC-1), sodium channel (NaV1.4), calcium channel (CaV1.1) and several potassium channels (Kir2.1, Kir2.6, Kir3.4). This review provides a synthesis of the mechanistic connections between functional defects of mutant ion channels, their impact on muscle excitability, how these changes cause clinical phenotypes, and approaches toward therapeutics. PMID:25880512

Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain.

PubMed

Bonanni, Laura; Chachar, Mushtaque; Jover-Mengual, Teresa; Li, Hongmei; Jones, Adrienne; Yokota, Hidenori; Ofengeim, Dimitry; Flannery, Richard J; Miyawaki, Takahiro; Cho, Chang-Hoon; Polster, Brian M; Pypaert, Marc; Hardwick, J Marie; Sensi, Stefano L; Zukin, R Suzanne; Jonas, Elizabeth A

2006-06-21

Transient global ischemia is a neuronal insult that induces delayed cell death. A hallmark event in the early post-ischemic period is enhanced permeability of mitochondrial membranes. The precise mechanisms by which mitochondrial function is disrupted are, as yet, unclear. Here we show that global ischemia promotes alterations in mitochondrial membrane contact points, a rise in intramitochondrial Zn2+, and activation of large, multi-conductance channels in mitochondrial outer membranes by 1 h after insult. Mitochondrial channel activity was associated with enhanced protease activity and proteolytic cleavage of BCL-xL to generate its pro-death counterpart, deltaN-BCL-xL. The findings implicate deltaN-BCL-xL in large, multi-conductance channel activity. Consistent with this, large channel activity was mimicked by introduction of recombinant deltaN-BCL-xL to control mitochondria and blocked by introduction of a functional BCL-xL antibody to post-ischemic mitochondria via the patch pipette. Channel activity was also inhibited by nicotinamide adenine dinucleotide, indicative of a role for the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane. In vivo administration of the membrane-impermeant Zn2+ chelator CaEDTA before ischemia or in vitro application of the membrane-permeant Zn2+ chelator tetrakis-(2-pyridylmethyl) ethylenediamine attenuated channel activity, suggesting a requirement for Zn2+. These findings reveal a novel mechanism by which ischemic insults disrupt the functional integrity of the outer mitochondrial membrane and implicate deltaN-BCL-xL and VDAC in the large, Zn2+-dependent mitochondrial channels observed in post-ischemic hippocampal mitochondria.

Zinc-Dependent Multi-Conductance Channel Activity in Mitochondria Isolated from Ischemic Brain

PubMed Central

Bonanni, Laura; Chachar, Mushtaque; Jover-Mengual, Teresa; Li, Hongmei; Jones, Adrienne; Yokota, Hidenori; Ofengeim, Dimitry; Flannery, Richard J.; Miyawaki, Takahiro; Cho, Chang-Hoon; Polster, Brian M.; Pypaert, Marc; Hardwick, J. Marie; Sensi, Stefano L.; Zukin, R. Suzanne; Jonas, Elizabeth A.

2015-01-01

Transient global ischemia is a neuronal insult that induces delayed cell death. A hallmark event in the early post-ischemic period is enhanced permeability of mitochondrial membranes. The precise mechanisms by which mitochondrial function is disrupted are, as yet, unclear.Here we show that global ischemia promotes alterations in mitochondrial membrane contact points, a rise in intramitochondrial Zn2+, and activation of large, multi-conductance channels in mitochondrial outer membranes by 1 h after insult. Mitochondrial channel activity was associated with enhanced protease activity and proteolytic cleavage of BCL-xL to generate its pro-death counterpart, ΔN-BCL-xL. The findings implicate ΔN-BCL-xL in large, multi-conductance channel activity. Consistent with this, large channel activity was mimicked by introduction of recombinant ΔN-BCL-xL to control mitochondria and blocked by introduction of a functional BCL-xL antibody to post-ischemic mitochondria via the patch pipette. Channel activity was also inhibited by nicotinamide adenine dinucleotide, indicative of a role for the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane. In vivo administration of the membrane-impermeant Zn2+ chelator CaEDTA before ischemia or in vitro application of the membrane-permeant Zn2+ chelator tetrakis-(2-pyridylmethyl) ethylenediamine attenuated channel activity, suggesting a requirement for Zn2+. These findings reveal a novel mechanism by which ischemic insults disrupt the functional integrity of the outer mitochondrial membrane and implicate ΔNBCL-xL and VDAC in the large, Zn2+-dependent mitochondrial channels observed in post-ischemic hippocampal mitochondria. PMID:16793892

Thapsigargin-induced activation of Ca(2+)-CaMKII-ERK in brainstem contributes to substance P release and induction of emesis in the least shrew.

PubMed

Zhong, Weixia; Chebolu, Seetha; Darmani, Nissar A

2016-04-01

Cytoplasmic calcium (Ca(2+)) mobilization has been proposed to be an important factor in the induction of emesis. The selective sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin, is known to deplete intracellular Ca(2+) stores, which consequently evokes extracellular Ca(2+) entry through cell membrane-associated channels, accompanied by a prominent rise in cytosolic Ca(2+). A pro-drug form of thapsigargin is currently under clinical trial as a targeted cancer chemotherapeutic. We envisioned that the intracellular effects of thapsigargin could cause emesis and planned to investigate its mechanisms of emetic action. Indeed, thapsigargin did induce vomiting in the least shrew in a dose-dependent and bell-shaped manner, with maximal efficacy (100%) at 0.5 mg/kg (i.p.). Thapsigargin (0.5 mg/kg) also caused increases in c-Fos immunoreactivity in the brainstem emetic nuclei including the area postrema (AP), nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNX), as well as enhancement of substance P (SP) immunoreactivity in DMNX. In addition, thapsigargin (0.5 mg/kg, i.p.) led to vomit-associated and time-dependent increases in phosphorylation of Ca(2+)/calmodulin kinase IIα (CaMKIIα) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) in the brainstem. We then explored the suppressive potential of diverse chemicals against thapsigargin-evoked emesis including antagonists of: i) neurokinin-1 receptors (netupitant), ii) the type 3 serotonin receptors (palonosetron), iii) store-operated Ca(2+) entry (YM-58483), iv) L-type Ca(2+) channels (nifedipine), and v) SER Ca(2+)-release channels inositol trisphosphate (IP3Rs) (2-APB)-, and ryanodine (RyRs) (dantrolene)-receptors. In addition, the antiemetic potential of inhibitors of CaMKII (KN93) and ERK1/2 (PD98059) were investigated. All tested antagonists/blockers attenuated emetic parameters to varying degrees except palonosetron, however a combination of non-effective doses of netupitant and palonosetron exhibited additive antiemetic efficacy. A low-dose combination of nifedipine and 2-APB plus dantrolene mixture completely abolished thapsigargin-evoked vomiting, CaMKII-ERK1/2 activation and SP elevation. In addition, pretreatment with KN93 or PD98059 suppressed thapsigargin-induced increases in SP and ERK1/2 activation. Intracerebroventricular injection of netupitant suppressed vomiting caused by thapsigargin which suggests that the principal site of evoked emesis is the brainstem. In sum, this is the first study to demonstrate that thapsigargin causes vomiting via the activation of the Ca(2+)-CaMKII-ERK1/2 cascade, which is associated with an increase in the brainstem tissue content of SP, and the evoked emesis occurs through SP-induced activation of neurokinin-1 receptors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Extension of depth-resolved reconstruction of attenuation coefficients in optical coherence tomography for slim samples

NASA Astrophysics Data System (ADS)

Hohmann, Martin; Lengenfelder, B.; Kanawade, R.; Klämpfl, F.; Schmidt, Michael

2015-12-01

Coherent light propagating through turbid media is attenuated due to scattering and absorption. The decrease of the intensity of the coherent light is described by the attenuation coefficient. The measured decay of the coherent light through turbid media with optical coherence tomography (OCT) can be used to reconstruct the attenuation coefficient. Since most of the OCT systems work in the near-infrared region, they are the optical window from 800-1400 nm in tissue. Hence, the most part of the attenuation coefficient is caused due to the scattering. Therefore, deriving the attenuation coefficient is one way to get an approximation of the scattering coefficient which is difficult to access even up to day. Moreover, OCT measurements are one of the few possibilities to derive physical properties with micrometre resolution of the media under investigation.

Corneal permeability for cement dust: prognosis for occupational safety

NASA Astrophysics Data System (ADS)

Kalmykov, R. V.; Popova, D. V.; Kamenskikh, T. G.; Genina, E. A.; Tuchin, V. V.; Bashkatov, A. N.

2018-02-01

The high dust content in air of a working zone causes prevalence of pathologies of the anterior segment of the eye of workers of cement production. Therefore, studying of features of cement dust impact on structure of a cornea and development of ways of eye protection from this influence is relevant. In this work experimental studies were carried out with twenty eyes of ten rabbits. OCTtomography was used to monitor the light attenuation coefficient of the cornea in vitro during the permeability of cement dust and/or keratoprotector (Systein Ultra). The permeability coefficients of the cornea for water, cement dust and keratoprotector were measured. A computer model allowing one to analyze the diffusion of these substances in the eye cornea was developed. It was shown that 1) the cement dust falling on the eye cornea caused pronounced dehydration of the tissue (thickness decreasing) and led to the increase of the attenuation coefficient, which could affect the deterioration of the eyesight of workers in the conditions of cement production; 2) the application of the keratoprotector to the eye cornea when exposed by cement dust, slowed significantly the dehydration process and did not cause the increase of the attenuation coefficient that characterized the stabilization of visual functions. At this, the keratoprotector itself did not cause dehydration and led to the decrease of the attenuation coefficient, which could allow it to be used for a long time in the order to protect the organ of vision from the negative effects of cement dust.

Serum starvation-induced voltage-gated potassium channel Kv7.5 expression and its regulation by Sp1 in canine osteosarcoma cells.

PubMed

Lee, Bo Hyung; Ryu, Pan Dong; Lee, So Yeong

2014-01-10

The KCNQ gene family, whose members encode Kv7 channels, belongs to the voltage-gated potassium (Kv) channel group. The roles of this gene family have been widely investigated in nerve and muscle cells. In the present study, we investigated several characteristics of Kv7.5, which is strongly expressed in the canine osteosarcoma cell line, CCL-183. Serum starvation upregulated Kv7.5 expression, and the Kv7 channel opener, flupirtine, attenuated cell proliferation by arresting cells in the G0/G1 phase. We also showed that Kv7.5 knockdown helps CCL-183 cells to proliferate. In an effort to find an endogenous regulator of Kv7.5, we used mithramycin A to reduce the level of the transcription factor Sp1, and it strongly inhibited the induction of Kv7.5 in CCL-183 cells. These results suggest that the activation of Kv7.5 by flupirtine may exert an anti-proliferative effect in canine osteosarcoma. Therefore, Kv7.5 is a possible molecular target for canine osteosarcoma therapy.

Disease-causing mutations C277R and C277Y modify gating of human ClC-1 chloride channels in myotonia congenita

PubMed Central

Weinberger, Sebastian; Wojciechowski, Daniel; Sternberg, Damien; Lehmann-Horn, Frank; Jurkat-Rott, Karin; Becher, Toni; Begemann, Birgit; Fahlke, Christoph; Fischer, Martin

2012-01-01

Myotonia congenita is a genetic condition that is caused by mutations in the muscle chloride channel gene CLCN1 and characterized by delayed muscle relaxation and muscle stiffness. We here investigate the functional consequences of two novel disease-causing missense mutations, C277R and C277Y, using heterologous expression in HEK293T cells and patch clamp recording. Both mutations reduce macroscopic anion currents in transfected cells. Since hClC-1 is a double-barrelled anion channel, this reduction in current amplitude might be caused by altered gating of individual protopores or of joint openings and closing of both protopores. We used non-stationary noise analysis and single channel recordings to separate the mutants’ effects on individual and common gating processes. We found that C277Y inverts the voltage dependence and reduces the open probabilities of protopore and common gates resulting in decreases of absolute open probabilities of homodimeric channels to values below 3%. In heterodimeric channels, C277R and C277Y also reduce open probabilities and shift the common gate activation curve towards positive potentials. Moreover, C277Y modifies pore properties of hClC-1. It reduces single protopore current amplitudes to about two-thirds of wild-type values, and inverts the anion permeability sequence to I− = NO3− > Br− > Cl−. Our findings predict a dramatic reduction of the muscle fibre resting chloride conductance and thus fully explain the disease-causing effects of mutations C277R and C277Y. Moreover, they provide additional insights into the function of C277, a residue recently implicated in common gating of ClC channels. PMID:22641783

Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: the role of GSK-3beta in the maintenance of steady-state levels of insulin receptor signaling molecules and Na(v)1.7 sodium channel in adrenal chromaffin cells.

