Membrane permeable local anesthetics modulate NaV1.5 mechanosensitivity

PubMed Central

Beyder, Arthur; Strege, Peter R.; Bernard, Cheryl; Farrugia, Gianrico

2012-01-01

Voltage-gated sodium selective ion channel NaV1.5 is expressed in the heart and the gastrointestinal tract, which are mechanically active organs. NaV1.5 is mechanosensitive at stimuli that gate other mechanosensitive ion channels. Local anesthetic and antiarrhythmic drugs act upon NaV1.5 to modulate activity by multiple mechanisms. This study examined whether NaV1.5 mechanosensitivity is modulated by local anesthetics. NaV1.5 channels wereexpressed in HEK-293 cells, and mechanosensitivity was tested in cell-attached and excised inside-out configurations. Using a novel protocol with paired voltage ladders and short pressure pulses, negative patch pressure (-30 mmHg) in both configurations produced a hyperpolarizing shift in the half-point of the voltage-dependence of activation (V1/2a) and inactivation (V1/2i) by about -10 mV. Lidocaine (50 µM) inhibited the pressure-induced shift of V1/2a but not V1/2i. Lidocaine inhibited the tonic increase in pressure-induced peak current in a use-dependence protocol, but it did not otherwise affect use-dependent block. The local anesthetic benzocaine, which does not show use-dependent block, also effectively blocked a pressure-induced shift in V1/2a. Lidocaine inhibited mechanosensitivity in NaV1.5 at the local anesthetic binding site mutated (F1760A). However, a membrane impermeable lidocaine analog QX-314 did not affect mechanosensitivity of F1760A NaV1.5 when applied from either side of the membrane. These data suggest that the mechanism of lidocaine inhibition of the pressure-induced shift in the half-point of voltage-dependence of activation is separate from the mechanisms of use-dependent block. Modulation of NaV1.5 mechanosensitivity by the membrane permeable local anesthetics may require hydrophobic access and may involve membrane-protein interactions. PMID:22874086

The future of VIS-IR hyperspectral remote sensing for the exploration of the solar system

NASA Astrophysics Data System (ADS)

Filacchione, Gianrico

2017-06-01

In the last 30 years our understanding of the Solar System has greatly advanced thanks to the introduction of VIS-IR imaging spectrometers which have provided hyperspectral views of planets, satellites, asteroids, comets and rings. By providing moderate resolution images and reflectance spectra for each pixel at the same time, these instruments allow to elaborate spectral-spatial models for very different targets: when used to observe surfaces, hyperspectral methods permit to retrieve endmembers composition (minerals, ices, organics, liquids), mixing state among endmembers (areal, intimate, intraparticle), physical properties (particle size, roughness, temperature) and to correlate these quantities with geological and morphological units. Similarly, morphological, dynamical and compositional studies of gaseous and aerosol species can be retrieved for planetary atmospheres, exospheres and auroras. To achieve these results, very different optical layouts, detectors technologies and observing techniques have been adopted in the last decades, going from very large and complex payloads, like ISM (IR Spectral Mapper) on russian mission Phobos to Mars and NIMS (Near IR Mapping Spectrometer) on US Galileo mission to Jupiter, which were the first hyperspectral imagers to flow aboard planetary missions, to more recent compact and performing experiments. The future of VIS-IR hyperspectral remote sensing is challenging because the complexity of modern planetary missions drives towards the realization of increasingly smaller, lighter and more performing payloads able to survive in harsh radiation and planetary protected environments or to operate from demanding platforms like landers, rovers and cubesats. As a development for future missions, one can foresee that apart instruments designed around well-consolidated optical solutions relying on prisms or gratings as dispersive elements, a new class of innovative hyperspectral imagers will rise: recent developments in

NavP: Structured and Multithreaded Distributed Parallel Programming

NASA Technical Reports Server (NTRS)

Pan, Lei; Xu, Jingling

2006-01-01

This slide presentation reviews some of the issues around distributed parallel programming. It compares and contrast two methods of programming: Single Program Multiple Data (SPMD) with the Navigational Programming (NAVP). It then reviews the distributed sequential computing (DSC) method and the methodology of NavP. Case studies are presented. It also reviews the work that is being done to enable the NavP system.

Nav1.7 expression is increased in painful human dental pulp.

PubMed

Luo, Songjiang; Perry, Griffin M; Levinson, S Rock; Henry, Michael A

2008-04-21

Animal studies and a few human studies have shown a change in sodium channel (NaCh) expression after inflammatory lesions, and this change is implicated in the generation of pain states. We are using the extracted human tooth as a model system to study peripheral pain mechanisms and here examine the expression of the Nav1.7 NaCh isoform in normal and painful samples. Pulpal sections were labeled with antibodies against: 1) Nav1.7, N52 and PGP9.5, and 2) Nav1.7, caspr (a paranodal protein used to identify nodes of Ranvier), and myelin basic protein (MBP), and a z-series of optically-sectioned images were obtained with the confocal microscope. Nav1.7-immunofluorescence was quantified in N52/PGP9.5-identified nerve fibers with NIH ImageJ software, while Nav1.7 expression in myelinated fibers at caspr-identified nodal sites was evaluated and further characterized as either typical or atypical as based on caspr-relationships. Results show a significant increase in nerve area with Nav1.7 expression within coronal and radicular fiber bundles and increased expression at typical and atypical caspr-identified nodal sites in painful samples. Painful samples also showed an augmentation of Nav1.7 within localized areas that lacked MBP, including those associated with atypical caspr-identified sites, thus identifying NaCh remodeling within demyelinating axons as the basis for a possible pulpal pain mechanism. This study identifies the increased axonal expression and augmentation of Nav1.7 at intact and remodeling/demyelinating nodes within the painful human dental pulp where these changes may contribute to constant, increased evoked and spontaneous pain responses that characterize the pain associated with toothache.

Visceral and somatic pain modalities reveal NaV1.7‐independent visceral nociceptive pathways

PubMed Central

Hockley, James R. F.; González‐Cano, Rafael; McMurray, Sheridan; Tejada‐Giraldez, Miguel A.; McGuire, Cian; Torres, Antonio; Wilbrey, Anna L.; Cibert‐Goton, Vincent; Nieto, Francisco R.; Pitcher, Thomas; Knowles, Charles H.; Baeyens, José Manuel; Wood, John N.; Winchester, Wendy J.; Bulmer, David C.; Cendán, Cruz Miguel

2017-01-01

Key points Voltage‐gated sodium channels play a fundamental role in determining neuronal excitability.Specifically, voltage‐gated sodium channel subtype NaV1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown.Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling.These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality‐specific manner and help to direct drug discovery efforts towards novel visceral analgesics. Abstract Voltage‐gated sodium channel NaV1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor‐specific NaV1.7 knockout mouse (NaV1.7Nav1.8) and selective small‐molecule NaV1.7 antagonist PF‐5198007. NaV1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve–gut preparations in mouse, or following antagonism of NaV1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage‐gated sodium channel α subunits revealed NaV1.7 mRNA transcripts in nearly all retrogradely

Ranolazine inhibits NaV1.5-mediated breast cancer cell invasiveness and lung colonization.

PubMed

Driffort, Virginie; Gillet, Ludovic; Bon, Emeline; Marionneau-Lambot, Séverine; Oullier, Thibauld; Joulin, Virginie; Collin, Christine; Pagès, Jean-Christophe; Jourdan, Marie-Lise; Chevalier, Stéphan; Bougnoux, Philippe; Le Guennec, Jean-Yves; Besson, Pierre; Roger, Sébastien

2014-12-11

Na(V)1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients' death. In breast cancer cells, Na(V)1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness. In this study, we showed that the extinction of Na(V)1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 μM) inhibited Na(V)1.5 currents in breast cancer cells and reduced Na(V)1.5-related cancer cell invasiveness in vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by Na(V)1.5-expressing human breast cancer cells. Taken together, our results demonstrate the importance of Na(V)1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with Na(V) activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments.

NEAR: Low-mass Planets in α Cen with VISIR

NASA Astrophysics Data System (ADS)

Kasper, M.; Arsenault, R.; Käufl, H.-U.; Jakob, G.; Fuenteseca, E.; Riquelme, M.; Siebenmorgen, R.; Sterzik, M.; Zins, G.; Ageorges, N.; Gutruf, S.; Reutlinger, A.; Kampf, D.; Absil, O.; Carlomagno, B.; Guyon, O.; Klupar, P.; Mawet, D.; Ruane, G.; Karlsson, M.; Pantin, E.; Dohlen, K.

2017-09-01

ESO, in collaboration with the Breakthrough Initiatives, is working to modify the Very Large Telescope mid-IR imager (VISIR) to greatly enhance its ability to search for potentially habitable planets around both components of the binary Alpha Centauri, part of the closest stellar system to the Earth. Much of the funding for the NEAR (New Earths in the Alpha Cen Region) project is provided by the Breakthrough Initiatives, and ESO mostly provides staff and observing time. The concept combines adaptive optics using the deformable secondary mirror at Unit Telescope 4, a new annular groove phase mask (AGPM) coronagraph optimised for the most sensitive spectral bandpass in the N-band, and a novel internal chopper system for noise filtering based on a concept for longer wavelengths invented by the microwave pioneer Robert Dicke. The NEAR experiment is relevant to the mid-infrared METIS instrument on the Extremely Large Telescope, as the knowledge gained and proof of concept will be transferable.

The SuperCam Remote Sensing Suite for MARS 2020: Nested and Co-Aligned LIBS, Raman, and VISIR Spectroscopies, and color micro-imaging

NASA Astrophysics Data System (ADS)

Fouchet, Thierry; Wiens, Roger; Maurice, Sylvestre; Johnson, Jeffrey R.; Clegg, Samuel; Sharma, Shiv; Rull, Fernando; Montmessin, Franck; Anderson, Ryan; Beyssac, Olivier; Bonal, Lydie; Deflores, Lauren; Dromart, Gilles; Fischer, William; Forni, Olivier; Gasnault, Olivier; Grotzinger, John P.; Mangold, Nicolas; Martinez-Frias, Jesus; MacLennan, Scott; McCabe, Kevin; cais, Philippe; Nelson, Tony; Angel, Stanley; Beck, Pierre; Benzerara, Karim; Bernard, Sylvain; Bousquet, Bruno; Bridges, Nathan; Cloutis, Edward; Fabre, Cécile; Grasset, Olivier; Lanza, Nina; Lasue, Jeremie; Le Mouélic, Stéphane; Leveille, Rich; Lewin, Eric; McConnochie, Timothy H.; Melikechi, Noureddine; Meslin, Pierre-Yves; Misra, Anupam; Montagnac, Gilles; Newsom, Horton; Ollila, Ann; Pinet, Patrick; Poulet, Francois; Sobron, Pablo

2016-10-01

As chartered by the Science Definition Team, the Mars 2020 mission addresses four primary objectives: A. Characterize the processes that formed and modified the geologic record within an astrobiologically relevant ancient environment, B. Perform astrobiologically relevant investigations to determine habitability, search for materials with biosignature presentation potential, and search for evidence of past life, C. Assemble a returnable cache of samples and D. Contribute to preparation for human exploration of Mars. The SuperCam instrument, selected for the Mars 2020 rover, as a suite of four instruments, provides nested and co-aligned remote investigations: Laser Induced Breakdown Spectroscopy (LIBS), Raman spectroscopy and time-resolved fluorescence (TRF), visible and near-infrared spectroscopy (VISIR), and high resolution color imaging (RMI). SuperCam appeals broadly to the four Mars 2020 objectives.In detail, SuperCam will perform:1. Microscale mineral identification by combining LIBS elemental and VISIR mineralogical spectroscopies, especially targeting secondary minerals2. Determine the sedimental stratigraphy through color imaging and LIBS and VISIR spectroscopy3. Search for organics and bio-signatures with LIBS and Raman spectroscopy4. Quantify the volatile content of the rocks by LIBS spectroscopy to determine the degree of aquaeous alteration5. Characterize the texture of the rocks by color imaging to determine their alteration processes6. Characterize the rocks' coatings by LIBS spectroscopy7. Characterize the soil and its potential for biosignature preservation8. Monitor the odd-oxygen atmospheric chemistry.To meet these goals SuperCam will perform LIBS spectroscopy on 0.5 mm spot up to 7-meter distance, perform Raman and time-resolved fluoresence up to 12-m distance with a 0.8 mrad angular resolution, a 100 ns time gating in the 534-850 nm spectral range, acquire VISIR spectra in the range 0.4-0.85 μm with a resolution of 0.35 nm, and in the IR range

Expression of Voltage-Gated Sodium Channel Nav1.8 in Human Prostate Cancer is Associated with High Histological Grade

PubMed Central

Suy, Simeng; Hansen, Todd P.; Auto, Heather D.; Kallakury, Bhaskar V.S.; Dailey, Vernon; Danner, Malika; MacArthur, Linda; Zhang, Ying; Miessau, Matthew J.; Collins, Sean P.; Brown, Milton L.

2013-01-01

Voltage-gated sodium (Nav) channels are required for impulse conductance in excitable tissues. Navs have been linked to human cancers, including prostate. The expression and distribution of Nav isoforms (Nav1.1-Nav1.9) in human prostate cancer are not well established. Here, we evaluated the expression of these isoforms and investigated the expression of Nav1.8 in human prostate cancer tissues. Nav1.8 was highly expressed in all examined cells. Expression of Nav1.1, Nav1.2, and Nav1.9 were high in DU-145, PC-3 and PC-3M cells compared to LNCaP (hormone-dependent), C4-2, C4-2B, and CWR22Rv-1 cells. Nav1.5 and Nav1.6 were expressed in all cells examined. Nav1.7 expression was absent in PC-3M and CWR22Rv-1, but expressed in the other cells examined. Immunohistochemistry revealed intensive Nav1.8 staining correlated with more advanced pathologic stage of disease. Increased intensity of nuclear Nav1.8 correlated with increased Gleason grade. Our results revealed that Nav1.8 is universally expressed in human prostate cancer cells. Nav1.8 expression statistically correlated with pathologic stage (P=0.04) and Gleason score (P=0.01) of human prostate tissue specimens. The aberrant nuclear localization of Nav1.8 with advanced prostate cancer tissues warrant further investigation into use of Nav1.8 as a potential biomarker to differentiate between early and advanced disease. PMID:24163825

Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain

PubMed Central

Osteen, Jeremiah D.; Herzig, Volker; Gilchrist, John; Emrick, Joshua J.; Zhang, Chuchu; Wang, Xidao; Castro, Joel; Garcia-Caraballo, Sonia; Grundy, Luke; Rychkov, Grigori Y.; Weyer, Andy D.; Dekan, Zoltan; Undheim, Eivind A. B.; Alewood, Paul; Stucky, Cheryl L.; Brierley, Stuart M.; Basbaum, Allan I.; Bosmans, Frank; King, Glenn F.; Julius, David

2016-01-01

Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Nav1.1-expressing fibers are modality-specific nociceptors: their activation elicits robust pain behaviors without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibers also express Nav1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Nav1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain. PMID:27281198

Remarkable alterations of Nav1.6 in reactive astrogliosis during epileptogenesis.

PubMed

Zhu, Hongyan; Zhao, Yuxiao; Wu, Hao; Jiang, Nan; Wang, Ziyi; Lin, Weide; Jin, Jiahui; Ji, Yonghua

2016-12-01

Voltage-gated sodium channels (VGSCs) play a vital role in controlling neuronal excitability. Nav1.6 is the most abundantly expressed VGSCs subtype in the adult central nervous system and has been found to contribute to facilitate the hyperexcitability of neurons after electrical induction of status epilepticus (SE). To clarify the exact expression patterns of Nav1.6 during epileptogenesis, we examined the expression of Nav1.6 at protein and mRNA levels in two distinct animal models of temporal lobe epilepsy (TLE) including a post-SE model induced by kainic acid (KA) intrahippocampal injection and a kindling model evoked by pentylenetetrazole (PTZ). A prominent, seizure intensity-dependent increase of Nav1.6 expression in reactive astrocytes was observed in ipsilateral hippocampus of post-SE rats, reaching the peak at 21 days after SE, a time point during the latent stage of epileptogenesis. However, Nav1.6 with low expression level was selectively expressed in the hippocampal neurons rather than astrocytes in PTZ-kindled animals. This seizure-related increase of a VGSCs subtype in reactive astrocytes after SE may represent a new mechanism for signal communication between neuron and glia in the course of epileptogenesis, facilitating the neuronal hyperexcitability.

Loss-of-function mutations in sodium channel Nav1.7 cause anosmia

PubMed Central

Weiss, Jan; Pyrski, Martina; Jacobi, Eric; Bufe, Bernd; Willnecker, Vivienne; Schick, Bernhard; Zizzari, Philippe; Gossage, Samuel J.; Greer, Charles A.; Leinders-Zufall, Trese; Woods, C. Geoffrey; Wood, John N.; Zufall, Frank

2013-01-01

Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Nav1.7, causes a congenital inability to experience pain in humans. Here we show that Nav1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Nav1.7 in odour perception, we generated conditional null mice in which Nav1.7 was removed from all olfactory sensory neurons. In the absence of Nav1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell. PMID:21441906

Loss-of-function mutations in sodium channel Nav1.7 cause anosmia.

PubMed

Weiss, Jan; Pyrski, Martina; Jacobi, Eric; Bufe, Bernd; Willnecker, Vivienne; Schick, Bernhard; Zizzari, Philippe; Gossage, Samuel J; Greer, Charles A; Leinders-Zufall, Trese; Woods, C Geoffrey; Wood, John N; Zufall, Frank

2011-04-14

Loss of function of the gene SCN9A, encoding the voltage-gated sodium channel Na(v)1.7, causes a congenital inability to experience pain in humans. Here we show that Na(v)1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na(v)1.7 in odour perception, we generated conditional null mice in which Na(v)1.7 was removed from all olfactory sensory neurons. In the absence of Na(v)1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell.

Lidocaine reduces the transition to slow inactivation in Nav1.7 voltage-gated sodium channels

PubMed Central

Sheets, Patrick L; Jarecki, Brian W; Cummins, Theodore R

2011-01-01

BACKGROUND AND PURPOSE The primary use of local anaesthetics is to prevent or relieve pain by reversibly preventing action potential propagation through the inhibition of voltage-gated sodium channels. The tetrodotoxin-sensitive voltage-gated sodium channel subtype Nav1.7, abundantly expressed in pain-sensing neurons, plays a crucial role in perception and transmission of painful stimuli and in inherited chronic pain syndromes. Understanding the interaction of lidocaine with Nav1.7 channels could provide valuable insight into the drug's action in alleviating pain in distinct patient populations. The aim of this study was to determine how lidocaine interacts with multiple inactivated conformations of Nav1.7 channels. EXPERIMENTAL APPROACH We investigated the interactions of lidocaine with wild-type Nav1.7 channels and a paroxysmal extreme pain disorder mutation (I1461T) that destabilizes fast inactivation. Whole cell patch clamp recordings were used to examine the activity of channels expressed in human embryonic kidney 293 cells. KEY RESULTS Depolarizing pulses that increased slow inactivation of Nav1.7 channels also reduced lidocaine inhibition. Lidocaine enhanced recovery of Nav1.7 channels from prolonged depolarizing pulses by decreasing slow inactivation. A paroxysmal extreme pain disorder mutation that destabilizes fast inactivation of Nav1.7 channels decreased lidocaine inhibition. CONCLUSIONS AND IMPLICATIONS Lidocaine decreased the transition of Nav1.7 channels to the slow inactivated state. The fast inactivation gate (domain III–IV linker) is important for potentiating the interaction of lidocaine with the Nav1.7 channel. PMID:21232038

Scorpion β-toxin interference with NaV channel voltage sensor gives rise to excitatory and depressant modes

PubMed Central

Leipold, Enrico; Borges, Adolfo

2012-01-01

Scorpion β toxins, peptides of ∼70 residues, specifically target voltage-gated sodium (NaV) channels to cause use-dependent subthreshold channel openings via a voltage–sensor trapping mechanism. This excitatory action is often overlaid by a not yet understood depressant mode in which NaV channel activity is inhibited. Here, we analyzed these two modes of gating modification by β-toxin Tz1 from Tityus zulianus on heterologously expressed NaV1.4 and NaV1.5 channels using the whole cell patch-clamp method. Tz1 facilitated the opening of NaV1.4 in a use-dependent manner and inhibited channel opening with a reversed use dependence. In contrast, the opening of NaV1.5 was exclusively inhibited without noticeable use dependence. Using chimeras of NaV1.4 and NaV1.5 channels, we demonstrated that gating modification by Tz1 depends on the specific structure of the voltage sensor in domain 2. Although residue G658 in NaV1.4 promotes the use-dependent transitions between Tz1 modification phenotypes, the equivalent residue in NaV1.5, N803, abolishes them. Gating charge neutralizations in the NaV1.4 domain 2 voltage sensor identified arginine residues at positions 663 and 669 as crucial for the outward and inward movement of this sensor, respectively. Our data support a model in which Tz1 can stabilize two conformations of the domain 2 voltage sensor: a preactivated outward position leading to NaV channels that open at subthreshold potentials, and a deactivated inward position preventing channels from opening. The results are best explained by a two-state voltage–sensor trapping model in that bound scorpion β toxin slows the activation as well as the deactivation kinetics of the voltage sensor in domain 2. PMID:22450487

Sodium channel Nav1.7 immunoreactivity in painful human dental pulp and burning mouth syndrome

PubMed Central

2010-01-01

Background Voltage gated sodium channels Nav1.7 are involved in nociceptor nerve action potentials and are known to affect pain sensitivity in clinical genetic disorders. Aims and Objectives To study Nav1.7 levels in dental pulpitis pain, an inflammatory condition, and burning mouth syndrome (BMS), considered a neuropathic orofacial pain disorder. Methods Two groups of patients were recruited for this study. One group consisted of patients with dental pulpitis pain (n = 5) and controls (n = 12), and the other patients with BMS (n = 7) and controls (n = 10). BMS patients were diagnosed according to the International Association for the Study of Pain criteria; a pain history was collected, including the visual analogue scale (VAS). Immunohistochemistry with visual intensity and computer image analysis were used to evaluate levels of Nav1.7 in dental pulp tissue samples from the dental pulpitis group, and tongue biopsies from the BMS group. Results There was a significantly increased visual intensity score for Nav1.7 in nerve fibres in the painful dental pulp specimens, compared to controls. Image analysis showed a trend for an increase of the Nav1.7 immunoreactive % area in the painful pulp group, but this was not statistically significant. When expressed as a ratio of the neurofilament % area, there was a strong trend for an increase of Nav1.7 in the painful pulp group. Nav1.7 immunoreactive fibres were seen in abundance in the sub-mucosal layer of tongue biopsies, with no significant difference between BMS and controls. Conclusion Nav1.7 sodium channel may play a significant role in inflammatory dental pain. Clinical trials with selective Nav1.7 channel blockers should prioritise dental pulp pain rather than BMS. PMID:20529324

Persistent modification of Nav1.9 following chronic exposure to insecticides and pyridostigmine bromide.

PubMed

Nutter, Thomas J; Cooper, Brian Y

2014-06-15

Many veterans of the 1991 Gulf War (GW) returned from that conflict with a widespread chronic pain affecting deep tissues. Recently, we have shown that a 60day exposure to the insecticides permethrin, chlorpyrifos, and pyridostigmine bromide (NTPB) had little influence on nociceptor action potential forming Nav1.8, but increased Kv7 mediated inhibitory currents 8weeks after treatment. Using the same exposure regimen, we used whole cell patch methods to examine whether the influences of NTPB could be observed on Nav1.9 expressed in muscle and vascular nociceptors. During a 60day exposure to NTPB, rats exhibited lowered muscle pain thresholds and increased rest periods, but these measures subsequently returned to normal levels. Eight and 12weeks after treatments ceased, DRG neurons were excised from the sensory ganglia. Whole cell patch studies revealed little change in voltage dependent activation and deactivation of Nav1.9, but significant increases in the amplitude of Nav1.9 were observed 8weeks after exposure. Cellular studies, at the 8week delay, revealed that NTPB also significantly prolonged action potential duration and afterhyperpolarization (22°C). Acute application of permethrin (10μM) also increased the amplitude of Nav1.9 in skin, muscle and vascular nociceptors. In conclusion, chronic exposure to Gulf War agents produced long term changes in the amplitude of Nav1.9 expressed in muscle and vascular nociceptors. The reported increases in Kv7 amplitude may have been an adaptive response to increased Nav1.9, and effectively suppressed behavioral pain measures in the post treatment period. Factors that alter the balance between Nav1.9 and Kv7 could release spontaneous discharge and produce chronic deep tissue pain. Copyright © 2014 Elsevier Inc. All rights reserved.

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

PubMed Central

Deuis, Jennifer R.; Dekan, Zoltan; Wingerd, Joshua S.; Smith, Jennifer J.; Munasinghe, Nehan R.; Bhola, Rebecca F.; Imlach, Wendy L.; Herzig, Volker; Armstrong, David A.; Rosengren, K. Johan; Bosmans, Frank; Waxman, Stephen G.; Dib-Hajj, Sulayman D.; Escoubas, Pierre; Minett, Michael S.; Christie, Macdonald J.; King, Glenn F.; Alewood, Paul F.; Lewis, Richard J.; Wood, John N.; Vetter, Irina

2017-01-01

Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40–1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective NaV1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective NaV1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted NaV1.7 inhibitors can only produce analgesia when administered in combination with an opioid. PMID:28106092

Nomenclatorial changes and redescriptions of three of Navás’ Leucochrysa (Nodita) species (Neuroptera, Chrysopidae)

PubMed Central

Catherine A., Tauber; Gilberto S., Albuquerque; Maurice J., Tauber

2011-01-01

Abstract Three species that Navás described – Leucochrysa (Nodita) azevedoi Navás, 1913, Leucochrysa (Nodita) camposi (Navás, 1933) and Leucochrysa (Nodita) morenoi (Navás, 1934) – have received recent taxonomic attention. All three have many similar external features; indeed Navás himself, as well as subsequent authors, have confused the species with each other. Here, (a) misidentifications are corrected; (b) a neotype of Leucochrysa azevedoi is designated; (c) Leucochrysa (Nodita) morenoi, previously synonymized with Leucochrysa (Nodita) camposi, is recognized as a valid species [Reinstated status] All three species are redescribed and illustrated, with special emphasis on the types. Leucochrysa (Nodita) azevedoi was found to be relatively common in agricultural areas along Brazil’s Atlantic coast. The two other species are known only from their type localities: Leucochrysa (Nodita) camposi – coastal Ecuador, and Leucochrysa (Nodita) morenoi – Quito, Ecuador. PMID:21594110

K+ Block Is the Mechanism of Functional Asymmetry in Bacterial Nav Channels

PubMed Central

Ngo, Van; Wang, Yibo; Haas, Stephan; Noskov, Sergei Y.; Farley, Robert A.

2016-01-01

Crystal structures of several bacterial Nav channels have been recently published and molecular dynamics simulations of ion permeation through these channels are consistent with many electrophysiological properties of eukaryotic channels. Bacterial Nav channels have been characterized as functionally asymmetric, and the mechanism of this asymmetry has not been clearly understood. To address this question, we combined non-equilibrium simulation data with two-dimensional equilibrium unperturbed landscapes generated by umbrella sampling and Weighted Histogram Analysis Methods for multiple ions traversing the selectivity filter of bacterial NavAb channel. This approach provided new insight into the mechanism of selective ion permeation in bacterial Nav channels. The non-equilibrium simulations indicate that two or three extracellular K+ ions can block the entrance to the selectivity filter of NavAb in the presence of applied forces in the inward direction, but not in the outward direction. The block state occurs in an unstable local minimum of the equilibrium unperturbed free-energy landscape of two K+ ions that can be ‘locked’ in place by modest applied forces. In contrast to K+, three Na+ ions move favorably through the selectivity filter together as a unit in a loose “knock-on” mechanism of permeation in both inward and outward directions, and there is no similar local minimum in the two-dimensional free-energy landscape of two Na+ ions for a block state. The useful work predicted by the non-equilibrium simulations that is required to break the K+ block is equivalent to large applied potentials experimentally measured for two bacterial Nav channels to induce inward currents of K+ ions. These results illustrate how inclusion of non-equilibrium factors in the simulations can provide detailed information about mechanisms of ion selectivity that is missing from mechanisms derived from either crystal structures or equilibrium unperturbed free-energy landscapes

Inhibitors of voltage-gated sodium channel Nav1.7: patent applications since 2010.

PubMed

Sun, Shaoyi; Cohen, Charles J; Dehnhardt, Christoph M

2014-09-01

There has been intense interest in developing inhibitors of the sodium channel Nav1.7 because genetic studies have established very strong validation for the efficacy to alleviate both inflammatory and neuropathic pain. This review summarizes patent applications targeting Nav1.7 since 2010 until May, 2014. We have classified the patents into three categories as follows: small molecules with well-defined molecular selectivity among sodium channel isoforms; biologicals with well-defined molecular selectivity; and, small molecules that inhibit Nav1.7 with unknown molecular selectivity. Most of the review is dedicated to small molecule selective compounds.

Localisation of SCN10A gene product Na(v)1.8 and novel pain-related ion channels in human heart.

PubMed

Facer, Paul; Punjabi, Prakash P; Abrari, Andleeb; Kaba, Riyaz A; Severs, Nicholas J; Chambers, John; Kooner, Jaspal S; Anand, Praveen

2011-01-01

We have shown that the gene SCN10A encoding the sodium channel Na(v)1.8 is a susceptibility factor for heart block and serious ventricular arrhythmia. Since Na(v)1.8 is known to be present in nerve fibres that mediate pain, it may be related to both cardiac pain and dysrhythmia. The localisation of Na(v)1.8 and other key nociceptive ion channels, including Na(v)1.7, Na(v)1.9, capsaicin receptor TRPV1, and purinergic receptor P2X(3), have not been reported in human heart. The aim of this study was to determine the distribution of Na(v)1.8, related sodium and other sensory channels in human cardiac tissue, and correlate their density with sympathetic nerves, regenerating nerves (GAP-43), and vascularity. Human heart atrial appendage tissues (n = 13) were collected during surgery for valve disease. Tissues were investigated by immunohistology using specific antibodies to Na(v)1.8 and other markers. Na(v)1.8 immunoreactivity was detected in nerve fibres and fascicles in the myocardium, often closely associated with small capillaries. Na(v)1.8 nerve fibres per mm(2) correlated significantly with vascular markers. Na(v)1.8-immunoreactivity was present also in cardiomyocytes with a similar distribution pattern to that seen with connexins, the specialised gap junction proteins of myocardial intercalated discs. Na(v)1.5-immunoreactivity was detected in cardiomyocytes but not in nerve fibres. Na(v)1.7, Na(v)1.9, TRPV1, P2X(3)/P2X(2), and GAP43 positive nerve fibres were relatively sparse, whereas sympathetic innervation and connexin43 were abundant. We conclude that sodium channel Na(v)1.8 is present in sensory nerves and cardiomyocytes of human heart. Na(v)1.8 and other pain channels provide new targets for the understanding and treatment of cardiac pain and dysrhythmia.

Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel

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

Gaudioso, Christelle; Carlier, Edmond; Youssouf, Fahamoe

2011-07-29

Highlights: {yields} Both Ca{sup ++}-Calmodulin (CaM) and Ca{sup ++}-free CaM bind to the C-terminal region of Nav1.1. {yields} Ca{sup ++} and CaM have both opposite and convergent effects on I{sub Nav1.1}. {yields} Ca{sup ++}-CaM modulates I{sub Nav1.1} amplitude. {yields} CaM hyperpolarizes the voltage-dependence of activation, and increases the inactivation rate. {yields} Ca{sup ++} alone antagonizes CaM for both effects, and depolarizes the voltage-dependence of inactivation. -- Abstract: Mutations in the neuronal Nav1.1 voltage-gated sodium channel are responsible for mild to severe epileptic syndromes. The ubiquitous calcium sensor calmodulin (CaM) bound to rat brain Nav1.1 and to the human Nav1.1 channelmore » expressed by a stably transfected HEK-293 cell line. The C-terminal region of the channel, as a fusion protein or in the yeast two-hybrid system, interacted with CaM via a consensus C-terminal motif, the IQ domain. Patch clamp experiments on HEK1.1 cells showed that CaM overexpression increased peak current in a calcium-dependent way. CaM had no effect on the voltage-dependence of fast inactivation, and accelerated the inactivation kinetics. Elevating Ca{sup ++} depolarized the voltage-dependence of fast inactivation and slowed down the fast inactivation kinetics, and for high concentrations this effect competed with the acceleration induced by CaM alone. Similarly, the depolarizing action of calcium antagonized the hyperpolarizing shift of the voltage-dependence of activation due to CaM overexpression. Fluorescence spectroscopy measurements suggested that Ca{sup ++} could bind the Nav1.1 C-terminal region with micromolar affinity.« less

Optogenetic Silencing of Nav1.8-Positive Afferents Alleviates Inflammatory and Neuropathic Pain123

PubMed Central

Daou, Ihab; Beaudry, Hélène; Ase, Ariel R.; Wieskopf, Jeffrey S.; Ribeiro-da-Silva, Alfredo; Mogil, Jeffrey S.

2016-01-01

Abstract We report a novel transgenic mouse model in which the terminals of peripheral nociceptors can be silenced optogenetically with high spatiotemporal precision, leading to the alleviation of inflammatory and neuropathic pain. Inhibitory archaerhodopsin-3 (Arch) proton pumps were delivered to Nav1.8+ primary afferents using the Nav1.8-Cre driver line. Arch expression covered both peptidergic and nonpeptidergic nociceptors and yellow light stimulation reliably blocked electrically induced action potentials in DRG neurons. Acute transdermal illumination of the hindpaws of Nav1.8-Arch+ mice significantly reduced mechanical allodynia under inflammatory conditions, while basal mechanical sensitivity was not affected by the optical stimulation. Arch-driven hyperpolarization of nociceptive terminals was sufficient to prevent channelrhodopsin-2 (ChR2)-mediated mechanical and thermal hypersensitivity in double-transgenic Nav1.8-ChR2+-Arch+mice. Furthermore, prolonged optical silencing of peripheral afferents in anesthetized Nav1.8-Arch+ mice led to poststimulation analgesia with a significant decrease in mechanical and thermal hypersensitivity under inflammatory and neuropathic conditions. These findings highlight the role of peripheral neuronal inputs in the onset and maintenance of pain hypersensitivity, demonstrate the plasticity of pain pathways even after sensitization has occurred, and support the involvement of Nav1.8+ afferents in both inflammatory and neuropathic pain. Together, we present a selective analgesic approach in which genetically identified subsets of peripheral sensory fibers can be remotely and optically inhibited with high temporal resolution, overcoming the compensatory limitations of genetic ablations. PMID:27022626

Global Nav1.7 Knockout Mice Recapitulate the Phenotype of Human Congenital Indifference to Pain

PubMed Central

Gingras, Jacinthe; Smith, Sarah; Matson, David J.; Johnson, Danielle; Nye, Kim; Couture, Lauren; Feric, Elma; Yin, Ruoyuan; Moyer, Bryan D.; Peterson, Matthew L.; Rottman, James B.; Beiler, Rudolph J.; Malmberg, Annika B.; McDonough, Stefan I.

2014-01-01

Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund’s adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain. PMID:25188265

ADULT AND JUVENILE RAT SODIUM CHANNEL (NAV1.2 AND NAV1.3) SENSITIVITY TO THE PYRETHROID INSECTICIDE DELTAMETHRIN.

EPA Science Inventory

Adult rats are less sensitive than juveniles to the acute neurotoxicity of the Type II pyrethroid insecticide deltamethrin (DLT). Voltage-sensitive sodium channels (VSSCs) are the primary target of DLT and are differentially expressed during development, with expression of Nav1.2...

Persistent Nav1.6 current at axon initial segments tunes spike timing of cerebellar granule cells

PubMed Central

Osorio, Nancy; Cathala, Laurence; Meisler, Miriam H; Crest, Marcel; Magistretti, Jacopo; Delmas, Patrick

2010-01-01

Cerebellar granule (CG) cells generate high-frequency action potentials that have been proposed to depend on the unique properties of their voltage-gated ion channels. To address the in vivo function of Nav1.6 channels in developing and mature CG cells, we combined the study of the developmental expression of Nav subunits with recording of acute cerebellar slices from young and adult granule-specific Scn8a KO mice. Nav1.2 accumulated rapidly at early-formed axon initial segments (AISs). In contrast, Nav1.6 was absent at early postnatal stages but accumulated at AISs of CG cells from P21 to P40. By P40–P65, both Nav1.6 and Nav1.2 co-localized at CG cell AISs. By comparing Na+ currents in mature CG cells (P66–P74) from wild-type and CG-specific Scn8a KO mice, we found that transient and resurgent Na+ currents were not modified in the absence of Nav1.6 whereas persistent Na+ current was strongly reduced. Action potentials in conditional Scn8a KO CG cells showed no alteration in threshold and overshoot, but had a faster repolarization phase and larger post-spike hyperpolarization. In addition, although Scn8a KO CG cells kept their ability to fire action potentials at very high frequency, they displayed increased interspike-interval variability and firing irregularity in response to sustained depolarization. We conclude that Nav1.6 channels at axon initial segments contribute to persistent Na+ current and ensure a high degree of temporal precision in repetitive firing of CG cells. PMID:20173079

Structural analyses of Ca2+/CaM interaction with NaV channel C-termini reveal mechanisms of calcium-dependent regulation

PubMed Central

Wang, Chaojian; Chung, Ben C.; Yan, Haidun; Wang, Hong-Gang; Lee, Seok-Yong; Pitt, Geoffrey S.

2014-01-01

Ca2+ regulates voltage-gated Na+ (NaV) channels and perturbed Ca2+ regulation of NaV function is associated with epilepsy syndromes, autism, and cardiac arrhythmias. Understanding the disease mechanisms, however, has been hindered by a lack of structural information and competing models for how Ca2+ affects NaV channel function. Here, we report the crystal structures of two ternary complexes of a human NaV cytosolic C-terminal domain (CTD), a fibroblast growth factor homologous factor, and Ca2+/calmodulin (Ca2+/CaM). These structures rule out direct binding of Ca2+ to the NaV CTD, and uncover new contacts between CaM and the NaV CTD. Probing these new contacts with biochemical and functional experiments allows us to propose a mechanism by which Ca2+ could regulate NaV channels. Further, our model provides hints towards understanding the molecular basis of the neurologic disorders and cardiac arrhythmias caused by NaV channel mutations. PMID:25232683

O-GlcNAcylation of cardiac Nav1.5 contributes to the development of arrhythmias in diabetic hearts.

PubMed

Yu, Peng; Hu, Lili; Xie, Jinyan; Chen, Sisi; Huang, Lin; Xu, Zixuan; Liu, Xiao; Zhou, Qiongqiong; Yuan, Ping; Yan, Xia; Jin, Jiejin; Shen, Yang; Zhu, Wengen; Fu, Linghua; Chen, Qi; Yu, Jianhua; Hu, Jianxin; Cao, Qing; Wan, Rong; Hong, Kui

2018-06-01

Cardiovascular complications are major causes of mortality and morbidity in diabetic patients. The mechanisms underlying the progression of diabetic heart (DH) to ventricular arrhythmias are unclear. O-linked GlcNAcylation (O-GlcNAc) is a reversible post-translational modification for the regulation of diverse cellular processes. The purpose of this study was to assess whether the cardiac voltage-gated sodium channel (Nav1.5) is subjected to O-linked GlcNAcylation (O-GlcNAc), which plays an essential role in DH-induced arrhythmias. In this study, Sprague-Dawley rats (male, 200-230 g) were treated with a single high-dose of streptozotocin (STZ, 80 mg/kg) to generate a rat model of diabetes. STZ-induced 3-month diabetic rats displayed increased susceptibility to ventricular arrhythmias. The elevated O-GlcNAc modification was correlated with decreases in both total and cytoplasmic Nav1.5 expression in vivo and in vitro. In addition, both co-immunoprecipitation and immunostaining assays demonstrated that hyperglycemia could increase the O-GlcNAc-modified Nav1.5 levels and decrease the interaction between Nav1.5 and Nav1.5-binding proteins Nedd4-2/SAP-97. Furthermore, patch-clamp measurements in HEK-293 T cells showed that Nav1.5 current densities decreased by 30% after high-glucose treatment, and the sodium currents increased via O-GlcNAc inhibition. Our data suggested that hyperglycemia increased the O-GlcNAc modification of Nav1.5 expression and decreased the interaction between Nav1.5 and Nedd4-2/SAP-97, which led to the abnormal expression and distribution of Nav1.5, loss of function of the sodium channel, and prolongation of the PR/QT interval. Excessive O-GlcNAc modification of Nav1.5 is a novel signaling event, which may be an underlying contributing factor for the development of the arrhythmogenesis in DH. Copyright © 2017. Published by Elsevier B.V.

Functional up-regulation of Nav1.8 sodium channel in Aβ afferent fibers subjected to chronic peripheral inflammation

PubMed Central

2014-01-01

Background Functional alterations in the properties of Aβ afferent fibers may account for the increased pain sensitivity observed under peripheral chronic inflammation. Among the voltage-gated sodium channels involved in the pathophysiology of pain, Nav1.8 has been shown to participate in the peripheral sensitization of nociceptors. However, to date, there is no evidence for a role of Nav1.8 in controlling Aβ-fiber excitability following persistent inflammation. Methods Distribution and expression of Nav1.8 in dorsal root ganglia and sciatic nerves were qualitatively or quantitatively assessed by immunohistochemical staining and by real time-polymerase chain reaction at different time points following complete Freund’s adjuvant (CFA) administration. Using a whole-cell patch-clamp configuration, we further determined both total INa and TTX-R Nav1.8 currents in large-soma dorsal root ganglia (DRG) neurons isolated from sham or CFA-treated rats. Finally, we analyzed the effects of ambroxol, a Nav1.8-preferring blocker on the electrophysiological properties of Nav1.8 currents and on the mechanical sensitivity and inflammation of the hind paw in CFA-treated rats. Results Our findings revealed that Nav1.8 is up-regulated in NF200-positive large sensory neurons and is subsequently anterogradely transported from the DRG cell bodies along the axons toward the periphery after CFA-induced inflammation. We also demonstrated that both total INa and Nav1.8 peak current densities are enhanced in inflamed large myelinated Aβ-fiber neurons. Persistent inflammation leading to nociception also induced time-dependent changes in Aβ-fiber neuron excitability by shifting the voltage-dependent activation of Nav1.8 in the hyperpolarizing direction, thus decreasing the current threshold for triggering action potentials. Finally, we found that ambroxol significantly reduces the potentiation of Nav1.8 currents in Aβ-fiber neurons observed following intraplantar CFA injection and

Distinct Roles of the DmNav and DSC1 Channels in the Action of DDT and Pyrethroids

PubMed Central

Rinkevich, Frank D.; Du, Yuzhe; Tolinski, Josh; Ueda, Atsushi; Wu, Chun-Fang; Zhorov, Boris S.; Dong, Ke

2015-01-01

Voltage-gated sodium channels (Nav channels) are critical for electrical signaling in the nervous system and are the primary targets of the insecticides DDT and pyrethroids. In Drosophila melanogaster, besides the canonical Nav channel, Para (also called DmNav), there is a sodium channel-like cation channel called DSC1 (Drosophila sodium channel 1). Temperature-sensitive paralytic mutations in DmNav (parats) confer resistance to DDT and pyrethroids, whereas DSC1 knockout flies exhibit enhanced sensitivity to pyrethroids. To further define the roles and interaction of DmNav and DSC1 channels in DDT and pyrethroid neurotoxicology, we generated a DmNav/DSC1 double mutant line by introducing a parats1 allele (carrying the I265N mutation) into a DSC1 knockout line. We confirmed that the I265N mutation reduced the sensitivity to two pyrethroids, permethrin and deltamethrin of a DmNav variant expressed in Xenopus oocytes. Computer modeling predicts that the I265N mutation confers pyrethroid resistance by allosterically altering the second pyrethroid receptor site on the DmNav channel. Furthermore, we found that I265N-mediated pyrethroid resistance in parats1 mutant flies was almost completely abolished in parats1;DSC1−/− double mutant flies. Unexpectedly, however, the DSC1 knockout flies were less sensitive to DDT, compared to the control flies (w1118A), and the parats1;DSC1−/− double mutant flies were even more resistant to DDT compared to the DSC1 knockout or parats1 mutant. Our findings revealed distinct roles of the DmNav and DSC1 channels in the neurotoxicology of DDT vs. pyrethroids and implicate the exciting possibility of using DSC1 channel blockers or modifiers in the management of pyrethroid resistance. PMID:25687544

Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids.

PubMed

Rinkevich, Frank D; Du, Yuzhe; Tolinski, Josh; Ueda, Atsushi; Wu, Chun-Fang; Zhorov, Boris S; Dong, Ke

2015-03-01

Voltage-gated sodium channels (Nav channels) are critical for electrical signaling in the nervous system and are the primary targets of the insecticides DDT and pyrethroids. In Drosophila melanogaster, besides the canonical Nav channel, Para (also called DmNav), there is a sodium channel-like cation channel called DSC1 (Drosophila sodium channel 1). Temperature-sensitive paralytic mutations in DmNav (para(ts)) confer resistance to DDT and pyrethroids, whereas DSC1 knockout flies exhibit enhanced sensitivity to pyrethroids. To further define the roles and interaction of DmNav and DSC1 channels in DDT and pyrethroid neurotoxicology, we generated a DmNav/DSC1 double mutant line by introducing a para(ts1) allele (carrying the I265N mutation) into a DSC1 knockout line. We confirmed that the I265N mutation reduced the sensitivity to two pyrethroids, permethrin and deltamethrin of a DmNav variant expressed in Xenopus oocytes. Computer modeling predicts that the I265N mutation confers pyrethroid resistance by allosterically altering the second pyrethroid receptor site on the DmNav channel. Furthermore, we found that I265N-mediated pyrethroid resistance in para(ts1) mutant flies was almost completely abolished in para(ts1);DSC1(-/-) double mutant flies. Unexpectedly, however, the DSC1 knockout flies were less sensitive to DDT, compared to the control flies (w(1118A)), and the para(ts1);DSC1(-/-) double mutant flies were even more resistant to DDT compared to the DSC1 knockout or para(ts1) mutant. Our findings revealed distinct roles of the DmNav and DSC1 channels in the neurotoxicology of DDT vs. pyrethroids and implicate the exciting possibility of using DSC1 channel blockers or modifiers in the management of pyrethroid resistance. Copyright © 2015 Elsevier Inc. All rights reserved.

Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway

PubMed Central

Li, Shao; Wang, Xi; Ma, Quan-Hong; Yang, Wu-lin; Zhang, Xiao-Gang; Dawe, Gavin S.; Xiao, Zhi-Cheng

2016-01-01

Amyloid precursor protein (APP), commonly associated with Alzheimer’s disease, also marks axonal degeneration. In the recent studies, we demonstrated that APP aggregated at nodes of Ranvier (NORs) in myelinated central nervous system (CNS) axons and interacted with Nav1.6. However, the physiological function of APP remains unknown. In this study, we described reduced sodium current densities in APP knockout hippocampal neurons. Coexpression of APP or its intracellular domains containing a VTPEER motif with Nav1.6 sodium channels in Xenopus oocytes resulted in an increase in peak sodium currents, which was enhanced by constitutively active Go mutant and blocked by a dominant negative mutant. JNK and CDK5 inhibitor attenuated increases in Nav1.6 sodium currents induced by overexpression of APP. Nav1.6 sodium currents were increased by APPT668E (mutant Thr to Glu) and decreased by T668A (mutant Thr to ALa) mutant, respectively. The cell surface expression of Nav1.6 sodium channels in the white matter of spinal cord and the spinal conduction velocity is decreased in APP, p35 and JNK3 knockout mice. Therefore, APP modulates Nav1.6 sodium channels through a Go-coupled JNK pathway, which is dependent on phosphorylation of APP at Thr668. PMID:28008944

Inhibition of human Na(v)1.5 sodium channels by strychnine and its analogs.

PubMed

Yuan, Chunhua; Sun, Lirong; Zhang, Meng; Li, Shuji; Wang, Xuemin; Gao, Tianming; Zhu, Xinhong

2011-08-15

Strychnine and brucine from the seeds of the plant Strychnos nux vomica have been shown to have interesting pharmacological effects on several neurotransmitter receptors. In this study, we have characterized the pharmacological properties of strychnine and its analogs on human Na(v)1.5 channels to assess their potential therapeutic advantage in certain arrhythmias. Among the eight alkaloids, only strychnine and icajine exhibited inhibition potency on the Na(v)1.5 channel with the half-maximum inhibition (IC(50)) values of 83.1μM and 104.6μM, respectively. Structure-function analysis indicated that the increased bulky methoxy groups on the phenyl ring or the negatively charged oxygen atom may account for this lack of inhibition on the Na(v)1.5 channel. Strychnine and icajine may bind to the channel by cation-π interactions. The substitution with a large side chain on the phenyl ring or the increased molecular volume may alter the optimized position for the compound close to the binding sites of the channel. Strychnine and icajine bind to the Na(v)1.5 channel with a new mechanism that is different from TTX and local anesthetics. They bind to the outer vestibule of the channel pore with fast association and dissociation rates at resting state. Strychnine and icajine had little effect on steady-state fast inactivation but markedly shifted the slow inactivation of Na(v)1.5 currents toward more hyperpolarized potentials. The property of icajine influencing slow-inactivated state of Na(v)1.5 channel would be potential therapeutic advantages in certain arrhythmias. Copyright © 2011 Elsevier Inc. All rights reserved.

Folding similarity of the outer pore region in prokaryotic and eukaryotic sodium channels revealed by docking of conotoxins GIIIA, PIIIA, and KIIIA in a NavAb-based model of Nav1.4

PubMed Central

Korkosh, Viacheslav S.; Zhorov, Boris S.

2014-01-01

Voltage-gated sodium channels are targets for many drugs and toxins. However, the rational design of medically relevant channel modulators is hampered by the lack of x-ray structures of eukaryotic channels. Here, we used a homology model based on the x-ray structure of the NavAb prokaryotic sodium channel together with published experimental data to analyze interactions of the μ-conotoxins GIIIA, PIIIA, and KIIIA with the Nav1.4 eukaryotic channel. Using Monte Carlo energy minimizations and published experimentally defined pairwise contacts as distance constraints, we developed a model in which specific contacts between GIIIA and Nav1.4 were readily reproduced without deformation of the channel or toxin backbones. Computed energies of specific interactions between individual residues of GIIIA and the channel correlated with experimental estimates. The predicted complexes of PIIIA and KIIIA with Nav1.4 are consistent with a large body of experimental data. In particular, a model of Nav1.4 interactions with KIIIA and tetrodotoxin (TTX) indicated that TTX can pass between Nav1.4 and channel-bound KIIIA to reach its binding site at the selectivity filter. Our models also allowed us to explain experimental data that currently lack structural interpretations. For instance, consistent with the incomplete block observed with KIIIA and some GIIIA and PIIIA mutants, our computations predict an uninterrupted pathway for sodium ions between the extracellular space and the selectivity filter if at least one of the four outer carboxylates is not bound to the toxin. We found a good correlation between computational and experimental data on complete and incomplete channel block by native and mutant toxins. Thus, our study suggests similar folding of the outer pore region in eukaryotic and prokaryotic sodium channels. PMID:25156117

Human Nav1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons

PubMed Central

Han, Chongyang; Estacion, Mark; Huang, Jianying; Vasylyev, Dymtro; Zhao, Peng; Dib-Hajj, Sulayman D.

2015-01-01

Although species-specific differences in ion channel properties are well-documented, little has been known about the properties of the human Nav1.8 channel, an important contributor to pain signaling. Here we show, using techniques that include voltage clamp, current clamp, and dynamic clamp in dorsal root ganglion (DRG) neurons, that human Nav1.8 channels display slower inactivation kinetics and produce larger persistent current and ramp current than previously reported in other species. DRG neurons expressing human Nav1.8 channels unexpectedly produce significantly longer-lasting action potentials, including action potentials with half-widths in some cells >10 ms, and increased firing frequency compared with the narrower and usually single action potentials generated by DRG neurons expressing rat Nav1.8 channels. We also show that native human DRG neurons recapitulate these properties of Nav1.8 current and the long-lasting action potentials. Together, our results demonstrate strikingly distinct properties of human Nav1.8, which contribute to the firing properties of human DRG neurons. PMID:25787950

A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief

PubMed Central

Lee, Jun-Ho; Park, Chul-Kyu; Chen, Gang; Han, Qingjian; Xie, Rou-Gang; Liu, Tong; Ji, Ru-Rong; Lee, Seok-Yong

2014-01-01

Summary Voltage-gated sodium (NaV) channels control the upstroke of the action potentials in excitable cells. Multiple studies have shown distinct roles of NaV channel subtypes in human physiology and diseases, but subtype-specific therapeutics are lacking and the current efforts have been limited to small molecules. Here we present a monoclonal antibody that targets the voltage-sensor paddle of NaV1.7, the subtype critical for pain sensation. This antibody not only inhibits NaV1.7 with high selectivity but also effectively suppresses inflammatory and neuropathic pain in mice. Interestingly, the antibody inhibits acute and chronic itch, despite well-documented differences in pain and itch modulation. Using this antibody, we discovered that NaV1.7 plays a key role in spinal cord nociceptive and pruriceptive synaptic transmission. Our studies reveal that NaV1.7 is a target for itch management and the antibody has therapeutic potential for suppressing pain and itch. Our antibody strategy may have broad applications for voltage-gated cation channels. PMID:24856969

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release

PubMed Central

Estacion, Mark; Turner, Jamie; Mis, Malgorzata A.; Wilbrey, Anna; Payne, Elizabeth C.; Gutteridge, Alex; Cox, Peter J.; Doyle, Rachel; Printzenhoff, David; Lin, Zhixin; Marron, Brian E.; West, Christopher; Swain, Nigel A.; Storer, R. Ian; Stupple, Paul A.; Castle, Neil A.; Hounshell, James A.; Rivara, Mirko; Randall, Andrew; Dib-Hajj, Sulayman D.; Krafte, Douglas; Waxman, Stephen G.; Patel, Manoj K.; Butt, Richard P.; Stevens, Edward B.

2016-01-01

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7’s role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission. PMID:27050761

The Role of Nav1.9 Channel in the Development of Neuropathic Orofacial Pain Associated with Trigeminal Neuralgia.

PubMed

Lulz, Ana Paula; Kopach, Olga; Santana-Varela, Sonia; Wood, John N

2015-01-01

Trigeminal neuralgia is accompanied by severe mechanical, thermal and chemical hypersensitivity of the orofacial area innervated by neurons of trigeminal ganglion (TG). We examined the role of the voltage-gated sodium channel subtype Nav1.9 in the development of trigeminal neuralgia. We found that Nav1.9 is required for the development of both thermal and mechanical hypersensitivity induced by constriction of the infraorbital nerve (CION). The CION model does not induce change on Nav1.9 mRNA expression in the ipsilateral TG neurons when evaluated 9 days after surgery. These results demonstrate that Nav1.9 channels play a critical role in the development of orofacial neuropathic pain. New routes for the treatment of orofacial neuropathic pain focussing on regulation of the voltage-gated Nav1.9 sodium channel activity should be investigated. © 2015 Luiz et al.

Fluoxetine Blocks Nav1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

PubMed Central

Poulin, Hugo; Bruhova, Iva; Timour, Quadiri; Theriault, Olivier; Beaulieu, Jean-Martin; Frassati, Dominique

2014-01-01

The voltage-gated Nav1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. Our study investigated the Nav1.5 blocking properties of fluoxetine, a selective serotonin reuptake inhibitor. Nav1.5 channels were expressed in HEK-293 cells, and Na+ currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC50 = 39 μM) and its optical isomers had a similar IC50 [40 and 47 μM for the (+) and (−) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 μM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Nav1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating Nav1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Nav1.5 was in agreement with mutational experiments in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Nav1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na+ channels should be taken into consideration when prescribing fluoxetine alone or in association with other drugs that may be cardiotoxic or for patients with conduction disorders. PMID:25028482

A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients

PubMed Central

Sun, Yishan; Paşca, Sergiu P; Portmann, Thomas; Goold, Carleton; Worringer, Kathleen A; Guan, Wendy; Chan, Karen C; Gai, Hui; Vogt, Daniel; Chen, Ying-Jiun J; Mao, Rong; Chan, Karrie; Rubenstein, John LR; Madison, Daniel V; Hallmayer, Joachim; Froehlich-Santino, Wendy M; Bernstein, Jonathan A; Dolmetsch, Ricardo E

2016-01-01

Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Nav1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons. DOI: http://dx.doi.org/10.7554/eLife.13073.001 PMID:27458797

ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors.

PubMed

Schmalhofer, William A; Calhoun, Jeffrey; Burrows, Rachel; Bailey, Timothy; Kohler, Martin G; Weinglass, Adam B; Kaczorowski, Gregory J; Garcia, Maria L; Koltzenburg, Martin; Priest, Birgit T

2008-11-01

Voltage-gated sodium (Na(V)1) channels play a critical role in modulating the excitability of sensory neurons, and human genetic evidence points to Na(V)1.7 as an essential contributor to pain signaling. Human loss-of-function mutations in SCN9A, the gene encoding Na(V)1.7, cause channelopathy-associated indifference to pain (CIP), whereas gain-of-function mutations are associated with two inherited painful neuropathies. Although the human genetic data make Na(V)1.7 an attractive target for the development of analgesics, pharmacological proof-of-concept in experimental pain models requires Na(V)1.7-selective channel blockers. Here, we show that the tarantula venom peptide ProTx-II selectively interacts with Na(V)1.7 channels, inhibiting Na(V)1.7 with an IC(50) value of 0.3 nM, compared with IC(50) values of 30 to 150 nM for other heterologously expressed Na(V)1 subtypes. This subtype selectivity was abolished by a point mutation in DIIS3. It is interesting that application of ProTx-II to desheathed cutaneous nerves completely blocked the C-fiber compound action potential at concentrations that had little effect on Abeta-fiber conduction. ProTx-II application had little effect on action potential propagation of the intact nerve, which may explain why ProTx-II was not efficacious in rodent models of acute and inflammatory pain. Mono-iodo-ProTx-II ((125)I-ProTx-II) binds with high affinity (K(d) = 0.3 nM) to recombinant hNa(V)1.7 channels. Binding of (125)I-ProTx-II is insensitive to the presence of other well characterized Na(V)1 channel modulators, suggesting that ProTx-II binds to a novel site, which may be more conducive to conferring subtype selectivity than the site occupied by traditional local anesthetics and anticonvulsants. Thus, the (125)I-ProTx-II binding assay, described here, offers a new tool in the search for novel Na(V)1.7-selective blockers.

Modeling the human Nav1.5 sodium channel: structural and mechanistic insights of ion permeation and drug blockade

PubMed Central

Ahmed, Marawan; Jalily Hasani, Horia; Ganesan, Aravindhan; Houghton, Michael; Barakat, Khaled

2017-01-01

Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer. Our model was comprehensively validated by using reported mutagenesis data, comparisons with previous models, and binding to a panel of known hNav1.5 blockers. The relatively long classical MD simulation was sufficient to observe a natural sodium permeation event across the channel’s selectivity filters to reach the channel’s central cavity, together with the identification of a unique role of the lysine residue. Electrostatic potential calculations revealed the existence of two potential binding sites for the sodium ion at the outer selectivity filters. To obtain further mechanistic insight into the permeation event from the central cavity to the intracellular region of the channel, we further employed “state-of-the-art” steered molecular dynamics (SMD) simulations. Our SMD simulations revealed two different pathways through which a sodium ion can be expelled from the channel. Further, the SMD simulations identified the key residues that are likely to control these processes. Finally, we discuss the potential binding modes of a panel of known hNav1.5 blockers to our structural model of hNav1.5. We believe that the data presented here will enhance our understanding of the structure–property relationships of the hNav1.5 ion channel and the underlying molecular mechanisms in sodium ion permeation and drug interactions. The results presented here could be useful for designing safer drugs that do not block the hNav1.5 channel

Human Na(v)1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons.

PubMed

Han, Chongyang; Estacion, Mark; Huang, Jianying; Vasylyev, Dymtro; Zhao, Peng; Dib-Hajj, Sulayman D; Waxman, Stephen G

2015-05-01

Although species-specific differences in ion channel properties are well-documented, little has been known about the properties of the human Nav1.8 channel, an important contributor to pain signaling. Here we show, using techniques that include voltage clamp, current clamp, and dynamic clamp in dorsal root ganglion (DRG) neurons, that human Na(v)1.8 channels display slower inactivation kinetics and produce larger persistent current and ramp current than previously reported in other species. DRG neurons expressing human Na(v)1.8 channels unexpectedly produce significantly longer-lasting action potentials, including action potentials with half-widths in some cells >10 ms, and increased firing frequency compared with the narrower and usually single action potentials generated by DRG neurons expressing rat Na(v)1.8 channels. We also show that native human DRG neurons recapitulate these properties of Na(v)1.8 current and the long-lasting action potentials. Together, our results demonstrate strikingly distinct properties of human Na(v)1.8, which contribute to the firing properties of human DRG neurons.

NAVS Alternatives Set the Standard for Humane Education.

ERIC Educational Resources Information Center

Petty, Linda

1997-01-01

Describes some alternatives to dissection offered to teachers through the National Anti-Vivisection Society (NAVS) and other sources. These include models, CD-ROMs, and software that enable students to click on scalpels, scissors, and other instruments to cut through videotaped specimens. Also details the Dissection Hotline and the Dissection…

Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway.

PubMed

Li, Shao; Wang, Xi; Ma, Quan-Hong; Yang, Wu-Lin; Zhang, Xiao-Gang; Dawe, Gavin S; Xiao, Zhi-Cheng

2016-12-23

Amyloid precursor protein (APP), commonly associated with Alzheimer's disease, also marks axonal degeneration. In the recent studies, we demonstrated that APP aggregated at nodes of Ranvier (NORs) in myelinated central nervous system (CNS) axons and interacted with Nav1.6. However, the physiological function of APP remains unknown. In this study, we described reduced sodium current densities in APP knockout hippocampal neurons. Coexpression of APP or its intracellular domains containing a VTPEER motif with Na v 1.6 sodium channels in Xenopus oocytes resulted in an increase in peak sodium currents, which was enhanced by constitutively active Go mutant and blocked by a dominant negative mutant. JNK and CDK5 inhibitor attenuated increases in Nav1.6 sodium currents induced by overexpression of APP. Nav1.6 sodium currents were increased by APPT668E (mutant Thr to Glu) and decreased by T668A (mutant Thr to ALa) mutant, respectively. The cell surface expression of Nav1.6 sodium channels in the white matter of spinal cord and the spinal conduction velocity is decreased in APP, p35 and JNK3 knockout mice. Therefore, APP modulates Nav1.6 sodium channels through a Go-coupled JNK pathway, which is dependent on phosphorylation of APP at Thr668.

Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V.

PubMed

Moyer, Bryan D; Murray, Justin K; Ligutti, Joseph; Andrews, Kristin; Favreau, Philippe; Jordan, John B; Lee, Josie H; Liu, Dong; Long, Jason; Sham, Kelvin; Shi, Licheng; Stöcklin, Reto; Wu, Bin; Yin, Ruoyuan; Yu, Violeta; Zou, Anruo; Biswas, Kaustav; Miranda, Les P

2018-01-01

Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C-fibers.

Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V

PubMed Central

Murray, Justin K.; Ligutti, Joseph; Andrews, Kristin; Favreau, Philippe; Jordan, John B.; Lee, Josie H.; Liu, Dong; Long, Jason; Sham, Kelvin; Shi, Licheng; Stöcklin, Reto; Wu, Bin; Yin, Ruoyuan; Yu, Violeta; Zou, Anruo; Biswas, Kaustav; Miranda, Les P.

2018-01-01

Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C

The neonatal splice variant of Nav1.5 potentiates in vitro invasive behaviour of MDA-MB-231 human breast cancer cells

PubMed Central

Brackenbury, William J.; Chioni, Athina-Myrto; Diss, James K. J.; Djamgoz, Mustafa B. A.

2014-01-01

Upregulation of functional voltage-gated Na+ channels (VGSCs) occurs in metastatic human breast cancer (BCa) in vitro and in vivo. The present study aimed to ascertain the specific involvement of the ‘neonatal’ splice variant of Nav1.5 (nNav1.5), thought to be predominant, in the VGSC-dependent invasive behaviour of MDA-MB-231 cells. Functional activity of nNav1.5 was suppressed by two different methods targeting nNav1.5: (i) small interfering RNA (siRNA), and (ii) a polyclonal antibody (NESO-pAb); effects upon migration and invasion were determined. nNav1.5 mRNA, protein and signalling were measured using real-time PCR, Western blotting, and patch clamp recording, respectively. Treatment with the siRNA rapidly reduced (by ~90 %) the level of nNav1.5 (but not adult Nav1.5) mRNA, but the protein reduction was much smaller (~30 %), even after 13 days. Nevertheless, the siRNA reduced peak VGSC current density by 33 %, and significantly increased the cells’ sensitivity to nanomolar tetrodotoxin (TTX). Importantly, the siRNA suppressed in vitro migration by 43 %, and eliminated the normally inhibitory effect of TTX. Migrated MDA-MB-231 cells expressed more nNav1.5 protein at the plasma membrane than non-migrated cells. Furthermore, NESO-pAb reduced migration by up to 42 %, in a dose-dependent manner. NESO-pAb also reduced Matrigel invasion without affecting proliferation. TTX had no effect on cells already treated with NESO-pAb. It was concluded that nNav1.5 is primarily responsible for the VGSC-dependent enhancement of invasive behaviour in MDA-MB-231 cells. Accordingly, targeting nNav1.5 expression/activity may be useful in clinical management of metastatic BCa. PMID:16838113

KIN-Nav navigation system for kinematic assessment in anterior cruciate ligament reconstruction: features, use, and perspectives.

PubMed

Martelli, S; Zaffagnini, S; Bignozzi, S; Lopomo, N F; Iacono, F; Marcacci, M

2007-10-01

In this paper a new navigation system, KIN-Nav, developed for research and used during 80 anterior cruciate ligament (ACL) reconstructions is described. KIN-Nav is a user-friendly navigation system for flexible intraoperative acquisitions of anatomical and kinematic data, suitable for validation of biomechanical hypotheses. It performs real-time quantitative evaluation of antero-posterior, internal-external, and varus-valgus knee laxity at any degree of flexion and provides a new interface for this task, suitable also for comparison of pre-operative and post-operative knee laxity and surgical documentation. In this paper the concept and features of KIN-Nav, which represents a new approach to navigation and allows the investigation of new quantitative measurements in ACL reconstruction, are described. Two clinical studies are reported, as examples of clinical potentiality and correct use of this methodology. In this paper a preliminary analysis of KIN-Nav's reliability and clinical efficacy, performed during blinded repeated measures by three independent examiners, is also given. This analysis is the first assessment of the potential of navigation systems for evaluating knee kinematics.

β1 subunit stabilises sodium channel Nav1.7 against mechanical stress.

PubMed

Körner, Jannis; Meents, Jannis; Machtens, Jan-Philipp; Lampert, Angelika

2018-06-01

The voltage-gated sodium channel Nav1.7 is a key player in neuronal excitability and pain signalling. In addition to voltage sensing, the channel is also modulated by mechanical stress. Using whole-cell patch-clamp experiments, we discovered that the sodium channel subunit β1 is able to prevent the impact of mechanical stress on Nav1.7. An intramolecular disulfide bond of β1 was identified to be essential for stabilisation of inactivation, but not activation, against mechanical stress using molecular dynamics simulations, homology modelling and site-directed mutagenesis. Our results highlight the role of segment 6 of domain IV in fast inactivation. We present a candidate mechanism for sodium channel stabilisation against mechanical stress, ensuring reliable channel functionality in living systems. Voltage-gated sodium channels are key players in neuronal excitability and pain signalling. Precise gating of these channels is crucial as even small functional alterations can lead to pathological phenotypes such as pain or heart failure. Mechanical stress has been shown to affect sodium channel activation and inactivation. This suggests that stabilising components are necessary to ensure precise channel gating in living organisms. Here, we show that mechanical shear stress affects voltage dependence of activation and fast inactivation of the Nav1.7 channel. Co-expression of the β1 subunit, however, protects both gating modes of Nav1.7 against mechanical shear stress. Using molecular dynamics simulation, homology modelling and site-directed mutagenesis, we identify an intramolecular disulfide bond of β1 (Cys21-Cys43) which is partially involved in this process: the β1-C43A mutant prevents mechanical modulation of voltage dependence of activation, but not of fast inactivation. Our data emphasise the unique role of segment 6 of domain IV for sodium channel fast inactivation and confirm previous reports that the intracellular process of fast inactivation can be

Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy

PubMed Central

Blesneac, Iulia; Themistocleous, Andreas C.; Fratter, Carl; Conrad, Linus J.; Ramirez, Juan D.; Cox, James J.; Tesfaye, Solomon; Shillo, Pallai R.; Rice, Andrew S.C.; Tucker, Stephen J.