PubMed

Nemoto, Takayuki; Yanagita, Toshihiko; Kanai, Tasuku; Wada, Akihiko

2009-02-01

Glycogen synthase kinase-3 (GSK-3) is constitutively active in nonstimulated cells, where the majority of its substrates undergo inactivation/proteolysis by phosphorylation. Extracellular stimuli (e.g., insulin) catalyze inhibitory Ser(9)-phosphorylation of GSK-3beta, turning on signaling and causing other biological consequences otherwise constitutively suppressed by GSK-3beta. Regulated and dysregulated activities of GSK-3beta are pivotal to health, disease, and therapeutics (e.g., insulin resistance, neurodegeneration, tumorigenesis, inflammation); however, the underlying mechanisms of multifunctional GSK-3beta remain elusive. In cultured bovine adrenal chromaffin cells, 1) constitutive and negatively-regulated activities of GSK-3beta up- and down-regulated insulin receptor, insulin receptor substrate-1 (IRS-1), IRS-2, and Akt levels via controlling proteasomal degradation and protein synthesis; 2) nicotinic receptor/protein kinase C-alpha (PKC-alpha)/extracellular signal-regulated kinase (ERK) pathway up-regulated IRS-1 and IRS-2 levels, enhancing insulin-induced the phosphoinositide 3-kinase (PI3K)/Akt/GSK-3beta pathway; 3) inhibition of calcineurin by cyclosporin A or FK506 down-regulated IRS-2 level, attenuating insulin-like growth factor-I (IGF-I)-induced ERK and GSK-3beta pathways; and 4) insulin, IGF-I or therapeutics (e.g., lithium) up-regulated the voltage-dependent Na(v)1.7 sodium channel.

The Role of Dopamine Receptors in the Neurobehavioral Syndrome Provoked by Activation of L-Type Calcium Channels in Rodents

PubMed Central

Kasim, Suhail; Blake, Bonita L.; Fan, Xueliang; Chartoff, Elena; Egami, Kiyoshi; Breese, George R.; Hess, Ellen J.; Jinnah, H.A.

2010-01-01

In rodents, activation of L-type calcium channels with ± BayK 8644 causes an unusual behavioral syndrome that includes dystonia and self-biting. Prior studies have linked both of these behaviors to dysfunction of dopaminergic transmission in the striatum. The current studies were designed to further elucidate the relationship between ± BayK 8644 and dopaminergic transmission in the expression of the behavioral syndrome. The drug does not appear to release presynaptic dopamine stores, since microdialysis of the striatum revealed dopamine release was unaltered by ± BayK 8644. In addition, the behaviors were preserved or even exaggerated in mice or rats with virtually complete dopamine depletion. On the other hand, pretreatment of mice with D3 or D1/5 dopamine receptor antagonists attenuated the behavioral effects of ± BayK 8644, while pretreatment with D2 or D4 antagonists had no effect. In D3 receptor knockout mice, ± BayK 8644 elicited both dystonia and self-biting, but these behaviors were less severe than in matched controls. In D1 receptor knockout mice, behavioral responses to ± BayK 8644 appeared exaggerated. These results argue that the behavioral effects of ± BayK 8644 are not mediated by a presynaptic influence. Instead, the behaviors appear to result from a postsynaptic activation of the drug, which does not require but can be modified by D3 or D1/5 receptors. PMID:17028428

Thrombospondin-4 divergently regulates voltage-gated Ca2+ channel subtypes in sensory neurons after nerve injury.

PubMed

Pan, Bin; Guo, Yuan; Wu, Hsiang-En; Park, John; Trinh, Van Nancy; Luo, Z David; Hogan, Quinn H

2016-09-01

Loss of high-voltage-activated (HVA) calcium current (ICa) and gain of low-voltage-activated (LVA) ICa after painful peripheral nerve injury cause elevated excitability in sensory neurons. Nerve injury is also accompanied by increased expression of the extracellular matrix glycoprotein thrombospondin-4 (TSP4), and interruption of TSP4 function can reverse or prevent behavioral hypersensitivity after injury. We therefore investigated TSP4 regulation of ICa in dorsal root ganglion (DRG) neurons. During depolarization adequate to activate HVA ICa, TSP4 decreases both N- and L-type ICa and the associated intracellular calcium transient. In contrast, TSP4 increases ICa and the intracellular calcium signal after low-voltage depolarization, which we confirmed is due to ICa through T-type channels. These effects are blocked by gabapentin, which ameliorates neuropathic pain by targeting the α2δ1 calcium subunit. Injury-induced changes of HVA and LVA ICa are attenuated in TSP4 knockout mice. In the neuropathic pain model of spinal nerve ligation, TSP4 application did not further regulate ICa of injured DRG neurons. Taken together, these findings suggest that elevated TSP4 after peripheral nerve injury may contribute to hypersensitivity of peripheral sensory systems by decreasing HVA and increasing LVA in DRG neurons by targeting the α2δ1 calcium subunit. Controlling TSP4 overexpression in peripheral sensory neurons may be a target for analgesic drug development for neuropathic pain.

Rupture Following Biceps-to-Triceps Tendon Transfer in Adolescents and Young Adults With Spinal Cord Injury:

PubMed Central

Merenda, Lisa A.; Rutter, Laure; Curran, Kimberly; Kozin, Scott H.

2012-01-01

Background: Tendon transfer surgery can restore elbow extension in approximately 70% of persons with tetraplegia and often results in antigravity elbow extension strength. However, we have noted an almost 15% rupture/attenuation rate. Objective: This investigation was conducted to analyze potential causes in adolescents/young adults with spinal cord injury (SCI) who experienced tendon rupture or attenuation after biceps-to-triceps transfer. Methods: Medical charts of young adults with SCI who underwent biceps-to-triceps transfer and experienced tendon rupture or attenuation were reviewed. Data collected by retrospective chart review included general demographics, surgical procedure(s), use and duration of antibiotic treatment, time from tendon transfer surgery to rupture/attenuation, and method of diagnosis. Results: Twelve subjects with tetraplegia (mean age, 19 years) who underwent biceps-to-triceps reconstruction with subsequent tendon rupture or attenuation were evaluated. Mean age at time of tendon transfer was 18 years (range, 14-21 years). A fluoroquinolone was prescribed for 42% (n=5) of subjects. Tendon rupture was noted in 67% (n=8), and attenuation was noted in 33% (n=4). Average length of time from surgery to tendon rupture/attenuation was 5.7 months (range, 3-10 months). Conclusion: Potential contributing causes of tendon rupture/attenuation after transfer include surgical technique, rehabilitation, co-contraction of the transfer, poor patient compliance, and medications. In this cohort, 5 subjects were prescribed fluoroquinolones that have a US Food and Drug Administration black box concerning tendon ruptures. Currently, all candidates for upper extremity tendon transfer reconstruction are counseled on the effects of fluoroquinolones and the potential risk for tendon rupture. PMID:23459326

TRPV1 channel-mediated bilateral allodynia induced by unilateral masseter muscle inflammation in rats.

PubMed

Simonic-Kocijan, Suncana; Zhao, Xuehong; Liu, Wen; Wu, Yuwei; Uhac, Ivone; Wang, KeWei

2013-12-30

Pain in masticatory muscles is among the most prominent symptoms of temperomandibular disorders (TMDs) that have diverse and complex etiology. A common complaint of TMD is that unilateral pain of craniofacial muscle can cause a widespread of bilateral pain sensation, although the underlying mechanism remains unknown. To investigate whether unilateral inflammation of masseter muscle can cause a bilateral allodynia, we generated masseter muscle inflammation induced by unilateral injection of complete Freund's adjuvant (CFA) in rats, and measured the bilateral head withdrawal threshold at different time points using a von Frey anesthesiometer. After behavioral assessment, both right and left trigeminal ganglia (TRG) were dissected and examined for histopathology and transient receptor potential vanilloid 1 (TRPV1) mRNA expression using quantitative real-time PCR analysis. A significant increase in TRPV1 mRNA expression occurred in TRG ipsilateral to CFA injected masseter muscle, whereas no significant alteration in TRPV1 occurred in the contralateral TRG. Interestingly, central injection of TRPV1 antagonist 5-iodoresiniferatoxin into the hippocampus significantly attenuated the head withdrawal response of both CFA injected and non-CFA injected contralateral masseter muscle. Our findings show that unilateral inflammation of masseter muscle is capable of inducing bilateral allodynia in rats. Upregulation of TRPV1 at the TRG level is due to nociception caused by inflammation, whereas contralateral nocifensive behavior in masticatory muscle nociception is likely mediated by central TRPV1, pointing to the involvement of altered information processing in higher centers.

Currents through Hv1 channels deplete protons in their vicinity.

PubMed

De-la-Rosa, Víctor; Suárez-Delgado, Esteban; Rangel-Yescas, Gisela E; Islas, León D

2016-02-01

Proton channels have evolved to provide a pH regulatory mechanism, affording the extrusion of protons from the cytoplasm at all membrane potentials. Previous evidence has suggested that channel-mediated acid extrusion could significantly change the local concentration of protons in the vicinity of the channel. In this work, we directly measure the proton depletion caused by activation of Hv1 proton channels using patch-clamp fluorometry recordings from channels labeled with the Venus fluorescent protein at intracellular domains. The fluorescence of the Venus protein is very sensitive to pH, thus behaving as a genetically encoded sensor of local pH. Eliciting outward proton currents increases the fluorescence intensity of Venus. This dequenching is related to the magnitude of the current and not to channel gating and is dependent on the pH gradient. Our results provide direct evidence of local proton depletion caused by flux through the proton-selective channel. © 2016 De-la-Rosa et al.

Chronic exposure to KATP channel openers results in attenuated glucose sensing in hypothalamic GT1-7 neurons.

PubMed

Haythorne, Elizabeth; Hamilton, D Lee; Findlay, John A; Beall, Craig; McCrimmon, Rory J; Ashford, Michael L J

2016-12-01

Individuals with Type 1 diabetes (T1D) are often exposed to recurrent episodes of hypoglycaemia. This reduces hormonal and behavioural responses that normally counteract low glucose in order to maintain glucose homeostasis, with altered responsiveness of glucose sensing hypothalamic neurons implicated. Although the molecular mechanisms are unknown, pharmacological studies implicate hypothalamic ATP-sensitive potassium channel (K ATP ) activity, with K ATP openers (KCOs) amplifying, through cell hyperpolarization, the response to hypoglycaemia. Although initial findings, using acute hypothalamic KCO delivery, in rats were promising, chronic exposure to the KCO NN414 worsened the responses to subsequent hypoglycaemic challenge. To investigate this further we used GT1-7 cells to explore how NN414 affected glucose-sensing behaviour, the metabolic response of cells to hypoglycaemia and K ATP activity. GT1-7 cells exposed to 3 or 24 h NN414 exhibited an attenuated hyperpolarization to subsequent hypoglycaemic challenge or NN414, which correlated with diminished K ATP activity. The reduced sensitivity to hypoglycaemia was apparent 24 h after NN414 removal, even though intrinsic K ATP activity recovered. The NN414-modified glucose responsiveness was not associated with adaptations in glucose uptake, metabolism or oxidation. K ATP inactivation by NN414 was prevented by the concurrent presence of tolbutamide, which maintains K ATP closure. Single channel recordings indicate that NN414 alters K ATP intrinsic gating inducing a stable closed or inactivated state. These data indicate that exposure of hypothalamic glucose sensing cells to chronic NN414 drives a sustained conformational change to K ATP , probably by binding to SUR1, that results in loss of channel sensitivity to intrinsic metabolic factors such as MgADP and small molecule agonists. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Plumes and Blooms: Modeling the Case II Waters of the Santa Barbara Channel. Chapter 15

NASA Technical Reports Server (NTRS)

Siegel, D. A.; Maritorena, S.; Nelson, N. B.

2003-01-01

The goal of the Plumes and Blooms (PnB) project is to develop, validate and apply to imagery state-of-the-art ocean color algorithms for quantifying sediment plumes and phytoplankton blooms for the Case II environment of the Santa Barbara Channel. We conduct monthly to twice-monthly transect observations across the Santa Barbara Channel to develop an algorithm development and product validation data set. The PnB field program started in the summer of 1996. At each of the 7 PnB stations, a complete verification bio-geo-optical data set is collected. Included are redundant measures of apparent optical properties (remote sensing reflectance and diffuse attenuation spectra), as well as in situ profiles of spectral absorption, beam attenuation and backscattering coefficients. Water samples are analyzed for component in vivo absorption spectra, fluorometric chlorophyll, phytoplankton pigment (by the SDSU CHORS laboratory), and inorganic nutrient concentrations. A primary goal is to use the PnB field data set to objectively tune semi-analytical models of ocean color for this site and apply them using available satellite imagery (SeaWiFS and MODIS). In support of this goal, we have also been addressing SeaWiFS ocean color and AVHRR SST imagery. We also are using the PnB data set to address time/space variability of water masses in the Santa Barbara Channel and its relationship to the 1997/1998 El Nino. However, the comparison between PnB field observations and satellite estimates of primary products has been disappointing. We find that field estimates of water-leaving radiance, L(sub wN)(lambda), correspond poorly to satellite estimates for both SeaWiFS and MODIS local area coverage imagery. We believe this is due to poor atmospheric correction due to complex mixtures of aerosol types found in these near-coastal regions. Last, we remain active in outreach activities.

Increased folding and channel activity of a rare cystic fibrosis mutant with CFTR modulators

PubMed Central

Grove, Diane E.; Houck, Scott A.