2018-01-01

Abstract Diabetic peripheral neuropathy (DPN) is a common disabling complication of diabetes. Almost half of the patients with DPN develop neuropathic pain (NeuP) for which current analgesic treatments are inadequate. Understanding the role of genetic variability in the development of painful DPN is needed for improved understanding of pain pathogenesis for better patient stratification in clinical trials and to target therapy more appropriately. Here, we examined the relationship between variants in the voltage-gated sodium channel NaV1.7 and NeuP in a deeply phenotyped cohort of patients with DPN. Although no rare variants were found in 78 participants with painless DPN, we identified 12 rare NaV1.7 variants in 10 (out of 111) study participants with painful DPN. Five of these variants had previously been described in the context of other NeuP disorders and 7 have not previously been linked to NeuP. Those patients with rare variants reported more severe pain and greater sensitivity to pressure stimuli on quantitative sensory testing. Electrophysiological characterization of 2 of the novel variants (M1852T and T1596I) demonstrated that gain of function changes as a consequence of markedly impaired channel fast inactivation. Using a structural model of NaV1.7, we were also able to provide further insight into the structural mechanisms underlying fast inactivation and the role of the C-terminal domain in this process. Our observations suggest that rare NaV1.7 variants contribute to the development NeuP in patients with DPN. Their identification should aid understanding of sensory phenotype, patient stratification, and help target treatments effectively. PMID:29176367

Reactive species modify NaV1.8 channels and affect action potentials in murine dorsal root ganglia neurons

PubMed Central

Schink, Martin; Leipolcf, Enrico; Schirmeyer, Jana; Schönherr, Roland; Hoshi, Toshinori; Heinemann, Stefan H.

2016-01-01

Dorsal root ganglia (DRG) neurons are important relay stations between the periphery and the central nervous system and are essential for somatosensory signaling. Reactive species are produced in a variety of physiological and pathophysiological conditions and are known to alter electric signaling. Here we studied the influence of reactive species on the electrical properties of DRG neurons from mice with the whole-cell patch-clamp method. Even mild stress induced by either low concentrations of chloramine-T (10 µM) or low-intensity blue-light irradiation profoundly diminished action potential frequency but prolonged single action potentials in wild-type neurons. The impact on evoked action potentials was much smaller in neurons deficient of the tetrodotoxin (TTX)-resistant voltage-gated sodium channel NaV1.8 (NaV1.8−/−), the channel most important for the action potential upstroke in DRG neurons. Low concentrations of chloramine-T caused a significant reduction of NaV1.8 peak current and at higher concentrations progressively slowed down inactivation. Blue light had a smaller effect on amplitude but slowed down NaV1.8 channel inactivation. The observed effects were less apparent for TTX-sensitive NaV channels. NaV1.8 is an important reactive-species-sensitive component in the electrical signaling of DRG neurons, potentially giving rise to loss-of-function and gain-of-function phenomena depending on the type of reactive species and their effective concentration and time of exposure. PMID:26383867

Reactive species modify NaV1.8 channels and affect action potentials in murine dorsal root ganglion neurons.

PubMed

Schink, Martin; Leipold, Enrico; Schirmeyer, Jana; Schönherr, Roland; Hoshi, Toshinori; Heinemann, Stefan H

2016-01-01

Dorsal root ganglion (DRG) neurons are important relay stations between the periphery and the central nervous system and are essential for somatosensory signaling. Reactive species are produced in a variety of physiological and pathophysiological conditions and are known to alter electric signaling. Here we studied the influence of reactive species on the electrical properties of DRG neurons from mice with the whole-cell patch-clamp method. Even mild stress induced by either low concentrations of chloramine-T (10 μM) or low-intensity blue light irradiation profoundly diminished action potential frequency but prolonged single action potentials in wild-type neurons. The impact on evoked action potentials was much smaller in neurons deficient of the tetrodotoxin (TTX)-resistant voltage-gated sodium channel NaV1.8 (NaV1.8(-/-)), the channel most important for the action potential upstroke in DRG neurons. Low concentrations of chloramine-T caused a significant reduction of NaV1.8 peak current and, at higher concentrations, progressively slowed down inactivation. Blue light had a smaller effect on amplitude but slowed down NaV1.8 channel inactivation. The observed effects were less apparent for TTX-sensitive NaV channels. NaV1.8 is an important reactive-species-sensitive component in the electrical signaling of DRG neurons, potentially giving rise to loss-of-function and gain-of-function phenomena depending on the type of reactive species and their effective concentration and time of exposure.

Mars Comm/Nav MicroSat Network Using the Multi-Mission Bus Launched Piggyback by Ariane 5

NASA Technical Reports Server (NTRS)

Hastrup, R. C.; Cesarone, R. J.; Morabito, D. D.

1999-01-01

Recently, NASA's Jet Propulsion Laboratory completed a Mars Exploration Program Architecture Definition Study with strong international participation. The recommendations of this study include establishment of a low cost in-situ communications and navigation satellite network to provide enabling and enhancing support for the international exploration of Mars. This would be the first step toward establishing a "virtual presence throughout the solar system" as called for in NASA's Strategic Plan. Response to the proposed comm/nav satellite network has been very favorably received, as reflected by the inclusion of a line item in NASA's budget submittal to Congress, which provides funding for implementation of the network with first launch in the 2003 opportunity. Funding has already been provided for a phase A study being conducted this year. This paper presents the planned implementation of the comm/nav network, which will utilize microsats based on a multi-mission spacecraft bus being designed for launch by the Ariane 5 as a secondary payload. A companion paper at this conference, entitled "The Multi-Purpose Mars Micro-Mission System Design Utilizing Ariane 5 Piggyback Launch", describes the multimission bus design. This paper addresses the application of the multi-mission bus to the comm/nav microsat mission. Following an introduction, which provides the background that has led to the proposed comm/nav network, the paper discusses the projected user needs with emphasis on the various possible robotic missions (landers, rovers, ascent vehicles, balloons, aircraft, etc.) progressing toward eventual piloted missions. Next, the paper describes the concept for an evolving network of comm/nav microsats and the expected capability to satisfy the user needs. Results of communications and navigation performance analysis are summarized for attractive satellite constellation configurations. The important comm/nav microsat functional requirements on the multi

Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin.

PubMed

Zhao, Fang; Li, Xichun; Jin, Liang; Zhang, Fan; Inoue, Masayuki; Yu, Boyang; Cao, Zhengyu

2016-02-16

Voltage-gated sodium channels (VGSCs) are responsible for the generation of the action potential. Among nine classified VGSC subtypes (Nav1.1-Nav1.9), Nav1.7 is primarily expressed in the sensory neurons, contributing to the nociception transmission. Therefore Nav1.7 becomes a promising target for analgesic drug development. In this study, we compared the influence of an array of VGSC agonists including veratridine, BmK NT1, brevetoxin-2, deltamethrin and antillatoxin (ATX) on membrane depolarization which was detected by Fluorescence Imaging Plate Reader (FLIPR) membrane potential (FMP) blue dye. In HEK-293 cells heterologously expressing hNav1.7 α-subunit, ATX produced a robust membrane depolarization with an EC50 value of 7.8 ± 2.9 nM whereas veratridine, BmK NT1, and deltamethrin produced marginal response. Brevetoxin-2 was without effect on membrane potential change. The ATX response was completely inhibited by tetrodotoxin suggesting that the ATX response was solely derived from hNav1.7 activation, which was consistent with the results where ATX produced a negligible response in null HEK-293 cells. Six VGSC antagonists including lidocaine, lamotrigine, phenytoin, carbamazepine, riluzole, and 2-amino-6-trifluoromethylthiobenzothiazole all concentration-dependently inhibited ATX response with IC50 values comparable to that reported from patch-clamp experiments. Considered together, we demonstrate that ATX is a unique efficacious hNav1.7 activator which offers a useful probe to develop a rapid throughput screening assay to identify hNav1.7 antagonists.

Development of a Rapid Throughput Assay for Identification of hNav1.7 Antagonist Using Unique Efficacious Sodium Channel Agonist, Antillatoxin

PubMed Central

Zhao, Fang; Li, Xichun; Jin, Liang; Zhang, Fan; Inoue, Masayuki; Yu, Boyang; Cao, Zhengyu

2016-01-01

Voltage-gated sodium channels (VGSCs) are responsible for the generation of the action potential. Among nine classified VGSC subtypes (Nav1.1–Nav1.9), Nav1.7 is primarily expressed in the sensory neurons, contributing to the nociception transmission. Therefore Nav1.7 becomes a promising target for analgesic drug development. In this study, we compared the influence of an array of VGSC agonists including veratridine, BmK NT1, brevetoxin-2, deltamethrin and antillatoxin (ATX) on membrane depolarization which was detected by Fluorescence Imaging Plate Reader (FLIPR) membrane potential (FMP) blue dye. In HEK-293 cells heterologously expressing hNav1.7 α-subunit, ATX produced a robust membrane depolarization with an EC50 value of 7.8 ± 2.9 nM whereas veratridine, BmK NT1, and deltamethrin produced marginal response. Brevetoxin-2 was without effect on membrane potential change. The ATX response was completely inhibited by tetrodotoxin suggesting that the ATX response was solely derived from hNav1.7 activation, which was consistent with the results where ATX produced a negligible response in null HEK-293 cells. Six VGSC antagonists including lidocaine, lamotrigine, phenytoin, carbamazepine, riluzole, and 2-amino-6-trifluoromethylthiobenzothiazole all concentration-dependently inhibited ATX response with IC50 values comparable to that reported from patch-clamp experiments. Considered together, we demonstrate that ATX is a unique efficacious hNav1.7 activator which offers a useful probe to develop a rapid throughput screening assay to identify hNav1.7 antagonists. PMID:26891306

A novel NaV1.5 voltage sensor mutation associated with severe atrial and ventricular arrhythmias.

PubMed

Wang, Hong-Gang; Zhu, Wandi; Kanter, Ronald J; Silva, Jonathan R; Honeywell, Christina; Gow, Robert M; Pitt, Geoffrey S

2016-03-01

Inherited autosomal dominant mutations in cardiac sodium channels (NaV1.5) cause various arrhythmias, such as long QT syndrome and Brugada syndrome. Although dozens of mutations throughout the protein have been reported, there are few reported mutations within a voltage sensor S4 transmembrane segment and few that are homozygous. Here we report analysis of a novel lidocaine-sensitive recessive mutation, p.R1309H, in the NaV1.5 DIII/S4 voltage sensor in a patient with a complex arrhythmia syndrome. We expressed the wild type or mutant NaV1.5 heterologously for analysis with the patch-clamp and voltage clamp fluorometry (VCF) techniques. p.R1309H depolarized the voltage-dependence of activation, hyperpolarized the voltage-dependence of inactivation, and slowed recovery from inactivation, thereby reducing the channel availability at physiologic membrane potentials. Additionally, p.R1309H increased the "late" Na(+) current. The location of the mutation in DIIIS4 prompted testing for a gating pore current. We observed an inward current at hyperpolarizing voltages that likely exacerbates the loss-of-function defects at resting membrane potentials. Lidocaine reduced the gating pore current. The p.R1309H homozygous NaV1.5 mutation conferred both gain-of-function and loss-of-function effects on NaV1.5 channel activity. Reduction of a mutation-induced gating pore current by lidocaine suggested a therapeutic mechanism. Copyright © 2016 Elsevier Ltd. All rights reserved.

LandingNav: a precision autonomous landing sensor for robotic platforms on planetary bodies

NASA Astrophysics Data System (ADS)

Katake, Anup; Bruccoleri, Chrisitian; Singla, Puneet; Junkins, John L.

2010-01-01

Increased interest in the exploration of extra terrestrial planetary bodies calls for an increase in the number of spacecraft landing on remote planetary surfaces. Currently, imaging and radar based surveys are used to determine regions of interest and a safe landing zone. The purpose of this paper is to introduce LandingNav, a sensor system solution for autonomous landing on planetary bodies that enables landing on unknown terrain. LandingNav is based on a novel multiple field of view imaging system that leverages the integration of different state of the art technologies for feature detection, tracking, and 3D dense stereo map creation. In this paper we present the test flight results of the LandingNav system prototype. Sources of errors due to hardware limitations and processing algorithms were identified and will be discussed. This paper also shows that addressing the issues identified during the post-flight test data analysis will reduce the error down to 1-2%, thus providing for a high precision 3D range map sensor system.

NaV channel variants in patients with painful and nonpainful peripheral neuropathy

PubMed Central

Wadhawan, Samir; Pant, Saumya; Golhar, Ryan; Kirov, Stefan; Thompson, John; Jacobsen, Leslie; Qureshi, Irfan; Ajroud-Driss, Senda; Freeman, Roy; Simpson, David M.; Smith, A. Gordon; Hoke, Ahmet

2017-01-01

Objective: To examine the incidence of nonsynonymous missense variants in SCN9A (NaV1.7), SCN10A (NaV1.8), and SCN11A (NaV1.9) in patients with painful and nonpainful peripheral neuropathy. Methods: Next-generation sequencing was performed on 457 patient DNA samples provided by the Peripheral Neuropathy Research Registry (PNRR). The patient diagnosis was as follows: 278 idiopathic peripheral neuropathy (67% painful and 33% nonpainful) and 179 diabetic distal polyneuropathy (77% painful and 23% nonpainful). Results: We identified 36 (SCN9A), 31 (SCN10A), and 15 (SCN11A) nonsynonymous missense variants, with 47.7% of patients carrying a low-frequency (minor allele frequency <5%) missense variant in at least 1 gene. The incidence of previously reported gain-of-function missense variants was low (≤3%), and these were detected in patients with and without pain. There were no significant differences in missense variant allele frequencies of any gene, or SCN9A haplotype frequencies, between PNRR patients with painful or nonpainful peripheral neuropathy. PNRR patient SCN9A and SCN11A missense variant allele frequencies were not significantly different from the Exome Variant Server, European American (EVS-EA) reference population. For SCN10A, there was a significant increase in the alternate allele frequency of the common variant p.V1073A and low-frequency variant pS509P in PNRR patients compared with EVS-EA and the 1000 Genomes European reference populations. Conclusions: These results suggest that identification of a genetically defined subpopulation for testing of NaV1.7 inhibitors in patients with peripheral neuropathy is unlikely and that additional factors, beyond expression of previously reported disease “mutations,” are more important for the development of painful neuropathy than previously discussed. PMID:29264398

Fixative Composition Alters Distributions of Immunoreactivity for Glutaminase and Two Markers of Nociceptive Neurons, Nav1.8 and TRPV1, in the Rat Dorsal Root Ganglion

PubMed Central

Hoffman, E. Matthew; Schechter, Ruben; Miller, Kenneth E.

2010-01-01

Most, if not all, dorsal root ganglion (DRG) neurons use the neurotransmitter glutamate. There are, however, conflicting reports of the percentages of DRG neurons that express glutaminase (GLS), the enzyme that synthesizes glutamate, ranging from 30% to 100% of DRG neurons. Defining DRG neuron populations by the expression of proteins like GLS, which indicates function, is routinely accomplished with immunolabeling techniques. Proper characterization of DRG neuron populations relies on accurate detection of such antigens. It is known intuitively that fixation can alter immunoreactivity (IR). In this study, we compared the effects of five formaldehyde concentrations between 0.25% and 4.0% (w/v) and five picric acid concentrations between 0.0% and 0.8% (w/v) on the IR of GLS, the voltage-gated sodium channel 1.8 (Nav1.8), and the capsaicin receptor TRPV1. We also compared the effects of five incubation time lengths from 2 to 192 hr, in primary antiserum on IR. Lowering formaldehyde concentration elevated IR for all three antigens, while raising picric acid concentration increased Nav1.8 and TRPV1 IR. Increasing IR improved detection sensitivity, which led to higher percentages of labeled DRG neurons. By selecting fixation conditions that optimized IR, we found that all DRG neurons express GLS, 69% of neurons express Nav1.8, and 77% of neurons express TRPV1, indicating that some previous studies may have underestimated the percentages of DRG neurons expressing these proteins. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 58:329–344, 2010) PMID:20026672

FHF2 isoforms differentially regulate Nav1.6 mediated resurgent sodium currents in dorsal root ganglion neurons

PubMed Central

Barbosa, Cindy; Xiao, Yucheng; Johnson, Andrew J.; Xie, Wenrui; Strong, Judith A.; Zhang, Jun-Ming; Cummins, Theodore R.

2017-01-01

Nav1.6 and Nav1.6 mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6 mediated resurgent currents by isoforms of Fibroblast growth Factor Homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas, FHF2B enhances resurgent currents. Overall our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies. PMID:27999940

Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.

PubMed

Yang, Yang; Huang, Jianying; Mis, Malgorzata A; Estacion, Mark; Macala, Lawrence; Shah, Palak; Schulman, Betsy R; Horton, Daniel B; Dib-Hajj, Sulayman D; Waxman, Stephen G

2016-07-13

Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we have studied a newly identified Nav1.7 mutation, Ala1632Gly, from a multigeneration family with IEM. Structural modeling suggests that Ala1632 is a molecular hinge and that the Ala1632Gly mutation may affect channel gating. Voltage-clamp recordings revealed that the Nav1.7-A1632G mutation hyperpolarizes activation and depolarizes fast-inactivation, both gain-of-function attributes at the channel level. Whole-cell current-clamp recordings demonstrated increased spontaneous firing, lower current threshold, and enhanced evoked firing in rat DRG neurons expressing Nav1.7-A1632G mutant channels. Multielectrode array recordings further revealed that intact rat DRG neurons expressing Nav1.7-A1632G mutant channels are more active than those expressing Nav1.7 WT channels. We also showed that physiologically relevant thermal stimuli markedly increase the mean firing frequencies and the number of active rat DRG neurons expressing Nav1.7-A1632G mutant channels, whereas the same thermal stimuli only increase these parameters slightly in rat DRG neurons expressing Nav1.7 WT channels. The response of DRG neurons expressing Nav1.7-A1632G mutant channels upon increase in temperature suggests a cellular basis for warmth-triggered pain in IEM. Inherited erythromelalgia (IEM), a severe pain syndrome characterized by episodes of intense burning pain triggered by warmth, is caused by mutations in sodium channel Nav

High spectral resolution spectroscopy of the SiO fundamental lines in red giants and red supergiants with VLT/VISIR

NASA Astrophysics Data System (ADS)

Ohnaka, K.

2014-01-01

Context. The mass-loss mechanism in red giants and red supergiants is not yet understood well. The SiO fundamental lines near 8 μm are potentially useful for probing the outer atmosphere, which is essential for clarifying the mass-loss mechanism. However, these lines have been little explored until now. Aims: We present high spectral resolution spectroscopic observations of the SiO fundamental lines near 8.1 μm in 16 bright red giants and red supergiants. Our sample consists of seven normal (i.e., non-Mira) K-M giants (from K1.5 to M6.5), three Mira stars, three optically bright red supergiants, two dusty red supergiants, and the enigmatic object GCIRS3 near the Galactic center. Methods: Our program stars were observed between 8.088 μm and 8.112 μm with a spectral resolution of 30 000 using VLT/VISIR. Results: We detected SiO fundamental lines in all of our program stars except for GCIRS3. The SiO lines in normal K and M giants as well as optically bright (i.e., not dusty) red supergiants do not show P-Cyg profiles or blueshifts, which means the absence of systematic outflows in the SiO line forming region. We detected P-Cyg profiles in the SiO lines in the dusty red supergiants VY CMa and VX Sgr, with the latter object being a new detection. These SiO lines originate in the outflowing gas with the thermal dust continuum emission seen as the background. The outflow velocities of the SiO line forming region in VY CMa and VX Sgr are estimated to be 27 km s-1 and 17 km s-1, respectively. We derived basic stellar parameters (effective temperature, surface gravity, luminosity, and mass) for the normal K-M giants and optically bright red supergiants in our sample and compared the observed VISIR spectra with synthetic spectra predicted from MARCS photospheric models. Most of the SiO lines observed in the program stars warmer than ~3400 K are reasonably reproduced by the MARCS models, which allowed us to estimate the silicon abundance as well as the 28Si/29Si and 28Si

67P/CG morphological units and VIS-IR spectral classes: a Rosetta/VIRTIS-M perspective

NASA Astrophysics Data System (ADS)

Filacchione, Gianrico; Capaccioni, Fabrizio; Ciarniello, Mauro; Raponi, Andrea; De Sanctis, Maria Cristina; Tosi, Federico; Piccioni, Giuseppe; Cerroni, Priscilla; Capria, Maria Teresa; Palomba, Ernesto; Longobardo, Andrea; Migliorini, Alessandra; Erard, Stephane; Arnold, Gabriele; Bockelee-Morvan, Dominique; Leyrat, Cedric; Schmitt, Bernard; Quirico, Eric; Barucci, Antonella; McCord, Thomas B.; Stephan, Katrin; Kappel, David

2015-11-01

VIRTIS-M, the 0.25-5.1 µm imaging spectrometer on Rosetta (Coradini et al., 2007), has mapped the surface of 67P/CG nucleus since July 2014 from a wide range of distances. Spectral analysis of global scale data indicate that the nucleus presents different terrains uniformly covered by a very dark (Ciarniello et al., 2015) and dehydrated organic-rich material (Capaccioni et al., 2015). The morphological units identified so far (Thomas et al., 2015; El-Maarry et al., 2015) include dust-covered brittle materials regions (like Ash, Ma'at), exposed material regions (Seth), large-scale depressions (like Hatmehit, Aten, Nut), smooth terrains units (like Hapi, Anubis, Imhotep) and consolidated surfaces (like Hathor, Anuket, Aker, Apis, Khepry, Bastet, Maftet). For each of these regions average VIRTIS-M spectra were derived with the aim to explore possible connections between morphology and spectral properties. Photometric correction (Ciarniello et al., 2015), thermal emission removal in the 3.5-5 micron range and georeferencing have been applied to I/F data in order to derive spectral indicators, e.g. VIS-IR spectral slopes, their crossing wavelength (CW) and the 3.2 µm organic material band’s depth (BD), suitable to identify and map compositional variations. Our analysis shows that smooth terrains have the lower slopes in VIS (<1.7E-3 1/µm) and IR (0.4E-3 1/µm), CW=0.75 µm and BD=8-12%. Intermediate VIS slope=1.7-1.9E-3 1/µm, and higher BD=10-12.8%, are typical of consolidated surfaces, some dust covered regions and Seth where the maximum BD=13% has been observed. Large-scale depressions and Imhotep are redder with a VIS slope of 1.9-2.1E-3 1/µm, CW at 0.85-0.9 µm and BD=8-11%. The minimum VIS-IR slopes are observed above the Hapi, in agreement with the presence of water ice sublimation and recondensation processes observed by VIRTIS in this region (De Sanctis et al., 2015).Authors acknowledge ASI, CNES, DLR and NASA financial support.References:-Coradini et al

Structure and function of splice variants of the cardiac voltage-gated sodium channel Na(v)1.5.

PubMed

Schroeter, Annett; Walzik, Stefan; Blechschmidt, Steve; Haufe, Volker; Benndorf, Klaus; Zimmer, Thomas

2010-07-01

Voltage-gated sodium channels mediate the rapid upstroke of the action potential in excitable tissues. The tetrodotoxin (TTX) resistant isoform Na(v)1.5, encoded by the SCN5A gene, is the predominant isoform in the heart. This channel plays a key role for excitability of atrial and ventricular cardiomyocytes and for rapid impulse propagation through the specific conduction system. During recent years, strong evidence has been accumulated in support of the expression of several Na(v)1.5 splice variants in the heart, and in various other tissues and cell lines including brain, dorsal root ganglia, breast cancer cells and neuronal stem cell lines. This review summarizes our knowledge on the structure and putative function of nine Na(v)1.5 splice variants detected so far. Attention will be paid to the distinct biophysical properties of the four functional splice variants, to the pronounced tissue- and species-specific expression, and to the developmental regulation of Na(v)1.5 splicing. The implications of alternative splicing for SCN5A channelopathies, and for a better understanding of genotype-phenotype correlations, are discussed. Copyright 2010 Elsevier Ltd. All rights reserved.

Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation

PubMed Central

2011-01-01

Background Intrathecal lidocaine reverses tactile allodynia after nerve injury, but whether neuropathic pain is attenuated by intrathecal lidocaine pretreatment is uncertain. Methods Sixty six adult male Sprague-Dawley rats were divided into three treatment groups: (1) sham (Group S), which underwent removal of the L6 transverse process; (2) ligated (Group L), which underwent left L5 spinal nerve ligation (SNL); and (3) pretreated (Group P), which underwent L5 SNL and was pretreated with intrathecal 2% lidocaine (50 μl). Neuropathic pain was assessed based on behavioral responses to thermal and mechanical stimuli. Expression of sodium channels (Nav1.3 and Nav1.8) in injured dorsal root ganglia and microglial proliferation/activation in the spinal cord were measured on post-operative days 3 (POD3) and 7 (POD7). Results Group L presented abnormal behavioral responses indicative of mechanical allodynia and thermal hyperalgesia, exhibited up-regulation of Nav1.3 and down-regulation of Nav1.8, and showed increased microglial activation. Compared with ligation only, pretreatment with intrathecal lidocaine before nerve injury (Group P), as measured on POD3, palliated both mechanical allodynia (p < 0.01) and thermal hyperalgesia (p < 0.001), attenuated Nav1.3 up-regulation (p = 0.003), and mitigated spinal microglial activation (p = 0.026) by inhibiting phosphorylation (activation) of p38 MAP kinase (p = 0.034). p38 activation was also suppressed on POD7 (p = 0.002). Conclusions Intrathecal lidocaine prior to SNL blunts the response to noxious stimuli by attenuating Nav1.3 up-regulation and suppressing activation of spinal microglia. Although its effects are limited to 3 days, intrathecal lidocaine pretreatment can alleviate acute SNL-induced neuropathic pain. PMID:21676267

Synergetic Action of Domain II and IV Underlies Persistent Current Generation in Nav1.3 as revealed by a tarantula toxin

PubMed Central

Tang, Cheng; Zhou, Xi; Zhang, Yunxiao; xiao, Zhaohua; Hu, Zhaotun; Zhang, Changxin; Huang, Ying; Chen, Bo; Liu, Zhonghua; Liang, Songping

2015-01-01

The persistent current (INaP) through voltage-gated sodium channels enhances neuronal excitability by causing prolonged depolarization of membranes. Nav1.3 intrinsically generates a small INaP, although the mechanism underlying its generation remains unclear. In this study, the involvement of the four domains of Nav1.3 in INaP generation was investigated using the tarantula toxin α-hexatoxin-MrVII (RTX-VII). RTX-VII activated Nav1.3 and induced a large INaP. A pre-activated state binding model was proposed to explain the kinetics of toxin-channel interaction. Of the four domains of Nav1.3, both domain II and IV might play important roles in the toxin-induced INaP. Domain IV constructed the binding site for RTX-VII, while domain II might not participate in interacting with RTX-VII but could determine the efficacy of RTX-VII. Our results based on the use of RTX-VII as a probe suggest that domain II and IV cooperatively contribute to the generation of INaP in Nav1.3. PMID:25784299

The IFSO Website (www.ifso.com): the Online Gateway to Obesity and Metabolic Disorders for Bariatric Surgery Professionals and Patients: On behalf of the IFSO Communications Committee.

PubMed

Khwaja, Haris; Coelho, António Jamel; Mazzarella, Manuela; Miller, Karl; Nimeri, Abdelrahman; Ponce, Jaime; Prachand, Vivek; Shikora, Scott; van Wagensveld, Bart; Weiner, Rudolf; Zundel, Natan

2015-11-01

The refurbished International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) website ( www.ifso.com ) showcases a wealth of high-quality information for bariatric surgery professionals and patients. The website provides free online access to the organisational structure of IFSO and useful information on IFSO-endorsed congresses, symposia and courses. Online access to the journal, Obesity Surgery, and the IFSO Newsletter can also be obtained via the IFSO website. There is also easy-to-understand information on the topics of obesity and the various bariatric/metabolic surgeries for our patients.

Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis

PubMed Central

Wu, Fenfen; Mi, Wentao; Fu, Yu; Struyk, Arie

2016-01-01

Over 60 mutations of SCN4A encoding the NaV1.4 sodium channel of skeletal muscle have been identified in patients with myotonia, periodic paralysis, myasthenia, or congenital myopathy. Most mutations are missense with gain-of-function defects that cause susceptibility to myotonia or periodic paralysis. Loss-of-function from enhanced inactivation or null alleles is rare and has been associated with myasthenia and congenital myopathy, while a mix of loss and gain of function changes has an uncertain relation to hypokalaemic periodic paralysis. To better define the functional consequences for a loss-of-function, we generated NaV1.4 null mice by deletion of exon 12. Heterozygous null mice have latent myasthenia and a right shift of the force-stimulus relation, without evidence of periodic paralysis. Sodium current density was half that of wild-type muscle and no compensation by retained expression of the foetal NaV1.5 isoform was detected. Mice null for NaV1.4 did not survive beyond the second postnatal day. This mouse model shows remarkable preservation of muscle function and viability for haploinsufficiency of NaV1.4, as has been reported in humans, with a propensity for pseudo-myasthenia caused by a marginal Na+ current density to support sustained high-frequency action potentials in muscle. PMID:27048647

High-Throughput Screening of Na(V)1.7 Modulators Using a Giga-Seal Automated Patch Clamp Instrument.

PubMed

Chambers, Chris; Witton, Ian; Adams, Cathryn; Marrington, Luke; Kammonen, Juha

2016-03-01

Voltage-gated sodium (Na(V)) channels have an essential role in the initiation and propagation of action potentials in excitable cells, such as neurons. Of these channels, Na(V)1.7 has been indicated as a key channel for pain sensation. While extensive efforts have gone into discovering novel Na(V)1.7 modulating compounds for the treatment of pain, none has reached the market yet. In the last two years, new compound screening technologies have been introduced, which may speed up the discovery of such compounds. The Sophion Qube(®) is a next-generation 384-well giga-seal automated patch clamp (APC) screening instrument, capable of testing thousands of compounds per day. By combining high-throughput screening and follow-up compound testing on the same APC platform, it should be possible to accelerate the hit-to-lead stage of ion channel drug discovery and help identify the most interesting compounds faster. Following a period of instrument beta-testing, a Na(V)1.7 high-throughput screen was run with two Pfizer plate-based compound subsets. In total, data were generated for 158,000 compounds at a median success rate of 83%, which can be considered high in APC screening. In parallel, IC50 assay validation and protocol optimization was completed with a set of reference compounds to understand how the IC50 potencies generated on the Qube correlate with data generated on the more established Sophion QPatch(®) APC platform. In summary, the results presented here demonstrate that the Qube provides a comparable but much faster approach to study Na(V)1.7 in a robust and reliable APC assay for compound screening.

Membrane protein Nav1.7 contributes to the persistent post-surgical pain regulated by p-p65 in dorsal root ganglion (DRG) of SMIR rats model.

PubMed

Li, Zhisong; Li, Yaru; Cao, Jing; Han, Xuemin; Cai, Weihua; Zang, Weidong; Xu, Jitian; Zhang, Wei

2017-11-07

Persistent post-surgical pain is a difficult clinical problem. In this study, we intend to explore the mechanism underlying the persistent post-surgical pain in SMIR (skin/muscle incision and retraction) rats. First of all, the expression of membrane protein Nav1.7 and p-p65 (Phosphorylation of p65) were detected in ipsilateral L4-6 DRGs of SMIR rats by western-blot and immunostaining. Then with ProTx-II (Nav1.7 blocker) or PDTC (p65 inhibitor) were intrathecally injected while the change of Nav1.7 expression and mechanical withdrawal threshold were detected. Finally chromatin immunoprecipitation assay method was used to detect whether could p-p65 bind in the Nav1.7 gene promoter region directly. The results shows that mechanical hyperalgesia occurs following SMIR model, from 5 day (d) and lasted more than 20d after surgery. Meanwhile, the expression of Nav1.7 was up-regulated at 10d, 15d and 20d after surgery compared with naïve group. The expression of p-p65 was up-regulated at 10d and 15d compared with incision group. The mechanical hyperalgesia induced by SMIR was reversed after blocking Nav1.7 or inhibiting p65. Furthermore, Nav1.7 expression was down-regulated when p-p65 was inhibited and p-p65 could combine with the Nav1.7 gene promoter region directly. Membrane protein Nav1.7 could participate in the peripheral sensitization of persistent post-surgical pain, which may be regulated by p-p65.

New ATCA, ALMA and VISIR observations of the candidate LBV SK -67 266 (S61): the nebular mass from modelling 3D density distributions

NASA Astrophysics Data System (ADS)

Agliozzo, C.; Nikutta, R.; Pignata, G.; Phillips, N. M.; Ingallinera, A.; Buemi, C.; Umana, G.; Leto, P.; Trigilio, C.; Noriega-Crespo, A.; Paladini, R.; Bufano, F.; Cavallaro, F.

2017-04-01

We present new observations of the nebula around the Magellanic candidate Luminous Blue Variable S61. These comprise high-resolution data acquired with the Australia Telescope Compact Array (ATCA), the Atacama Large Millimetre/Submillimetre Array (ALMA), and the VLT Imager and Spectrometer for mid Infrared (VISIR) at the Very Large Telescope. The nebula was detected only in the radio, up to 17 GHz. The 17 GHz ATCA map, with 0.8 arcsec resolution, allowed a morphological comparison with the Hα Hubble Space Telescope image. The radio nebula resembles a spherical shell, as in the optical. The spectral index map indicates that the radio emission is due to free-free transitions in the ionized, optically thin gas, but there are hints of inhomogeneities. We present our new public code RHOCUBE to model 3D density distributions and determine via Bayesian inference the nebula's geometric parameters. We applied the code to model the electron density distribution in the S61 nebula. We found that different distributions fit the data, but all of them converge to the same ionized mass, ˜ 0.1 M⊙, which is an order of magnitude smaller than previous estimates. We show how the nebula models can be used to derive the mass-loss history with high-temporal resolution. The nebula was probably formed through stellar winds, rather than eruptions. From the ALMA and VISIR non-detections, plus the derived extinction map, we deduce that the infrared emission observed by space telescopes must arise from extended, diffuse dust within the ionized region.

Knockdown of sodium channel NaV1.6 blocks mechanical pain and abnormal bursting activity of afferent neurons in inflamed sensory ganglia

PubMed Central

Xie, Wenrui; Strong, Judith A.; Ye, Ling; Mao, Ju-Xian; Zhang, Jun-Ming

2013-01-01

Inflammatory processes in the sensory ganglia contribute to many forms of chronic pain. We previously showed that local inflammation of the lumbar sensory ganglia rapidly leads to prolonged mechanical pain behaviors and high levels of spontaneous bursting activity in myelinated cells. Abnormal spontaneous activity of sensory neurons occurs early in many preclinical pain models, and initiates many other pathological changes, but its molecular basis is not well understood. The sodium channel isoform NaV1.6 can underlie repetitive firing and excitatory persistent and resurgent currents. We used in vivo knockdown of this channel via local injection of siRNA to examine its role in chronic pain following local inflammation of the rat lumbar sensory ganglia. In normal DRG, quantitative PCR showed that cells capable of firing repetitively had significantly higher relative expression of NaV1.6. In inflamed DRG, spontaneously active bursting cells expressed high levels of NaV1.6′ immunoreactivity. In vivo knockdown of NaV1.6 locally in the lumbar DRG at the time of DRG inflammation completely blocked development of pain behaviors and abnormal spontaneous activity, while having only minor effects on unmyelinated C-cells. Current research on isoform-specific sodium channel blockers for chronic pain is largely focused on NaV1.8, because it is present primarily in unmyelinated C fiber nociceptors, or on NaV1.7, because lack of this channel causes congenital indifference to pain. However, the results suggest that NaV1.6 may be a useful therapeutic target for chronic pain, and that some pain conditions may be primarily mediated by myelinated A-fiber sensory neurons. PMID:23622763

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

PubMed Central

Wu, Fenfen; Mi, Wentao; Burns, Dennis K.; Fu, Yu; Gray, Hillery F.; Struyk, Arie F.; Cannon, Stephen C.

2011-01-01

Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K+. HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (CaV1.1) and a sodium channel (NaV1.4) have been identified in HypoPP families. Mutations of NaV1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the NaV1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the NaV1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K+ challenge, insensitivity to high-K+ challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na+/K+-ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant NaV1.4 channels. PMID:21881211

The CpG island searcher: a new WWW resource.

PubMed

Takai, Daiya; Jones, Peter A

2003-01-01

Clusters of CpG dinucleotides in GC rich regions of the genome called "CpG islands" frequently occur in the 5' ends of genes. Methylation of CpG islands plays a role in transcriptional silencing in higher organisms in certain situations. We have established a CpG-island-extraction algorithm, which we previously developed [Takai and Jones, 2002], on a web site which has a simple user interface to identify CpG islands from submitted sequences of up to 50kb. The web site determines the locations of CpG islands using parameters (lower limit of %GC, ObsCpG/ExpCpG, length) set by the user, to display the value of parameters on each CpG island, and provides a graphical map of CpG dinucleotide distribution and borders of CpG islands. A command-line version of the CpG islands searcher has also been developed for larger sequences. The CpG Island Searcher was applied to the latest sequence and mapping information of human chromosomes 20, 21 and 22, and a total of 2345 CpG islands were extracted and 534 (23%) of them contained first coding exons and 650 (28%) contained other exons. The CpG Island Searcher is available on the World Wide Web at http://www.cpgislands.com or http://www.uscnorris.com/cpgislands/cpg.cgi.

Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats.

PubMed

He, Wan-You; Zhang, Bin; Xiong, Qing-Ming; Yang, Cheng-Xiang; Zhao, Wei-Cheng; He, Jian; Zhou, Jun; Wang, Han-Bing

2016-04-21

The mammalian target of rapamycin (mTOR) is a key regulator of mRNA translation and protein synthesis, and it is specifically inhibited by rapamycin. In chronic pain conditions, mTOR-mediated local protein synthesis is crucial for neuronal hyperexcitability and synaptic plasticity. The tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 plays a major role in action potential initiation and propagation and cellular excitability in DRG (dorsal root ganglion) neurons. In this study, we investigated if mTOR modulates the phosphorylation of Nav1.8 that is associated with neuronal hyperexcitability and behavioral hypersensitivity in STZ-induced diabetic rats. Painful diabetic neuropathy (PDN) was induced in Sprague-Dawley rats by intraperitoneal injection with streptozotocin (STZ) at 60mg/kg. After the onset of PDN, the rats received daily intrathecal administrations of rapamycin (1μg, 3μg, or 10μg/day) for 7 days; other diabetic rats received the same volumes of dimethyl sulfoxide (DMSO). Herein, we demonstrate a marked increase in protein expression of total mTOR and phospho-mTOR (p-mTOR) together with the up-regulation of phosphor-Nav1.8 (p-Nav1.8) prior to the mechanical withdrawal threshold reaching a significant reduction in dorsal root ganglions (DRGs). Furthermore, the intrathecal administration of rapamycin, inhibiting the activity of mTOR, suppressed the phosphorylation of DRG Nav1.8, reduced the TTX-R current density, heightened the voltage threshold for activation and lowered the voltage threshold for inactivation and relieved mechanical hypersensitivity in diabetic rats. An intrathecal injection (i.t.) of rapamycin inhibited the phosphorylation and enhanced the functional availability of DRG Nav1.8 attenuated STZ-induced hyperalgesia. These results suggest that rapamycin is a potential therapeutic intervention for clinical PDN. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation.

PubMed

Eberhardt, Mirjam; Nakajima, Julika; Klinger, Alexandra B; Neacsu, Cristian; Hühne, Kathrin; O'Reilly, Andrias O; Kist, Andreas M; Lampe, Anne K; Fischer, Kerstin; Gibson, Jane; Nau, Carla; Winterpacht, Andreas; Lampert, Angelika

2014-01-24

Inherited erythromelalgia (IEM) causes debilitating episodic neuropathic pain characterized by burning in the extremities. Inherited "paroxysmal extreme pain disorder" (PEPD) differs in its clinical picture and affects proximal body areas like the rectal, ocular, or jaw regions. Both pain syndromes have been linked to mutations in the voltage-gated sodium channel Nav1.7. Electrophysiological characterization shows that IEM-causing mutations generally enhance activation, whereas mutations leading to PEPD alter fast inactivation. Previously, an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD was reported (Estacion, M., Dib-Hajj, S. D., Benke, P. J., Te Morsche, R. H., Eastman, E. M., Macala, L. J., Drenth, J. P., and Waxman, S. G. (2008) NaV1.7 Gain-of-function mutations as a continuum. A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J. Neurosci. 28, 11079-11088), displaying a shift of both activation and fast inactivation. Here, we characterize a new mutation of Nav1.7, A1632T, found in a patient suffering from IEM. Although transfection of A1632T in sensory neurons resulted in hyperexcitability and spontaneous firing of dorsal root ganglia (DRG) neurons, whole-cell patch clamp of transfected HEK cells revealed that Nav1.7 activation was unaltered by the A1632T mutation but that steady-state fast inactivation was shifted to more depolarized potentials. This is a characteristic normally attributed to PEPD-causing mutations. In contrast to the IEM/PEPD crossover mutation A1632E, A1632T failed to slow current decay (i.e. open-state inactivation) and did not increase resurgent currents, which have been suggested to contribute to high-frequency firing in physiological and pathological conditions. Reduced fast inactivation without increased resurgent currents induces symptoms of IEM, not PEPD, in the new Nav1.7 mutation, A1632T. Therefore

Effect of down-regulation of voltage-gated sodium channel Nav1.7 on activation of astrocytes and microglia in DRG in rats with cancer pain.

PubMed

Pan, Jun; Lin, Xiang-Jin; Ling, Zhi-Heng; Cai, You-Zhi

2015-05-01

To evaluate the effect of down-regulation of Nav1.7 on the activation of astrocytes and microglia in DRG of rats with cancer pain, and explore the transmission of the nociceptive information. Lentiviral vector harboring RNAi sequence targeting the Nav1.7 gene was constructed, and Walker 256 breast cancer cell and morphine was injected to build the bone cancer pain model and morphine tolerance model in rats. Lentiviral vector was injected. Rats in each model were divided into 4 groups: model group, PBS group, vehicle group and LV-Nav1.7 group. The expression levels of GFAP and OX42 in dorsal root ganglia (DRG) were measured. After the animal model was built, the level of Nav1.7, GFAP and OX42 was improved obviously with the time prolonged, which was statistically significant (P<0.05). The expression level of GFAP and OX42 in the DRG in the LV-Nav1.7 group declined obviously compared to the model group, PBS group and vehicle group (P<0.05). Intrathecal injection of Navl.7 shRNA lentiviral vector can reduce the expression of Nav1.7 and inhibit the activation of astrocytes and microglia in DRG. The effort is also effective in morphine tolerance bone cancer pain model rats. Copyright © 2015 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

http://www.D-MELD.com, the Italian survival calculator to optimize donor to recipient matching and to identify the unsustainable matches in liver transplantation.

PubMed

Avolio, Alfonso W; Agnes, Salvatore; Cillo, Umberto; Lirosi, Maria C; Romagnoli, Renato; Baccarani, Umberto; Zamboni, Fausto; Nicolini, Daniele; Donataccio, Matteo; Perrella, Alessandro; Ettorre, Giuseppe M; Romano, Marina; Morelli, Nicola; Vennarecci, Giovanni; de Waure, Chiara; Fagiuoli, Stefano; Burra, Patrizia; Cucchetti, Alessandro

2012-03-01

Optimization of donor-recipient match is one of the exciting challenges in liver transplantation. Using algorithms obtained by the Italian D-MELD study (5256 liver transplants, 21 Centers, 2002-2009 period), a web-based survival calculator was developed. The calculator is available online at the URL http://www.D-MELD.com. The access is free. Registration and authentication are required. The website was developed using PHP scripting language on HTML platform and it is hosted by the web provider Aruba.it. For a given donor (expressed by donor age) and for three potential recipients (expressed by values of bilirubin, creatinine, INR, and by recipient age, HCV, HBV, portal thrombosis, re-transplant status), the website calculates the patient survival at 90days, 1year, 3years, and allows the identification of possible unsustainable matches (i.e. donor-recipient matches with predicted patient survival less than 50% at 5 years). This innovative approach allows the selection of the best recipient for each referred donor, avoiding the allocation of a high-risk graft to a high-risk recipient. The use of the D-MELD.com website can help transplant surgeons, hepatologists, and transplant coordinators in everyday practice of matching donors and recipients, by selecting the more appropriate recipient among various candidates with different prognostic factors. © 2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.

Osteoarthritis-dependent changes in antinociceptive action of Nav1.7 and Nav1.8 sodium channel blockers: An in vivo electrophysiological study in the rat.

PubMed

Rahman, W; Dickenson, A H

2015-06-04

Voltage-gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA)-induced OA we used in vivo electrophysiology to assess the effects of the Nav1.7- and Nav1.8-selective antagonists, ProTxII and A-803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field. These studies allow examination of the roles of these channels in suprathreshold stimuli, not amenable to behavioral threshold measures. Spinal administration of ProTxII significantly reduced neuronal responses evoked by mechanical punctate (von Frey (vF) 8-60g) and noxious thermal (45 and 48°C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8-60g and 48°C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26-60g and 40-48°C stimuli after systemic administration; significantly inhibited the electrically evoked Aδ-, C-fiber, post-discharge, Input and wind-up responses and the brush, vFs 8-60g and 45-48°C evoked neuronal responses after intra plantar injection in the MIA group. In comparison A-803467 effects in the sham group were minimal and included a reduction of the neuronal response evoked by vF 60g and 45°C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45°C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA-treated group suggests an increased role of Nav1.7 and 1.8 within nociceptive pathways in the arthritic condition, located at peripheral and central sites. These findings demonstrate the importance of, and add to, the mechanistic understanding of these channels in

Osteoarthritis-dependent changes in antinociceptive action of Nav1.7 and Nav1.8 sodium channel blockers: An in vivo electrophysiological study in the rat

PubMed Central

Rahman, W.; Dickenson, A.H.

2015-01-01

Voltage-gated sodium channel blockers are not traditionally recommended for osteoarthritis (OA) pain therapy, but given the large peripheral drive that follows OA development there is a rationale for their use. Using a rat model of monosodium iodoacetate (MIA)-induced OA we used in vivo electrophysiology to assess the effects of the Nav1.7- and Nav1.8-selective antagonists, ProTxII and A-803467 respectively, on the evoked activity of spinal dorsal horn neurons in response to electrical, mechanical and thermal stimuli applied to the peripheral receptive field. These studies allow examination of the roles of these channels in suprathreshold stimuli, not amenable to behavioral threshold measures. Spinal administration of ProTxII significantly reduced neuronal responses evoked by mechanical punctate (von Frey (vF) 8–60 g) and noxious thermal (45 and 48 °C) stimuli in MIA rats only. A-803467 significantly inhibited neuronal responses evoked by vF 8–60 g and 48 °C heat after spinal administration; significantly inhibited responses evoked by brush, vFs 26–60 g and 40–48 °C stimuli after systemic administration; significantly inhibited the electrically evoked Aδ-, C-fiber, post-discharge, Input and wind-up responses and the brush, vFs 8–60 g and 45–48 °C evoked neuronal responses after intra plantar injection in the MIA group. In comparison A-803467 effects in the sham group were minimal and included a reduction of the neuronal response evoked by vF 60 g and 45 °C heat stimulation after spinal administration, no effect after systemic administration and an inhibition of the evoked response to 45 °C heat after intra plantar injection only. The observed selective inhibitory effect of ProTxII and A-803467 for the MIA-treated group suggests an increased role of Nav1.7 and 1.8 within nociceptive pathways in the arthritic condition, located at peripheral and central sites. These findings demonstrate the importance of, and add to, the mechanistic

Verb and sentence production and comprehension in aphasia: Northwestern Assessment of Verbs and Sentences (NAVS)

PubMed Central

Cho-Reyes, Soojin; Thompson, Cynthia K.

2015-01-01

Background Verbs and sentences are often impaired in individuals with aphasia, and differential impairment patterns are associated with different types of aphasia. With currently available test batteries, however, it is challenging to provide a comprehensive profile of aphasic language impairments because they do not examine syntactically important properties of verbs and sentences. Aims This study presents data derived from the Northwestern Assessment of Verbs and Sentences (NAVS; Thompson, 2011), a new test battery designed to examine syntactic deficits in aphasia. The NAVS includes tests for verb naming and comprehension, and production of verb argument structure in simple active sentences, with each examining the effects of the number and optionality of arguments. The NAVS also tests production and comprehension of canonical and non-canonical sentences. Methods & Procedures A total of 59 aphasic participants (35 agrammatic and 24 anomic) were tested using a set of action pictures. Participants produced verbs or sentences for the production subtests and identified pictures corresponding to auditorily provided verbs or sentences for the comprehension subtests. Outcomes & Results The agrammatic group, compared to the anomic group, performed significantly more poorly on all subtests except verb comprehension, and for both groups comprehension was less impaired than production. On verb naming and argument structure production tests both groups exhibited difficulty with three-argument verbs, affected by the number and optionality of arguments. However, production of sentences using three-argument verbs was more impaired in the agrammatic, compared to the anomic, group. On sentence production and comprehension tests, the agrammatic group showed impairments in all types of non-canonical sentences, whereas the anomic group exhibited difficulty primarily with the most difficult, object relative, structures. Conclusions Results show that verb and sentence deficits seen in

The NavTrax fleet management system

NASA Astrophysics Data System (ADS)

McLellan, James F.; Krakiwsky, Edward J.; Schleppe, John B.; Knapp, Paul L.

The NavTrax System, a dispatch-type automatic vehicle location and navigation system, is discussed. Attention is given to its positioning, communication, digital mapping, and dispatch center components. The positioning module is a robust GPS (Global Positioning System)-based system integrated with dead reckoning devices by a decentralized-federated filter, making the module fault tolerant. The error behavior and characteristics of GPS, rate gyro, compass, and odometer sensors are discussed. The communications module, as presently configured, utilizes UHF radio technology, and plans are being made to employ a digital cellular telephone system. Polling and automatic smart vehicle reporting are also discussed. The digital mapping component is an intelligent digital single line road network database stored in vector form with full connectivity and address ranges. A limited form of map matching is performed for the purposes of positioning, but its main purpose is to define location once position is determined.

WWW.2CHEAT.COM.

ERIC Educational Resources Information Center

Rooks, Clay D.

This paper addresses the subject of cheating and plagiarism via the World Wide Web. After spending just a few hours browsing on the Internet, the author found dozens of "cheat" sites that offered term papers of all kinds. Some sites charge a fee for papers, some sites only request that students join by sending in one of their papers to add to the…

Transesophageal echocardiography in critically ill acute postoperative infants: comparison of AcuNav intracardiac echocardiographic and microTEE miniaturized transducers.

PubMed

Ferns, Sunita; Komarlu, Rukmini; Van Bergen, Andrew; Multani, Kanwar; Cui, Vivian Wei; Roberson, David A

2012-08-01

Multiple barriers to transthoracic echocardiography are present in critically ill infants immediately after surgery. Transesophageal echocardiography (TEE) is sometimes needed to obtain specific important information that transthoracic echocardiography fails to demonstrate. Formerly, the investigators used the AcuNav intracardiac echocardiographic (ICE) intravascular ultrasound transducer (8 Fr, 2.5 mm, 64-element crystal array, multifrequency [5.5-10 MHz], single longitudinal plane, linear phased array [Siemens Medical Solutions USA, Inc., Mountain View, CA]). Recently, the investigators have also used the microTEE transducer (8-mm transducer tip, 5.2-mm shaft, multifrequency [3-8 MHz], multiplane phased array, 32-element probe [Philips Medical Systems, Andover, MA]). Both transducers have two-dimensional, M-mode, color Doppler, and pulsed-wave and continuous-wave Doppler capabilities. The aim of this study was to compare the efficacy, safety, ease of insertion, capabilities, utilization, and cost of the AcuNav ICE transducer versus those of the microTEE transducer. A retrospective review of all 50 postoperative critically ill infants who underwent TEE using the AcuNav and microTEE in the past 5 years was conducted. TEE was performed as ordered by the attending physician to answer a specific question not answered by transthoracic echocardiography. In all cases, the clinical information sought was obtained. The AcuNav ICE transducer was safe, easy to insert through the transnasal route, and did not require paralysis; however, it had a limited number of echocardiographic views and had greater sterilization cost. The microTEE transducer had greater echocardiographic capabilities and lower sterilization cost; however, it was slightly more difficult to insert, had a few manageable complications, and required more sedation and paralysis. TEE in this setting has increased because of demonstrated efficacy and safety. Both the AcuNav ICE and microTEE transducers are useful

Optimized expression and purification of NavAb provide the structural insight into the voltage dependence.

PubMed

Irie, Katsumasa; Haga, Yukari; Shimomura, Takushi; Fujiyoshi, Yoshinori

2018-01-01

Voltage-gated sodium channels are crucial for electro-signalling in living systems. Analysis of the molecular mechanism requires both fine electrophysiological evaluation and high-resolution channel structures. Here, we optimized a dual expression system of NavAb, which is a well-established standard of prokaryotic voltage-gated sodium channels, for E. coli and insect cells using a single plasmid vector to analyse high-resolution protein structures and measure large ionic currents. Using this expression system, we evaluated the voltage dependence and determined the crystal structures of NavAb wild-type and two mutants, E32Q and N49K, whose voltage dependence were positively shifted and essential interactions were lost in voltage sensor domain. The structural and functional comparison elucidated the molecular mechanisms of the voltage dependence of prokaryotic voltage-gated sodium channels. © 2017 Federation of European Biochemical Societies.

Ca2+ toxicity due to reverse Na+/Ca2+ exchange contributes to degeneration of neurites of DRG neurons induced by a neuropathy-associated Nav1.7 mutation

PubMed Central

Estacion, M.; Vohra, B. P. S; Liu, S.; Hoeijmakers, J.; Faber, C. G.; Merkies, I. S. J.; Lauria, G.; Black, J. A.

2015-01-01

Gain-of-function missense mutations in voltage-gated sodium channel Nav1.7 have been linked to small-fiber neuropathy, which is characterized by burning pain, dysautonomia and a loss of intraepidermal nerve fibers. However, the mechanistic cascades linking Nav1.7 mutations to axonal degeneration are incompletely understood. The G856D mutation in Nav1.7 produces robust changes in channel biophysical properties, including hyperpolarized activation, depolarized inactivation, and enhanced ramp and persistent currents, which contribute to the hyperexcitability exhibited by neurons containing Nav1.8. We report here that cell bodies and neurites of dorsal root ganglion (DRG) neurons transfected with G856D display increased levels of intracellular Na+ concentration ([Na+]) and intracellular [Ca2+] following stimulation with high [K+] compared with wild-type (WT) Nav1.7-expressing neurons. Blockade of reverse mode of the sodium/calcium exchanger (NCX) or of sodium channels attenuates [Ca2+] transients evoked by high [K+] in G856D-expressing DRG cell bodies and neurites. We also show that treatment of WT or G856D-expressing neurites with high [K+] or 2-deoxyglucose (2-DG) does not elicit degeneration of these neurites, but that high [K+] and 2-DG in combination evokes degeneration of G856D neurites but not WT neurites. Our results also demonstrate that 0 Ca2+ or blockade of reverse mode of NCX protects G856D-expressing neurites from degeneration when exposed to high [K+] and 2-DG. These results point to [Na+] overload in DRG neurons expressing mutant G856D Nav1.7, which triggers reverse mode of NCX and contributes to Ca2+ toxicity, and suggest subtype-specific blockade of Nav1.7 or inhibition of reverse NCX as strategies that might slow or prevent axon degeneration in small-fiber neuropathy. PMID:26156380

ModerateDrinking.com and Moderation Management: Outcomes of a Randomized Clinical Trial with Non-Dependent Problem Drinkers

ERIC Educational Resources Information Center

Hester, Reid K.; Delaney, Harold D.; Campbell, William

2011-01-01

Objective: To evaluate the effectiveness of a web-based protocol, ModerateDrinking.com (MD; "www.moderatedrinking.com") combined with use of the online resources of Moderation Management (MM; "www.moderation.org") as opposed to the use of the online resources of MM alone. Method: We randomly assigned 80 problem drinkers to…

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity

PubMed Central

Song, Weihua; Xiao, Yucheng; Chen, Hanying; Ashpole, Nicole M; Piekarz, Andrew D; Ma, Peilin; Hudmon, Andy; Cummins, Theodore R; Shou, Weinian

2012-01-01

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.5 and alters action potential firing in heterologous expression systems (human embryonic kidney (HEK) 293 cells) and their native cardiomyocyte background. Cells expressing hNav1.5-F1486del exhibited a loss-of-function alteration, reflected by an 80% reduction of peak current density, and several gain-of-function alterations, including reduced channel inactivation, enlarged window current, substantial augmentation of persistent late sodium current and an increase in ramp current. We also observed substantial action potential duration (APD) prolongation and prominent early afterdepolarizations (EADs) in neonatal cardiomyocytes expressing the F1486del channels, as well as in computer simulations of myocyte activity. In addition, lidocaine sensitivity was dramatically reduced, which probably contributed to the poor therapeutic outcome observed in the patient carrying the hNav1.5-F1486del mutation. Therefore, despite the significant reduction in peak current density, the F1486del mutation also leads to substantial gain-of-function alterations that are sufficient to cause APD prolongation and EADs, the predominant characteristic of LQTs. These data demonstrate that hNav1.5 mutations can have complex functional consequences and highlight the importance of identifying the specific molecular defect when evaluating potential treatments for individuals with prolonged QT intervals. PMID:22826127

SODIUM CHANNELS (NAV1.2/B1) EXPRESSED IN XENOPUS OOCYTES DEMONSTRATE SENSITIVITY TO PYRETHROIDS.

EPA Science Inventory

Voltage-sensitive sodium channels (VSSCs) are hypothesized to be a primary target of pyrethroid insecticides. However, multiple isoforms of VSSCs exist and the sensitivity of different isoforms to pyrethroids has not been well characterized. The Nav1.2/1 channel predominates in a...

Safety and Effectiveness of the Nav-6 Filter in Preventing Distal Embolization During Jetstream Atherectomy of Infrainguinal Peripheral Artery Lesions.

PubMed

Banerjee, Avantika; Sarode, Karan; Mohammad, Atif; Brilakis, Emmanouil S; Banerjee, Subhash; Shammas, Gail A; Shammas, Nicolas W

2016-08-01

The risk of distal embolization (DE) during infrainguinal peripheral artery interventions (PAI) is often mitigated by the use of embolic protection devices. There are limited data on the use of filters with the Jetstream (JS) atherectomy device, a rotational cutter with aspiration capacity. The Nav-6 filter is uniquely suited for use with the JS due to its wire compatibility and detachment from the filter; however, data on the off-label use of this combination have not been reported. Consecutive patients between October 2008 and April 2015 undergoing endovascular infrainguinal PAI with JS were analyzed as part of the Excellence in Peripheral Artery Disease (XL-PAD) registry (NCT01904851). Patients were divided into two subgroups with Nav-6 filter use vs no filter use. Descriptive and univariate analyses were performed. Among 141 patients (mean age, 67.8 ± 10.8 years; 169 lesions) included in this study, the Nav-6 filter was used in 82 (59%). Use of a filter was more frequent in longer lesions (146 ± 106 mm vs 91 ± 72 mm; P=.01), in more severe stenoses (95% vs 87%; P=.04), and in chronic total occlusions (33% vs 8.3%; P=.01). Patients receiving filters had longer procedure duration (102 ± 51 min vs 66 ± 41 min; P=.01) and longer fluoroscopy times (31 ± 16 min vs 21 ± 10 min; P<.001). Use of the Nav-6 filter with the JS during PAI was associated with numerically lower rates of DE (1.8% vs 8%; P=.10) and similar rates of death and amputation. At 12 months, the target-lesion revascularization rate was higher in the filter group (22% vs 2.7%; P=.02), likely secondary to use of the filter in more complex lesions. Nav-6 filter during JS atherectomy was predominantly used during complex infrainguinal PAI and was associated with less occurrence of DE.

Development of a μO-Conotoxin Analogue with Improved Lipid Membrane Interactions and Potency for the Analgesic Sodium Channel NaV1.8*

PubMed Central

Deuis, Jennifer R.; Dekan, Zoltan; Inserra, Marco C.; Lee, Tzong-Hsien; Aguilar, Marie-Isabel; Craik, David J.; Lewis, Richard J.; Alewood, Paul F.; Mobli, Mehdi; Schroeder, Christina I.; Henriques, Sónia Troeira; Vetter, Irina

2016-01-01

The μO-conotoxins MrVIA, MrVIB, and MfVIA inhibit the voltage-gated sodium channel NaV1.8, a well described target for the treatment of pain; however, little is known about the residues or structural elements that define this activity. In this study, we determined the three-dimensional structure of MfVIA, examined its membrane binding properties, performed alanine-scanning mutagenesis, and identified residues important for its activity at human NaV1.8. A second round of mutations resulted in (E5K,E8K)MfVIA, a double mutant with greater positive surface charge and greater affinity for lipid membranes compared with MfVIA. This analogue had increased potency at NaV1.8 and was analgesic in the mouse formalin assay. PMID:27026701

δ-Conotoxins synthesized using an acid-cleavable solubility tag approach reveal key structural determinants for NaV subtype selectivity.

PubMed

Peigneur, Steve; Paolini-Bertrand, Marianne; Gaertner, Hubert; Biass, Daniel; Violette, Aude; Stöcklin, Reto; Favreau, Philippe; Tytgat, Jan; Hartley, Oliver

2014-12-19

Conotoxins are venom peptides from cone snails with multiple disulfide bridges that provide a rigid structural scaffold. Typically acting on ion channels implicated in neurotransmission, conotoxins are of interest both as tools for pharmacological studies and as potential new medicines. δ-Conotoxins act by inhibiting inactivation of voltage-gated sodium channels (Nav). Their pharmacology has not been extensively studied because their highly hydrophobic character makes them difficult targets for chemical synthesis. Here we adopted an acid-cleavable solubility tag strategy that facilitated synthesis, purification, and directed disulfide bridge formation. Using this approach we readily produced three native δ-conotoxins from Conus consors plus two rationally designed hybrid peptides. We observed striking differences in Nav subtype selectivity across this group of compounds, which differ in primary structure at only three positions: 12, 23, and 25. Our results provide new insights into the structure-activity relationships underlying the Nav subtype selectivity of δ-conotoxins. Use of the acid-cleavable solubility tag strategy should facilitate synthesis of other hydrophobic peptides with complex disulfide bridge patterns. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Romania’s Intelligence Community: From an Instrument of Dictatorship to Serving Democracy

DTIC Science & Technology

2007-01-01

Control of Armed Forces (DCAF), (Bucharest, 2004). 32 Profil, nr. 7, March 2005, p. 9. http://www.sri.ro/index.php?nav= biblioteca &subnav=publicatii&tabela...pp. 14–17, http://www.sri.ro/ index.php?nav= biblioteca &subnav=publicatii&tabela=publicatii_bl 66 Interview by Ion Petrescu with General Lieutenant dr... biblioteca &subnav=publicatii&tabela=publicatii_bl 83 Radu Tudor, ‘‘Romania Creates New Counterterrorism Unit,’’ Jane’s Intelligence Review, 1 January 2005

Revision of the Phenomenological Characteristics of the Algol-Type Stars Using the Nav Algorithm

NASA Astrophysics Data System (ADS)

Tkachenko, M. G.; Andronov, I. L.; Chinarova, L. L.

Phenomenological characteristics of the sample of the Algol-type stars are revised using a recently developed NAV ("New Algol Variable") algorithm (2012Ap.....55..536A, 2012arXiv 1212.6707A) and compared to that obtained using common methods of Trigonometric Polynomial Fit (TP) or local Algebraic Polynomial (A) fit of a fixed or (alternately) statistically optimal degree (1994OAP.....7...49A, 2003ASPC..292..391A). The computer program NAV is introduced, which allows to determine the best fit with 7 "linear" and 5 "nonlinear" parameters and their error estimates. The number of parameters is much smaller than for the TP fit (typically 20-40, depending on the width of the eclipse, and is much smaller (5-20) for the W UMa and β Lyrae-type stars. This causes more smooth approximation taking into account the reflection and ellipsoidal effects (TP2) and generally different shapes of the primary and secondary eclipses. An application of the method to two-color CCD photometry to the recently discovered eclipsing variable 2MASS J18024395 + 4003309 = VSX J180243.9 +400331 (2015JASS...32..101A) allowed to make estimates of the physical parameters of the binary system based on the phenomenological parameters of the light curve. The phenomenological parameters of the light curves were determined for the sample of newly discovered EA and EW-type stars (VSX J223429.3+552903, VSX J223421.4+553013, VSX J223416.2+553424, USNO-B1.0 1347-0483658, UCAC3-191-085589, VSX J180755.6+074711= UCAC3 196-166827). Despite we have used original observations published by the discoverers, the accuracy estimates of the period using the NAV method are typically better than the original ones.

Insulin therapy for type 2 diabetes - are we there yet? The d-Nav® story.

PubMed

Hodish, I

2018-01-01

Insulin replacement therapy is mostly used by patients with type 2 diabetes who become insulin deficient and have failed other therapeutic options. They comprise about a quarter of those with diabetes, endures the majority of the complications and consumes the majority of the resources. Adequate insulin replacement therapy can prevent complications and reduce expenses, as long as therapy goals are achieved and maintained. Sadly, these therapy goals are seldom achieved and outcomes have not improved for decades despite advances in pharmacotherapy and technology. There is a growing recognition that the low success rate of insulin therapy results from intra-individual and inter-individual variations in insulin requirements. Total insulin requirements per day vary considerably between patients and constantly change without achieving a steady state. Thus, the key element in effective insulin therapy is unremitting and frequent dosage adjustments that can overcome those dynamics. In practice, insulin adjustments are done sporadically during outpatient clinic. Due to time constraints, providers are not able to deliver appropriate insulin dosage optimization. The d-Nav® Insulin Guidance Service has been developed to provide appropriate insulinization in insulin users without increasing the burden on healthcare systems. It relies on dedicated clinicians and a spectrum of technological solutions. Patients are provided with a handheld device called d-Nav® which advises them what dose of insulin to administer during each injection and automatically adjust insulin dosage when needed. The d-Nav care specialists periodically follow-up with users through telephone calls and in-person consultations to bestow user confidence, correct usage errors, triage, and identify uncharacteristic clinical courses. The following review provide details about the service and its clinical outcomes.