2011-01-01

Cystic fibrosis (CF) is a lethal recessive genetic disease caused by mutations in the CFTR gene. The gene product is a PKA-regulated anion channel that is important for fluid and electrolyte transport in the epithelia of lung, gut, and ducts of the pancreas and sweat glands. The most common CFTR mutation, ΔF508, causes a severe, but correctable, folding defect and gating abnormality, resulting in negligible CFTR function and disease. There are also a large number of rare CF-related mutations where disease is caused by CFTR misfolding. Yet the extent to which defective biogenesis of these CFTR mutants can be corrected is not clear. CFTRV232D is one such mutant that exhibits defective folding and trafficking. CFTRΔF508 misfolding is difficult to correct, but defective biogenesis of CFTRV232D is corrected to near wild-type levels by small-molecule folding correctors in development as CF therapeutics. To determine if CFTRV232D protein is competent as a Cl− channel, we utilized single-channel recordings from transfected human embryonic kidney (HEK-293) cells. After PKA stimulation, CFTRV232D channels were detected in patches with a unitary Cl− conductance indistinguishable from that of CFTR. Yet the frequency of detecting CFTRV232D channels was reduced to ∼20% of patches compared with 60% for CFTR. The folding corrector Corr-4a increased the CFTRV232D channel detection rate and activity to levels similar to CFTR. CFTRV232D-corrected channels were inhibited with CFTRinh-172 and stimulated fourfold by the CFTR channel potentiator VRT-532. These data suggest that CF patients with rare mutations that cause CFTR misfolding, such as CFTRV232D, may benefit from treatment with folding correctors and channel potentiators in development to restore CFTRΔF508 function. PMID:21642448

Differentiation dependent expression of TRPA1 and TRPM8 channels in IMR-32 human neuroblastoma cells.

PubMed

Louhivuori, Lauri M; Bart, Genevieve; Larsson, Kim P; Louhivuori, Verna; Näsman, Johnny; Nordström, Tommy; Koivisto, Ari-Pekka; Akerman, Karl E O

2009-10-01

TRPA1 and TRPM8 are transient receptor potential (TRP) channels involved in sensory perception. TRPA1 is a non-selective calcium permeable channel activated by irritants and proalgesic agents. TRPM8 reacts to chemical cooling agents such as menthol. The human neuroblastoma cell line IMR-32 undergoes a remarkable differentiation in response to treatment with 5-bromo-2-deoxyuridine. The cells acquire a neuronal morphology with increased expression of N-type voltage gated calcium channels and neurotransmitters. Here we show using RT-PCR, that mRNA for TRPA1 and TRPM8 are strongly upregulated in differentiating IMR-32 cells. Using whole cell patch clamp recordings, we demonstrate that activators of these channels, wasabi, allyl-isothiocyanate (AITC) and menthol activate membrane currents in differentiated cells. Calcium imaging experiments demonstrated that AITC mediated elevation of intracellular calcium levels were attenuated by ruthenium red, spermine, and HC-030031 as well as by siRNA directed against the channel. This indicates that the detected mRNA level correlate with the presence of functional channels of both types in the membrane of differentiated cells. Although the differentiated IMR-32 cells responded to cooling many of the cells showing this response did not respond to TRPA1/TRPM8 channel activators (60% and 90% for AITC and menthol respectively). Conversely many of the cells responding to these activators did not respond to cooling (30%). This suggests that these channels have also other functions than cold perception in these cells. Furthermore, our results suggest that IMR-32 cells have sensory characteristics and can be used to study native TRPA1 and TRPM8 channel function as well as developmental expression. Copyright 2009 Wiley-Liss, Inc.

Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide.

PubMed

Gupte, Raeesa P; Kadunganattil, Suraj; Shepherd, Andrew J; Merrill, Ronald; Planer, William; Bruchas, Michael R; Strack, Stefan; Mohapatra, Durga P

2016-02-01

The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is secreted by both neuronal and non-neuronal cells in the brain and spinal cord, in response to pathological conditions such as stroke, seizures, chronic inflammatory and neuropathic pain. PACAP has been shown to exert various neuromodulatory and neuroprotective effects. However, direct influence of PACAP on the function of intrinsically excitable ion channels that are critical to both hyperexcitation as well as cell death, remain largely unexplored. The major dendritic K(+) channel Kv4.2 is a critical regulator of neuronal excitability, back-propagating action potentials in the dendrites, and modulation of synaptic inputs. We identified, cloned and characterized the downstream signaling originating from the activation of three PACAP receptor (PAC1) isoforms that are expressed in rodent hippocampal neurons that also exhibit abundant expression of Kv4.2 protein. Activation of PAC1 by PACAP leads to phosphorylation of Kv4.2 and downregulation of channel currents, which can be attenuated by inhibition of either PKA or ERK1/2 activity. Mechanistically, this dynamic downregulation of Kv4.2 function is a consequence of reduction in the density of surface channels, without any influence on the voltage-dependence of channel activation. Interestingly, PKA-induced effects on Kv4.2 were mediated by ERK1/2 phosphorylation of the channel at two critical residues, but not by direct channel phosphorylation by PKA, suggesting a convergent phosphomodulatory signaling cascade. Altogether, our findings suggest a novel GPCR-channel signaling crosstalk between PACAP/PAC1 and Kv4.2 channel in a manner that could lead to neuronal hyperexcitability. Copyright © 2015 Elsevier Ltd. All rights reserved.

Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

PubMed Central

Hristov, Kiril L.; Smith, Amy C.; Parajuli, Shankar P.; Malysz, John; Rovner, Eric S.

2016-01-01

Transient receptor potential melastatin 4 (TRPM4) channels are Ca2+-activated nonselective cation channels that have been recently identified as regulators of detrusor smooth muscle (DSM) function in rodents. However, their expression and function in human DSM remain unexplored. We provide insights into the functional role of TRPM4 channels in human DSM under physiological conditions. We used a multidisciplinary experimental approach, including RT-PCR, Western blotting, immunohistochemistry and immunocytochemistry, patch-clamp electrophysiology, and functional studies of DSM contractility. DSM samples were obtained from patients without preoperative overactive bladder symptoms. RT-PCR detected mRNA transcripts for TRPM4 channels in human DSM whole tissue and freshly isolated single cells. Western blotting and immunohistochemistry with confocal microscopy revealed TRPM4 protein expression in human DSM. Immunocytochemistry further detected TRPM4 protein expression in DSM single cells. Patch-clamp experiments showed that 9-phenanthrol, a selective TRPM4 channel inhibitor, significantly decreased the transient inward cation currents and voltage step-induced whole cell currents in freshly isolated human DSM cells. In current-clamp mode, 9-phenanthrol hyperpolarized the human DSM cell membrane potential. Furthermore, 9-phenanthrol attenuated the spontaneous phasic, carbachol-induced and nerve-evoked contractions in human DSM isolated strips. Significant species-related differences in TRPM4 channel activity between human, rat, and guinea pig DSM were revealed, suggesting a more prominent physiological role for the TRPM4 channel in the regulation of DSM function in humans than in rodents. In conclusion, TRPM4 channels regulate human DSM excitability and contractility and are critical determinants of human urinary bladder function. Thus, TRPM4 channels could represent promising novel targets for the pharmacological or genetic control of overactive bladder. PMID:26791488

Calcium Montmorillonite-based dietary supplement attenuates Necrotic Enteritis induced by Eimeria maxima and Clostridium perfringens in broilers

USDA-ARS?s Scientific Manuscript database

We provide the first description of Dietary Supplement of sorbent minerals attenuates Necrotic Enteritis Induced by Eimeria maxima and Clostridium perfringens in Broilers. Necrotic enteritis (NE) is a poultry disease caused by Clostridium perfringens and characterized by severe intestinal necrosis....

High-Frequency Ground-Motion Parameters from Weak-Motion Data in the Sicily Channel and Surrounding Regions

NASA Astrophysics Data System (ADS)

D'Amico, Sebastiano; Akinci, Aybige; Pischiutta, Marta

2018-03-01

In this paper we characterize the high frequency (1.0 - 10 Hz) seismic wave crustal attenuation and the source excitation in the Sicily Channel and surrounding regions using background seismicity from weak-motion database. The data set includes 15995 waveforms related to earthquakes having local magnitude ranging from 2.0 to 4.5 recorded between 2006 and 2012. The observed and predicted ground motions form the weak-motion data are evaluated in several narrow frequency bands from 0.25 to 20.0 Hz. The filtered observed peaks are regressed to specify a proper functional form for the regional attenuation, excitation and site specific term separately. The results are then used to calibrate effective theoretical attenuation and source excitation models using the Random Vibration Theory (RVT). In the log-log domain, the regional seismic wave attenuation and the geometrical spreading coefficient are modeled together. The geometrical spreading coefficient, g (r), modeled with a bilinear piecewise functional form and given as g (r) ∝ r-1.0 for the short distances (r < 50 km) and as g (r) ∝ r-0.8 for the larger distances (r < 50 km). A frequency-dependent quality factor, inverse of the seismic attenuation parameter, Q(f) = 160 f/fref 0. 35 (where fref = 1.0 Hz), is combined to the geometrical spreading. The source excitation terms are defined at a selected reference distance with a magnitude independent roll-off spectral parameter, κ 0.04 s and with a Brune stress drop parameter increasing with moment magnitude, from Δσ = 2 MPa for Mw = 2.0 to Δσ = 13 MPa for Mw = 4.5. For events M≤4.5 (being Mwmax = 4.5 available in the dataset) the stress parameters are obtained by correlating the empirical/excitation source spectra with the Brune spectral model as function of magnitude. For the larger magnitudes (Mw>4.5) outside the range available in the calibration dataset where we do not have recorded data, we extrapolate our results through the calibration of the stress parameters of the Brune source spectrum over the Bindi et al. (2011) ground motion prediction equation (GMPE) selected as a reference model (hereafter also ITA10).

Process and apparatus for separation of components of a gas stream

DOEpatents

Bryan, Charles R.; Torczynski, John R.; Brady, Patrick V.; Gallis, Michail; Brooks, Carlton F.

2014-06-17

A process and apparatus for separating a gas mixture comprising providing a slot in a gas separation channel (conceptualized as a laterally elongated Clusius-Dickel column), having a length through which a net cross-flow of the gas mixture may be established; applying a higher temperature to one side of the channel and a lower temperature on an opposite side of the channel thereby causing thermal-diffusion and buoyant-convection flow to occur in the slot; and establishing a net cross-flow of a gas mixture comprising at least one higher density gas component and at least one lower density gas component along the length of the slot, wherein the cross-flow causes, in combination with the convection flow, a spiraling flow in the slot; and wherein the spiral flow causes an increasing amount of separation of the higher density gas from the lower density gas along the length of the channel. The process may use one or more slots and/or channels.

Process and apparatus for separation of components of a gas stream

DOEpatents

Bryan, Charles R; Torczynski, John R; Brady, Patrick V; Gallis, Michail; Brooks, Carlton F

2013-09-17

A process and apparatus for separating a gas mixture comprising providing a slot in a gas separation channel (conceptualized as a laterally elongated Clusius-Dickel column), having a length through which a net cross-flow of the gas mixture may be established; applying a higher temperature to one side of the channel and a lower temperature on an opposite side of the channel thereby causing thermal-diffusion and buoyant-convection flow to occur in the slot; and establishing a net cross-flow of a gas mixture comprising at least one higher density gas component and at least one lower density gas component along the length of the slot, wherein the cross-flow causes, in combination with the convection flow, a spiraling flow in the slot; and wherein the spiral flow causes an increasing amount of separation of the higher density gas from the lower density gas along the length of the channel. The process may use one or more slots and/or channels.

Process and apparatus for separation of components of a gas stream

DOEpatents

Bryan, Charles R; Torczynski, John R; Brady, Patrick V; Gallis, Michail; Brooks, Carlton F

2013-11-19

A process and apparatus for separating a gas mixture comprising providing a slot in a gas separation channel (conceptualized as a laterally elongated Clusius-Dickel column), having a length through which a net cross-flow of the gas mixture may be established; applying a higher temperature to one side of the channel and a lower temperature on an opposite side of the channel thereby causing thermal-diffusion and buoyant-convection flow to occur in the slot; and establishing a net cross-flow of a gas mixture comprising at least one higher density gas component and at least one lower density gas component along the length of the slot, wherein the cross-flow causes, in combination with the convection flow, a spiraling flow in the slot; and wherein the spiral flow causes an increasing amount of separation of the higher density gas from the lower density gas along the length of the channel. The process may use one or more slots and/or channels.

Severe pain as a possible cause of dropped head syndrome that was attenuated after amputation of an ischemic lower limb.

PubMed

Maki, Satoshi; Koda, Masao; Furuya, Takeo; Takahashi, Kazuhisa; Yamazaki, Masashi

2016-03-02

Dropped head syndrome (DHS) is defined as weakness of the neck extensor muscles causing a correctable chin-on-the-chest deformity. Here we report the case of a patient with severe pain from lower leg ischemia showing DHS whose symptoms were attenuated by pain relief after amputation of the severely ischemic lower leg. To our knowledge this is the first report indicating that severe pain can cause DHS. A 64-year-old Asian woman was referred to our department with a 1-month history of DHS. She also suffered from severe right foot pain because of limb ischemia. She began to complain of DHS as her gangrenous foot pain worsened. She had neck pain and difficulty with forward gaze. We found no clinical or laboratory findings of neuromuscular disorder or isolated neck extensor myopathy. We amputated her leg below the knee because of progressive foot gangrene. Her severe foot pain resolved after the surgery and her DHS was attenuated. Severe pain can cause DHS. If a patient with DHS has severe pain in another part of the body, we recommend considering aggressive pain relief as a treatment option.

Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy*

PubMed Central

Rahman, Md Habibur; Jha, Mithilesh Kumar; Kim, Jong-Heon; Nam, Youngpyo; Lee, Maan Gee; Go, Younghoon; Harris, Robert A.; Park, Dong Ho; Kook, Hyun; Lee, In-Kyu; Suk, Kyoungho

2016-01-01

The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy. PMID:26769971

DCPIB, a potent volume-regulated anion channel antagonist, attenuates microglia-mediated inflammatory response and neuronal injury following focal cerebral ischemia.