Crystal Structure of the Ternary Complex of a NaV C-Terminal Domain, a Fibroblast Growth Factor Homologous Factor, and Calmodulin

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

Wang, Chaojian; Chung, Ben C.; Yan, Haidun

2012-11-13

Voltage-gated Na{sup +} (Na{sub V}) channels initiate neuronal action potentials. Na{sub V} channels are composed of a transmembrane domain responsible for voltage-dependent Na{sup +} conduction and a cytosolic C-terminal domain (CTD) that regulates channel function through interactions with many auxiliary proteins, including fibroblast growth factor homologous factors (FHFs) and calmodulin (CaM). Most ion channel structural studies have focused on mechanisms of permeation and voltage-dependent gating but less is known about how intracellular domains modulate channel function. Here we report the crystal structure of the ternary complex of a human NaV CTD, an FHF, and Ca{sup 2+}-free CaM at 2.2 {angstrom}.more » Combined with functional experiments based on structural insights, we present a platform for understanding the roles of these auxiliary proteins in NaV channel regulation and the molecular basis of mutations that lead to neuronal and cardiac diseases. Furthermore, we identify a critical interaction that contributes to the specificity of individual NaV CTD isoforms for distinctive FHFs.« less

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

PubMed Central

Du, Yi-mei; Xia, Cheng-kun; Zhao, Ning; Dong, Qian; Lei, Ming; Xia, Jia-hong

2012-01-01

Aim: To compare the effects of two stereoisomeric forms of glycyrrhetinic acid on different components of Na+ current, HERG and Kv1.5 channel currents. Methods: Wild-type (WT) and long QT syndrome type 3 (LQT-3) mutant ΔKPQ Nav1.5 channels, as well as HERG and Kv1.5 channels were expressed in Xenopus oocytes. In addition, isolated human atrial myocytes were used. Two-microelectrode voltage-clamp technique was used to record the voltage-activated currents. Results: Superfusion of 18β-glycyrrhetinic acid (18β-GA, 1–100 μmol/L) blocked both the peak current (INa,P) and late current (INa,L) generated by WT and ΔKPQ Nav1.5 channels in a concentration-dependent manner, while 18α-glycyrrhetinic acid (18α-GA) at the same concentrations had no effects. 18β-GA preferentially blocked INa,L (IC50=37.2±14.4 μmol/L) to INa,P (IC50=100.4±11.2 μmol/L) generated by ΔKPQ Nav1.5 channels. In human atrial myocytes, 18β-GA (30 μmol/L) inhibited 47% of INa,P and 87% of INa,L induced by Anemonia sulcata toxin (ATX-II, 30 nmol/L). Superfusion of 18β-GA (100 μmol/L) had no effects on HERG and Kv1.5 channel currents. Conclusion: 18β-GA preferentially blocked the late Na current without affecting HERG and Kv1.5 channels. PMID:22609834

Repeated functional convergent effects of NaV1.7 on acid insensitivity in hibernating mammals

PubMed Central

Liu, Zhen; Wang, Wei; Zhang, Tong-Zuo; Li, Gong-Hua; He, Kai; Huang, Jing-Fei; Jiang, Xue-Long; Murphy, Robert W.; Shi, Peng

2014-01-01

Hibernating mammals need to be insensitive to acid in order to cope with conditions of high CO2; however, the molecular basis of acid tolerance remains largely unknown. The African naked mole-rat (Heterocephalus glaber) and hibernating mammals share similar environments and physiological features. In the naked mole-rat, acid insensitivity has been shown to be conferred by the functional motif of the sodium ion channel NaV1.7. There is now an opportunity to evaluate acid insensitivity in other taxa. In this study, we tested for functional convergence of NaV1.7 in 71 species of mammals, including 22 species that hibernate. Our analyses revealed a functional convergence of amino acid sequences, which occurred at least six times independently in mammals that hibernate. Evolutionary analyses determined that the convergence results from both parallel and divergent evolution of residues in the functional motif. Our findings not only identify the functional molecules responsible for acid insensitivity in hibernating mammals, but also open new avenues to elucidate the molecular underpinnings of acid insensitivity in mammals. PMID:24352952

Repeated functional convergent effects of NaV1.7 on acid insensitivity in hibernating mammals.

PubMed

Liu, Zhen; Wang, Wei; Zhang, Tong-Zuo; Li, Gong-Hua; He, Kai; Huang, Jing-Fei; Jiang, Xue-Long; Murphy, Robert W; Shi, Peng

2014-02-07

Hibernating mammals need to be insensitive to acid in order to cope with conditions of high CO2; however, the molecular basis of acid tolerance remains largely unknown. The African naked mole-rat (Heterocephalus glaber) and hibernating mammals share similar environments and physiological features. In the naked mole-rat, acid insensitivity has been shown to be conferred by the functional motif of the sodium ion channel NaV1.7. There is now an opportunity to evaluate acid insensitivity in other taxa. In this study, we tested for functional convergence of NaV1.7 in 71 species of mammals, including 22 species that hibernate. Our analyses revealed a functional convergence of amino acid sequences, which occurred at least six times independently in mammals that hibernate. Evolutionary analyses determined that the convergence results from both parallel and divergent evolution of residues in the functional motif. Our findings not only identify the functional molecules responsible for acid insensitivity in hibernating mammals, but also open new avenues to elucidate the molecular underpinnings of acid insensitivity in mammals.

Characteristics of sensory neuronal groups in CGRP-cre-ER reporter mice: Comparison to Nav1.8-cre, TRPV1-cre and TRPV1-GFP mouse lines.

PubMed

Patil, Mayur J; Hovhannisyan, Anahit H; Akopian, Armen N

2018-01-01

Peptidergic sensory neurons play a critical role in nociceptive pathways. To precisely define the function and plasticity of sensory neurons in detail, new tools such as transgenic mouse models are needed. We employed electrophysiology and immunohistochemistry to characterize in detail dorsal root ganglion (DRG) neurons expressing an inducible CGRPcre-ER (CGRP-cre+); and compared them to DRG neurons expressing Nav1.8cre (Nav1.8-cre+), TRPV1cre (TRPV1-cre+) and TRPV1-GFP (V1-GFP+). Tamoxifen effectively induced CGRPcre-ER production in DRG. ≈87% of CGRPcre-ER-expressing neurons were co-labeled CGRP antibody. Three small and two medium-large-sized (5HT3a+/NPY2R- and NPY2R+) neuronal groups with unique electrophysiological profiles were CGRP-cre+. Nav1.8-cre+ neurons were detected in all CGRP-cre+ groups, as well as in 5 additional neuronal groups: MrgprD+/TRPA1-, MrgprD+/TRPA1+, TRPV1+/CGRP-, vGLUT3+ and ≈30% of trkC+ neurons. Differences between TRPV1cre and Nav1.8cre reporters were that unlike TRPV1-cre+, Nav1.8-cre+ expression was detected in non-nociceptive vGLUT3+ and trkC+ populations. Many TRPV1-cre+ neurons did not respond to capsaicin. In contrast, V1-GFP+ neurons were in 4 groups, each of which was capsaicin-sensitive. Finally, none of the analyzed reporter lines showed cre-recombination in trkB+, calbindin+, 70% of trkC+ or parvalbumin+ neurons, which together encompassed ≈20% of Nav1.8-cre- DRG neurons. The data presented here increases our knowledge of peptidergic sensory neuron characteristics, while showing the efficiency and specificity manipulation of peptidergic neurons by the CGRPcre-ER reporter. We also demonstrate that manipulation of all C- and A-nociceptors is better achieved with TRPV1-cre reporter. Finally, the described approach for detailed characterization of sensory neuronal groups can be applied to a variety of reporter mice.

Compound-Specific Effects of Mutations at Val787 in DII-S6 of Nav1.4 Sodium Channels on the Action of Sodium Channel Inhibitor Insecticides

PubMed Central

von Stein, Richard T.; Soderlund, David M.

2012-01-01

Sodium channel inhibitor (SCI) insecticides are hypothesized to inhibit voltage-gated sodium channels by binding selectively to the slow-inactivated state. Replacement of valine at position 787 in the S6 segment of homology domain II of the rat Nav1.4 sodium channel by lysine (V787K) enchances slow inactivation of this channel whereas replacement by alanine or cysteine (V787A, V787C) inhibits slow inactivation. To test the hypothesis that SCI insecticides bind selectively to the slow-inactivated state, we constructed mutated Nav1.4/V787A, Nav1.4/V787C, and Nav1.4/V787K cDNAs, expressed wildtype and mutated channels with the auxiliary β1 subunit in Xenopus oocytes, and used the two-electrode voltage clamp technique to examine the effects of these mutations on channel inhibition by four SCI insecticides (indoxacarb, its bioactivated metabolite DCJW, metaflumizone, and RH3421). Mutations at Val787 affected SCI insecticide sensitivity in a manner that was independent of mutation-induced changes in slow inactivation gating. Sensitivity to inhibition by 10 μM indoxacarb was significantly increased in all three mutated channels, whereas sensitivity to inhibition by 10 μM metaflumizone was significantly reduced in Nav1.4/V787A channels and completely abolished in Nav1.4/V787K channels. The effects of Val787 mutations on metaflumizone were correlated with the hydrophobicity of the substituted amino acid rather than the extent of slow inactivation. None of the mutations at Val787 significantly affected the sensitivity to inhibition by DCJW or RH3421. These results demonstrate that the impact of mutations at Val787 on sodium channel inhibition by SCI insecticides depends on the specific insecticide examined and is independent of mutation-induced changes in slow inactivation gating. We propose that Val787 may be a unique determinant of metaflumizone binding. PMID:22983119

A simple web-based risk calculator (www.anastomoticleak.com) is superior to the surgeon's estimate of anastomotic leak after colon cancer resection.

PubMed

Sammour, T; Lewis, M; Thomas, M L; Lawrence, M J; Hunter, A; Moore, J W

2017-01-01

Anastomotic leak can be a devastating complication, and early prediction is difficult. The aim of this study is to prospectively validate a simple anastomotic leak risk calculator and compare its predictive value with the estimate of the primary operating surgeon. Consecutive patients undergoing elective or emergency colon cancer surgery with a primary anastomosis over a 1-year period were prospectively included. A recently published anastomotic leak risk nomogram was converted to an online calculator ( www.anastomoticleak.com ). The calculator-derived risk of anastomotic leak and the risk estimated by the primary operating surgeon were recorded at the completion of surgery. The primary outcome was anastomotic leak within 90 days as defined by previously published criteria. Area under receiver operating characteristic curve analysis (AUROC) was performed for both risk estimates. A total of 105 patients were screened for inclusion during the study period, of whom 83 met the inclusion criteria. The overall anastomotic leak rate was 9.6%. The anastomotic leak calculator was highly predictive of anastomotic leak (AUROC 0.84, P = 0.002), whereas the surgeon estimate was not predictive (AUROC 0.40, P = 0.243). A simple anastomotic leak risk calculator is significantly better at predicting anastomotic leak than the estimate of the primary surgeon. Further external validation on a larger data set is required.

[WWW.2CHEAT.COM] Update

ERIC Educational Resources Information Center

Rooks, Clay D.

2006-01-01

This paper is an updated presentation on the subject of cheating and plagiarism via the World Wide Web. In a few hours searching the Internet, the author found even more "cheat" sites than in 1998 that offered not only all types of term and research papers, but college admission letters, reviews, case studies, even dissertations as well. Most now…

Depolarized inactivation overcomes impaired activation to produce DRG neuron hyperexcitability in a Nav1.7 mutation in a patient with distal limb pain.

PubMed

Huang, Jianying; Yang, Yang; Dib-Hajj, Sulayman D; van Es, Michael; Zhao, Peng; Salomon, Jody; Drenth, Joost P H; Waxman, Stephen G

2014-09-10

Sodium channel Nav1.7, encoded by SCN9A, is expressed in DRG neurons and regulates their excitability. Genetic and functional studies have established a critical contribution of Nav1.7 to human pain disorders. We have now characterized a novel Nav1.7 mutation (R1279P) from a female human subject with distal limb pain, in which depolarized fast inactivation overrides impaired activation to produce hyperexcitability and spontaneous firing in DRG neurons. Whole-cell voltage-clamp recordings in human embryonic kidney (HEK) 293 cells demonstrated that R1279P significantly depolarizes steady-state fast-, slow-, and closed-state inactivation. It accelerates deactivation, decelerates inactivation, and facilitates repriming. The mutation increases ramp currents in response to slow depolarizations. Our voltage-clamp analysis showed that R1279P depolarizes channel activation, a change that was supported by our multistate structural modeling. Because this mutation confers both gain-of-function and loss-of-function attributes on the Nav1.7 channel, we tested the impact of R1279P expression on DRG neuron excitability. Current-clamp studies reveal that R1279P depolarizes resting membrane potential, decreases current threshold, and increases firing frequency of evoked action potentials within small DRG neurons. The populations of spontaneously firing and repetitively firing neurons were increased by expressing R1279P. These observations indicate that the dominant proexcitatory gating changes associated with this mutation, including depolarized steady-state fast-, slow-, and closed-state inactivation, faster repriming, and larger ramp currents, override the depolarizing shift of activation, to produce hyperexcitability and spontaneous firing of nociceptive neurons that underlie pain. Copyright © 2014 the authors 0270-6474/14/3412328-13$15.00/0.

PKCepsilon-dependent potentiation of TTX-resistant Nav1.8 current by neurokinin-1 receptor activation in rat dorsal root ganglion neurons.

PubMed

Cang, Chun-Lei; Zhang, Hua; Zhang, Yu-Qiu; Zhao, Zhi-Qi

2009-06-30

Substance P (SP), which mainly exists in a subtype of small-diameter dorsal root ganglion (DRG) neurons, is an important signal molecule in pain processing in the spinal cord. Our previous results have proved the expression of SP receptor neurokinin-1 (NK-1) on DRG neurons and its interaction with transient receptor potential vanilloid 1 (TRPV1) receptor. In this study we investigated the effect of NK-1 receptor agonist on Na(v)1.8, a tetrodotoxin (TTX)-resistant sodium channel, in rat small-diameter DRG neurons employing whole-cell patch clamp recordings. NK-1 agonist [Sar(9), Met(O2)(11)]-substance P (Sar-SP) significantly enhanced the Na(v)1.8 currents in a subgroup of small-diameter DRG neurons under both the normal and inflammatory situation, and the enhancement was blocked by NK-1 antagonist Win51708 and protein kinase C (PKC) inhibitor bisindolylmaleimide (BIM), but not the protein kinase A (PKA) inhibitor H89. In particular, the inhibitor of PKCepsilon, a PKC isoform, completely blocked this effect. Under current clamp model, Sar-SP reduced the amount of current required to evoke action potentials and increased the firing rate in a subgroup of DRG neurons. These data suggest that activation of NK-1 receptor potentiates Na(v)1.8 sodium current via PKCepsilon-dependent signaling pathway, probably participating in the generation of inflammatory hyperalgesia.

Defective Fast Inactivation Recovery of Nav1.4 in Congenital Myasthenic Syndrome

PubMed Central

Arnold, W. David; Feldman, Daniel H.; Ramirez, Sandra; He, Liuyuan; Kassar, Darine; Quick, Adam; Klassen, Tara L.; Lara, Marian; Nguyen, Joanna; Kissel, John T.; Lossin, Christoph; Maselli, Ricardo A.

2015-01-01

Objective To describe the unique phenotype and genetic findings in a 57-year-old female with a rare form of congenital myasthenic syndrome (CMS) associated with longstanding muscle fatigability, and to investigate the underlying pathophysiology. Methods We used whole-cell voltage clamping to compare the biophysical parameters of wild-type and Arg1457His-mutant Nav1.4. Results Clinical and neurophysiological evaluation revealed features consistent with CMS. Sequencing of candidate genes indicated no abnormalities. However, analysis of SCN4A, the gene encoding the skeletal muscle sodium channel Nav1.4, revealed a homozygous mutation predicting an arginine-to-histidine substitution at position 1457 (Arg1457His), which maps to the channel’s voltage sensor, specifically D4/S4. Whole-cell patch clamp studies revealed that the mutant required longer hyperpolarization to recover from fast inactivation, which produced a profound use-dependent current attenuation not seen in the wild type. The mutant channel also had a marked hyperpolarizing shift in its voltage dependence of inactivation as well as slowed inactivation kinetics. Interpretation We conclude that Arg1457His compromises muscle fiber excitability. The mutant fast-inactivates with significantly less depolarization, and it recovers only after extended hyperpolarization. The resulting enhancement in its use dependence reduces channel availability, which explains the patient’s muscle fatigability. Arg1457His offers molecular insight into a rare form of CMS precipitated by sodium channel inactivation defects. Given this channel’s involvement in other muscle disorders such as paramyotonia congenita and hyperkalemic periodic paralysis, our study exemplifies how variations within the same gene can give rise to multiple distinct dysfunctions and phenotypes, revealing residues important in basic channel function. PMID:25707578

Comparing Commercial WWW Browsers.

ERIC Educational Resources Information Center

Notess, Greg R.

1995-01-01

Four commercial World Wide Web browsers are evaluated for features such as handling of WWW protocols and different URLs: FTP, Telnet, Gopher and WAIS, and e-mail and news; bookmark capabilities; navigation features; file management; and security support. (JKP)

Build a WWW Homepage for Your School!

ERIC Educational Resources Information Center

Chrobak, Kimberly

1995-01-01

Discusses the use of World Wide Web (WWW) Homepage for school information. Topics include school sites; installation of a WWW browser; file tags; sites for beginner's guides to the language (HTML); two Usenet discussion groups; and a sample lesson plan including objective, procedure, and evaluation. (AEF)

Mu opioid receptors on primary afferent nav1.8 neurons contribute to opiate-induced analgesia: insight from conditional knockout mice.

PubMed

Weibel, Raphaël; Reiss, David; Karchewski, Laurie; Gardon, Olivier; Matifas, Audrey; Filliol, Dominique; Becker, Jérôme A J; Wood, John N; Kieffer, Brigitte L; Gaveriaux-Ruff, Claire

2013-01-01

Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund's Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain.

Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice

PubMed Central

Karchewski, Laurie; Gardon, Olivier; Matifas, Audrey; Filliol, Dominique; Becker, Jérôme A. J.; Wood, John N.; Kieffer, Brigitte L.; Gaveriaux-Ruff, Claire

2013-01-01

Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund’s Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain. PMID:24069332

A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors

PubMed Central

Favreau, Philippe; Benoit, Evelyne; Hocking, Henry G; Carlier, Ludovic; D' hoedt, Dieter; Leipold, Enrico; Markgraf, René; Schlumberger, Sébastien; Córdova, Marco A; Gaertner, Hubert; Paolini-Bertrand, Marianne; Hartley, Oliver; Tytgat, Jan; Heinemann, Stefan H; Bertrand, Daniel; Boelens, Rolf; Stöcklin, Reto; Molgó, Jordi

2012-01-01

BACKGROUND AND PURPOSE The µ-conopeptide family is defined by its ability to block voltage-gated sodium channels (VGSCs), a property that can be used for the development of myorelaxants and analgesics. We characterized the pharmacology of a new µ-conopeptide (µ-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant. EXPERIMENTAL APPROACH µ-CnIIIC was sequenced, synthesized and characterized by its direct block of elicited twitch tension in mouse skeletal muscle and action potentials in mouse sciatic and pike olfactory nerves. µ-CnIIIC was also studied on HEK-293 cells expressing various rodent VGSCs and also on voltage-gated potassium channels and nicotinic acetylcholine receptors (nAChRs) to assess cross-interactions. Nuclear magnetic resonance (NMR) experiments were carried out for structural data. KEY RESULTS Synthetic µ-CnIIIC decreased twitch tension in mouse hemidiaphragms (IC50= 150 nM), and displayed a higher blocking effect in mouse extensor digitorum longus muscles (IC = 46 nM), compared with µ-SIIIA, µ-SmIIIA and µ-PIIIA. µ-CnIIIC blocked NaV1.4 (IC50= 1.3 nM) and NaV1.2 channels in a long-lasting manner. Cardiac NaV1.5 and DRG-specific NaV1.8 channels were not blocked at 1 µM. µ-CnIIIC also blocked the α3β2 nAChR subtype (IC50= 450 nM) and, to a lesser extent, on the α7 and α4β2 subtypes. Structure determination of µ-CnIIIC revealed some similarities to α-conotoxins acting on nAChRs. CONCLUSION AND IMPLICATIONS µ-CnIIIC potently blocked VGSCs in skeletal muscle and nerve, and hence is applicable to myorelaxation. Its atypical pharmacological profile suggests some common structural features between VGSCs and nAChR channels. PMID:22229737

Description of the final-instar larva and pupa of Neoneuromus ignobilis Navás, 1932 (Megaloptera: Corydalidae).

PubMed

Cao, Chengquan; Liu, Fangqing; Tong, Chao; Fang, Yaqian; Xu, Huimin; Li, Xin; Liu, Xingyue

2018-02-11

The immature stages of only one species of the dobsonfly genus Neoneuromus van der Weele are known. The final-instar larva and pupa of N. ignobilis Navás, 1932, the most common and widespread species of the genus, is herein described for the first time. Several morphological features of the larvae were found to distinguish N. ignobilis from other dobsonfly species with similar large-sized mature larvae.

IRNSS/NavIC L5 Attitude Determination

PubMed Central

Zaminpardaz, Safoora; Teunissen, Peter J.G.; Nadarajah, Nandakumaran

2017-01-01

The Indian Regional Navigation Satellite System (IRNSS) has recently (May 2016) become fully-operational and has been provided with the operational name of NavIC (Navigation with Indian Constellation). It has been developed by the Indian Space Research Organization (ISRO) with the objective of offering positioning, navigation and timing (PNT) to the users in its service area. This contribution provides for the first time an assessment of the IRNSS L5-signal capability to achieve instantaneous attitude determination on the basis of data collected in Perth, Australia. Our evaluations are conducted for both a linear array of two antennas and a planar array of three antennas. A pre-requisite for precise and fast IRNSS attitude determination is the successful resolution of the double-differenced (DD) integer carrier-phase ambiguities. In this contribution, we will compare the performances of different such methods, amongst which the unconstrained and the multivariate-constrained LAMBDA method for both linear and planar arrays. It is demonstrated that the instantaneous ambiguity success rates increase from 15% to 90% for the linear array and from 5% to close to 100% for the planar array, thus showing that standalone IRNSS can realize 24-h almost instantaneous precise attitude determination with heading and elevation standard deviations of 0.05° and 0.10°, respectively. PMID:28146107

Web-based Data Exploration, Exploitation and Visualization Tools for Satellite Sensor VIS/IR Calibration Applications

NASA Astrophysics Data System (ADS)

Gopalan, A.; Doelling, D. R.; Scarino, B. R.; Chee, T.; Haney, C.; Bhatt, R.

2016-12-01

The CERES calibration group at NASA/LaRC has developed and deployed a suite of online data exploration and visualization tools targeted towards a range of spaceborne VIS/IR imager calibration applications for the Earth Science community. These web-based tools are driven by the open-source R (Language for Statistical Computing and Visualization) with a web interface for the user to customize the results according to their application. The tool contains a library of geostationary and sun-synchronous imager spectral response functions (SRF), incoming solar spectra, SCIAMACHY and Hyperion Earth reflected visible hyper-spectral data, and IASI IR hyper-spectral data. The suite of six specific web-based tools was designed to provide critical information necessary for sensor cross-calibration. One of the challenges of sensor cross-calibration is accounting for spectral band differences and may introduce biases if not handled properly. The spectral band adjustment factors (SBAF) are a function of the earth target, atmospheric and cloud conditions or scene type and angular conditions, when obtaining sensor radiance pairs. The SBAF will need to be customized for each inter-calibration target and sensor pair. The advantages of having a community open source tool are: 1) only one archive of SCIAMACHY, Hyperion, and IASI datasets needs to be maintained, which is on the order of 50TB. 2) the framework will allow easy incorporation of new satellite SRFs and hyper-spectral datasets and associated coincident atmospheric and cloud properties, such as PW. 3) web tool or SBAF algorithm improvements or suggestions when incorporated can benefit the community at large. 4) The customization effort is on the user rather than on the host. In this paper we discuss each of these tools in detail and explore the variety of advanced options that can be used to constrain the results along with specific use cases to highlight the value-added by these datasets.

Quora.com: Another Place for Users to Ask Questions

ERIC Educational Resources Information Center

Ovadia, Steven

2011-01-01

Quora (www.quora.com) is a contemporary, web-based take on reference. Users post questions within Quora and other users answer the questions. Users can vote for and against answers (or not vote at all). It is users asking questions of friends and strangers and then sorting through the results. If the model sounds familiar, it's because it is.…

Magnetization and Hall effect under high pressure in NaV 6O 11

NASA Astrophysics Data System (ADS)

Naka, T.; Matsumoto, T.; Kanke, Y.; Murata, K.

1995-02-01

We have investigated the pressure dependences of magnetization and the Hall coefficient in the ferromagnetic vanadium oxide NaV 6O 11 up to 1.2 GPa. Structural transitions (hexagonal-hexagonal-orthorhombic) occur at TH = 245 K and TL = 35 K at ambient pressure. Meanwhile, the susceptibility obeys the Curie-Weiss law X = C/( T - θ) with antiferromagnetic correlation of θ < 0 at T > TH, with ferromagnetic correlation of θ < 0 at T < TH. The spontaneous magnetization appears below Tc = 64.2 K. With increasing pressure, Tc and magnetization M( T < Tc) decrease, while TH increases. The sign of the Hall coefficient changes continuously (negative-positive-negative) at around T ≈ 170 K and 75 K.

Predicting a double mutant in the twilight zone of low homology modeling for the skeletal muscle voltage-gated sodium channel subunit beta-1 (Nav1.4 β1)

PubMed Central

Scior, Thomas; Paiz-Candia, Bertin; Islas, Ángel A.; Sánchez-Solano, Alfredo; Millan-Perez Peña, Lourdes; Mancilla-Simbro, Claudia; Salinas-Stefanon, Eduardo M.

2015-01-01

The molecular structure modeling of the β1 subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4) was carried out in the twilight zone of very low homology. Structural significance can per se be confounded with random sequence similarities. Hence, we combined (i) not automated computational modeling of weakly homologous 3D templates, some with interfaces to analogous structures to the pore-bearing Nav1.4 α subunit with (ii) site-directed mutagenesis (SDM), as well as (iii) electrophysiological experiments to study the structure and function of the β1 subunit. Despite the distant phylogenic relationships, we found a 3D-template to identify two adjacent amino acids leading to the long-awaited loss of function (inactivation) of Nav1.4 channels. This mutant type (T109A, N110A, herein called TANA) was expressed and tested on cells of hamster ovary (CHO). The present electrophysiological results showed that the double alanine substitution TANA disrupted channel inactivation as if the β1 subunit would not be in complex with the α subunit. Exhaustive and unbiased sampling of “all β proteins” (Ig-like, Ig) resulted in a plethora of 3D templates which were compared to the target secondary structure prediction. The location of TANA was made possible thanks to another “all β protein” structure in complex with an irreversible bound protein as well as a reversible protein–protein interface (our “Rosetta Stone” effect). This finding coincides with our electrophysiological data (disrupted β1-like voltage dependence) and it is safe to utter that the Nav1.4 α/β1 interface is likely to be of reversible nature. PMID:25904995

Predicting a double mutant in the twilight zone of low homology modeling for the skeletal muscle voltage-gated sodium channel subunit beta-1 (Nav1.4 β1).

PubMed

Scior, Thomas; Paiz-Candia, Bertin; Islas, Ángel A; Sánchez-Solano, Alfredo; Millan-Perez Peña, Lourdes; Mancilla-Simbro, Claudia; Salinas-Stefanon, Eduardo M

2015-01-01

The molecular structure modeling of the β1 subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4) was carried out in the twilight zone of very low homology. Structural significance can per se be confounded with random sequence similarities. Hence, we combined (i) not automated computational modeling of weakly homologous 3D templates, some with interfaces to analogous structures to the pore-bearing Nav1.4 α subunit with (ii) site-directed mutagenesis (SDM), as well as (iii) electrophysiological experiments to study the structure and function of the β1 subunit. Despite the distant phylogenic relationships, we found a 3D-template to identify two adjacent amino acids leading to the long-awaited loss of function (inactivation) of Nav1.4 channels. This mutant type (T109A, N110A, herein called TANA) was expressed and tested on cells of hamster ovary (CHO). The present electrophysiological results showed that the double alanine substitution TANA disrupted channel inactivation as if the β1 subunit would not be in complex with the α subunit. Exhaustive and unbiased sampling of "all β proteins" (Ig-like, Ig) resulted in a plethora of 3D templates which were compared to the target secondary structure prediction. The location of TANA was made possible thanks to another "all β protein" structure in complex with an irreversible bound protein as well as a reversible protein-protein interface (our "Rosetta Stone" effect). This finding coincides with our electrophysiological data (disrupted β1-like voltage dependence) and it is safe to utter that the Nav1.4 α/β1 interface is likely to be of reversible nature.

RNAi-mediated knockdown of the voltage gated sodium ion channel TcNav causes mortality in Tribolium castaneum.

PubMed

Abd El Halim, Hesham M; Alshukri, Baida M H; Ahmad, Munawar S; Nakasu, Erich Y T; Awwad, Mohammed H; Salama, Elham M; Gatehouse, Angharad M R; Edwards, Martin G

2016-07-14

The voltage-gated sodium ion channel (VGSC) belongs to the largest superfamily of ion channels. Since VGSCs play key roles in physiological processes they are major targets for effective insecticides. RNA interference (RNAi) is widely used to analyse gene function, but recently, it has shown potential to contribute to novel strategies for selectively controlling agricultural insect pests. The current study evaluates the delivery of dsRNA targeted to the sodium ion channel paralytic A (TcNav) gene in Tribolium castaneum as a viable means of controlling this insect pest. Delivery of TcNav dsRNA caused severe developmental arrest with larval mortalities up to 73% post injection of dsRNA. Injected larvae showed significant (p < 0.05) knockdown in gene expression between 30-60%. Expression was also significantly (p < 0.05) reduced in pupae following injection causing 30% and 42% knockdown for early and late pupal stages, respectively. Oral delivery of dsRNA caused dose-dependant mortalities of between 19 and 51.34%; this was accompanied by significant (p < 0.05) knockdown in gene expression following 3 days of continuous feeding. The majority of larvae injected with, or fed, dsRNA died during the final larval stage prior to pupation. This work provides evidence of a viable RNAi-based strategy for insect control.

Efficacy, safety, and tolerability of lacosamide in patients with gain-of-function Nav1.7 mutation-related small fiber neuropathy: study protocol of a randomized controlled trial-the LENSS study.

PubMed

de Greef, Bianca T A; Merkies, Ingemar S J; Geerts, Margot; Faber, Catharina G; Hoeijmakers, Janneke G J

2016-06-30

Small fiber neuropathy generally leads to considerable pain and autonomic symptoms. Gain-of-function mutations in the SCN9A- gene, which codes for the Nav1.7 voltage-gated sodium channel, have been reported in small fiber neuropathy, suggesting an underlying genetic basis in a subset of patients. Currently available sodium channel blockers lack selectivity, leading to cardiac and central nervous system side effects. Lacosamide is an anticonvulsant, which blocks Nav1.3, Nav1.7, and Nav1.8, and stabilizes channels in the slow-inactivation state. Since multiple Nav1.7 mutations in small fiber neuropathy showed impaired slow-inactivation, lacosamide might be effective. The Lacosamide-Efficacy-'N'-Safety in Small fiber neuropathy (LENSS) study is a randomized, double-blind, placebo-controlled, crossover trial in patients with SCN9A-associated small fiber neuropathy, with the primary objective to evaluate the efficacy of lacosamide versus placebo. Eligible patients (the aim is to recruit 25) fulfilling the inclusion and exclusion criteria will be randomized to receive lacosamide (200 mg b.i.d.) or placebo during the first double-blinded treatment period (8 weeks), which is preceded by a titration period (3 weeks). The first treatment period will be followed by a tapering period (2 weeks). After a 2-week washout period, patients will crossover to the alternate arm for the second period consisting of an equal titration phase, treatment period, and tapering period. The primary efficacy endpoint will be the proportion of patients demonstrating a 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. We assume a response rate of approximately 60 % based on the criteria composed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group for measurement of pain. Patients withdrawing from the study will be considered non- responders. Secondary outcomes will include changes in maximum

Using the WWW to Make YOHKOH SXT Images Available to the Public: The YOHKOH Public Outreach Project

NASA Astrophysics Data System (ADS)

Larson, M.; McKenzie, D.; Slater, T.; Acton, L.; Alexander, D.; Freeland, S.; Lemen, J.; Metcalf, T.

1997-05-01

The Yohkoh Public Outreach Project (YPOP) is funded by NASA as one of the Information Infrastructure Technology and Applications Cooperative Agreement Teams to create public access to high quality Yohkoh SXT data via the World Wide Web. These products are being made available to the scientific research community, K-12 schools, and informal education centers including planetaria, museums, and libraries. The project aims to utilize the intrinsic excitement of the SXT data, and in particular the SXT movies, to develop science learning tools and classroom activities. The WWW site at URL: http://www.space.lockheed.com/YPOP/ uses a movie theater theme to highlight available Yohkoh movies in a non-intimidating and entertaining format for non-scientists. The site features lesson plans, 'solar' activities, slide shows and, of course, a variety of movies about the Sun. Classroom activities are currently undergoing development with a team of scientists and K-12 teachers for distribution in late 1997. We will display the products currently online, which include a solar classroom with activities for teachers, background resources, and a virtual tour of our Sun.

WWW database of optical constants for astronomy

NASA Astrophysics Data System (ADS)

Henning, Th.; Il'In, V. B.; Krivova, N. A.; Michel, B.; Voshchinnikov, N. V.

1999-04-01

The database we announce contains references to the papers, data files and links to the Internet resources related to measurements and calculations of the optical constants of the materials of astronomical interest: different silicates, ices, oxides, sulfides, carbides, carbonaceous species from amorphous carbon to graphite and diamonds, etc. We describe the general structure and content of the database which has now free access via Internet: http://www.astro.spbu.ru/JPDOC/entry.html\\ or \\ http:// www. astro.uni-jena.de/Users/database/entry.html

Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life.

PubMed

Lehmann-Horn, Frank; D'Amico, Adele; Bertini, Enrico; Lomonaco, Mauro; Merlini, Luciano; Nelson, Kevin R; Philippi, Heike; Siciliano, Gabriele; Spaans, Frank; Jurkat-Rott, Karin

2017-09-01

Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.

Image Reference Database in Teleradiology: Migrating to WWW

NASA Astrophysics Data System (ADS)

Pasqui, Valdo

The paper presents a multimedia Image Reference Data Base (IRDB) used in Teleradiology. The application was developed at the University of Florence in the framework of the European Community TELEMED Project. TELEMED overall goals and IRDB requirements are outlined and the resulting architecture is described. IRDB is a multisite database containing radiological images, selected because their scientific interest, and their related information. The architecture consists of a set of IRDB Installations which are accessed from Viewing Stations (VS) located at different medical sites. The interaction between VS and IRDB Installations follows the client-server paradigm and uses an OSI level-7 protocol, named Telemed Communication Language. After reviewing Florence prototype implementation and experimentation, IRDB migration to World Wide Web (WWW) is discussed. A possible scenery to implement IRDB on the basis of WWW model is depicted in order to exploit WWW servers and browsers capabilities. Finally, the advantages of this conversion are outlined.

Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life

PubMed Central

LEHMANN-HORN, FRANK; D’AMICO, ADELE; BERTINI, ENRICO; LOMONACO, MAURO; MERLINI, LUCIANO; NELSON, KEVIN R.; PHILIPPI, HEIKE; SICILIANO, GABRIELE; SPAANS, FRANK; JURKAT-ROTT, KARIN

2017-01-01

Introduction Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. Methods Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. Results In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. Discussion Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling. PMID:29774303

Elevated Neuronal Excitability Due to Modulation of the Voltage-Gated Sodium Channel Nav1.6 by Aβ1−42

PubMed Central

Wang, Xi; Zhang, Xiao-Gang; Zhou, Ting-Ting; Li, Na; Jang, Chun-Yan; Xiao, Zhi-Cheng; Ma, Quan-Hong; Li, Shao

2016-01-01

Aberrant increases in neuronal network excitability may contribute to the cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability are not fully understood. Such overexcitation of neuronal networks has been detected in the brains of APP/PS1 mice. In the present study, using current-clamp recording techniques, we observed that 12 days in vitro (DIV) primary cultured pyramidal neurons from P0 APP/PS1 mice exhibited a more prominent action potential burst and a lower threshold than WT littermates. Moreover, after treatment with Aβ1−42 peptide, 12 DIV primary cultured neurons showed similar changes, to a greater degree than in controls. Voltage-clamp recordings revealed that the voltage-dependent sodium current density of neurons incubated with Aβ1−42 was significantly increased, without change in the voltage-dependent sodium channel kinetic characteristics. Immunohistochemistry and western blot results showed that, after treatment with Aβ1−42, expressions of Nav and Nav1.6 subtype increased in cultured neurons or APP/PS1 brains compared to control groups. The intrinsic neuronal hyperexcitability of APP/PS1 mice might thus be due to an increased expression of voltage-dependent sodium channels induced by Aβ1−42. These results may illuminate the mechanism of aberrant neuronal networks in AD. PMID:27013956

[eLearning-radiology.com--sustainability for quality assurance].

PubMed

Ketelsen, D; Talanow, R; Uder, M; Grunewald, M

2009-04-01

The aim of the study was to analyze the availability of published radiological e-learning tools and to establish a solution for quality assurance. Substantial pubmed research was performed to identify radiological e-learning tools. 181 e-learning programs were selected. As examples two databases expanding their programs with external links, Compare (n = 435 external links) and TNT-Radiology (n = 1078 external links), were evaluated. A concept for quality assurance was developed by an international taskforce. At the time of assessment, 56.4 % (102 / 181) of the investigated e-learning tools were accessible at their original URL. A subgroup analysis of programs published 5 to 8 years ago showed significantly inferior availability to programs published 3 to 5 years ago (p < 0.01). The analysis of external links showed 49.2 % and 61.0 % accessible links for the programs Compare (published 2003) and TNT-Radiology (published 2006), respectively. As a consequence, the domain www.eLearning-radiology.com was developed by the taskforce and published online. This tool allows authors to present their programs and users to evaluate the e-learning tools depending on several criteria in order to remove inoperable links and to obtain information about the complexity and quality of the e-learning tools. More than 50 % of investigated radiological e-learning tools on the Internet were not accessible after a period of 5 to 8 years. As a consequence, an independent, international tool for quality assurance was designed and published online under www.eLearning-radiology.com .

Radiatively driven Rayleigh-Taylor instability candidates around a forming massive star system. NACO adaptive optics and VISIR study of G333.6-0.2

NASA Astrophysics Data System (ADS)

Kumar, M. S. N.

2013-10-01

The formation of the highest mass stars are thought to be dominated by instabilities resulting from gravitation and radiation. Instabilities due to gravitation are commonly demonstrated by observations of fragmentation, but those due to effects of radiation have thus far not been found. Here I report on the NACO adaptive optics and mid-infrared diffraction-limited VISIR imaging data of an extemely luminous ultra-compact HII region G333.6-0.2. Two infrared sources, one bright in the near-infrared (appearing point-like) and another in the mid-infrared (resolved with an elliptical shape) are uncovered through this data, which are located at the heart of this region. These infrared sources appear to be embedded in the waist of a bipolar-shaped nebula and UCHII region, the lobes of which are separated by a dark patch. Dense filamentary features with finger/hook morphology are found; they appear to be connected to the two bright infrared sources and the sizes of these hook features are sharply limited to <5000 AU. The observed properties of this target and a large amount of previous data obtained from the literature are compared together with the results of various numerical simulations of high-mass star formation. This comparison favours the interpretation that the finger/hook-like structures likely represent radiatively driven Rayleigh-Taylor instabilities arising in the outflow cavity of a forming high-mass binary star system.

The New WWW: Whatever, Whenever, Wherever

ERIC Educational Resources Information Center

March, Tom

2006-01-01

We are entering an age of instant media gratification, in which a "multimedia aura" will "accompany us wherever we go," writes Tom March. The New WWW, says March, offers us whatever we want, whenever and wherever we want it. The effect on our children may be unrealistic expectations, premature disillusionment, and unhappiness. To counterbalance…

Nonlinear effects of hyperpolarizing shifts in activation of mutant Nav1.7 channels on resting membrane potential

PubMed Central

Estacion, Mark

2017-01-01

The Nav1.7 sodium channel is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function mutations that cause the painful disorder inherited erythromelalgia (IEM) shift channel activation in a hyperpolarizing direction. When expressed within DRG neurons, these mutations produce a depolarization of resting membrane potential (RMP). The biophysical basis for the depolarized RMP has to date not been established. To explore the effect on RMP of the shift in activation associated with a prototypical IEM mutation (L858H), we used dynamic-clamp models that represent graded shifts that fractionate the effect of the mutation on activation voltage dependence. Dynamic-clamp recording from DRG neurons using a before-and-after protocol for each cell made it possible, even in the presence of cell-to-cell variation in starting RMP, to assess the effects of these graded mutant models. Our results demonstrate a nonlinear, progressively larger effect on RMP as the shift in activation voltage dependence becomes more hyperpolarized. The observed differences in RMP were predicted by the “late” current of each mutant model. Since the depolarization of RMP imposed by IEM mutant channels is known, in itself, to produce hyperexcitability of DRG neurons, the development of pharmacological agents that normalize or partially normalize activation voltage dependence of IEM mutant channels merits further study. NEW & NOTEWORTHY Inherited erythromelalgia (IEM), the first human pain disorder linked to a sodium channel, is widely regarded as a genetic model of neuropathic pain. IEM is produced by Nav1.7 mutations that hyperpolarize activation. These mutations produce a depolarization of resting membrane potential (RMP) in dorsal root ganglion neurons. Using dynamic clamp to explore the effect on RMP of the shift in activation, we demonstrate a nonlinear effect on RMP as the shift in activation voltage dependence becomes more hyperpolarized. PMID

Compositional maps and VIS-IR spectral indicators of Vesta's surface retrieved from VIR hyperspectral data

NASA Astrophysics Data System (ADS)

Filacchione, G.; Ammannito, E.; Coradini, A.; De sanctis, M.; Capaccioni, F.; Tosi, F.; Capria, M. T.; Palomba, E.; Magni, G.; Fonte, S.; Carraro, F.; McSween, H. Y.; Raymond, C. A.; Russell, C. T.; McCord, T. B.; Pieters, C. M.; Sunshine, J. M.; Titus, T. N.; Combe, J.; Dawn Science Team

2011-12-01

In July 2011, VIR-MS, Visible and Infrared Mapping Spectrometer, aboard the Dawn mission has started a systematic exploration of minor planet Vesta from a 5000 km polar orbit (approach phase). Since then, the instrument has returned hyperspectral cubes in the 0.25-5 μm range with both global and regional views of Vesta's surface. Thanks to the high spatial (250 μrad IFOV, corresponding to a 1.25 km/pixel scale from a 5000 km altitude orbit) and spectral resolution (2 nm/band between 0.25-1 μm and 10 nm/band in the 1-5 μm range), VIR has the capabilities to infer the mineralogical composition of the crust, to discriminate among the very different compositional units, to map their distribution across the surface and to correlate composition with geological features. Since the amount of information provided by each VIR pixel is very large (864 channels), we have developed the VIR Mineralogical Tool (VMT) with the scope of measuring some specific spectral quantities which are tuned to identify the different howarditic, eucritic and diogenitic (HED) components of the crust, thanks to laboratory measurements and ground-based observations of HED meteorites. Continuum levels, VIS-IR band ratios, band I-II properties (center, depth, width, asymmetry), spectral slopes and their mutual correlations are among the principal spectral indicators used to infer the crustal basaltic composition. As a general rule for basaltic materials: 1) the ratio of band I/II areas gives the Band Area Ratio (BAR) which is function of the relative abundance of olivine/orthopyroxene; 2) the value of the I Vs. II band depths is an indicator of the composition, allowing to discriminate among HEDs. An alternative method is based on the correlation between band I width and 0.7-1.3 μm slope or the band I depth Vs. the 0.67-0.95 μm slope; 3) the amount of Fs, Wo and Mg is retrieved from the band I center and band II minima wavelengths; 4) the alteration of the surface, induced by weathering

Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.

PubMed

Männikkö, Roope; Wong, Leonie; Tester, David J; Thor, Michael G; Sud, Richa; Kullmann, Dimitri M; Sweeney, Mary G; Leu, Costin; Sisodiya, Sanjay M; FitzPatrick, David R; Evans, Margaret J; Jeffrey, Iona J M; Tfelt-Hansen, Jacob; Cohen, Marta C; Fleming, Peter J; Jaye, Amie; Simpson, Michael A; Ackerman, Michael J; Hanna, Michael G; Behr, Elijah R; Matthews, Emma

2018-04-14

Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS. We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system. Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057). Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy

How to use the WWW to distribute STI

NASA Technical Reports Server (NTRS)

Roper, Donna G.

1994-01-01

This presentation explains how to use the World Wide Web (WWW) to distribute scientific and technical information as hypermedia. WWW clients and servers use the HyperText Transfer Protocol (HTTP) to transfer documents containing links to other text, graphics, video, and sound. The standard language for these documents is the HyperText MarkUp Language (HTML). These are simply text files with formatting codes that contain layout information and hyperlinks. HTML documents can be created with any text editor or with one of the publicly available HTML editors or convertors. HTML can also include links to available image formats. This presentation is available online. The URL is http://sti.larc.nasa. (followed by) gov/demos/workshop/introtext.html.

Docking Simulation of the Binding Interactions of Saxitoxin Analogs Produced by the Marine Dinoflagellate Gymnodinium catenatum to the Voltage-Gated Sodium Channel Nav1.4.

PubMed

Durán-Riveroll, Lorena M; Cembella, Allan D; Band-Schmidt, Christine J; Bustillos-Guzmán, José J; Correa-Basurto, José

2016-05-06

Saxitoxin (STX) and its analogs are paralytic alkaloid neurotoxins that block the voltage-gated sodium channel pore (Nav), impeding passage of Na⁺ ions into the intracellular space, and thereby preventing the action potential in the peripheral nervous system and skeletal muscle. The marine dinoflagellate Gymnodinium catenatum produces an array of such toxins, including the recently discovered benzoyl analogs, for which the mammalian toxicities are essentially unknown. We subjected STX and its analogs to a theoretical docking simulation based upon two alternative tri-dimensional models of the Nav1.4 to find a relationship between the binding properties and the known mammalian toxicity of selected STX analogs. We inferred hypothetical toxicities for the benzoyl analogs from the modeled values. We demonstrate that these toxins exhibit different binding modes with similar free binding energies and that these alternative binding modes are equally probable. We propose that the principal binding that governs ligand recognition is mediated by electrostatic interactions. Our simulation constitutes the first in silico modeling study on benzoyl-type paralytic toxins and provides an approach towards a better understanding of the mode of action of STX and its analogs.

Docking Simulation of the Binding Interactions of Saxitoxin Analogs Produced by the Marine Dinoflagellate Gymnodinium catenatum to the Voltage-Gated Sodium Channel Nav1.4

PubMed Central

Durán-Riveroll, Lorena M.; Cembella, Allan D.; Band-Schmidt, Christine J.; Bustillos-Guzmán, José J.; Correa-Basurto, José

2016-01-01

Saxitoxin (STX) and its analogs are paralytic alkaloid neurotoxins that block the voltage-gated sodium channel pore (Nav), impeding passage of Na+ ions into the intracellular space, and thereby preventing the action potential in the peripheral nervous system and skeletal muscle. The marine dinoflagellate Gymnodinium catenatum produces an array of such toxins, including the recently discovered benzoyl analogs, for which the mammalian toxicities are essentially unknown. We subjected STX and its analogs to a theoretical docking simulation based upon two alternative tri-dimensional models of the Nav1.4 to find a relationship between the binding properties and the known mammalian toxicity of selected STX analogs. We inferred hypothetical toxicities for the benzoyl analogs from the modeled values. We demonstrate that these toxins exhibit different binding modes with similar free binding energies and that these alternative binding modes are equally probable. We propose that the principal binding that governs ligand recognition is mediated by electrostatic interactions. Our simulation constitutes the first in silico modeling study on benzoyl-type paralytic toxins and provides an approach towards a better understanding of the mode of action of STX and its analogs. PMID:27164145

Organization and dissemination of multimedia medical databases on the WWW.

PubMed

Todorovski, L; Ribaric, S; Dimec, J; Hudomalj, E; Lunder, T

1999-01-01

In the paper, we focus on the problem of building and disseminating multimedia medical databases on the World Wide Web (WWW). The current results of the ongoing project of building a prototype dermatology images database and its WWW presentation are presented. The dermatology database is part of an ambitious plan concerning an organization of a network of medical institutions building distributed and federated multimedia databases of a much wider scale.

Identification of the Sensory Neuron Specific Regulatory Region for the Mouse Gene Encoding the Voltage Gated Sodium Channel Nav1.8

PubMed Central

Puhl, Henry L.; Ikeda, Stephen R.

2008-01-01

Voltage-gated sodium channels (VGSC) are critical membrane components that participate in the electrical activity of excitable cells. The type one VGSC family includes the tetrodotoxin insensitive sodium channel, Nav1.8, encoded by the Scn10a gene. Nav1.8 expression is restricted to small and medium diameter nociceptive sensory neurons of the dorsal root (DRG) and cranial sensory ganglia. In order to understand the stringent transcriptional regulation of the Scn10a gene, the sensory neuron specific promoter was functionally identified. While identifying the mRNA 5’ end, alternative splicing within the 5’ UTR was observed to create heterogeneity in the RNA transcript. Four kilobases of upstream genomic DNA was cloned and the presence of tissue specific promoter activity was tested by microinjection and adenoviral infection of fluorescent protein reporter constructs into primary mouse and rat neurons, and cell lines. The region contained many putative transcription factor binding sites and strong homology with the predicted rat ortholog. Homology to the predicted human ortholog was limited to the proximal end and several conserved cis elements were noted. Two regulatory modules were identified by microinjection of reporter constructs into DRG and superior cervical ganglia neurons: a neuron specific proximal promoter region between −1.6 and −0.2kb of the transcription start site cluster, and a distal sensory neuron switch region beyond −1.6kb that restricted fluorescent protein expression to a subset of primary sensory neurons. PMID:18466327

Nuclear Data on the WWW

NASA Astrophysics Data System (ADS)

Firestone, Richard B.; Chu, S. Y. Frank; Ekstrom, L. Peter; Wu, Shiu-Chin; Singh, Balraj

1997-10-01

The Isotopes Project is developing Internet home pages to provide data for radioactive decay, nuclear structure, nuclear astrophysics, spontaneous fission, thermal neutron capture, and atomic masses. These home pages can be accessed from the Table of Isotopes home page at http://isotopes.lbl.gov/isotopes/toi.html. Data from the Evaluated Nuclear Structure Data File (ENSDF) is now available on the WWW in Nuclear Data Sheet style tables, complete with comments and hypertext linked footnotes. Bibliographic information from the Nuclear Science Reference (NSR) file can be searched on the WWW by combinations of author, A, Z, reaction, and various keywords. Decay gamma-ray data from several databases can be searched by energy. The Table of Superdeformed Nuclear Bands and Fission Isomers is continously updated. Reaction rates from Hoffman and Woosley and from Thielemann, fission yields from England and Rider, thermal neutron cross-sections from BNL-325, atomic masses from Audi, and skeleton scheme drawings and nuclear charts from the Table of Isotopes are among the information available through these websites. The nuclear data home pages are accessed by over 3500 different users each month.

User Interface Design for WWW-Based Courses: Building upon Student Evaluations.

ERIC Educational Resources Information Center

van Rennes, Linda; Collis, Betty

This paper describes how student reactions shaped the design of a WWW (World Wide Web)-based course environment at the University of Twente (Netherlands), using the example of a first year course. The first section discusses the importance of user interface (re)design for WWW-based courses. The University's focus on student evaluations of…

Industry Partners

Science.gov Websites

Partnerships University Partners Government Partners Industry Partners Ansys, Inc. www.ansys.com AVL North www.ncode.com Henkel North America www.henkel-northamerica.com Quantum Signal LLC www.quantumsignal.com RAMDO Solutions ramdosolutions.com Rolls-Royce North America www.rolls-royce.com Soar Technology www.soartech.com

76 FR 1477 - Self-Regulatory Organizations; NYSE Arca, Inc.; Notice of Filing of Proposed Rule Change Relating...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-10

... site at http://www.factorshares.net or a Fund's periodic reports on Form 10-Q and/ or Form 10-K as... leveraged basis, each Fund will seek to rebalance daily both its long and short positions around the net asset value (``NAV'') Calculation Time (as described below under ``Net Asset Value''). The purpose of...

Russian and CIS Library Internet Service: An Analysis of WWW-Server Development.

ERIC Educational Resources Information Center

Shraiberg, Yakov

This paper traces the expansion of the Internet into Russian and Commonwealth of Independent States (CIS) libraries from basic access to the development of World Wide Web (WWW) servers. An analysis of the most representative groups of library WWW-servers arranged by projects, by corporate library network, or by geographical characteristics is…

Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families.

PubMed

Okuda, Hiroko; Noguchi, Atsuko; Kobayashi, Hatasu; Kondo, Daiki; Harada, Kouji H; Youssefian, Shohab; Shioi, Hirotomo; Kabata, Risako; Domon, Yuki; Kubota, Kazufumi; Kitano, Yutaka; Takayama, Yasunori; Hitomi, Toshiaki; Ohno, Kousaku; Saito, Yoshiaki; Asano, Takeshi; Tominaga, Makoto; Takahashi, Tsutomu; Koizumi, Akio

2016-01-01

Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations.

Dose-related ethanol intake, Cx43 and Nav1.5 remodeling: Exploring insights of altered ventricular conduction and QRS fragmentation in excessive alcohol users.

PubMed

Hung, Chung-Lieh; Lai, Yu-Jun; Chi, Po-Ching; Chen, Liang-Chia; Tseng, Ya-Ming; Kuo, Jen-Yuan; Lin, Cheng-I; Chen, Yao-Chang; Lin, Shing-Jong; Yeh, Hung-I

2018-01-01

Chronic, excessive ethanol intake has been linked with various electrical instabilities, conduction disturbances, and even sudden cardiac death, but the underlying cause for the latter is insufficiently delineated. We studied surface electrocardiography (ECG) in a community-dwelling cohort with moderate-to-heavy daily alcohol intake (grouped as >90g/day, ≤90g/day, and nonintake). Compared with nonintake, heavier alcohol users showed markedly widened QRS duration and higher prevalence of QRS fragmentation (64.3%, 50.9%, and 33.7%, respectively, χ 2 12.0, both p<0.05) on surface ECG across the 3 groups. These findings were successfully recapitulated in 14-week-old C57BL/6 mice that were chronically given a 4% or 6% alcohol diet and showed dose-related slower action potential upstroke, reduced resting membrane potential, and disorganized or decreased intraventricular conduction (all p<0.05). Immunodetection further revealed increased ventricular collagen I depots with Cx43 downregulation and remodeling, together with clustered and diminished membrane Nav1.5 distribution. Administration of Cx43 blocker (heptanol) and Nav1.5 inhibitor (tetrodotoxin) in the mice each attenuated the suppression ventricular conduction compared with nonintake mice (p<0.05). Chronic excessive alcohol ingestion is associated with dose-related phenotypic intraventricular conduction disturbances and QRS fragmentation that can be recapitulated in mice. The mechanisms may involve suppressed gap junction and sodium channel functions, together with enhanced cardiac fibrosis that may contribute to arrhythmogenesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of recombinant cell line co-expressing mutated Nav1.5, Kir2.1, and hERG for the safety assay of drug candidates.

PubMed

Fujii, Masato; Ohya, Susumu; Yamamura, Hisao; Imaizumi, Yuji

2012-07-01

To provide a high-throughput screening method for human ether-a-go-go-gene-related gene (hERG) K(+) channel inhibition, a new recombinant cell line, in which single action potential (AP)-induced cell death was produced by gene transfection. Mutated human cardiac Na(+) channel Nav1.5 (IFM/Q3), which shows extremely slow inactivation, and wild-type inward rectifier K(+) channel, Kir2.1, were stably co-expressed in HEK293 cells (IFM/Q3+Kir2.1). In IFM/Q3+Kir2.1, application of single electrical stimulation (ES) elicited a long AP lasting more than 30 s and led cells to die by more than 70%, whereas HEK293 co-transfected with wild-type Nav1.5 and Kir2.1 fully survived. The additional expression of hERG K(+) channels in IFM/Q3+Kir2.1 shortened the duration of evoked AP and thereby markedly reduced the cell death. The treatment of the cells with hERG channel inhibitors such as nifekalant, E-4031, cisapride, terfenadine, and verapamil, recovered the prolonged AP and dose-dependently facilitated cell death upon ES. The EC(50) values to induce the cell death were 3 µM, 19 nM, 17 nM, 74 nM, and 3 µM, respectively, whereas 10 µM nifedipine did not induce cell death. Results indicate the high utility of this cell system for hERG K(+) channel safety assay.

Port Needs Study (Vessel Traffic Services Benefits) : Volume 2. Appendices, Part 1.

DOT National Transportation Integrated Search

1991-08-01

Volume II focuses on organization and presentation of information for each individual study zone. It contains the appendix tables of input data, output statistics and the documentation of the candidate Vessel Traffic Service (VTS) Design by NavCom Sy...

Port Needs Study (Vessel Traffic Services Benefits) : Volume 2. Appendices, Part 2.

DOT National Transportation Integrated Search

1991-01-01

Volume II focuses on organization and presentation of information for each individual study zone. It contains the appendix tables of input data, output statistics and the documentation of the candidate Vessel Traffic Services (VTS) Design by NavCom S...

Private Military Industry Analysis: Private and Public Companies

DTIC Science & Technology

2007-12-01

Consulting info@mushriquiconsulting.com (800) 567 2821/(484) 452 6523 www.mushriquiconsulting.com/ MVM , Inc. (703) 790 3138 www.mvminc.com...Website.” www.mushriquiconsulting.com/ (assessed September 2007). “ MVM , Inc. Official Website.” www.mvminc.com/ (assessed September 2007). “MZM

CancerNet redistribution via WWW.

PubMed

Quade, G; Püschel, N; Far, F

1996-01-01

CancerNet from the National Cancer Institute contains nearly 500 ASCII-files, updated monthly, with up-to-date information about cancer and the "Golden Standard" in tumor therapy. Perl scripts are used to convert these files to HTML-documents. A complex algorithm, using regular expression matching and extensive exception handling, detects headlines, listings and other constructs of the original ASCII-text and converts them into their HTML-counterparts. A table of contents is also created during the process. The resulting files are indexed for full-text search via WAIS. Building the complete CancerNet WWW redistribution takes less than two hours with a minimum of manual work. For 26,000 requests of information from our service per month the average costs for the worldwide delivery of one document is about 19 cents.

A WWW-Based Archive and Retrieval System for Multimedia

NASA Technical Reports Server (NTRS)

Hyon, J.; Sorensen, S.; Martin, M.; Kawasaki, K.; Takacs, M.

1996-01-01

This paper describes the Data Distribution Laboratory (DDL) and discusses issues involved in building multimedia CD-ROMs. It describes the modeling philosophy for cataloging multimedia products and the worldwide-web (WWW)-based multimedia archive and retrieval system (Webcat) built on that model.

A World Wide Web (WWW) server database engine for an organelle database, MitoDat.

PubMed

Lemkin, P F; Chipperfield, M; Merril, C; Zullo, S

1996-03-01

We describe a simple database search engine "dbEngine" which may be used to quickly create a searchable database on a World Wide Web (WWW) server. Data may be prepared from spreadsheet programs (such as Excel, etc.) or from tables exported from relationship database systems. This Common Gateway Interface (CGI-BIN) program is used with a WWW server such as available commercially, or from National Center for Supercomputer Algorithms (NCSA) or CERN. Its capabilities include: (i) searching records by combinations of terms connected with ANDs or ORs; (ii) returning search results as hypertext links to other WWW database servers; (iii) mapping lists of literature reference identifiers to the full references; (iv) creating bidirectional hypertext links between pictures and the database. DbEngine has been used to support the MitoDat database (Mendelian and non-Mendelian inheritance associated with the Mitochondrion) on the WWW.

A Framework for WWW Query Processing

NASA Technical Reports Server (NTRS)

Wu, Binghui Helen; Wharton, Stephen (Technical Monitor)

2000-01-01

Query processing is the most common operation in a DBMS. Sophisticated query processing has been mainly targeted at a single enterprise environment providing centralized control over data and metadata. Submitting queries by anonymous users on the web is different in such a way that load balancing or DBMS' accessing control becomes the key issue. This paper provides a solution by introducing a framework for WWW query processing. The success of this framework lies in the utilization of query optimization techniques and the ontological approach. This methodology has proved to be cost effective at the NASA Goddard Space Flight Center Distributed Active Archive Center (GDAAC).

Web-phreeq: a WWW instructional tool for modeling the distribution of chemical species in water

NASA Astrophysics Data System (ADS)

Saini-Eidukat, Bernhardt; Yahin, Andrew

1999-05-01

A WWW-based tool, WEB-PHREEQ, was developed for classroom teaching and for routine calculation of low temperature aqueous speciation. Accessible with any computer that has an internet-connected forms-capable WWW-browser, WEB-PHREEQ provides user interface and other support for modeling, creates a properly formatted input file, passes it to the public domain program PHREEQC and returns the output to the WWW browser. Users can calculate the equilibrium speciation of a solution over a range of temperatures or can react solid minerals or gases with a particular water and examine the resulting chemistry. WEB-PHREEQ is one of a number of interactive distributed-computing programs available on the WWW that are of interest to geoscientists.

WWW Entrez: A Hypertext Retrieval Tool for Molecular Biology.

ERIC Educational Resources Information Center

Epstein, Jonathan A.; Kans, Jonathan A.; Schuler, Gregory D.

This article describes the World Wide Web (WWW) Entrez server which is based upon the National Center for Biotechnology Information's (NCBI) Entrez retrieval database and software. Entrez is a molecular sequence retrieval system that contains an integrated view of portions of Medline and all publicly available nucleotide and protein databases,…

Characterization of comQ and comX, Two Genes Required for Production of ComX Pheromone in Bacillus subtilis

PubMed Central

Schneider, Katherine Bacon; Palmer, Tanya M.; Grossman, Alan D.

2002-01-01

Many microbes use secreted peptide-signaling molecules to stimulate changes in gene expression in response to high population density, a process called quorum sensing. ComX pheromone is a modified 10-amino-acid peptide used by Bacillus subtilis to modulate changes in gene expression in response to crowding. comQ and comX are required for production of ComX pheromone. We found that accumulation of ComX pheromone in culture supernatant paralleled cell growth, indicating that there was no autoinduction of production of ComX pheromone. We overexpressed comQ and comX separately and together and found that overexpression of comX alone was sufficient to cause an increase in production of ComX pheromone and early induction of a quorum-responsive promoter. These results indicate that the extracellular concentration of ComX pheromone plays a major role in determining the timing of the quorum response and that expression of comX is limiting for production of ComX pheromone. We made alanine substitutions in the residues that comprise the peptide backbone of ComX pheromone. Analysis of these mutants highlighted the importance of the modification for ComX pheromone function and identified three residues (T50, G54, and D55) that are unlikely to interact with proteins involved in production of or response to ComX pheromone. We have also identified and mutated a putative isoprenoid binding domain of ComQ. Mutations in this domain eliminated production of ComX pheromone, consistent with the hypothesis that ComQ is involved in modifying ComX pheromone and that the modification is likely to be an isoprenoid. PMID:11751817

Prospective motion correction with volumetric navigators (vNavs) reduces the bias and variance in brain morphometry induced by subject motion.

PubMed

Tisdall, M Dylan; Reuter, Martin; Qureshi, Abid; Buckner, Randy L; Fischl, Bruce; van der Kouwe, André J W

2016-02-15

Recent work has demonstrated that subject motion produces systematic biases in the metrics computed by widely used morphometry software packages, even when the motion is too small to produce noticeable image artifacts. In the common situation where the control population exhibits different behaviors in the scanner when compared to the experimental population, these systematic measurement biases may produce significant confounds for between-group analyses, leading to erroneous conclusions about group differences. While previous work has shown that prospective motion correction can improve perceived image quality, here we demonstrate that, in healthy subjects performing a variety of directed motions, the use of the volumetric navigator (vNav) prospective motion correction system significantly reduces the motion-induced bias and variance in morphometry. Copyright © 2015 Elsevier Inc. All rights reserved.

Ionospheric Electron/Ion Densities Temperatures on CD-ROM and WWW

NASA Technical Reports Server (NTRS)

Bilitza, Dieter; Papitashvili, Natasha; Schar, Bill; Grebowsky, Joseph

2002-01-01

As part of this project a large volume of ionospheric satellite insitu data from the sixties, seventies and early eighties were made accessible online in ASCII format for public use. This includes 14 data sets from the BE-B, Alouette 2, DME-A, AE-B, ISIS-1, ISIS-2, OGO-6, DE-2, AEROS-A, AE-C, AE-D, AE-E, and Hinotori satellites. The original data existed in various machine-specific, highly compressed, binary encoding on 7-, or 9-track magnetic tapes. The data were decoded and converted to a common ASCII data format, solar and magnetic indices were added, and some quality control measures were taken. The original intent of producing CD-ROMs with these data was overtaken by the rapid development of the Internet. Most users now prefer to obtain the data directly online and greatly value WWW-interfaces to browse, plot and subset the data. Accordingly the data were made available online on the anonymous ftp site of NASA's National Space Science Data Center (NSSDC) at ftp://nssdcftp.gsfc.nasa.gov/spacecraft data/ and on NSSDC's ATMOWeb (http://nssdc.gsfc.nasa.gov/atmoweb/), a WWW-interface for plotting, subsetting, and downloading the data. Several new features were implemented into ATMOWeb as part of this project including a filtering and scatter plot capability. The availability of this new database and WWW system was announced through several electronic mailer (AGU, CEDAR, IRI, etc) and through talks and posters during scientific meetings.

CFD Data Sets on the WWW for Education and Testing

NASA Technical Reports Server (NTRS)

Globus, Al; Lasinski, T. A. (Technical Monitor)

1995-01-01

The Numerical Aerodynamic Simulation (NAS) Systems Division at NASA Ames Research Center has begun the development of a Computational Fluid Dynamics (CFD) data set archive on the World Wide Web (WWW) at URL http://www.nas.nasa.gov/NAS/DataSets/. Data sets are integrated with related information such as research papers, metadata, visualizations, etc. In this paper, four classes of users are identified and discussed: students, visualization developers, CFD practitioners, and management. Bandwidth and security issues are briefly reviewed and the status of the archive as of May 1995 is examined. Routine network distribution of data sets is likely to have profound implications for the conduct of science. The exact nature of these changes is subject to speculation, but the ability for anyone to examine the data, in addition to the investigator's analysis, may well play an important role in the future.

The WWW Cabinet of Curiosities: A Serendipitous Research Tool

ERIC Educational Resources Information Center

Arnold, Josie

2012-01-01

This paper proposes that the WWW is able to be fruitfully understood as a research tool when we utilise the metaphor of the cabinet of curiosities, the wunderkammer. It unpeels some of the research attributes of the metaphor as it reveals the multiplicity of connectivity on the web that provides serendipitous interactions between unexpected…

A Business Case Study of Open Source Software

DTIC Science & Technology

2001-07-01

LinuxPPC LinuxPPC www.linuxppc.com MandrakeSoft Linux -Mandrake www.linux-mandrake.com/ en / CLE Project CLE cle.linux.org.tw/CLE/e_index.shtml Red Hat... en Coyote Linux www2.vortech.net/coyte/coyte.htm MNIS www.mnis.fr Data-Portal www.data-portal.com Mr O’s Linux Emporium www.ouin.com DLX Linux www.wu...1998 1999 Year S h ip m en ts ( in m ill io n s) Source: IDC, 2000. Figure 11. Worldwide New Linux Shipments (Client and Server) 3.2.2 Market

Publisher Correction: N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications.

PubMed

Wang, Yang; Li, Yue; Yue, Minghui; Wang, Jun; Kumar, Sandeep; Wechsler-Reya, Robert J; Zhang, Zhaolei; Ogawa, Yuya; Kellis, Manolis; Duester, Gregg; Zhao, Jing Crystal

2018-06-07

In the version of this article initially published online, there were errors in URLs for www.southernbiotech.com, appearing in Methods sections "m6A dot-blot" and "Western blot analysis." The first two URLs should be https://www.southernbiotech.com/?catno=4030-05&type=Polyclonal#&panel1-1 and the third should be https://www.southernbiotech.com/?catno=6170-05&type=Polyclonal. In addition, some Methods URLs for bioz.com, www.abcam.com and www.sysy.com were printed correctly but not properly linked. The errors have been corrected in the PDF and HTML versions of this article.

A mid-IR study of the circumstellar environment of Herbig Be stars

NASA Astrophysics Data System (ADS)

Verhoeff, A. P.; Waters, L. B. F. M.; van den Ancker, M. E.; Min, M.; Stap, F. A.; Pantin, E.; van Boekel, R.; Acke, B.; Tielens, A. G. G. M.; de Koter, A.