PubMed

Han, Qingdong; Liu, Shengwen; Li, Zhengwei; Hu, Feng; Zhang, Qiang; Zhou, Min; Chen, Jingcao; Lei, Ting; Zhang, Huaqiu

2014-01-13

Accumulating evidence indicates that extensive microglia activation-mediated local inflammation contributes to neuronal injury in cerebral ischemia. We have previously shown that 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), a potent volume-regulated anion channel (VRAC) inhibitor, suppresses pathological glutamate release and excitatory neurotoxicity in reversible middle cerebral artery occlusion (rMCAO) model in vivo. In the present study, we sought to determine whether DCPIB also attenuates microglia activation that could contribute to neuronal injury in the cerebral ischemia/reperfusion pathology. We show that oxygen-glucose deprivation (OGD) induced microglia proliferation, migration, and secretion of cytokines and all these pathological changes were effectively inhibited by DCPIB in vitro. In the microglia/neuron co-cultures, OGD induced neuronal damage was reduced markedly in the presence of DCPIB. In rat rMCAO animal model, DCPIB significantly attenuated microglia activation and neuronal death. Activation of mitogen-activated protein kinase (MAPK) signaling pathway is known to be a critical signaling pathway for microglia activation. We further explored a potential involvement of DCPIB in this pathway by western blot analysis. Under the conditions that MAPK pathway was activated either by lipopolysaccharides (LPS) or OGD, the levels of phosphorylated ERK1/2, JNK and p38 were reduced significantly in the presence of DCPIB. Altogether, our study demonstrated that DCPIB inhibits microglia activation potently under ischemic conditions both in vitro and in vivo. The DCPIB effect is likely attributable to both direct inhibition VRAC and indirect inhibition of MAPK pathway in microglia that are beneficial for the survival of neurons in cerebral ischemic conditions. © 2013 Elsevier B.V. All rights reserved.

Ka-Band Site Characterization of the NASA Near Earth Network in Svalbard, Norway

NASA Technical Reports Server (NTRS)

Acosta, R.; Morse, J.; Nessel, J.; Zemba, M.; Tuttle, K.; Caroglanian, A.; Younes, B.; Pedersen, Sten-Chirstian

2011-01-01

Critical to NASA s rapid migration toward Ka-Band is the comprehensive characterization of the communication channels at NASA's ground sites to determine the effects of the atmosphere on signal propagation and the network's ability to support various classes of users in different orbits. Accordingly, NASA has initiated a number of studies involving the ground sites of its Near Earth and Deep Space Networks. Recently, NASA concluded a memorandum of agreement (MOA) with the Norwegian Space Centre of the Kingdom of Norway and began a joint site characterization study to determine the atmospheric effects on Ka-Band links at the Svalbard Satellite Station in Norway, which remains a critical component of NASA s Near Earth Communication Network (NEN). System planning and design for Ka-band links at the Svalbard site cannot be optimally achieved unless measured attenuation statistics (e.g. cumulative distribution functions (CDF)) are obtained. In general, the CDF will determine the necessary system margin and overall system availability due to the atmospheric effects. To statistically characterize the attenuation statistics at the Svalbard site, NASA has constructed a ground-based monitoring station consisting of a multi-channel total power radiometer (25.5 - 26.5 GHz) and a weather monitoring station to continuously measure (at 1 second intervals) attenuation and excess noise (brightness temperature). These instruments have been tested in a laboratory environment as well as in an analogous outdoor climate (i.e. winter in Northeast Ohio), and the station was deployed in Svalbard, Norway in May 2011. The measurement campaign is planned to last a minimum of 3 years but not exceeding a maximum of 5 years.

Dispersion of sound in a combustion duct by fuel droplets and soot particles

NASA Technical Reports Server (NTRS)

Miles, J. H.; Raftopoulos, D. D.

1979-01-01

Dispersion and attenuation of acoustic plane wave disturbances propagating in a ducted combustion system are studied. The dispersion and attenuation are caused by fuel droplet and soot emissions from a jet engine combustor. The attenuation and dispersion are due to heat transfer and mass transfer and viscous drag forces between the emissions and the ambient gas. Theoretical calculations show sound propagation at speeds below the isentropic speed of sound at low frequencies. Experimental results are in good agreement with the theory.

A Prospective, Randomized Investigation of Plasma First Resuscitation for Traumatic Hemorrhage and Attenuation of the Acute Coagulopathy of Trauma

DTIC Science & Technology

2013-08-01

Investigation of "Plasma First Resuscitation" for Traumatic Hemorrhage and Attenuation of the Acute Coagulopathy of Trauma PRINCIPAL INVESTIGATOR...34Plasma First Resuscitation" for Traumatic Hemorrhage and Attenuation of the Acute Coagulopathy of Trauma 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH...is the most preventable cause of death in trauma patients. Coagulopathy has been documented in up to one third of trauma patients upon arrival to the

Pharmacological rescue of trafficking-impaired ATP-sensitive potassium channels

PubMed Central

Martin, Gregory M.; Chen, Pei-Chun; Devaraneni, Prasanna; Shyng, Show-Ling

2013-01-01

ATP-sensitive potassium (KATP) channels link cell metabolism to membrane excitability and are involved in a wide range of physiological processes including hormone secretion, control of vascular tone, and protection of cardiac and neuronal cells against ischemic injuries. In pancreatic β-cells, KATP channels play a key role in glucose-stimulated insulin secretion, and gain or loss of channel function results in neonatal diabetes or congenital hyperinsulinism, respectively. The β-cell KATP channel is formed by co-assembly of four Kir6.2 inwardly rectifying potassium channel subunits encoded by KCNJ11 and four sulfonylurea receptor 1 subunits encoded by ABCC8. Many mutations in ABCC8 or KCNJ11 cause loss of channel function, thus, congenital hyperinsulinism by hampering channel biogenesis and hence trafficking to the cell surface. The trafficking defects caused by a subset of these mutations can be corrected by sulfonylureas, KATP channel antagonists that have long been used to treat type 2 diabetes. More recently, carbamazepine, an anticonvulsant that is thought to target primarily voltage-gated sodium channels has been shown to correct KATP channel trafficking defects. This article reviews studies to date aimed at understanding the mechanisms by which mutations impair channel biogenesis and trafficking and the mechanisms by which pharmacological ligands overcome channel trafficking defects. Insight into channel structure-function relationships and therapeutic implications from these studies are discussed. PMID:24399968

Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations*

PubMed Central

Martin, Gregory M.; Rex, Emily A.; Devaraneni, Prasanna; Denton, Jerod S.; Boodhansingh, Kara E.; DeLeon, Diva D.; Stanley, Charles A.; Shyng, Show-Ling

2016-01-01

ATP-sensitive potassium (KATP) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to β-cell membrane potential. Loss of KATP channel function due to mutations in ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects. In the present study, we identified 13 novel SUR1 mutations that cause channel trafficking defects, the majority of which are amenable to pharmacological rescue by glibenclamide and carbamazepine. By contrast, none of the mutant channels were rescued by KATP channel openers. Cross-linking experiments showed that KATP channel inhibitors promoted interactions between the N terminus of Kir6.2 and SUR1, whereas channel openers did not, suggesting the inhibitors enhance intersubunit interactions to overcome channel biogenesis and trafficking defects. Functional studies of rescued mutant channels indicate that most mutants rescued to the cell surface exhibited WT-like sensitivity to ATP, MgADP, and diazoxide. In intact cells, recovery of channel function upon trafficking rescue by reversible sulfonylureas or carbamazepine was facilitated by the KATP channel opener diazoxide. Our study expands the list of KATP channel trafficking mutations whose function can be recovered by pharmacological ligands and provides further insight into the structural mechanism by which channel inhibitors correct channel biogenesis and trafficking defects. PMID:27573238

Assessment of the Performance of a Dual-Frequency Surface Reference Technique

NASA Technical Reports Server (NTRS)

Meneghini, Robert; Liao, Liang; Tanelli, Simone; Durden, Stephen

2013-01-01

The high correlation of the rain-free surface cross sections at two frequencies implies that the estimate of differential path integrated attenuation (PIA) caused by precipitation along the radar beam can be obtained to a higher degree of accuracy than the path-attenuation at either frequency. We explore this finding first analytically and then by examining data from the JPL dual-frequency airborne radar using measurements from the TC4 experiment obtained during July-August 2007. Despite this improvement in the accuracy of the differential path attenuation, solving the constrained dual-wavelength radar equations for parameters of the particle size distribution requires not only this quantity but the single-wavelength path attenuation as well. We investigate a simple method of estimating the single-frequency path attenuation from the differential attenuation and compare this with the estimate derived directly from the surface return.

The effect of hydrate content on seismic attenuation: A case study for Mallik 2L-38 well data, Mackenzie delta, Canada

NASA Astrophysics Data System (ADS)

Chand, Shyam; Minshull, Tim A.

2004-07-01

Observations of velocities in sediments containing gas hydrates show that the strength of sediments increases with hydrate saturation. Hence it is expected that the attenuation of these sediments will decrease with increasing hydrate saturation. However, sonic log measurements in the Mallik 2L-38 well and cross hole tomography measurements in the Mallik field have shown that attenuation increases with hydrate saturation. We studied a range of mechanisms by which increasing hydrate saturation could cause increased attenuation. We found that a difference in permeability between the host sediment and the newly formed hydrate can produce the observed effect. We modelled attenuation in terms of Biot and squirt flow mechanisms in composite media. We have used our model to predict observed attenuations in the Mallik 2L-38 well, Mackenzie Delta, Canada.

Decreased accumulation of subgenomic RNA in human cells infected with vaccine candidate DEN4Δ30 increases viral susceptibility to type I interferon.

PubMed

Bustos-Arriaga, José; Gromowski, Gregory D; Tsetsarkin, Konstantin A; Firestone, Cai-Yen; Castro-Jiménez, Tannya; Pletnev, Alexander G; Cedillo-Barrón, Leticia; Whitehead, Stephen S

2018-06-07

The NIH has developed live attenuated dengue virus (DENV) vaccine candidates by deletion of 30 nucleotides (Δ30) from the untranslated region of the viral genome. Although this attenuation strategy has proven to be effective in generating safe and immunogenic vaccine strains, the molecular mechanism of attenuation is largely unknown. To examine the mediators of the observed attenuation phenotype, differences in translation efficiency, genome replication, cytotoxicity, and type I interferon susceptibility were compared between wild type parental DENV and DENVΔ30 attenuated vaccine candidates. We observed that decreased accumulation of subgenomic RNA (sfRNA) from the vaccine candidates in infected human cells causes increased type I IFN susceptibility and propose this as one of the of attenuation mechanisms produced by the 3' UTR Δ30 mutation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Adaptive Control for Uncertain Nonlinear Multi-Input Multi-Output Systems

NASA Technical Reports Server (NTRS)

Cao, Chengyu (Inventor); Hovakimyan, Naira (Inventor); Xargay, Enric (Inventor)

2014-01-01

Systems and methods of adaptive control for uncertain nonlinear multi-input multi-output systems in the presence of significant unmatched uncertainty with assured performance are provided. The need for gain-scheduling is eliminated through the use of bandwidth-limited (low-pass) filtering in the control channel, which appropriately attenuates the high frequencies typically appearing in fast adaptation situations and preserves the robustness margins in the presence of fast adaptation.

Rollover of Apparent Wave Attenuation in Ice Covered Seas

NASA Astrophysics Data System (ADS)

Li, Jingkai; Kohout, Alison L.; Doble, Martin J.; Wadhams, Peter; Guan, Changlong; Shen, Hayley H.

2017-11-01

Wave attenuation from two field experiments in the ice-covered Southern Ocean is examined. Instead of monotonically increasing with shorter waves, the measured apparent attenuation rate peaks at an intermediate wave period. This "rollover" phenomenon has been postulated as the result of wind input and nonlinear energy transfer between wave frequencies. Using WAVEWATCH III®, we first validate the model results with available buoy data, then use the model data to analyze the apparent wave attenuation. With the choice of source parameterizations used in this study, it is shown that rollover of the apparent attenuation exists when wind input and nonlinear transfer are present, independent of the different wave attenuation models used. The period of rollover increases with increasing distance between buoys. Furthermore, the apparent attenuation for shorter waves drops with increasing separation between buoys or increasing wind input. These phenomena are direct consequences of the wind input and nonlinear energy transfer, which offset the damping caused by the intervening ice.

Glyburide is associated with attenuated vasogenic edema in stroke patients.

PubMed

Kimberly, W Taylor; Battey, Thomas W K; Pham, Ly; Wu, Ona; Yoo, Albert J; Furie, Karen L; Singhal, Aneesh B; Elm, Jordan J; Stern, Barney J; Sheth, Kevin N

2014-04-01

Brain edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death. Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4. However, the relevance of this pathway to the development of cerebral edema in stroke patients is not known. Using a case-control design, we retrospectively assessed neuroimaging and blood markers of cytotoxic and vasogenic edema in subjects who were enrolled in the glyburide advantage in malignant edema and stroke-pilot (GAMES-Pilot) trial. We compared serial brain magnetic resonance images (MRIs) to a cohort with similar large volume infarctions. We also compared matrix metalloproteinase-9 (MMP-9) plasma level in large hemispheric stroke. We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level. Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke. Verification of these potential imaging and blood biomarkers is warranted in the context of a randomized, placebo-controlled trial.

A dual inhibitor of FAAH and TRPV1 channels shows dose-dependent effect on depression-like behaviour in rats.

PubMed

Kirkedal, Christian; Wegener, Gregers; Moreira, Fabricio; Joca, Sâmia Regiane Lourenco; Liebenberg, Nico

2017-12-01

The cannabinoid receptor 1 (CB1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are proposed to mediate opposite behavioural responses. Their common denominator is the endocannabinoid ligand anandamide (AEA), which is believed to mediate antidepressant-like effect via CB1-R stimulation and depressive-like effect via TRPV1 activation. This is supposed to explain the bell-shaped dose-response curve for anandamide in preclinical models. We investigated this assumption by administering the dual inhibitor of AEA hydrolysis and TRPV1 activation N-arachidonoyl-serotonin (AA-5HT) into the medial prefrontal cortex of rats. AA-5HT was given in three different doses (0.125, 0.250, 0.500 nmol/0.4 µl/side) and rat behaviour was assessed in the forced swim test. Our results show significant antidepressant-like effect of AA-5HT (0.250 nmol) but no effects of low or high doses. The effect of 0.250 nmol AA-5HT was partially attenuated when coadministering the inverse CB1-agonist rimonabant (1.6 µg). A 0.250 nmol of AA-5HT administration into the medial prefrontal cortex induced a significant antidepressant-like effect that was partially attenuated by locally blocking CB1-receptor.

Fast monitoring of dissolved organic and suspended matter using data of beam attenuation coefficient in Black Sea

NASA Astrophysics Data System (ADS)

Mankovskaya, E. V.; Korchemkina, E. N.; Latushkin, A. A.

2017-11-01

A method allowing to obtain estimates of dissolved organic and suspended matter content in Black Sea waters using beam attenuation coefficient (BAC) measurements in two spectral channels is proposed. It makes possible to assess the composition, bio-productivity and ecological state of waters in real time, and to validate the data of satellite scanners. The method is based on retrieval the spectral distribution of BAC by orthogonal functions. Full spectral distribution in range 416 - 677 nm allows to select spectral sites with a dominant contribution of certain substance in BAC and to obtain the content of yellow substance and suspended matter using specially designed optimization technique. Calculated values are in good agreement with the satellite data obtained from MODIS scanner.

Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABAB and mGlu2/3 receptors

PubMed Central

Kupferschmidt, David A; Lovinger, David M

2015-01-01

Cortical inputs to the dorsolateral striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS-associated circuit function, behaviour and pathology. Presynaptic GABAB and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 to assess presynaptic Ca2+ in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca2+ and striatal field potential recordings, we report that relative to P/Q-type Ca2+ channels, N-type channels preferentially contributed to evoked presynaptic Ca2+ influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABAB or mGlu2/3 receptors inhibited both evoked presynaptic Ca2+ transients and striatal field potentials. mGlu2/3 receptor-mediated depression did not require functional N-type Ca2+ channels, but was attenuated by blockade of P/Q-type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires. Key points Plastic changes at cortical inputs to the dorsolateral striatum (DLS) underlie skill learning and habit formation, so characterizing the mechanisms by which these inputs are regulated is important for understanding the neural basis of action control. We developed a novel approach using the genetically encoded calcium (Ca2+) indicator GCaMP6 and brain slice photometry to assess evoked presynaptic Ca2+ transients in cortical inputs to the DLS and study their regulation by GABAB and mGlu2/3 receptors. GABAB and mGlu2/3 receptor activation caused clear reductions in electrical stimulus-evoked presynaptic Ca2+ transients in corticostriatal inputs to the DLS. Functional P/Q-type voltage-gated Ca2+ channels were required for the normal inhibitory action of corticostriatal mGlu2/3 receptors. We provide direct evidence of presynaptic Ca2+ inhibition by G protein-coupled receptors at corticostriatal projections. PMID:25781000

Alternative mitochondrial electron transfer as a novel strategy for neuroprotection.

PubMed

Wen, Yi; Li, Wenjun; Poteet, Ethan C; Xie, Luokun; Tan, Cong; Yan, Liang-Jun; Ju, Xiaohua; Liu, Ran; Qian, Hai; Marvin, Marian A; Goldberg, Matthew S; She, Hua; Mao, Zixu; Simpkins, James W; Yang, Shao-Hua

2011-05-06

Neuroprotective strategies, including free radical scavengers, ion channel modulators, and anti-inflammatory agents, have been extensively explored in the last 2 decades for the treatment of neurological diseases. Unfortunately, none of the neuroprotectants has been proved effective in clinical trails. In the current study, we demonstrated that methylene blue (MB) functions as an alternative electron carrier, which accepts electrons from NADH and transfers them to cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB derivative, with the redox center disabled by N-acetylation, had no effect on mitochondrial complex activities. MB increases cellular oxygen consumption rates and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective against various insults in vitro at low nanomolar concentrations. Our data indicate that MB has a unique mechanism and is fundamentally different from traditional antioxidants. We examined the effects of MB in two animal models of neurological diseases. MB dramatically attenuates behavioral, neurochemical, and neuropathological impairment in a Parkinson disease model. Rotenone caused severe dopamine depletion in the striatum, which was almost completely rescued by MB. MB rescued the effects of rotenone on mitochondrial complex I-III inhibition and free radical overproduction. Rotenone induced a severe loss of nigral dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB significantly reduced cerebral ischemia reperfusion damage in a transient focal cerebral ischemia model. The present study indicates that rerouting mitochondrial electron transfer by MB or similar molecules provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.

Excitotoxicity in the Lung: N-Methyl-D-Aspartate-Induced, Nitric Oxide-Dependent, Pulmonary Edema is Attenuated by Vasoactive Intestinal Peptide and by Inhibitors of Poly(ADP-Ribose) Polymerase

NASA Astrophysics Data System (ADS)

Said, Sami I.; Berisha, Hasan I.; Pakbaz, Hedayatollah

1996-05-01

Excitatory amino acid toxicity, resulting from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors, is a major mechanism of neuronal cell death in acute and chronic neurological diseases. We have investigated whether excitotoxicity may occur in peripheral organs, causing tissue injury, and report that NMDA receptor activation in perfused, ventilated rat lungs triggered acute injury, marked by increased pressures needed to ventilate and perfuse the lung, and by high-permeability edema. The injury was prevented by competitive NMDA receptor antagonists or by channel-blocker MK-801, and was reduced in the presence of Mg2+. As with NMDA toxicity to central neurons, the lung injury was nitric oxide (NO) dependent: it required L-arginine, was associated with increased production of NO, and was attenuated by either of two NO synthase inhibitors. The neuropeptide vasoactive intestinal peptide and inhibitors of poly(ADP-ribose) polymerase also prevented this injury, but without inhibiting NO synthesis, both acting by inhibiting a toxic action of NO that is critical to tissue injury. The findings indicate that: (i) NMDA receptors exist in the lung (and probably elsewhere outside the central nervous system), (ii) excessive activation of these receptors may provoke acute edematous lung injury as seen in the ``adult respiratory distress syndrome,'' and (iii) this injury can be modulated by blockade of one of three critical steps: NMDA receptor binding, inhibition of NO synthesis, or activation of poly(ADP-ribose) polymerase.

Contribution of voltage-dependent K+ channels to metabolic control of coronary blood flow

PubMed Central

Berwick, Zachary C.; Dick, Gregory M.; Moberly, Steven P.; Kohr, Meredith C.; Sturek, Michael; Tune, Johnathan D.

2011-01-01

The purpose of this investigation was to test the hypothesis that KV channels contribute to metabolic control of coronary blood flow and that decreases in KV channel function and/or expression significantly attenuate myocardial oxygen supply-demand balance in the metabolic syndrome (MetS). Experiments were conducted in conscious, chronically instrumented Ossabaw swine fed either a normal maintenance diet or an excess calorie atherogenic diet that produces the clinical phenotype of early MetS. Data were obtained under resting conditions and during graded treadmill exercise before and after inhibition of KV channels with 4-aminopyridine (4-AP, 0.3 mg/kg, i.v.). In lean-control swine, 4-AP reduced coronary blood flow ~15% at rest and ~20% during exercise. Inhibition of KV channels also increased aortic pressure (P < 0.01) while reducing coronary venous Po2 (P < 0.01) at a given level of myocardial oxygen consumption (MVo2). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous Po2 in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a ~20% reduction in coronary KV current (P < 0.01) and decreased expression of KV1.5 channels in coronary arteries (P < 0.01). Together, these data demonstrate that KV channels play an important role in balancing myocardial oxygen delivery with metabolism at rest and during exercise-induced increases in MVo2. Our findings also indicate that decreases in KV channel current and expression contribute to impaired control of coronary blood flow in the MetS. PMID:21771599

Pharmacological preconditioning by diazoxide downregulates cardiac L-type Ca2+ channels

PubMed Central

González, G; Zaldívar, D; Carrillo, ED; Hernández, A; García, MC; Sánchez, JA

2010-01-01

BACKGROUND AND PURPOSE Pharmacological preconditioning (PPC) with mitochondrial ATP-sensitive K+ (mitoKATP) channel openers such as diazoxide, leads to cardioprotection against ischaemia. However, effects on Ca2+ homeostasis during PPC, particularly changes in Ca2+ channel activity, are poorly understood. We investigated the effects of PPC on cardiac L-type Ca2+ channels. EXPERIMENTAL APPROACH PPC was induced in isolated hearts and enzymatically dissociated cardiomyocytes from adult rats by preincubation with diazoxide. We measured reactive oxygen species (ROS) production and Ca2+ signals associated with action potentials using fluorescent probes, and L-type currents using a whole-cell patch-clamp technique. Levels of the α1c subunit of L-type channels in the cellular membrane were measured by Western blot. KEY RESULTS PPC was accompanied by a 50% reduction in α1c subunit levels, and by a reversible fall in L-type current amplitude and Ca2+ transients. These effects were prevented by the ROS scavenger N-acetyl-L-cysteine (NAC), or by the mitoKATP channel blocker 5-hydroxydecanoate (5-HD). PPC signficantly reduced infarct size, an effect blocked by NAC and 5-HD. Nifedipine also conferred protection against infarction when applied during the reperfusion period. Downregulation of the α1c subunit and Ca2+ channel function were prevented in part by the protease inhibitor leupeptin. CONCLUSIONS AND IMPLICATIONS PPC downregulated the α1c subunit, possibly through ROS. Downregulation involved increased degradation of the Ca2+ channel, which in turn reduced Ca2+ influx, which may attenuate Ca2+ overload during reperfusion. PMID:20636393

Chlamydia psittaci Genetic Variants Differ in Virulence by Modulation of Host Immunity

PubMed Central

Laxton, Jonathan D.; Wang, Xiaofei; Obert, Caroline A.; Arva Tatireddigari, Venkat R. R.; van Rooijen, Nico; Hatch, Thomas P.; Byrne, Gerald I.

2011-01-01

Background. Psittacosis is a zoonosis caused by Chlamydia psittaci and is characterized by severe pneumonia and systemic infection. We sought to determine the basis of the 1000-fold difference in lethal dose of 2 C. psittaci 6BC strains in mice. Methods. Genomes of the strains were sequenced. Mice were infected intraperitoneally and the growth kinetics, immune responses, and pathology were compared. Results. The 2 strains differed by the presence of a 7.5-kb plasmid in the attenuated strain and 7 nonsynonomous single-nucleotide polymorphisms between the chromosomes, including a serine/threonine protein kinase gene pkn5. The plasmid was cured from the attenuated strain, but it remained nonlethal. Strains did not differ in growth kinetics in vitro or in vivo. Infection with the attenuated strain led to influx of activated macrophages with relatively minor organ damage. In contrast, the virulent strain caused an influx of nonactivated macrophages, neutrophils, and significant end organ damage. Mice infected with the virulent strain survived challenge when coinfected with either the plasmid-positive or plasmid-negative attenuated strain, indicating that an active process elicited by the attenuated strain reduces inflammation and disease. Conclusions. C. psittaci modulates virulence by alteration of host immunity, which is conferred by small differences in the chromosome. PMID:21791668

Chlamydia psittaci genetic variants differ in virulence by modulation of host immunity.

PubMed

Miyairi, Isao; Laxton, Jonathan D; Wang, Xiaofei; Obert, Caroline A; Arva Tatireddigari, Venkat R R; van Rooijen, Nico; Hatch, Thomas P; Byrne, Gerald I

2011-08-15

Psittacosis is a zoonosis caused by Chlamydia psittaci and is characterized by severe pneumonia and systemic infection. We sought to determine the basis of the 1000-fold difference in lethal dose of 2 C. psittaci 6BC strains in mice. Genomes of the strains were sequenced. Mice were infected intraperitoneally and the growth kinetics, immune responses, and pathology were compared. The 2 strains differed by the presence of a 7.5-kb plasmid in the attenuated strain and 7 nonsynonomous single-nucleotide polymorphisms between the chromosomes, including a serine/threonine protein kinase gene pkn5. The plasmid was cured from the attenuated strain, but it remained nonlethal. Strains did not differ in growth kinetics in vitro or in vivo. Infection with the attenuated strain led to influx of activated macrophages with relatively minor organ damage. In contrast, the virulent strain caused an influx of nonactivated macrophages, neutrophils, and significant end organ damage. Mice infected with the virulent strain survived challenge when coinfected with either the plasmid-positive or plasmid-negative attenuated strain, indicating that an active process elicited by the attenuated strain reduces inflammation and disease. C. psittaci modulates virulence by alteration of host immunity, which is conferred by small differences in the chromosome.