2012-02-01

Context. The study of the formation of massive stars is complicated because of the short times scales, large distances, and obscuring natal clouds. There are observational and theoretical indications that the circumstellar environment of Herbig Be (HBe) stars is substantially different from that of their lower mass counterparts, the T Tauri and Herbig Ae stars. Aims: We map the spatial distribution and mineralogy of the warm circumstellar dust of a sample of HBe stars. We compare our results to a sample of less massive Herbig Ae stars. Methods: We used literature photometry to obtain optical extinctions and stellar parameters of the targets. We obtained N-band imaging and long-slit spectroscopic data with the VISIR instrument at the VLT and we analyzed these data. We performed photometry of the images and extracted spatial information. We corrected the spectra for extinction and performed mineralogical fits. We fitted Gaussian profiles to characterize the spatial extent of the spectra along the VISIR slit. Results: We find that the mid-infrared (IR) emission of the HBe stars is typically characterized by a circumstellar disk that efficiently reprocesses a substantial portion of the stellar flux. The mid-IR flux levels, the spatial compactness, and the dust composition are quite similar to those of the Herbig Ae stars. We find upper limits to the full-width-at-half-maximum (FWHM) size of the mid-IR emission of ~500 AU. The main differences with the lower mass stars are the lower overall IR excess with a greater variety in shapes, the weaker PAH reprocessing power, and the lack of a silica-forsterite relation. The discrepancies between VISIR and IRAS photometry, the far-IR contributions and the large PAH sizes of HBe stars are attributed to natal clouds. Conclusions: Our results suggest that the Herbig Be disks are flatter than those around lower mass stars and they are likely truncated from the outside by photoevaporation. Based on observations collected at the

[Learning from regional differences: online platform: http://www.versorgungsatlas.de].

PubMed

Mangiapane, S

2014-02-01

In 2011, the Central Research Institute of Ambulatory Health Care in Germany (ZI) published the website http://www.versorgungsatlas.de, a portal that presents research results from regional health services in Germany. The Web portal provides a publicly accessible source of information and a growing number of selected analyses focusing on regional variation in health care. Each topic is presented in terms of interactive maps, tables, and diagrams and is supplemented by a paper that examines the results in detail and provides an explanation of the findings. The portal has been designed to provide a forum on which health service researchers can publish their results derived from various data sources of different institutions in Germany and can comment on results already available on http://www.versorgungsatlas.de. For health policy actors, the discussion of regional differences offers a new, previously unavailable basis for determining the region-specific treatment needs and for providing health-care management with the goal of high-quality care for each resident.

Navigating the Road to Recovery: Assessment of the Coordination, Communication, and Financing of the Disaster Case Management Pilot in Louisiana

DTIC Science & Technology

2010-01-01

analysis methodology called constant comparative analysis ( Lincoln and Guba, 1985; Denzin and Lincoln , 2000). First, two RAND researchers independently...and Yvonna S. Lincoln , “Introduction: The Discipline and Practice of Qualitative Research,” in Norman K. Denzin and Yvonna S. Lincoln , eds...Management Services,” undated web page. As of June 3, 2010: http://www.coastandards.org/standards.php?navView=private§ion_id=114 Denzin , Norman K

FTIR spectra of the solid solutions (Na0.88K0.12)VO3, (Na0.5K0.5)VO3, and Na(V0.66P0.34)O3

NASA Astrophysics Data System (ADS)

de Waal, D.; Heyns, A. M.

1992-03-01

It is known that three different solid solutions, (Na0.88K0.12)VO3, (Na0.5K0.5)VO3 and Na(V0.66P0.34)O3, form in the (Na,K)(V,P)O3 system. These compounds all have monoclinic crystal structures similar to the pure alkali metal metavanadates containing small cations, e.g. Li+ and Na+ (Space group C2/c). Metavanadates with large cations like K+, Rb+, C+s and NH+4 form orthorhombic crystals, space group Pbcm. All those are structurally related to the silicate pyroxenes. Na(V0.66P0.34)O3 and (Na0.88K0.12)VO3 have the same modified diopside structure as (alpha) - NaVO3 while (Na0.5K0.5)VO3 adopts the true diopside structure. The infrared spectra of the three solid solutions are reported here in comparison with those of (alpha) -NaVO3 and KVO3. The results are also correlated with those obtained in two independent high pressure Raman studies of NH4VO3 and RbVO3 as the introduction of a larger cation like K+ should increase the pressure in the structure.

[Development of laboratory sequence analysis software based on WWW and UNIX].

PubMed

Huang, Y; Gu, J R

2001-01-01

Sequence analysis tools based on WWW and UNIX were developed in our laboratory to meet the needs of molecular genetics research in our laboratory. General principles of computer analysis of DNA and protein sequences were also briefly discussed in this paper.

D-dimer Test

MedlinePlus

... http://www.beckmancoulter.com . Began, T. (2002 October). Elisa D-Dimer: How Accurate For PE Diagnosis? PulmonaryReviews. ... at http://www.pulmonaryreviews.com/oct02/pr_oct02_ELISA.html through http://www.pulmonaryreviews.com . Cortese Hassett, ...

Highly Interactive WWW Services: A New Type of Information Sources.

ERIC Educational Resources Information Center

Vanouplines, Patrick; Nieuwenhuysen, P.

The World Wide Web is evolving from a collection of texts linked by hypertext and hypermedia toward services that operate interactively with the information user, and which offer results through use of a broad spectrum of tools. This paper presents a collection of interactive WWW services. The services are classified on the basis of the client…

Chromate Free Magnesium Gearbox Protection System

DTIC Science & Technology

2014-11-01

default.cfm?page=375 Ref 5: Rolls-Royce Front Frame example Ref 6: http://www.volksworld.com/blog/staff-blogs/jons-blog/stripping- down-a-donor- beetle ...www.fwtec.com/FW/nanosolution.html# Ref 10 http://www.arl.army.mil/www/default.cfm?page=375 Ref 5: Rolls-Royce Front Frame example Ref 6: http://www.volksworld.com/blog/staff-blogs/jons-blog/stripping- down-a-donor- beetle -engine/

Visualization of Client-Side Web Browsing and Email Activity

DTIC Science & Technology

2009-06-01

mantenimiento the amazing race dustin & candice oskar schindler mythbusters femjoy 080814-kathi in peace anna_ac_-_elixia miley cyrus mapa linea 12 metro... mantenimiento www.google.com.mx alcohol isopropilico www.google.com.mx descargas rapidshare corta final firefox www.google.com.mx desactivar

Virtual dermatohistopathology at http://www.pathowiki.org.

PubMed

Roßner, Mathias; Roßner, Florian; Zwönitzer, Ralf; Hofmann, Harald; Sterry, Wolfram; Kalinski, Thomas

2012-04-01

PATHOWIKI (http://www.pathowiki.org) is a new specialized information system in the form of a web-based wiki with content from all sub-disciplines of human pathology. Essential components are articles and specimens which are located thematically in dermatopathology. The project is presented on the basis of impressive examples and possibilities. The ability to link all kinds of content and integrate pattern analysis theories creates an effective tool for teaching and training in dermatopathology. Collaborative work ensures the effective usage of available resources and a continually growing amount of content, the quality of which depends on the number of users and should be as high as possible. Therefore, all interested colleagues are invited to support the project. © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.

Use of the WWW as a Collaborative Tool in a Large HEP Collaboration

NASA Astrophysics Data System (ADS)

Bower, G.; Dubois, R.; Johnson, A. S.; Moss, L.; Perl, J.; Langston, M.; Weiss, E.

As the phenomenal growth of the WWW continues it is easy to view it purely as a tool for PR and advertising, and to forget its roots as a collaborative tool for HEP research. The SLD collaboration has made extensive use of WWW in this latter role, using it to allow collaborators to sign up for shifts, to monitor physics data-taking in near real time, and as a tool to educate and inform collaborators. By their nature such tools are accessible to all collaborators wherever they are located. In this talk we will describe our current system and comment on its effectiveness, and discuss possible enhancements based on forthcoming more powerful web browsers.

Improved Coast Guard Communications Using Commercial Satellites and WWW Technology: Slide Presentation

DOT National Transportation Integrated Search

1997-06-18

The slides in this file amplify a paper that was presented at International Mobile Satellite Conference, (IMSC-97), Pasadena CA on 18 June 1997. The text of that presentation can be found at http://www.bts.gov/NTL/data/imsc.pdf.

Public Support As A Center Of Gravity For National Space Power

DTIC Science & Technology

2014-04-01

Musk, CEO of Space Exploration Technologies Corp ( SpaceX ), “oversees development of rockets and spacecraft for missions to Earth orbit and ultimately...University Press, 2002. Space Camp, “About Space Camp,” http://www.spacecamp.com/about SpaceX , “Company,” SpaceX.com, http://www.spacex.com/about...Accessed 9 April 2014). SpaceX , “Leadership,” SpaceX.com, http://www.spacex.com/about/leadership (Accessed 9 April 2014). Tate, Karl. Columbia

A reappraisal of the Middle Triassic chirotheriid Chirotherium ibericus Navás, 1906 (Iberian Range NE Spain), with comments on the Triassic tetrapod track biochronology of the Iberian Peninsula

PubMed Central

Castanera, Diego; Gasca, José Manuel; Canudo, José Ignacio

2015-01-01

Triassic vertebrate tracks are known from the beginning of the 19th century and have a worldwide distribution. Several Triassic track ichnoassemblages and ichnotaxa have a restricted stratigraphic range and are useful in biochronology and biostratigraphy. The record of Triassic tracks in the Iberian Peninsula has gone almost unnoticed although more than 25 localities have been described since 1897. In one of these localities, the naturalist Longinos Navás described the ichnotaxon Chirotherium ibericus in 1906.The vertebrate tracks are in two sandy slabs from the Anisian (Middle Triassic) of the Moncayo massif (Zaragoza, Spain). In a recent revision, new, previously undescribed vertebrate tracks have been identified. The tracks considered to be C. ibericus as well as other tracks with the same morphology from both slabs have been classified as Chirotherium barthii. The rest of the tracks have been assigned to Chirotheriidae indet., Rhynchosauroides isp. and undetermined material. This new identification of C. barthii at the Navás site adds new data to the Iberian record of this ichnotaxon, which is characterized by the small size of the tracks when compared with the main occurrences of this ichnotaxon elsewhere. As at the Navás tracksite, the Anisian C. barthii-Rhynchosauroides ichnoassemblage has been found in other coeval localities in Iberia and worldwide. This ichnoassemblage belongs to the upper Olenekian-lower Anisian interval according to previous biochronological proposals. Analysis of the Triassic Iberian record of tetrapod tracks is uneven in terms of abundance over time. From the earliest Triassic to the latest Lower Triassic the record is very scarce, with Rhynchosauroides being the only known ichnotaxon. Rhynchosauroides covers a wide temporal range and gives poor information for biochronology. The record from the uppermost Lower Triassic to the Middle Triassic is abundant. The highest ichnodiversity has been reported for the Anisian with an

[Preparation of the database and the Internet (WWW) homepage for regulations on chemicals in Japan].

PubMed

Yamamoto, M; Morita, M; Kaminuma, T

1999-01-01

We prepared a database on chemical regulations in Japan. The regulations consist of "The Law concerning the Examination and Regulation of Manufacture, etc., of Chemical Substances", "Poisonous and Deleterious Substances", Control Law", "Waterworks Law", "Law for the Control of Household Products containing Harmful Substances", and Pesticide Residues in Food Sanitation Law". We also set up a World Wide Web (WWW) homepage containing an explanation of the law as well as chemical names, CAS registry numbers, and standards. The WWW pages contain lists of chemicals and the retrieval page for the database.

Yahoo! Alternatives.

ERIC Educational Resources Information Center

Pack, Thomas

1999-01-01

Presents overviews of three relatively new sites that have much in common with the directory "Yahoo!"-Snap (http://www.snap.com), LookSmart (http://www.looksmart.com), and eBLAST (http://www.eBLAST.com). Describes findings of sample searches to help users compare and contrast the type of results that can be expected from each directory.…

A WWW-based information system on resistance of bacteria to antibiotics.

PubMed

Schindler, J; Schindler, Z; Schindler, J

1998-01-01

The information system on resistance of bacteria to antibiotics (WARN--World Antibiotic Resistance Network) is implemented as a WWW server at Charles University in Prague (http:/(/)www.warn.cas.cz). Its main goal is to give information about problems of antibiotic resistance of bacteria and to process data on isolated strains. The WARN web-site contains six main topics. Four of them form the core of the system: Topics of Interest bring information on selected timely topics in antibiotic resistance--pneumococci, staphylococci, beta-lactamases, glycopeptide--and aminoglycoside resistance. Global Monitor brings references and reports on resistance in the world as well as recommended method of surveillance. The topic Data contains raw data on strains in particular countries and hospitals. Data can be viewed in their original form as a list of records (strains) or processed to provide statistics about the resistance rates in the selected country or hospital respectively. The topic Search allows one to search for one or several terms in the whole document. Counts of accessed pages show, that there is a standing demand for information about the serious problems of antibiotic therapy of infectious diseases.

Wheezing

MedlinePlus

... in adults. http://www.uptodate.com/home. Accessed March 24, 2017. Oo S, et al. The wheezing child: An ... Elsevier Saunders; 2017. http://www.clinicalkey.com. Accessed March 24, 2017. Wheezing. Merck Manual Professional Version. http://www. ...

Are You Considering a Complementary Health Approach?

MedlinePlus

... nih.nccih ), Twitter ( www.twitter.com/nih_nccih ), YouTube ( www.youtube.com/c/nih_nccih ), and Pinterest ( www.pinterest. ... links Facebook Read our disclaimer about external links YouTube Read our disclaimer about external links Google+ Read ...

RQ-2 Pioneer: The Flawed System that Redefined US Unmanned Aviation

DTIC Science & Technology

2012-02-01

Periscope.com, “RQ-2 Pioneer,” http://www.militaryperiscope.com/weapons/aircraft/rpv- dron /w0004685.html 28 Ibid. 29 Jane’s Unmanned Aerial...Military Periscope.com, “RQ-2 Pioneer.” http://www.militaryperiscope.com/weapons/aircraft/rpv- dron /w0004685.html Polmar, Norman, The Naval

NASA Parts Selection List (NPSL) WWW Site http://nepp.nasa.gov/npsl

NASA Technical Reports Server (NTRS)

Brusse, Jay

2000-01-01

The NASA Parts Selection List (NPSL) is an on-line resource for electronic parts selection tailored for use by spaceflight projects. The NPSL provides a list of commonly used electronic parts that have a history of satisfactory use in spaceflight applications. The objective of this www site is to provide NASA projects, contractors, university experimenters, et al with an easy to use resource that provides a baseline of electronic parts from which designers are encouraged to select. The NPSL is an ongoing resource produced by Code 562 in support of the NASA HQ funded NASA Electronic Parts and Packaging (NEPP) Program. The NPSL is produced as an electronic format deliverable made available via the referenced www site administered by Code 562. The NPSL does not provide information pertaining to patented or proprietary information. All of the information contained in the NPSL is available through various other public domain resources such as US Military procurement specifications for electronic parts, NASA GSFC's Preferred Parts List (PPL-21), and NASA's Standard Parts List (MIL-STD975).

Adding Nonlinear Tools to the Strategist’s Toolbox

DTIC Science & Technology

2001-06-01

between interests. Idealists base their arguments on the pioneers like Hugo Grotius (1583-1645) and Immanuel Kant (1724-1804). The Idealist school based...12Blupete, [website]: available from http://www.blupete.com/Literature/ Biographies / Philosophy/Popper.htm; Internet. 13Glesne and Peshkin, 24. 39...www.blupete.com/Literature/ Biographies / Philosophy/Popper.htm. Internet. Dean Robbins, Brent. Mythos and Logos. Available from http://www.geocities.com/ Athens

Lab Note: Training the Cyber Defensive Line

DTIC Science & Technology

2016-05-02

available at http://www.nextgov.com/cybersecurity/2013/03/how-many-cyberattacks-hit-united-states-last- year/61775/. 2 “Verizon 2015 Data Breach Investigation...at http://www.prnewswire.com/news-releases/verizon-2015- data - breach -investigations-report-finds- cyberthreats-are-increasing-in-sophistication-yet...Verizon’s Data Breach Investigations Report (available on request from http://www.verizonenterprise.com/DBIR/). The blue team must ensure that their

Alternatives to Center of Gravity Analysis

DTIC Science & Technology

2013-04-04

Field Manual 3-0 Operations (FM 3-0), A-1-A-4, and Mission & Values, McDonalds. http://www.aboutmcdonalds.com/ mcd /our_ company...Porter, Competitive Strategy, 1980. “Mission & Values,” McDonalds. http://www.aboutmcdonalds.com/ mcd /our_ company/mission_and_values.html...Thailand and Cambodia reach deal on temple border,”BBC.com, December 11, 2011. http://www.bbc.co.uk/news/world- asia -pacific-16294309. “The

Onco-Regulon: an integrated database and software suite for site specific targeting of transcription factors of cancer genes

PubMed Central

Tomar, Navneet; Mishra, Akhilesh; Mrinal, Nirotpal; Jayaram, B.

2016-01-01

Transcription factors (TFs) bind at multiple sites in the genome and regulate expression of many genes. Regulating TF binding in a gene specific manner remains a formidable challenge in drug discovery because the same binding motif may be present at multiple locations in the genome. Here, we present Onco-Regulon (http://www.scfbio-iitd.res.in/software/onco/NavSite/index.htm), an integrated database of regulatory motifs of cancer genes clubbed with Unique Sequence-Predictor (USP) a software suite that identifies unique sequences for each of these regulatory DNA motifs at the specified position in the genome. USP works by extending a given DNA motif, in 5′→3′, 3′ →5′ or both directions by adding one nucleotide at each step, and calculates the frequency of each extended motif in the genome by Frequency Counter programme. This step is iterated till the frequency of the extended motif becomes unity in the genome. Thus, for each given motif, we get three possible unique sequences. Closest Sequence Finder program predicts off-target drug binding in the genome. Inclusion of DNA-Protein structural information further makes Onco-Regulon a highly informative repository for gene specific drug development. We believe that Onco-Regulon will help researchers to design drugs which will bind to an exclusive site in the genome with no off-target effects, theoretically. Database URL: http://www.scfbio-iitd.res.in/software/onco/NavSite/index.htm PMID:27515825

Calendar

NASA Astrophysics Data System (ADS)

2004-04-01

MAY 2004 GARP's 3rd Credit & Counterparty Risk Summit, London, UK 21-23 May 2004 Andreas Simou (andreas.simou@garp.com), +44 (0)20 7626 9301, www.garp.com/events/3rdcred IMA Workshop 9: Financial Data Analysis and Applications, University of Minnesota, MN, USA 24-28 May 2004 www.ima.umn.edu/complex/spring/c9.html Global Derivatives & Risk Management 2004, NH Eurobuilding, Madrid, Spain 25-28 May 2004 Aden Watkins, ICBI (awatkins@iirltd.co.uk), +44 (0)20 7915 5198, www.icbi-uk.com/globalderivatives/ WEHIA'04 9th Workshop on Economics and Heterogeneous Interacting Agents, Kyodai-Kaikan, Kyoto, Japan 27-29 May 2004 www.nda.ac.jp/cs/AI/wehia04/ JUNE 2004 Semimartingale Theory and Practice in Finance, Pacific Institute for the Mathematical Sciences, Vancouver, BC, Canada 5-10 June 2004 www.pims.math.ca/birs/workshops/2004/04w5032/ MC2QMC 2004 International Conference on Monte Carlo and Quasi-Monte Carlo Methods, Juan-les-Pins, Côte d'Azur, France 7-10 June 2004 Monique Simonetti (Monique.Simonetti@sophia.inria.fr), +33 4 92 38 78 64, www-sop.inria.fr/omega/MC2QMC2004/ GAIM'04 10th Annual Global Alternative Investment Management Forum, The Beaulieu Centre, Lausanne, Switzerland 8-11 June 2004 +44 (0)20 7915 5103, www.icbi-uk.com/gaim/ 3rd Annual Conference Ri$k Management 2004, Fairmont Hotel, Dubai, United Arab Emirates 12-15 June 2004 www.iirme.com/risk/ 10th Annual Risk USA Congress, Boston, MA, USA 21-24 June 2004 Aristotle Liu (aliu@riskwaters.com), +44 (0)207 484 9700, www.riskusa.com Mannheim Empirical Research Summer School, Mannheim University, Germany 22 June-2 July 2004 oliver@kirchkamp.de, www.sfb504.uni-mannheim.de/merss 9th Annual Conference on Econometric Modelling for Africa, Cape Town, South Africa 30 June-2 July 2004 aesinfo@commerce.uct.ac.za, www.commerce.uct.ac.za/economics/AES2004Conference/ 4th Congress of Nonlinear Analysts. Special Session on Mathematical Methods in Theoretical Finance, Hyatt Grand Cypress Resort, Orlando, FL, USA 30 June-7 July

Extracellular Identification of a Processed Type II ComR/ComS Pheromone of Streptococcus mutans

PubMed Central

Khan, Rabia; Rukke, Håkon V.; Ricomini Filho, Antonio Pedro; Fimland, Gunnar; Arntzen, Magnus Ø.; Thiede, Bernd

2012-01-01

The competence-stimulating peptide (CSP) and the sigX-inducing peptide (XIP) are known to induce Streptococcus mutans competence for genetic transformation. For both pheromones, direct identification of the native peptides has not been accomplished. The fact that extracellular XIP activity was recently observed in a chemically defined medium devoid of peptides, as mentioned in an accompanying paper (K. Desai, L. Mashburn-Warren, M. J. Federle, and D. A. Morrison, J. Bacteriol. 194:3774–3780, 2012), provided ideal conditions for native XIP identification. To search for the XIP identity, culture supernatants were filtered to select for peptides of less than 3 kDa, followed by C18 extraction. One peptide, not detected in the supernatant of a comS deletion mutant, was identified by tandem mass spectrometry (MS/MS) fragmentation as identical to the ComS C-terminal sequence GLDWWSL. ComS processing did not require Eep, a peptidase involved in processing or import of bacterial small hydrophobic peptides, since eep deletion had no inhibitory effect on XIP production or on synthetic XIP response. We investigated whether extracellular CSP was also produced. A reporter assay for CSP activity detection, as well as MS analysis of supernatants, revealed that CSP was not present at detectable levels. In addition, a mutant with deletion of the CSP-encoding gene comC produced endogenous XIP levels similar to those of a nondeletion mutant. The results indicate that XIP pheromone production is a natural phenomenon that may occur in the absence of natural CSP pheromone activity and that the heptapeptide GLDWWSL is an extracellular processed form of ComS, possibly the active XIP pheromone. This is the first report of direct identification of a ComR/ComS pheromone. PMID:22609914

NEW METABOLITES FROM THE MICROBIAL OXIDATION OF FLUORINATED AROMATIC COMPOUNDS. (R826113)

EPA Science Inventory

Abstract

m-Bromo-www.sciencedirect.com/scidirimg/entities/alpha.gif" alt="small alpha, Greek" border=0>,www.sciencedirect.com/scidirimg/entities/alpha.gif" alt="small alpha, Greek" border=0>,www.sciencedirect.co...

Leg Swelling

MedlinePlus

... painful swelling. Sterns RH. Pathophysiology and etiology of edema in adults. www.uptodate.com/home. Accessed Dec. 29, 2016. Edema. Merck Manual Professional Version. http://www.merckmanuals.com/ ...

Insights on WWW-based geoscience teaching: Climbing the first year learning cliff

NASA Astrophysics Data System (ADS)

Lamberson, Michelle N.; Johnson, Mark; Bevier, Mary Lou; Russell, J. Kelly

1997-06-01

In early 1995, The University of British Columbia Department of Geological Sciences (now Earth and Ocean Sciences) initiated a project that explored the effectiveness of the World Wide Web as a teaching and learning medium. Four decisions made at the onset of the project have guided the department's educational technology plan: (1) over 90% of funding recieved from educational technology grants was committed towards personnel; (2) materials developed are modular in design; (3) a data-base approach was taken to resource development; and (4) a strong commitment to student involvement in courseware development. The project comprised development of a web site for an existing core course: Geology 202, Introduction to Petrology. The web site is a gateway to course information, content, resources, exercises, and several searchable data-bases (images, petrologic definitions, and minerals in thin section). Material was developed on either an IBM or UNIX machine, ported to a UNIX platform, and is accessed using the Netscape browser. The resources consist primarily of HTML files or CGI scripts with associated text, images, sound, digital movies, and animations. Students access the web site from the departmental student computer facility, from home or a computer station in the petrology laboratory. Results of a survey of the Geol 202 students indicate that they found the majority of the resources useful, and the site is being expanded. The Geology 202 project had a "trickle-up" effect throughout the department: prior to this project, there was minimal use of Internet resources in lower-level geology courses. By the end of the 1996-1997 academic year, we anticipate that at least 17 Earth and Ocean Science courses will have a WWW site for one or all of the following uses: (1) presenting basic information; (2) accessing lecture images; (3) providing a jumping-off point for exploring related WWW sites; (4) conducting on-line exercises; and/or (5) providing a communications forum

PHYSICS EDUCATION AND THE INTERNET: A beginner's guide to a physicist starting out on an Internet journey

NASA Astrophysics Data System (ADS)

Burton, Paul

1998-05-01

Thirty useful physics-related sites are listed to help get you started. I hope you will find some of the following sites of use in your teaching or good for pointing your pupils in the right direction when doing research. I have not attempted to rank or sort them in any order. However, by the time you read this issue of Physics Education some of the sites may not be available; this is the nature of the net. Those not wishing to retype each address can access them from my school's physics page (http://www.bootham.demon.co.uk/physics/links.html) or e-mail me at pkb@bootham.demon.co.uk and I can send you a document with the hypertext live links in. The new IOP sponsored 16-19 Physics project is promising great things with its own Internet site. You will be able to download information, updates, worksheets etc. Any queries about the development of this project at present can be sent to Evelyn van Dyk at: 16-19project@iop.org Engineering and Physical Sciences Research Councilhttp://www.epsrc.ac.uk Particle Physics and Astronomy Research Councilhttp://www.pparc.ac.uk American Institute of Physicshttp://www.aip.org Usenet Physics FAQ (frequently asked questions)http://www.weburbia.demon.co.uk/physics/faq.html CERNhttp://www.cern.ch/ BBC Educationhttp://www.bbc.co.uk/education/ Useful data on the Periodic Tablehttp://www.shef.ac.uk/chemistry/web-elements/ JET WWW index page:http://www.jet.uk NERC satellite station, Dundee Universityhttp://www.sat.dundee.ac.uk/ The Meteorological Officehttp://www.meto.govt.uk/ The Smithsonian Institute, Washington, DChttp://www.si.edu/newstart.htm Frequently asked questions on time and frequencyhttp://www.boulder.nist.gov/timefreq/faq/faq.htm Physics newshttp://www.het.brown.edu/news/index.html TIPTOP: The Internet Pilot to Physicshttp://www.tp.umu.se/TIPTOP/ A Dictionary of Scientific Quotationshttp://naturalscience.com/dsqhome.html ScI-Journal: an on-line publication for science studentshttp://www.soton.ac.uk/~plf/ScI-Journal/ Science On-linehttp://www

Association of Regulatory Boards of Optometry

MedlinePlus

... Fraud contact number) or https://www.chase.com/credit-cards/customer-service . In addition, individuals may also consider reviewing their current credit reports at https://www.annualcreditreport.com/index.action . ...

Are There Any Natural Remedies That Reduce Chronic Fatigue Associated with Chronic Fatigue Syndrome?

MedlinePlus

... management of chronic fatigue syndrome. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Accessed Feb. 23, 2015. Magnesium. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Accessed Feb. 24, 2015. ...

Molecular Characterization of Voltage-Gated Sodium Channels and Their Relations with Paralytic Shellfish Toxin Bioaccumulation in the Pacific Oyster Crassostrea gigas

PubMed Central

Boullot, Floriane; Castrec, Justine; Bidault, Adeline; Dantas, Natanael; Payton, Laura; Perrigault, Mickael; Tran, Damien; Amzil, Zouher; Boudry, Pierre; Soudant, Philippe; Hégaret, Hélène; Fabioux, Caroline

2017-01-01

Paralytic shellfish toxins (PST) bind to voltage-gated sodium channels (Nav) and block conduction of action potential in excitable cells. This study aimed to (i) characterize Nav sequences in Crassostrea gigas and (ii) investigate a putative relation between Nav and PST-bioaccumulation in oysters. The phylogenetic analysis highlighted two types of Nav in C. gigas: a Nav1 (CgNav1) and a Nav2 (CgNav2) with sequence properties of sodium-selective and sodium/calcium-selective channels, respectively. Three alternative splice transcripts of CgNav1 named A, B and C, were characterized. The expression of CgNav1, analyzed by in situ hybridization, is specific to nervous cells and to structures corresponding to neuromuscular junctions. Real-time PCR analyses showed a strong expression of CgNav1A in the striated muscle while CgNav1B is mainly expressed in visceral ganglia. CgNav1C expression is ubiquitous. The PST binding site (domain II) of CgNav1 variants possess an amino acid Q that could potentially confer a partial saxitoxin (STX)-resistance to the channel. The CgNav1 genotype or alternative splicing would not be the key point determining PST bioaccumulation level in oysters. PMID:28106838

Erectile Dysfunction Herbs: A Natural Treatment for ED?

MedlinePlus

... Analysis. 2015;102:476. DHEA. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Accessed Nov. 1, 2015. L-arginine. Natural Medicines Comprehensive Database. http://www.naturaldatabase.com. Accessed Nov. 1, 2015. ...

Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures

PubMed Central

Mantegazza, Massimo; Gambardella, Antonio; Rusconi, Raffaella; Schiavon, Emanuele; Annesi, Ferdinanda; Cassulini, Rita Restano; Labate, Angelo; Carrideo, Sara; Chifari, Rosanna; Canevini, Maria Paola; Canger, Raffaele; Franceschetti, Silvana; Annesi, Grazia; Wanke, Enzo; Quattrone, Aldo

2005-01-01

Febrile seizures (FS) affect 5–12% of infants and children up to 6 years of age. There is now epidemiological evidence that FS are associated with subsequent afebrile and unprovoked seizures in ≈7% of patients, which is 10 times more than in the general population. Extensive genetic studies have demonstrated that various loci are responsible for familial FS, and the FEB3 autosomal-dominant locus has been identified on chromosome 2q23–24, where the SCN1A gene is mapped. However, gene mutations causing simple FS have not been found yet. Here we show that the M145T mutation of a well conserved amino acid in the first transmembrane segment of domain I of the human Nav1.1 channel α-subunit cosegregates in all 12 individuals of a large Italian family affected by simple FS. Functional studies in mammalian cells demonstrate that the mutation causes a 60% reduction of current density and a 10-mV positive shift of the activation curve. Thus, M145T is a loss-of-function mutant. These results show that monogenic FS should also be considered a channelopathy. PMID:16326807

Seeing and Reading Red: Hue and Color-word Correlation in Images and Attendant Text on the WWW

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

Newsam, S

2004-07-12

This work represents an initial investigation into determining whether correlations actually exist between metadata and content descriptors in multimedia datasets. We provide a quantitative method for evaluating whether the hue of images on the WWW is correlated with the occurrence of color-words in metadata such as URLs, image names, and attendant text. It turns out that such a correlation does exist: the likelihood that a particular color appears in an image whose URL, name, and/or attendant text contains the corresponding color-word is generally at least twice the likelihood that the color appears in a randomly chosen image on the WWW.more » While this finding might not be significant in and of itself, it represents an initial step towards quantitatively establishing that other, perhaps more useful correlations exist. These correlations form the basis for exciting novel approaches that leverage semi-supervised datasets, such as the WWW, to overcome the semantic gap that has hampered progress in multimedia information retrieval for some time now.« less

www.elearnSCI.org: a global educational initiative of ISCoS.

PubMed

Chhabra, H S; Harvey, L A; Muldoon, S; Chaudhary, S; Arora, M; Brown, D J; Biering-Sorensen, F; Wyndaele, J J; Charlifue, S; Horsewell, J; Ducharme, S; Green, D; Simpson, D; Glinsky, J; Weerts, E; Upadhyay, N; Aito, S; Wing, P; Katoh, S; Kovindha, A; Krassioukov, A; Weeks, C; Srikumar, V; Reeves, R; Siriwardane, C; Hasnan, N; Kalke, Y B; Lanig, I

2013-03-01

To develop a web-based educational resource for health professionals responsible for the management of spinal cord injury (SCI). The resource:www.elearnSCI.org is comprised of seven learning modules, each subdivided into various submodules. Six of the seven modules address the educational needs of all disciplines involved in comprehensive SCI management. The seventh module addresses prevention of SCI. Each submodule includes an overview, activities, self-assessment questions and references. Three hundred and thirty-two experts from The International Spinal Cord Society (ISCoS) and various affiliated societies from 36 countries were involved in developing the resource through 28 subcommittees. The content of each submodule was reviewed and approved by the Education and Scientific Committees of ISCoS and finally by an Editorial Committee of 23 experts. The content of the learning modules is relevant to students and to new as well as experienced SCI healthcare professionals. The content is applicable globally, has received consumer input and is available at no cost. The material is presented on a website underpinned by a sophisticated content-management system, which allows easy maintenance and ready update of all the content. The resource conforms to key principles of e-learning, including appropriateness of curriculum, engagement of learners, innovative approaches, effective learning, ease of use, inclusion, assessment, coherence, consistency, transparency, cost effectiveness and feedback. www.elearnSCI.org provides a cost effective way of training healthcare professionals that goes beyond the textbook and traditional face-to-face teaching.

Zero-fluoroscopy permanent pacemaker implantation using Ensite NavX system: Clinical viability or fanciful technique?

PubMed

Guo, Ping; Qiu, Jie; Wang, Yan; Chen, Guangzhi; Proietti, Riccardo; Fadhle, Al-Selmi; Zhao, Chunxia; Wen Wang, Dao

2018-02-01

Fluoroscopy is the imaging modality routinely used for cardiac device implantation and electrophysiological procedures. Due to the rising concern regarding the harmful effects of radiation exposure to both the patients and operation staffs, novel 3D mapping systems have been developed and implemented in electrophysiological procedure for the navigation of catheters inside the heart chambers. Their applicability in cardiac device implantation has been rarely reported. Our aim is to evaluate the feasibility and safety of permanent pacemaker implantation without fluoroscopy. From January 2012 to June 2016, six patients (50 ± 15 years, four of six were female, one of who was at the 25th week of gestation) who underwent permanent pacemaker implantation were included (zero-fluoroscopy group). Data from 20 consecutive cases of implantation performed under fluoroscopy guidance were chosen as a control group (fluoroscopy group). Total implantation procedure time for single-chamber pacemaker was 51.3 ± 13.1 minutes in the zero-fluoroscopy group and 42.6 ± 7.4 minutes in the fluoroscopy group (P  =  0.155). The implantation procedural time for a dual-chamber pacemaker was 88.3 ± 19.6 minutes and 67.3 ± 7.6 minutes in the zero-fluoroscopy and fluoroscopy groups (P  =  0.013), respectively. No complications were observed during the procedure and the follow-up in the two groups, and all pacemakers worked with satisfactory parameters. Ensite NavX system can be used as a reliable and safe zero-fluoroscopy approach for the implantation of single- or dual-chamber permanent pacemakers in specific patients, such as pregnant women or in extreme situations when the x-ray machine is not available. © 2017 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals, Inc.