Tracking down the origins of Advanced LIGO noise: 2 examples

NASA Astrophysics Data System (ADS)

Berger, Beverly K.; LIGO Scientific Collaboration Collaboration

2016-03-01

For Advanced LIGO to reach design sensitivity various sources of instrumental and environmental noise must be identified and ameliorated. We discuss 2 efforts to search for the origin of noise bursts (glitches) at LIGO Hanford. Advanced LIGO monitors thousands of channels in addition to the gravitational wave channel. These can be studied to find correlations between the gravitational wave channel and other sensor signals. The first type of glitch had a frequency of 50 Hz and a rate of 1 per minute. It was found that the glitches were correlated with ground motion in the end station of the X-arm where the offending air compressor was tracked down and turned off. The second example manifests itself as a sudden, but brief, drop in the range occurring, typically, several times per day at LIGO Hanford and less frequently at LIGO Livingston. These range-drop glitches appear in the gravitational-wave channel. Although correlations with these glitches can be seen in many channels, it cannot be easily determined whether these channels are responding as an effect of this type of very strong glitch or whether they might be related to their cause or causes. To date, the cause of the range-drop glitches is not known.

Attenuation, transmission, and immunogenicity of an ORF-C gene deleted strain of infectious laryngotracheitis virus (ILTV) in specific pathogen free chickens

USDA-ARS?s Scientific Manuscript database

Infectious laryngotracheitis (ILT) is a very serious and widespread respiratory disease of chickens caused by infectious laryngotracheitis virus (ILTV). Conventional attenuated ILT vaccines, obtained by continuous passages in chicken embryos and tissue culture, had been the main tools utilized by th...

Association of the host immune response with protection using a live attenuated African swine fever virus model

USDA-ARS?s Scientific Manuscript database

African swine fever virus (ASFV) causes a lethal disease of swine. Infection with attenuated strains protect against challenge but there is limited knowledge of the immune mechanisms generating that protection. ASFV Pret4 produces a fatal disease, while its derivative, lacking virulence-associated g...

Rational development of an attenuated recombinant cyprinid herpesvirus 3 vaccine using prokaryotic mutagenesis and in vivo bioluminescent imaging

USDA-ARS?s Scientific Manuscript database

Cyprinid herpesvirus 3 (CyHV-3) is causing severe economic losses worldwide in the carp industry, and a safe and efficacious attenuated vaccine compatible with mass vaccination is needed. We produced single deleted recombinants using prokaryotic mutagenesis. When producing a recombinant lacking open...

Identification of major backscattering sources in trees and shrubs at 10 GHz

NASA Technical Reports Server (NTRS)

Zoughi, R.; Wu, L. K.; Moore, R. K.

1986-01-01

A short-range very-fine-resolution FM-CW radar scatterometer has been used to identify the primary contributors to 10-GHz radar backscatter from pine, pin oak, American sycamore and sugar maple trees, and from creeping juniper shrubs. This system provided a range resolution of 11 cm and gave a 16-cm diameter illumination area at the target range of about 4 m. For a pine tree, the needles caused the strongest backscatter as well as the strongest attenuation in the radar signal. Cones, although insignificant contributors to the total backscatter, were more important for backscattering than for attenuation. For the rest of the trees, leaves were the strongest cause of backscattering and attenuation. However, in the absence of leaves, the petioles, small twigs, and branches gave relatively strong backscatter. For American sycamore and sugar maple trees, the fruits did not affect the total backscatter unless they were packed in clusters. For creeping juniper the backscattered energy and attenuation in the radar signal were mainly due to the top two layers of the evergreen scales. The contribution of the tree trunks was not determined.

Ageing and gastrointestinal sensory function: altered colonic mechanosensory and chemosensory function in the aged mouse

PubMed Central

Keating, Christopher; Nocchi, Linda; Yu, Yang; Donovan, Jemma; Grundy, David

2016-01-01

Key points Remarkably little is known about how age affects the sensory signalling pathways in the gastrointestinal tract despite age‐related gastrointestinal dysfunction being a prime cause of morbidity amongst the elderly populationHigh‐threshold gastrointestinal sensory nerves play a key role in signalling distressing information from the gut to the brain.We found that ageing is associated with attenuated high‐threshold afferent mechanosensitivity in the murine colon, and associated loss of TRPV1 channel function.These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease. Abstract Ageing has a profound effect upon gastrointestinal function through mechanisms that are poorly understood. Here we investigated the effect of age upon gastrointestinal sensory signalling pathways in order to address the mechanisms underlying these changes. In vitro mouse colonic and jejunal preparations with attached splanchnic and mesenteric nerves were used to study mechanosensory and chemosensory afferent function in 3‐, 12‐ and 24‐month‐old C57BL/6 animals. Quantitative RT‐PCR was used to investigate mRNA expression in colonic tissue and dorsal root ganglion (DRG) cells isolated from 3‐ and 24‐month animals, and immunohistochemistry was used to quantify the number of 5‐HT‐expressing enterochromaffin (EC) cells. Colonic and jejunal afferent mechanosensory function was attenuated with age and these effects appeared earlier in the colon compared to the jejunum. Colonic age‐related loss of mechanosensory function was more pronounced in high‐threshold afferents compared to low‐threshold afferents. Chemosensory function was attenuated in the 24‐month colon, affecting TRPV1 and serotonergic signalling pathways. High‐threshold mechanosensory afferent fibres and small‐diameter DRG neurons possessed lower functional TRPV1 receptor responses, which occurred without a change in TRPV1 mRNA expression. Serotonergic signalling was attenuated at 24 months, but TPH1 and TPH2 mRNA expression was elevated in colonic tissue. In conclusion, we saw an age‐associated decrease in afferent mechanosensitivity in the mouse colon affecting HT units. These units have the capacity to sensitise in response to injurious events, and their loss in ageing may predispose the elderly to lower awareness of GI injury or disease. PMID:26592729

Possible developments for ex situ phytoremediation of contaminated sediments, in tropical and subtropical regions - Review.

PubMed

Pittarello, Marco; Busato, Jader Galba; Carletti, Paolo; Dobbss, Leonardo Barros

2017-09-01

The growing problem of remediation of contaminated sediments dredged from harbor channels needs to be resolved by a cost effective and sustainable technology. Phytoremediation, by ex situ remediation plants, seems to have the potential to replace traditional methods in case of moderately contaminated sediments. On the other side, the need to mix sediments with soil and/or sand to allow an easier establishment of most employed species causes an increase of the volume of the processed substrate up to 30%. Moreover the majority of phytoremediating species are natives of temperate climate belt. Mangroves, with a special focus on the genus Avicennia - a salt secreting species - should represent an effective alternative in terms of adaptation to salty, anoxic sediments and an opportunity to develop ex situ phytoremediation plants in tropical and subtropical regions. The use of humic acid to increase root development, cell antioxidant activity and the potential attenuation of the "heavy metals exclusion strategy" to increase phytoextraction potentials of mangroves will be reviewed. Copyright © 2017. Published by Elsevier Ltd.

Instrumental research of lithodynamic processes in estuaries of the White Sea

NASA Astrophysics Data System (ADS)

Rimsky-Korsakov, Nikolai; Korotaev, Vladislav; Ivanov, Vadim

2017-04-01

The report provides a comparative analysis of morphological lithodynamic processes in estuaries and river deltas on the basis of 2013-2015 field geophysical and hydrographic surveys held by IO RAS and MSU. Studies performed using side scan sonar (Imagenex YellowFin SSS), bathymetric (FortXXI Scat Echo sounder) and navigation (DGPS/GLONASS Sigma Ashtek receiver) equipment. North Dvina modern delta can be classified as multi-arm delta estuary lagoon performance. Areas of modern river waters occupy a large accumulation of deltaic arms. It formed a young island with elevations of about 1 m. The islands are composed of river alluvium and annually flooded during the flood period. Onega river mouth area is unique due to the specific geological conditions. Short, wellhead site is the cause of the anomalous attenuation of the tidal wave and the limited range of penetration of salt water seashore only to Kokorinskogo threshold. Morphological lithodynamic processes in high tide Mezen estuaries (syzygy - 8.5 m) are caused by tidal currents, river runoff, wind waves and sediment longshore drift. Due to the movement of huge masses of sediment in the Mezen estuary occur intense deformation silty-sand banks, reshaping of the bottom channel trenches and displacement of navigable waterways. Thus, the specificity of the morphological lithodynamic processes in high tidal estuaries is a lack of modern delta, the development of mobile local sediment structures inside the estuary and the formation of a broad mouth bar on the open wellhead coast. In multi-arm deltas an intense process of increasing marine edge of the delta is observed due to wellhead delta arms elongation and the formation of small estuarine bars at the mouths of the underwater channel trenches coming out into the open coast. Simultaneously, the process of filling the river sediments of residual waters within the subaerial delta and the formation of marine coastal bars on the outer perimeter edge of the sea ground delta.

The roles of KCa, KATP, and KV channels in regulating cutaneous vasodilation and sweating during exercise in the heat.

PubMed

Louie, Jeffrey C; Fujii, Naoto; Meade, Robert D; McNeely, Brendan D; Kenny, Glen P

2017-05-01

We recently showed the varying roles of Ca 2+ -activated (K Ca ), ATP-sensitive (K ATP ), and voltage-gated (K V ) K + channels in regulating cholinergic cutaneous vasodilation and sweating in normothermic conditions. However, it is unclear whether the respective contributions of these K + channels remain intact during dynamic exercise in the heat. Eleven young (23 ± 4 yr) men completed a 30-min exercise bout at a fixed rate of metabolic heat production (400 W) followed by a 40-min recovery period in the heat (35°C, 20% relative humidity). Cutaneous vascular conductance (CVC) and local sweat rate were assessed at four forearm skin sites perfused via intradermal microdialysis with: 1 ) lactated Ringer solution (control); 2 ) 50 mM tetraethylammonium (nonspecific K Ca channel blocker); 3 ) 5 mM glybenclamide (selective K ATP channel blocker); or 4 ) 10 mM 4-aminopyridine (nonspecific K V channel blocker). Responses were compared at baseline and at 10-min intervals during and following exercise. K Ca channel inhibition resulted in greater CVC versus control at end exercise ( P = 0.04) and 10 and 20 min into recovery (both P < 0.01). K ATP channel blockade attenuated CVC compared with control during baseline ( P = 0.04), exercise (all P ≤ 0.04), and 10 min into recovery ( P = 0.02). No differences in CVC were observed with K V channel inhibition during baseline ( P = 0.15), exercise (all P ≥ 0.06), or recovery (all P ≥ 0.14). With the exception of K V channel inhibition augmenting sweating during baseline ( P = 0.04), responses were similar to control with all K + channel blockers during each time period (all P ≥ 0.07). We demonstrated that K Ca and K ATP channels contribute to the regulation of cutaneous vasodilation during rest and/or exercise and recovery in the heat. Copyright © 2017 the American Physiological Society.

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Endolysosomal Two-pore Channels Modulate Membrane Excitability and Stimulus-Secretion Coupling in Mouse Pancreatic β Cells*

PubMed Central

Arredouani, Abdelilah; Ruas, Margarida; Collins, Stephan C.; Parkesh, Raman; Clough, Frederick; Pillinger, Toby; Coltart, George; Rietdorf, Katja; Royle, Andrew; Johnson, Paul; Braun, Matthias; Zhang, Quan; Sones, William; Shimomura, Kenju; Morgan, Anthony J.; Lewis, Alexander M.; Chuang, Kai-Ting; Tunn, Ruth; Gadea, Joaquin; Teboul, Lydia; Heister, Paula M.; Tynan, Patricia W.; Bellomo, Elisa A.; Rutter, Guy A.; Rorsman, Patrik; Churchill, Grant C.; Parrington, John; Galione, Antony

2015-01-01

Pancreatic β cells are electrically excitable and respond to elevated glucose concentrations with bursts of Ca2+ action potentials due to the activation of voltage-dependent Ca2+ channels (VDCCs), which leads to the exocytosis of insulin granules. We have examined the possible role of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca2+ release from intracellular stores during stimulus-secretion coupling in primary mouse pancreatic β cells. NAADP-regulated Ca2+ release channels, likely two-pore channels (TPCs), have recently been shown to be a major mechanism for mobilizing Ca2+ from the endolysosomal system, resulting in localized Ca2+ signals. We show here that NAADP-mediated Ca2+ release from endolysosomal Ca2+ stores activates inward membrane currents and depolarizes the β cell to the threshold for VDCC activation and thereby contributes to glucose-evoked depolarization of the membrane potential during stimulus-response coupling. Selective pharmacological inhibition of NAADP-evoked Ca2+ release or genetic ablation of endolysosomal TPC1 or TPC2 channels attenuates glucose- and sulfonylurea-induced membrane currents, depolarization, cytoplasmic Ca2+ signals, and insulin secretion. Our findings implicate NAADP-evoked Ca2+ release from acidic Ca2+ storage organelles in stimulus-secretion coupling in β cells. PMID:26152717

Block by Extracellular Divalent Cations of Drosophila Big Brain Channels Expressed in Xenopus Oocytes

PubMed Central

Yanochko, Gina M.; Yool, Andrea J.

2004-01-01

Drosophila Big Brain (BIB) is a transmembrane protein encoded by the neurogenic gene big brain (bib), which is important for early development of the fly nervous system. BIB expressed in Xenopus oocytes is a monovalent cation channel modulated by tyrosine kinase signaling. Results here demonstrate that the BIB conductance shows voltage- and dose-dependent block by extracellular divalent cations Ca2+ and Ba2+ but not by Mg2+ in wild-type channels. Site-directed mutagenesis of negatively charged glutamate (Glu274) and aspartate (Asp253) residues had no effect on divalent cation block. However, mutation of a conserved glutamate at position 71 (Glu71) in the first transmembrane domain (M1) altered channel properties. Mutation of Glu71 to Asp introduced a new sensitivity to block by extracellular Mg2+; substitutions with asparagine or glutamine decreased whole-cell conductance; and substitution with lysine compromised plasma membrane expression. Block by divalent cations is important in other ion channels for voltage-dependent function, enhanced signal resolution, and feedback regulation. Our data show that the wild-type BIB conductance is attenuated by external Ca2+, suggesting that endogenous divalent cation block might be relevant for enhancing signal resolution or voltage dependence for the native signaling process in neuronal cell fate determination. PMID:14990474

Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO

PubMed Central

Sun, Junhui; Xin, Chunlin; Eu, Jerry P.; Stamler, Jonathan S.; Meissner, Gerhard

2001-01-01

We have shown previously that at physiologically relevant oxygen tension (pO2 ≈ 10 mmHg), NO S-nitrosylates 1 of ≈50 free cysteines per ryanodine receptor 1 (RyR1) subunit and transduces a calcium-sensitizing effect on the channel by means of calmodulin (CaM). It has been suggested that cysteine-3635 is part of a CaM-binding domain, and its reactivity is attenuated by CaM [Porter Moore, C., Zhang, J. Z., Hamilton, S. L. (1999) J. Biol. Chem. 274, 36831–36834]. Therefore, we tested the hypothesis that the effect of NO was mediated by C3635. The full-length RyR1 single-site C3635A mutant was generated and expressed in HEK293 cells. The mutation resulted in the loss of CaM-dependent NO modulation of channel activity and reduced S-nitrosylation by NO to background levels but did not affect NO-independent channel modulation by CaM or the redox sensitivity of the channel to O2 and glutathione. Our results reveal that different cysteines within the channel have been adapted to serve in nitrosative and oxidative responses, and that S-nitrosylation of the cysteine-containing CaM-binding domain underlies the mechanism of CaM-dependent regulation of RyR1 by NO. PMID:11562475

Effects of 4-phenyl butyric acid on high glucose-induced alterations in dorsal root ganglion neurons.

PubMed

Sharma, Dilip; Singh, Jitendra Narain; Sharma, Shyam S

2016-12-02

Mechanisms and pathways involving in diabetic neuropathy are still not fully understood but can be unified by the process of overproduction of reactive oxygen species (ROS) such as superoxide, endoplasmic reticulum (ER) stress, downstream intracellular signaling pathways and their modulation. Susceptibility of dorsal root ganglion (DRG) to internal/external hyperglycemic environment stress contributes to the pathogenesis and progression of diabetic neuropathy. ER stress leads to abnormal ion channel function, gene expression, transcriptional regulation, metabolism and protein folding. 4-phenyl butyric acid (4-PBA) is a potent and selective chemical chaperone; which may inhibit ER stress. It may be hypothesized that 4-PBA could attenuate via channels in DRG in diabetic neuropathy. Effects of 4-PBA were determined by applying different parameters of oxidative stress, cell viability, apoptosis assays and channel expression in cultured DRG neurons. Hyperglycemia-induced apoptosis in the DRG neuron was inhibited by 4-PBA. Cell viability of DRG neurons was not altered by 4-PBA. Oxidative stress was significantly blocked by the 4-PBA. Sodium channel expression was not altered by the 4-PBA. Our data provide evidence that the hyperglycemia-induced alteration may be reduced by the 4-PBA without altering the sodium channel expression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Decay of grid turbulence in superfluid helium-4: Mesh dependence

NASA Astrophysics Data System (ADS)

Yang, J.; Ihas, G. G.

2018-03-01

Temporal decay of grid turbulence is experimentally studied in superfluid 4He in a large square channel. The second sound attenuation method is used to measure the turbulent vortex line density (L) with a phase locked tracking technique to minimize frequency shift effects induced by temperature fluctuations. Two different grids (0.8 mm and 3.0 mm mesh) are pulled to generate turbulence. Different power laws for decaying behavior are predicted by a theory. According to this theory, L should decay as t‑11/10 when the length scale of energy containing eddies grows from the grid mesh size to the size of the channel. At later time, after the energy containing eddy size becomes comparable to the channel, L should follow t‑3/2. Our recent experimental data exhibit evidence for t‑11/10 during the early time and t‑2 instead of t‑3/2 for later time. Moreover, a consistent bump/plateau feature is prominent between the two decay regimes for smaller (0.8 mm) grid mesh holes but absent with a grid mesh hole of 3.0 mm. This implies that in the large channel different types of turbulence are generated, depending on mesh hole size (mesh Reynolds number) compared to channel Reynolds number.

Dissecting the IRX-β dust attenuation relation: exploring the physical origin of observed variations in galaxies

NASA Astrophysics Data System (ADS)

Popping, Gergö; Puglisi, Annagrazia; Norman, Colin A.

2017-12-01

The use of ultraviolet (UV) emission as a tracer of galaxy star formation rate (SFR) is hampered by dust obscuration. The empirical relationship between UV-slope, β, and the ratio between far-infrared and UV luminosity, IRX, is commonly employed to account for obscured UV emission. We present a simple model that explores the physical origin of variations in the IRX-β dust attenuation relation. A relative increase in FUV compared to NUV attenuation and an increasing stellar population age cause variations towards red UV-slopes for a fixed IRX. Dust geometry effects (turbulence, dust screen with holes, mixing of stars within the dust screen, two-component dust model) cause variations towards blue UV-slopes. Poor photometric sampling of the UV spectrum causes additional observational variations. We provide an analytic approximation for the IRX-β relation invoking a subset of the explored physical processes (dust type, stellar population age, turbulence). We discuss observed variations in the IRX-β relation for local (sub-galactic scales) and high-redshift (normal and dusty star-forming galaxies, galaxies during the epoch of reionization) galaxies in the context of the physical processes explored in our model. High spatial resolution imaging of the UV and sub-mm emission of galaxies can constrain the IRX-β dust attenuation relation for different galaxy types at different epochs, where different processes causing variations may dominate. These constraints will allow the use of the IRX-β relation to estimate intrinsic SFRs of galaxies, despite the lack of a universal relation.

Estimation of Seismic Attenuation beneath Tateyama Volcano, Central Japan by Using Peak Delay

NASA Astrophysics Data System (ADS)

Iwata, K.; Kawakata, H.; Hirano, S.; Doi, I.

2015-12-01

The Hida Mountain Range located in central Japan has a lot of active volcanoes. Katsumata et al. (1995, GJI) suggested the presence of regions with low-velocity and low-density as well as low Qanomaly at 5-15 km deep beneath the range. Tateyama volcano is located in the northern part of the range. Iwata et al. (2014, AGU Fall Meeting) quantitatively estimated strength of S-wave attenuation beneath Tateyama volcano using twofold spectral ratios and suggested that regions with high seismic attenuation exist in the south or the southeast of Tateyama volcano. However, it is difficult to estimate the contribution of scattering loss and intrinsic absorption to total attenuation on the basis of this method. In the present study, we focused on the peak delay (Takahashi et al., 2007, GJI) in seismic envelopes. We used seismograms observed at five NIED Hi-net stations near Tateyama volcano for 31 local earthquakes (MJMA2.5-4.0). We found seismograms recorded after passing below the southern part of the Hida Mountain Range show longer peak delay than those recorded before passing below the region, while there are no clear difference in peak delay for pairs of seismograms before and after passing below Tateyama volcano. It suggests that causes of the attenuation beneath Tateyama volcano and the southern part of the Hida Mountain Range are different. We used the peak delay values to evaluate the strength of intrinsic absorption. We assumed that the difference of whole peak delay between two seismograms for the same earthquake was caused by intrinsic absorption beneath the region between the two seismic stations. Wecalculated the change in amplitude and peak delay on the basis of a theory suggested by Azimi et al. (1966, Izvestia, Earth Physics). In case of the two envelopes are quite similar to each other, we conclude that intrinsic absorption is a major cause of total attenuation. If not so, we need to take into account the contribution of scattering attenuation and some others.

Enhanced Microfluidic Electromagnetic Measurements

NASA Technical Reports Server (NTRS)

Ricco, Antonio J. (Inventor); Kovacs, Gregory (Inventor); Giovangrandi, Laurent (Inventor)

2015-01-01

Techniques for enhanced microfluidic impedance spectroscopy include causing a core fluid to flow into a channel between two sheath flows of one or more sheath fluids different from the core fluid. Flow in the channel is laminar. A dielectric constant of a fluid constituting either sheath flow is much less than a dielectric constant of the core fluid. Electrical impedance is measured in the channel between at least a first pair of electrodes. In some embodiments, enhanced optical measurements include causing a core fluid to flow into a channel between two sheath flows of one or more sheath fluids different from the core fluid. An optical index of refraction of a fluid constituting either sheath flow is much less than an optical index of refraction of the core fluid. An optical property is measured in the channel.

Fine-grained channel margin (FGCM) deposits conditioned by Large Woody Debris (LWD) in a gravel-bed river

NASA Astrophysics Data System (ADS)

Skalak, K. J.; Pizzuto, J. E.

2006-12-01

The purpose of this research is to examine the origin, occurrence, persistence, residence time and general significance of fine-grained channel margin storage in South River, a steep gravel-bedded stream in western Virginia. Fine-grained channel margin (FGCM) deposits in this study refers to specific in-channel deposits of mud and sand. These deposits occur primarily in the margins and near-banks regions of the channel. Fine- grained sediment storage in the near-bank regions is a result of reduced velocity caused by the bank obstructions. Nearly all of these obstructions consist of LWD accumulations in the channel. Storage occurs in four different geomorphic settings: 1) long pooled sections caused by bedrock or old mill dams, 2) the upstream ends of pools in channel margins with LWD accumulations, 3) bank obstructions usually caused by trees, 4) side channel backwaters where flow separates around islands. In approximately 38 km of river, there is 3000 m3 of fine-grained sediment stored in these features. The channel stores approximately 15 percent its total annual suspended load as fine-grained channel margin deposits. Consequently, these features represent a significant component of an annual sediment budget for this river. On average, the FGCM deposits are about 35 cm deep, 20 m long, and 4 m wide. They average 30 percent mud, 68 percent sand, and 2 percent gravel. These deposits have been cored and analyzed for Hg, grain size, loss-on-ignition, and bomb radiocarbon. Results from bomb radiocarbon analysis indicate that these features have an average age of 13 years. High Hg concentrations in fish tissue are an ongoing problem along South River, further motivating detailed study of these deposits.

Comparative effects of sodium channel blockers in short term rat whole embryo culture

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nilsson, Mats F, E-mail: Mats.Nilsson@farmbio.uu.se; Sköld, Anna-Carin; Ericson, Ann-Christin

2013-10-15

This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effectmore » on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development.« less

Biomass conversion inhibitors furfural and 5-hydroxymethylfurfural induce formation of messenger RNP granules and attenuate translation activity in Saccharomyces cerevisiae.

PubMed

Iwaki, Aya; Kawai, Takao; Yamamoto, Yosuke; Izawa, Shingo

2013-03-01

Various forms of stress can cause an attenuation of bulk translation activity and the accumulation of nontranslating mRNAs into cytoplasmic messenger RNP (mRNP) granules termed processing bodies (P-bodies) and stress granules (SGs) in eukaryotic cells. Furfural and 5-hydroxymethylfurfural (HMF), derived from lignocellulosic biomass, inhibit yeast growth and fermentation as stressors. Since there is no report regarding their effects on the formation of cytoplasmic mRNP granules, here we investigated whether furfural and HMF cause the assembly of yeast P-bodies and SGs accompanied by translational repression. We found that furfural and HMF cause the attenuation of bulk translation activity and the assembly of cytoplasmic mRNP granules in Saccharomyces cerevisiae. Notably, a combination of furfural and HMF induced the remarkable repression of translation initiation and SG formation. These findings provide new information about the physiological effects of furfural and HMF on yeast cells, and also suggest the potential usefulness of cytoplasmic mRNP granules as a warning sign or index of the deterioration of cellular physiological status in the fermentation of lignocellulosic hydrolysates.

Biomass Conversion Inhibitors Furfural and 5-Hydroxymethylfurfural Induce Formation of Messenger RNP Granules and Attenuate Translation Activity in Saccharomyces cerevisiae

PubMed Central

Iwaki, Aya; Kawai, Takao; Yamamoto, Yosuke

2013-01-01

Various forms of stress can cause an attenuation of bulk translation activity and the accumulation of nontranslating mRNAs into cytoplasmic messenger RNP (mRNP) granules termed processing bodies (P-bodies) and stress granules (SGs) in eukaryotic cells. Furfural and 5-hydroxymethylfurfural (HMF), derived from lignocellulosic biomass, inhibit yeast growth and fermentation as stressors. Since there is no report regarding their effects on the formation of cytoplasmic mRNP granules, here we investigated whether furfural and HMF cause the assembly of yeast P-bodies and SGs accompanied by translational repression. We found that furfural and HMF cause the attenuation of bulk translation activity and the assembly of cytoplasmic mRNP granules in Saccharomyces cerevisiae. Notably, a combination of furfural and HMF induced the remarkable repression of translation initiation and SG formation. These findings provide new information about the physiological effects of furfural and HMF on yeast cells, and also suggest the potential usefulness of cytoplasmic mRNP granules as a warning sign or index of the deterioration of cellular physiological status in the fermentation of lignocellulosic hydrolysates. PMID:23275506

A cytoplasmically transmissible hypovirulence phenotype associated with mitochondrial DNA mutations in the chestnut blight fungus Cryphonectria parasitica.

PubMed Central

Monteiro-Vitorello, C B; Bell, J A; Fulbright, D W; Bertrand, H

1995-01-01

Mutations causing mitochondrial defects were induced in a virulent strain of the chestnut blight fungus Cryphonectria parasitica (Murr.) Barr. Virulence on apples and chestnut trees was reduced in four of six extensively characterized mutants. Relative to the virulent progenitor, the attenuated mutants had reduced growth rates, abnormal colony morphologies, and few asexual spores, and they resembled virus-infected strains. The respiratory defects and attenuated virulence phenotypes (hypovirulence) were transmitted from two mutants to a virulent strain by hyphal contact. The infectious transmission of hypovirulence occurred independently of the transfer of nuclei, did not involve a virus, and dynamically reflects fungal diseases caused by mitochondrial mutations. In these mutants, mitochondrial mutations are further implicated in generation of the attenuated state by (i) uniparental (maternal) inheritance of the trait, (ii) presence of high levels of cyanide-insensitive mitochondrial alternative oxidase activity, (iii) cytochrome deficiencies, and (iv) structural abnormalities in the mtDNA. Hence, cytoplasmically transmissible hypovirulence phenotypes found in virus-free strains of C. parasitica from recovering trees may be caused by mutant forms of mtDNA. Images Fig. 2 Fig. 4 PMID:11607549

Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations.

PubMed

Martin, Gregory M; Rex, Emily A; Devaraneni, Prasanna; Denton, Jerod S; Boodhansingh, Kara E; DeLeon, Diva D; Stanley, Charles A; Shyng, Show-Ling

2016-10-14

ATP-sensitive potassium (K ATP ) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to β-cell membrane potential. Loss of K ATP channel function due to mutations in ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects. In the present study, we identified 13 novel SUR1 mutations that cause channel trafficking defects, the majority of which are amenable to pharmacological rescue by glibenclamide and carbamazepine. By contrast, none of the mutant channels were rescued by K ATP channel openers. Cross-linking experiments showed that K ATP channel inhibitors promoted interactions between the N terminus of Kir6.2 and SUR1, whereas channel openers did not, suggesting the inhibitors enhance intersubunit interactions to overcome channel biogenesis and trafficking defects. Functional studies of rescued mutant channels indicate that most mutants rescued to the cell surface exhibited WT-like sensitivity to ATP, MgADP, and diazoxide. In intact cells, recovery of channel function upon trafficking rescue by reversible sulfonylureas or carbamazepine was facilitated by the K ATP channel opener diazoxide. Our study expands the list of K ATP channel trafficking mutations whose function can be recovered by pharmacological ligands and provides further insight into the structural mechanism by which channel inhibitors correct channel biogenesis and trafficking defects. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Antinociceptive action of carbamazepine on thermal hypersensitive pain at spinal level in a rat model of adjuvant-induced chronic inflammation.

PubMed

Iwamoto, Tatsushige; Takasugi, Yoshihiro; Higashino, Hideaki; Ito, Hiroyuki; Koga, Yoshihisa; Nakao, Shinichi

2011-02-01

Systemic carbamazepine, a voltage-gated sodium channel blocker, has been reported to dose-dependently reduce inflammatory hyperalgesia. However, the antinociceptive effects of carbamazepine on the spinal cord in inflammatory conditions are unclear. The aim of the present study was to evaluate the antinociceptive effects of carbamazepine on the spinal cord in a chronic inflammatory condition. In Sprague-Dawley rats, a chronic inflammatory condition was induced by complete Freund's adjuvant (CFA) inoculation into the tail. Tail flick (TF) latencies were measured following intraperitoneal carbamazepine, or intrathecal carbamazepine or tetrodotoxin injection in intact rats and in the chronic inflammatory rats. From the values of TF latency at 60 min after drug injection, the effective dose required to produce 50% response (ED(50)) of each drug was derived. Carbamazepine attenuated thermal responses with both systemic and intrathecal administration. The effect was more evident in rats with chronic inflammation than in intact rats; the ED(50s) of intraperitoneal carbamazepine in intact and inflamed rats were 12.39 and 1.54 mg/kg, and those of intrathecal carbamazepine were 0.311 and 0.048 nmol, respectively. Intrathecal tetrodotoxin also clearly inhibited the response, with ED(50s) of 1.006 pmol in intact rats and 0.310 pmol in inflamed rats. The relative potencies of intrathecal carbamazepine versus tetrodotoxin for inhibition were approximately 1:150-1:300 in intact and inflamed rats. These results indicate that the inhibition of voltage-gated sodium channels, at least tetrodotoxin-sensitive channels, may contribute to the antinociceptive effect of carbamazepine on CFA-induced inflammatory pain, since lower doses of intrathecal carbamazepine and tetrodotoxin attenuated thermal responses to a greater extent in inflamed rats than in intact rats.

Functional Adaptation of the N-Methyl-d-aspartate Receptor to Inhibition by Ethanol Is Modulated by Striatal-Enriched Protein Tyrosine Phosphatase and p38 Mitogen-Activated Protein Kinase

PubMed Central

Coultrap, Steven J.; Browning, Michael D.; Proctor, William R.

2011-01-01

The hippocampal N-methyl-d-aspartate receptor (NMDAR) activity plays important roles in cognition and is a major substrate for ethanol-induced memory dysfunction. This receptor is a glutamate-gated ion channel, which is composed of NR1 and NR2 subunits in various brain areas. Although homomeric NR1 subunits form an active ion channel that conducts Na+ and Ca2+ currents, the incorporation of NR2 subunits allows this channel to be modulated by the Src family of kinases, phosphatases, and by simple molecules such as ethanol. We have found that short-term ethanol application inhibits the NMDAR activity via striatal enriched protein tyrosine phosphatase (STEP)-regulated mechanisms. The genetic deletion of the active form of STEP, STEP61, leads to marked attenuation of ethanol inhibition of NMDAR currents. In addition, STEP61 negatively regulates Fyn and p38 mitogen-activated protein kinase (MAPK), and these proteins are members of the NMDAR super molecular complex. Here we demonstrate, using whole-cell electrophysiological recording, Western blot analysis, and pharmacological manipulations, that neurons exposed to a 3-h, 45 mM ethanol treatment develop an adaptive attenuation of short-term ethanol inhibition of NMDAR currents in brain slices. Our results suggest that this adaptation of NMDAR responses is associated with a partial inactivation of STEP61, an activation of p38 MAPK, and a requirement for NR2B activity. Together, these data indicate that altered STEP61 and p38 MAPK signaling contribute to the modulation of ethanol inhibition of NMDARs in brain neurons. PMID:21680777

Effects of Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) on contractile activity of circular smooth muscle of the rat distal colon.

PubMed

Kito, Yoshihiko; Teramoto, Noriyoshi

2012-11-01

The Japanese Kampo medicines Hange-shashin-to (TJ-14) and Keishi-ka-shakuyaku-to (TJ-60) have been used to treat symptoms of human diarrhea on an empirical basis as Japanese traditional medicines. However, it remains unclear how these drugs affect smooth muscle tissues in the distal colon. The aim of the present study was to investigate the effects of TJ-14 and TJ-60 on the contractile activity of circular smooth muscle from the rat distal colon. TJ-14 and TJ-60 (both 1 mg/ml) inhibited spontaneous contractions of circumferentially cut preparations with the mucosa intact. Blockade of nitric oxide (NO) synthase or soluble guanylate cyclase activity abolished the inhibitory effects of TJ-60 but only attenuated the inhibitory effects of TJ-14. Apamin (1 μM), a blocker of small-conductance Ca(2+)-activated K(+) channels (SK channels), attenuated the inhibitory effects of 5 mg/ml TJ-60 but not those of 5 mg/ml TJ-14. TJ-14 suppressed contractile responses (phasic contractions and off-contractions) evoked by transmural nerve stimulation and increased basal tone, whereas TJ-60 had little effect on these parameters. These results suggest that 1 mg/ml TJ-14 or TJ-60 likely inhibits spontaneous contractions of the rat distal colon through the production of NO. Activation of SK channels seems to be involved in the inhibitory effects of 5 mg/ml TJ-60. Since TJ-14 has potent inhibitory effects on myogenic and neurogenic contractile activity, TJ-14 may be useful in suppressing gastrointestinal motility.

TRPV2 knockout mice demonstrate an improved cardiac performance following myocardial infarction due to attenuated activity of peri-infarct macrophages.

PubMed

Entin-Meer, Michal; Cohen, Lena; Hertzberg-Bigelman, Einat; Levy, Ran; Ben-Shoshan, Jeremy; Keren, Gad

2017-01-01

We have recently shown that the expression of the transient receptor potential vanilloid 2 channel, TRPV2, is upregulated in the peri-infarct zone 3-5 days following an acute myocardial infarction (AMI). Further analysis has demonstrated that invading monocytes maturing to macrophages merely harbor the documented elevated expression of this channel. Assess cardiac function in TRPV2-KO mice compared to TRPV2-WT following AMI and analyze the potential involvement of TRPV2-expressing macrophages in the recovery process. TRPV2-KO or WT mice were induced with AMI by ligation of the left anterior descending artery (LAD). In another set of experiments, TRPV2-KO mice induced with AMI, were intravenously (IV) injected with WT or TRPV2-KO peritoneal macrophages in order to directly assess the potential contribution of TRPV2-expressing macrophages to cardiac healing. Cardiac parameters were obtained by echocardiography 1 day and 30 days post infarction. The relative changes in the ejection fraction (EF) and additional cardiac parameters between baseline (day 1) and day 30 were calculated and statistical significance was determined (SPSS). The in vivo study showed that while EF was significantly decreased in the WT animals between baseline and day 30, EF was only slightly and insignificantly reduced in the KO animals. Likewise LVESD and LVESA were significantly modified exclusively in the WT animals. Moreover, intravenous administration of peritoneal WT macrophages, but not KO macrophages, significantly reduced survival of post-MI TRPV2-KO mice. The data suggest that knockout of the TRPV2 channel may attenuate macrophage-dependent pro-inflammatory processes and result in better cardiac recovery. TRPV2 may thus represent a novel therapeutic target for treatment of patients undergoing an acute MI.

Gating currents from Kv7 channels carrying neuronal hyperexcitability mutations in the voltage-sensing domain.

PubMed

Miceli, Francesco; Vargas, Ernesto; Bezanilla, Francisco; Taglialatela, Maurizio

2012-03-21

Changes in voltage-dependent gating represent a common pathogenetic mechanism for genetically inherited channelopathies, such as benign familial neonatal seizures or peripheral nerve hyperexcitability caused by mutations in neuronal K(v)7.2 channels. Mutation-induced changes in channel voltage dependence are most often inferred from macroscopic current measurements, a technique unable to provide a detailed assessment of the structural rearrangements underlying channel gating behavior; by contrast, gating currents directly measure voltage-sensor displacement during voltage-dependent gating. In this work, we describe macroscopic and gating current measurements, together with molecular modeling and molecular-dynamics simulations, from channels carrying mutations responsible for benign familial neonatal seizures and/or peripheral nerve hyperexcitability; K(v)7.4 channels, highly related to K(v)7.2 channels both functionally and structurally, were used for these experiments. The data obtained showed that mutations affecting charged residues located in the more distal portion of S(4) decrease the stability of the open state and the active voltage-sensing domain configuration but do not directly participate in voltage sensing, whereas mutations affecting a residue (R4) located more proximally in S(4) caused activation of gating-pore currents at depolarized potentials. These results reveal that distinct molecular mechanisms underlie the altered gating behavior of channels carrying disease-causing mutations at different voltage-sensing domain locations, thereby expanding our current view of the pathogenesis of neuronal hyperexcitability diseases. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Cyclooxygenase activity contributes to the monoaminergic damage caused by serial exposure to stress and methamphetamine

PubMed Central

Northrop, Nicole A.; Yamamoto, Bryan K.

2013-01-01

Methamphetamine (Meth) is a widely abused psychostimulant that causes long-term dopamine (DA) and serotonin (5-HT) depletions. Stress and Meth abuse are comorbid events in society and stress exacerbates Meth-induced monoaminergic terminal damage. Stress is also known to produce neuroinflammation. This study examined the role of the neuroinflammatory mediator, cyclooxygenase (COX), in the depletions of monoamines caused by serial exposure to chronic unpredictable stress (CUS) and Meth. CUS produced an increase in COX-2 protein expression and enhanced Meth-induced monoaminergic depletions in the striatum and hippocampus. The enhanced DA and 5-HT depletions in the striatum, but not the hippocampus, were prevented by pretreatment with COX inhibitor, ketoprofen, during stress or during Meth; however, ketoprofen did not attenuate the monoaminergic damage caused by Meth alone. The COX-dependent enhancement by stress of Meth-induced monoaminergic depletions was independent of hyperthermia, as ketoprofen did not attenuate Meth-induced hyperthermia. In addition, the EP1 receptor antagonist, SC-51089, did not attenuate DA or 5-HT depletions caused by stress and Meth. These findings illustrate that COX activity, but not activation of the EP1 receptor, is responsible for the potentiation of Meth-induced damage to striatal monoamine terminals by stress and suggests the use of anti-inflammatory drugs for mitigating the neurotoxic effects associated with the combination of stress and Meth. PMID:23643743