NMR investigation of the isolated second voltage-sensing domain of human Nav1.4 channel.

PubMed

Paramonov, A S; Lyukmanova, E N; Myshkin, M Yu; Shulepko, M A; Kulbatskii, D S; Petrosian, N S; Chugunov, A O; Dolgikh, D A; Kirpichnikov, M P; Arseniev, A S; Shenkarev, Z O

2017-03-01

Voltage-gated Na + channels are essential for the functioning of cardiovascular, muscular, and nervous systems. The α-subunit of eukaryotic Na + channel consists of ~2000 amino acid residues and encloses 24 transmembrane (TM) helices, which form five membrane domains: four voltage-sensing (VSD) and one pore domain. The structural complexity significantly impedes recombinant production and structural studies of full-sized Na + channels. Modular organization of voltage-gated channels gives an idea for studying of the isolated second VSD of human skeletal muscle Nav1.4 channel (VSD-II). Several variants of VSD-II (~150a.a., four TM helices) with different N- and C-termini were produced by cell-free expression. Screening of membrane mimetics revealed low stability of VSD-II samples in media containing phospholipids (bicelles, nanodiscs) associated with the aggregation of electrically neutral domain molecules. The almost complete resonance assignment of 13 C, 15 N-labeled VSD-II was obtained in LPPG micelles. The secondary structure of VSD-II showed similarity with the structures of bacterial Na + channels. The fragment of S4 TM helix between the first and second conserved Arg residues probably adopts 3 10 -helical conformation. Water accessibility of S3 helix, observed by the Mn 2+ titration, pointed to the formation of water-filled crevices in the micelle embedded VSD-II. 15 N relaxation data revealed characteristic pattern of μs-ms time scale motions in the VSD-II regions sharing expected interhelical contacts. VSD-II demonstrated enhanced mobility at ps-ns time scale as compared to isolated VSDs of K + channels. These results validate structural studies of isolated VSDs of Na + channels and show possible pitfalls in application of this 'divide and conquer' approach. Copyright © 2017 Elsevier B.V. All rights reserved.

Prospects for automated diagnosis of verbal autopsies.

PubMed

Garenne, Michel

2014-02-04

Verbal autopsy is a method for assessing probable causes of death from lay reporting of signs, symptoms and circumstances by family members or caregivers of a deceased person. Several methods of automated diagnoses of causes of death from standardized verbal autopsy questionnaires have been developed recently (Inter-VA, Tariff, Random Forest and King-Lu). Their performances have been assessed in a series of papers in BMC Medicine. Overall, and despite high specificity, the current strategies of automated computer diagnoses lead to relatively low sensitivity and positive predictive values, even for causes which are expected to be easily assessed by interview. Some methods have even abnormally low sensitivity for selected diseases of public health importance and could probably be improved. Ways to improve the current strategies are proposed: more detailed questionnaires; using more information on disease duration; stratifying for large groups of causes of death by age, sex and main category; using clusters of signs and symptoms rather than quantitative scores or ranking; separating indeterminate causes; imputing unknown cause with appropriate methods. Please see related articles: http://www.biomedcentral.com/1741-7015/12/5; http://www.biomedcentral.com/1741-7015/12/19; http://www.biomedcentral.com/1741-7015/12/20; http://www.biomedcentral.com/1741-7015/12/21; http://www.biomedcentral.com/1741-7015/12/22; http://www.biomedcentral.com/1741-7015/12/23.

Uninhabited Combat Aerial Vehicles: Airpower by the People, for the People, But Not With the People

DTIC Science & Technology

1999-06-01

Internet, April 17, 1999, available from http://www.ipcress.com/writer/ area51 /rainbow.html. 92 procurement of UAVs because of their comparatively low...www.ipcress.com/writer/ area51 /rainbow.html. “Reaching for the Stars.” Air Force News, 2 pages. On-line. Internet, March 15, 1999. Available from http://www.af.mil

Emission analysis of large number of various passenger electronic devices in aircraft

NASA Astrophysics Data System (ADS)

Schüür, Jens; Oppermann, Lukas; Enders, Achim; Nunes, Rafael R.; Oertel, Carl-Henrik

2016-09-01

The ever increasing use of PEDs (passenger or portable electronic devices) has put pressure on the aircraft industry as well as operators and administrations to reevaluate established restrictions in PED-use on airplanes in the last years. Any electronic device could cause electromagnetic interference to the electronics of the airplane, especially interference at receiving antennas of sensitive wireless navigation and communication (NAV/COM) systems. This paper presents a measurement campaign in an Airbus A320. 69 test passengers were asked to actively use a combination of about 150 electronic devices including many attached cables, preferentially with a high data load on their buses, to provoke maximal emissions. These emissions were analysed within the cabin as well as at the inputs of aircraft receiving antennas outside of the fuselage. The emissions of the electronic devices as well as the background noise are time-variant, so just comparing only one reference and one transmission measurement is not sufficient. Repeated measurements of both cases lead to a more reliable first analysis. Additional measurements of the absolute received power at the antennas of the airplane allow a good estimation of the real interference potential to aircraft NAV/COM systems. Although there were many measured emissions within the cabin, there were no disturbance signals detectable at the aircraft antennas.

Visible-Infrared Hyperspectral Image Projector

NASA Technical Reports Server (NTRS)

Bolcar, Matthew

2013-01-01

The VisIR HIP generates spatially-spectrally complex scenes. The generated scenes simulate real-world targets viewed by various remote sensing instruments. The VisIR HIP consists of two subsystems: a spectral engine and a spatial engine. The spectral engine generates spectrally complex uniform illumination that spans the wavelength range between 380 nm and 1,600 nm. The spatial engine generates two-dimensional gray-scale scenes. When combined, the two engines are capable of producing two-dimensional scenes with a unique spectrum at each pixel. The VisIR HIP can be used to calibrate any spectrally sensitive remote-sensing instrument. Tests were conducted on the Wide-field Imaging Interferometer Testbed at NASA s Goddard Space Flight Center. The device is a variation of the calibrated hyperspectral image projector developed by the National Institute of Standards and Technology in Gaithersburg, MD. It uses Gooch & Housego Visible and Infrared OL490 Agile Light Sources to generate arbitrary spectra. The two light sources are coupled to a digital light processing (DLP(TradeMark)) digital mirror device (DMD) that serves as the spatial engine. Scenes are displayed on the DMD synchronously with desired spectrum. Scene/spectrum combinations are displayed in rapid succession, over time intervals that are short compared to the integration time of the system under test.

Active and Passive Supplier Assessment Program (ASAP & PSAP) WWW Sites http://nepp.nasa.gov/imd/asap http://nepp.nasa.gov/imd/psap

NASA Technical Reports Server (NTRS)

Brusse, Jay

2000-01-01

The Active and Passive Supplier Assessment Programs (ASAP and PSAP) WWW Sites provide general information to the electronic parts community regarding the availability of electronic parts. They also provide information to NASA regarding modifications to commonly used procurement specifications and test methods. The ASAP and PSAP www sites are ongoing resources produced by Code 562 in support of the NASA HQ funded NASA Electronic Parts and Packaging (NEPP) Program. These WWW sites do not provide information pertaining to patented or proprietary information. All of the information contained in these www sites is available through various other public domain resources such as US Military Qualified Producers Listings (QPLs) and Qualified Manufacturer Listings (QMLs) and industry working groups such as the Electronics Industry Alliance (EIA) and the Space Parts Working Group (SPWG).

Organizational Structure of Deep Ground Reconnaissance for Future Divisions and Corps

DTIC Science & Technology

2006-05-25

reinforced and inspired by proper training; trust in equipment, unit pride, and the confidence in their companions . This can best be accomplished... Shakespeare , eNotes: William Shakespeare . Ed. Penny Satoris. Seattle: Enotes.com LLC, October 2002. 14 January 2006. http://www.enotes.com/ shakespeare ... Shakespeare , William, eNotes: William Shakespeare , Ed. Penny Satoris. Seattle: Enotes.com LLC, October 2002. 14 January 2006. http://www.enotes.com

Trafficking regulates the subcellular distribution of voltage-gated sodium channels in primary sensory neurons.

PubMed

Bao, Lan

2015-09-30

Voltage-gated sodium channels (Navs) comprise at least nine pore-forming α subunits. Of these, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 are the most frequently studied in primary sensory neurons located in the dorsal root ganglion and are mainly localized to the cytoplasm. A large pool of intracellular Navs raises the possibility that changes in Nav trafficking could alter channel function. The molecular mediators of Nav trafficking mainly consist of signals within the Navs themselves, interacting proteins and extracellular factors. The surface expression of Navs is achieved by escape from the endoplasmic reticulum and proteasome degradation, forward trafficking and plasma membrane anchoring, and it is also regulated by channel phosphorylation and ubiquitination in primary sensory neurons. Axonal transport and localization of Navs in afferent fibers involves the motor protein KIF5B and scaffold proteins, including contactin and PDZ domain containing 2. Localization of Nav1.6 to the nodes of Ranvier in myelinated fibers of primary sensory neurons requires node formation and the submembrane cytoskeletal protein complex. These findings inform our understanding of the molecular and cellular mechanisms underlying Nav trafficking in primary sensory neurons.

Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States

PubMed Central

Jo, Sooyeon

2017-01-01

Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at −120 mV (3% inhibition by 100 µM lacosamide) but greatly enhanced at −80 mV (43% inhibition by 100 µM lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at −120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at −40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 µM lidocaine or 300 µM carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding. PMID:28119481

Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States.

PubMed

Jo, Sooyeon; Bean, Bruce P

2017-04-01

Lacosamide is an antiseizure agent that targets voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin, which bind tightly to fast-inactivated states. Using heterologously expressed human Nav1.7 sodium channels, we examined the state-dependent effects of lacosamide. Lacosamide induced a reversible shift in the voltage dependence of fast inactivation studied with 100-millisecond prepulses, suggesting binding to fast-inactivated states. Using steady holding potentials, lacosamide block was very weak at -120 mV (3% inhibition by 100 µ M lacosamide) but greatly enhanced at -80 mV (43% inhibition by 100 µ M lacosamide), where there is partial fast inactivation but little or no slow inactivation. During long depolarizations, lacosamide slowly (over seconds) put channels into states that recovered availability slowly (hundreds of milliseconds) at -120 mV. This resembles enhancement of slow inactivation, but the effect was much more pronounced at -40 mV, where fast inactivation is complete, but slow inactivation is not, than at 0 mV, where slow inactivation is maximal, more consistent with slow binding to fast-inactivated states than selective binding to slow-inactivated states. Furthermore, inhibition by lacosamide was greatly reduced by pretreatment with 300 µ M lidocaine or 300 µ M carbamazepine, suggesting that lacosamide, lidocaine, and carbamazepine all bind to the same site. The results suggest that lacosamide binds to fast-inactivated states in a manner similar to other antiseizure agents but with slower kinetics of binding and unbinding. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

CloudStackProjectsNContributions

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

Nielsen, Roy

2017-07-12

Collection of applications and cloud templates. Project currently based on www.packer.io for automation, www.github.com/boxcutter templates and the www.github.com/csd-dev-tools/ClockworkVMs application for wrapping both of the above for easy creation of virtual systems. Will in future also contain cloud templates tuned for various services, applications and purposes.

Military Review: The Professional Journal of the U.S. Army. Volume 81, Number 4, July-August 2001

DTIC Science & Technology

2001-08-01

commerce should The Promise of e-Commerce to Defense: The Road to Savings J. Michael Brower InsightsRM help counter Amazon.com CEO Jeff Bezos ...www.crn.com>. 4. Tichakorn Hill, Defense News (23 October 2000), 62; Jeff Bezos , The Industrial Standard (2 Octo- ber 2000), 41; <www.thestandard.com>. See

A Few New Things

ERIC Educational Resources Information Center

Valenza, Joyce Kasman

2008-01-01

Citing the website "43 Things" (http://www.43things.com/) and derivatives Learning 2.0 (http://plcmcl2-about.blogspot.com/) and California's School Library Learning 2.0 (http://www.schoollibrarylearning2.blogspot.com/), the author suggests other activities to help librarians and teacher-librarians train themselves for leadership in new information…

Factors predicting publication of spinal cord injury trials registered on www.ClinicalTrials. gov.

PubMed

DePasse, J Mason; Park, Sara; Eltorai, Adam E M; Daniels, Alan H

2018-02-06

Treatment options for spinal cord injuries are currently limited, but multiple clinical trials are underway for a variety of interventions, drugs, and devices. The Food and Drug Administration website www.ClinicalTrials.gov catalogues these trials and includes information on the status of the trial, date of initiation and completion, source of funding, and region. This investigation assesses the factors associated with publication and the publication rate of spinal cord injury trials. Retrospective analysis of publically available data on www.ClinicalTrials.gov. The www.ClinicalTrials.gov was queried for all trials on patients with spinal cord injury, and these trials were assessed for status, type of intervention, source of funding, and region. Multiple literature searches were performed on all completed trials to determine publication status. There were 626 studies identified concerning the treatment of patients with spinal cord injury, of which 250 (39.9%) were completed. Of these, only 119 (47.6%) were published. There was no significant difference in the rate of publication between regions (p> 0.16) or by study type (p> 0.29). However, trials that were funded by the NIH were more likely to be published than trials funded by industry (p= 0.01). The current publication rate of spinal cord injury trials is only 47.6%, though this rate is similar to the publication rate for trials in other fields. NIH-funded trials are significantly more likely to become published than industry-funded trials, which could indicate that some trials remain unpublished due to undesirable results. However, it is also likely that many trials on spinal cord injury yield negative results, as treatments are often ineffective.

Lessons from Afar: A Review of www.daisakuikeda.org, Official Website of Daisaku Ikeda

ERIC Educational Resources Information Center

Arauz, Luis

2012-01-01

Daisaku Ikeda (1928- ) is a Buddhist leader, peace builder, school founder, and poet. His own biography and lifework provide a model for how one can transform adversity into alternative opportunities for some of the most disenfranchised students. Scrutinizing Ikeda's official website (www.daisakuikeda.org) reveals an extensive collection of his…

Petechiae

MedlinePlus

... diagnosis. In: Dermatology. 4th ed. Philadelphia, Pa.: Saunders Elsevier; 2018. https://www.clinicalkey.com. Accessed March 28, ... Illustrated Colour Text. 6th ed. Edinburgh, U.K.: Elsevier; 2017. https://www.clinicalkey.com. Accessed March 28, ...

Global NATO: Transformation of a Regional Alliance

DTIC Science & Technology

2015-06-01

www.nytimes.com/2014/12/17/world/europe/turkeys-religious-schools-rise- as- erdogan -exerts-sway.html?_r=1. 72 Vladimir Putin announced the re-routing of...Defying Parents.” NYTimes.com, December 16, 2014. http://www.nytimes.com/2014/12/17/world/europe/turkeys-religious- schools-rise-as- erdogan -exerts-sway.html?_r=1.

Wikis, Digital Literacies, and Professional Growth

ERIC Educational Resources Information Center

Knobel, Michele; Lankshear, Colin

2009-01-01

The Internet is becoming an interactive and collaborative experience. Popular social software used to interact with the Internet includes blogs and microblogs for keeping track of things that interest you or for letting others know what you're up to (www.blogger.com, www.livejournal.com, twitter.com) and sites like Facebook for bringing together…

Interns_In_Their_Natural_Habitat

NASA Image and Video Library

2017-08-10

Discover internship opportunities at the NASA Johnson Space Center! This video shows some of the places interns work and some of the projects they contribute to. Interns work to make their mark and enjoy the entirety of the internship experience which includes touring laboratories and facilities, hearing lectures from astronauts and NASA’s leaders, participating in professional and social committees (like Video Committee) in spare time, and much more. Start your journey! For more on NASA internships: https://intern.nasa.gov/ https://nasajobs.nasa.gov/studentopps/default.htm For Johnson Space Center specific internships: https://pathways.jsc.nasa.gov/ https://www.nasa.gov/centers/johnson/education/interns/index.html --------------------------------- FOLLOW JOHNSON SPACE CENTER INTERNS! Facebook: @NASA.JSC.Students https://www.facebook.com/NASA.JSC.Students/ Instagram: @nasajscstudents https://www.instagram.com/nasajscstudents/ Twitter: @NASAJSCStudents https://twitter.com/nasajscstudents FOLLOW NASA INTERNS! Facebook: @NASAInterns https://www.facebook.com/NASAInterns/ Twitter: @NASAInterns https://twitter.com/nasainterns

America’s Collision Course with the Caucasus: Is Military Intervention Inevitable?

DTIC Science & Technology

2001-05-01

50 INTERNET RESEARCH (links valid 05 MAR 2001...Department of State, Office of the Spokesman. 4 Oct 2000 < http://secretary.state.gov/www/policy_remarks/2000/001004_wolf_btcpipeline.html> INTERNET ... RESEARCH (links valid 05 MAR 2001) AzeriNews.com—Azerbaijan News <www.Azerbaijan.com> Azerbaijan International Magazine <azer.com> Caucasus Watch.Com

Alzheimer's Prevention Education: If We Build It, Will They Come? www.AlzU.org.

PubMed

Isaacson, R S; Haynes, N; Seifan, A; Larsen, D; Christiansen, S; Berger, J C; Safdieh, J E; Lunde, A M; Luo, A; Kramps, M; McInnis, M; Ochner, C N

2014-01-01

Internet-based educational interventions may be useful for impacting knowledge and behavioral change. However, in AD prevention, little data exists about which educational tools work best in terms of learning and interest in participating in clinical trials. Primary: Assess effectiveness of interactive webinars vs. written blog-posts on AD prevention learning. Secondary: Evaluate the effect of AD prevention education on interest in participating in clinical trials; Assess usability of, and user perceptions about, an online AD education research platform; Classify target populations (demographics, learning needs, interests). Observational. Online. Men/Women, aged 25+, recruited via facebook.com. Alzheimer's Universe (www.AlzU.org) education research platform. Pre/post-test performance, self-reported Likert-scale ratings, completion rates. Over two-weeks, 4268 visits were generated. 503 signed-up for a user account (11.8% join rate), 196 participated in the lessons (39.0%) and 100 completed all beta-testing steps (19.9%). Users randomized to webinar instruction about AD prevention and the stages of AD demonstrated significant increases (p=0.01) in pre vs. post-testing scores compared to blog-post intervention. Upon joining, 42% were interested in participating in a clinical trial in AD prevention. After completing all beta-test activities, interest increased to 86%. Users were primarily women and the largest category was children of AD patients. 66.3% joined to learn more about AD prevention, 65.3% to learn more about AD treatment. Webinar-based education led to significant improvements in learning about AD prevention and the stages of AD. AlzU.org participation more than doubled interest in AD prevention clinical trial participation. Subjects were quickly and cost-effectively recruited, and highly satisfied with the AD education research platform. Based on these data, we will further refine AlzU.org prior to public launch and aim to study the effectiveness of 25

Thirdhand Smoke: What Are the Dangers to Nonsmokers?

MedlinePlus

... M.D. Samet JM, et al. Secondhand smoke exposure: Effects in children. https://www.uptodate.com/home. Accessed June 9, 2017. Samet JM, et al. Control of secondhand smoke exposure. https://www.uptodate.com/home. Accessed June 9, ...

Adaptive evolution of voltage-gated sodium channels: The first 800 million years

PubMed Central

Zakon, Harold H.

2012-01-01

Voltage-gated Na+-permeable (Nav) channels form the basis for electrical excitability in animals. Nav channels evolved from Ca2+ channels and were present in the common ancestor of choanoflagellates and animals, although this channel was likely permeable to both Na+ and Ca2+. Thus, like many other neuronal channels and receptors, Nav channels predated neurons. Invertebrates possess two Nav channels (Nav1 and Nav2), whereas vertebrate Nav channels are of the Nav1 family. Approximately 500 Mya in early chordates Nav channels evolved a motif that allowed them to cluster at axon initial segments, 50 million years later with the evolution of myelin, Nav channels “capitalized” on this property and clustered at nodes of Ranvier. The enhancement of conduction velocity along with the evolution of jaws likely made early gnathostomes fierce predators and the dominant vertebrates in the ocean. Later in vertebrate evolution, the Nav channel gene family expanded in parallel in tetrapods and teleosts (∼9 to 10 genes in amniotes, 8 in teleosts). This expansion occurred during or after the late Devonian extinction, when teleosts and tetrapods each diversified in their respective habitats, and coincided with an increase in the number of telencephalic nuclei in both groups. The expansion of Nav channels may have allowed for more sophisticated neural computation and tailoring of Nav channel kinetics with potassium channel kinetics to enhance energy savings. Nav channels show adaptive sequence evolution for increasing diversity in communication signals (electric fish), in protection against lethal Nav channel toxins (snakes, newts, pufferfish, insects), and in specialized habitats (naked mole rats). PMID:22723361

Prospective Heart Tracking for Whole-heart Magnetic Resonance Angiography

PubMed Central

Moghari, Mehdi H.; Geva, Tal; Powell, Andrew J.

2015-01-01

Purpose To develop a prospective respiratory-gating technique (Heart-NAV) for use with contrast-enhanced 3D inversion recovery (IR) whole-heart magnetic resonance angiography (MRA) acquisitions that directly tracks heart motion without creating image inflow artifact. Methods With Heart-NAV, 1 of the startup pulses for the whole-heart steady-state free precession MRA sequence is used to collect the centerline of k-space, and its 1-dimensional reconstruction is fed into the standard diaphragm-navigator (NAV) signal analysis process to prospectively gate and track respiratory-induced heart displacement. Ten healthy volunteers underwent non-contrast whole-heart MRA acquisitions using the conventional diaphragm-NAV and Heart-NAV with 5 and 10 mm acceptance windows in a 1.5T scanner. Five patients underwent contrast-enhanced IR whole-heart MRA using a diaphragm-NAV and Heart-NAV with a 5 mm acceptance window. Results For non-contrast whole-heart MRA with both the 5 and 10 mm acceptance windows, Heart-NAV yielded coronary artery vessel sharpness and subjective visual scores that were not significantly different than those using a conventional diaphragm-NAV. Scan time for Heart-NAV was 10% shorter (p<0.05). In patients undergoing contrast-enhanced IR whole-heart MRA, inflow artifact was seen with the diaphragm-NAV but not with Heart-NAV. Conclusion Compared to a conventional diaphragm-NAV, Heart-NAV achieves similar image quality in a slightly shorter scan time and eliminates inflow artifact. PMID:26843458

Factors influencing clicking of banner ads on the WWW.

PubMed

Cho, Chang-Hoan

2003-04-01

This paper explores various factors influencing the clicking of banner ads on the WWW. The study indicates that several important variables affect the clicking of banner ads: (1) level of product involvement, (2) congruency between the content of a vehicle and the product category of a banner ad, (3) attitude toward the vehicle, and (4) overall attitude toward web advertising. For methodology, this study employed a between-group experimental design and measured real click-through rates with the aid of an online data collection technology called FileMaker Pro. Results of logistic regressions show that people are more likely to click banner ads if they are highly involved with products, perceive high synergy between web pages and ads, have a favorable attitude toward a vehicle, or have a favorable attitude toward web advertising in general. A total of 756 subjects participated in this research.

Turkey’s New Regional Security Role: Implications for the United States

DTIC Science & Technology

2014-09-01

Hurryietdai- lynews.Com, December 22, 2012, available from www.hurriyetdaily- news.com/eu-may-chase-turkey-soon-german-fm.aspx?pageID=238& n ID=37410...March 13, 2014, available from https://sg.news. yahoo.com/turkey-fears-tatar-minority-ukraine-174324104.html. 184. Vitaly Naumkin, “Russia manages...October 4, 2011, available from www. hurriyetdailynews.com/default.aspx?pageid=438& n =turkey-extends- isaf8217s-command-one-more-year-2011-10-04. 201

Yellow Tongue

MedlinePlus

... Dermatology. 7th ed. New York, N.Y.: The McGraw-Hill Companies; 2013. http://www.accessmedicine.com. Accessed Jan. ... Medicine. 18th ed. New York, N.Y.: The McGraw-Hill Companies; 2012. http://www.accessmedicine.com. Accessed Jan. ...

Ovarian Cysts and Fertility: Is There a Connection?

MedlinePlus

... Accessed Oct. 6, 2015. Levy BS, et al. Diagnosis and management of ovarian endometriomas. http://www.uptodate.com/home. Accessed Oct. 6, 2015. Barbieri RL, et al. Clinical manifestations of polycystic ovary syndrome in adults. http://www.uptodate.com/home. Accessed ...

VisNAV 100: a robust, compact imaging sensor for enabling autonomous air-to-air refueling of aircraft and unmanned aerial vehicles

NASA Astrophysics Data System (ADS)

Katake, Anup; Choi, Heeyoul

2010-01-01

To enable autonomous air-to-refueling of manned and unmanned vehicles a robust high speed relative navigation sensor capable of proving high accuracy 3DOF information in diverse operating conditions is required. To help address this problem, StarVision Technologies Inc. has been developing a compact, high update rate (100Hz), wide field-of-view (90deg) direction and range estimation imaging sensor called VisNAV 100. The sensor is fully autonomous requiring no communication from the tanker aircraft and contains high reliability embedded avionics to provide range, azimuth, elevation (3 degrees of freedom solution 3DOF) and closing speed relative to the tanker aircraft. The sensor is capable of providing 3DOF with an error of 1% in range and 0.1deg in azimuth/elevation up to a range of 30m and 1 deg error in direction for ranges up to 200m at 100Hz update rates. In this paper we will discuss the algorithms that were developed in-house to enable robust beacon pattern detection, outlier rejection and 3DOF estimation in adverse conditions and present the results of several outdoor tests. Results from the long range single beacon detection tests will also be discussed.

Design Structure Matrix (DSM) Methods and Applications for Naval Ship Design

DTIC Science & Technology

2013-05-23

Fax: 817-257-7227 E-mail: t.browninufetcu.edu Web : www. t vsonbrown i ng. com Administrative/Business Contact: Mrs. Teresa Miles Hendrix, MPA...mail: t.browninu(ajtcii.edu Web : www.tvsonbrownina.com Administrative/Business Contact: Mrs. Teresa Miles Hendrix, MPA Assistant Director of...STAKEHOLDER COM ABORDAGEM DE SISTEMAS ADAPTATIVOS A COMPLEXIDADE John Findlay, Ph D. e Abby Straus, M. Div. IMPLEMENTANDO FLEXIBILIDADE

Prospective heart tracking for whole-heart magnetic resonance angiography.

PubMed

Moghari, Mehdi H; Geva, Tal; Powell, Andrew J

2017-02-01

To develop a prospective respiratory-gating technique (Heart-NAV) for use with contrast-enhanced three-dimensional (3D) inversion recovery (IR) whole-heart magnetic resonance angiography (MRA) acquisitions that directly tracks heart motion without creating image inflow artifact. With Heart-NAV, one of the startup pulses for the whole-heart steady-state free precession MRA sequence is used to collect the centerline of k-space, and its one-dimensional reconstruction is fed into the standard diaphragm-navigator (NAV) signal analysis process to prospectively gate and track respiratory-induced heart displacement. Ten healthy volunteers underwent non-contrast whole-heart MRA acquisitions using the conventional diaphragm-NAV and Heart-NAV with 5 and 10-mm acceptance windows in a 1.5T scanner. Five patients underwent contrast-enhanced IR whole-heart MRA using a diaphragm-NAV and Heart-NAV with a 5-mm acceptance window. For non-contrast whole-heart MRA with both the 5 and 10-mm acceptance windows, Heart-NAV yielded coronary artery vessel sharpness and subjective visual scores that were not significantly different than those using a conventional diaphragm-NAV. Scan time for Heart-NAV was 10% shorter (p < 0.05). In patients undergoing contrast-enhanced IR whole-heart MRA, inflow artifact was seen with the diaphragm-NAV but not with Heart-NAV. Compared with a conventional diaphragm-NAV, Heart-NAV achieves similar image quality in a slightly shorter scan time and eliminates inflow artifact. Magn Reson Med 77:759-765, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

We Tell the Crew What To Do

NASA Image and Video Library

2017-03-07

You probably don’t know what you’ll be doing six months from today, but there’s a group at NASA’s Marshall Space Flight Center in Huntsville, Alabama, that’s making just such a plan for scientific research on the International Space Station. Learn how these men and women map out science activity for the crew in space to support the cutting-edge research now underway that’s benefitting life on Earth. For more on ISS science, visit us online: https://www.nasa.gov/mission_pages/station/research/index.html www.twitter.com/iss_research _______________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/

MED40/472: A WWW Multimedia Textbook of Internal Propedeutics

PubMed Central

Zelenková, J; Vejvalka, J; Holá, D; Segethová, J

1999-01-01

Introduction Traditional ways of teaching techniques of physical examinations in the first clinical courses are rather demanding in terms of teacher involvement and a pool of patients suitable for demonstrations. For a long time, various audio-visual tools have been used to save teachers' and students' time and patients' patience. The modern technology of WWW publishing of multimedia allows good access to such teaching materials - and there already exist several collections of heart sounds, breath sounds etc. The aim of our project is to design and set up a comprehensive multimedia textbook of internal propedeutics that would present various physiological and pathological findings (auscultation, inspection, basic imaging) in the context of diagnostic patient investigation - the status praesens - as it is taught in the first clinical courses. Methods Unlike classical textbooks, hypertext presentation allows to ogranize the material into several structures - reflecting various approaches: systemic (digestive, cardiovascular etc.) approach, nosological, differential diagnoses, etc. To identify and implement the various useful approaches is the most difficult part of the task. The accompanying illustrative material is being prepared with the use of modern technologies - digital camera, scanner, video-camera and digitizer, digital audio recording, etc. Results In the first year of the project, the skeleton of the multimedia presentation is being constructed - corresponding to the various approaches to the subject. Concurrently, suitable illustrative material is being gathered from cases of the Internal Clinic. Various existing WWW presentations dealing with heart and breath sounds and other relevant investigations have been searched and listed. Discussion Experience and feedback from other projects of this type confirm that a rather elaborate logical and technical construction of multimedia textbooks is rewarded by a good acceptance by both students and teachers. Good

Mechanism and molecular basis for the sodium channel subtype specificity of µ-conopeptide CnIIIC

PubMed Central

Markgraf, René; Leipold, Enrico; Schirmeyer, Jana; Paolini-Bertrand, Marianne; Hartley, Oliver; Heinemann, Stefan H

2012-01-01

BACKGROUND AND PURPOSE Voltage-gated sodium channels (NaV channels) are key players in the generation and propagation of action potentials, and selective blockade of these channels is a promising strategy for clinically useful suppression of electrical activity. The conotoxin µ-CnIIIC from the cone snail Conus consors exhibits myorelaxing activity in rodents through specific blockade of skeletal muscle (NaV1.4) NaV channels. EXPERIMENTAL APPROACH We investigated the activity of µ-CnIIIC on human NaV channels and characterized its inhibitory mechanism, as well as the molecular basis, for its channel specificity. KEY RESULTS Similar to rat paralogs, human NaV1.4 and NaV1.2 were potently blocked by µ-CnIIIC, the sensitivity of NaV1.7 was intermediate, and NaV1.5 and NaV1.8 were insensitive. Half-channel chimeras revealed that determinants for the insensitivity of NaV1.8 must reside in both the first and second halves of the channel, while those for NaV1.5 are restricted to domains I and II. Furthermore, domain I pore loop affected the total block and therefore harbours the major determinants for the subtype specificity. Domain II pore loop only affected the kinetics of toxin binding and dissociation. Blockade by µ-CnIIIC of NaV1.4 was virtually irreversible but left a residual current of about 5%, reflecting a ‘leaky’ block; therefore, Na+ ions still passed through µ-CnIIIC-occupied NaV1.4 to some extent. TTX was excluded from this binding site but was trapped inside the pore by µ-CnIIIC. CONCLUSION AND IMPLICATIONS Of clinical significance, µ-CnIIIC is a potent and persistent blocker of human skeletal muscle NaV1.4 that does not affect activity of cardiac NaV1.5. PMID:22537004

Maritime-Based UAVs: A Key to Success for the Joint Force Commander

DTIC Science & Technology

2015-05-18

both cases, the UAVs encountered icing conditions inevitably losing control and crashing into the water.xxiii Land-based UAVs as well as manned...www2.l- 3com.com/csw/ProductsAndServices/ DataSheets /VORTEX Sales-Sheet WEB.pdf. xxviii L3 Communication Systems, “ROVER 5 Handheld,” accessed on...May 2, 2015, http://www2.l-3com.com/csw/ProductsAndServices/ DataSheets /ROVER-5_Sales- Sheet_WEB.pdf. xxix National Research Council, Autonomous

ModerateDrinking.com and Moderation Management: Outcomes of a randomized clinical trial with non-dependent problem drinkers1

PubMed Central

Hester, Reid K.; Delaney, Harold D.; Campbell, William

2011-01-01

Objective To evaluate the effectiveness of a web-based protocol, Moderate Drinking (MD) (www.moderatedrinking.com) combined with use of the online resources of Moderation Management (MM) (www.moderation.org) as opposed to the use of the online resources of MM alone. Method We randomly assigned 80 problem drinkers to either the experimental or control group with follow-ups at 3, 6, and 12 months. Results Seventy-five participants (94%) had outcome data at one or more follow-up points and 59 (73%) were assessed at all three follow-ups. Comparing baseline measures to the average outcomes at follow-ups indicated a significant overall reduction in both groups in alcohol-related problems and consumption variables. Compared to the control group, the experimental group had better outcomes on percent days abstinent (PDA). There was an interaction between intensity of drinking at baseline and treatment in determining outcomes assessing drinking. Less heavy drinkers in the experimental group had better outcomes on log Mean BAC per drinking day compared to the control group. Heavier drinkers did not differentially benefit from the MD program on this measure. Mixed model analyses in general corroborated these outcomes. Conclusion The outcome data provide partial evidence for the effectiveness of the MD web application combined with MM, compared to the effectiveness of the resources available online at MM by themselves. PMID:21319896

Calendar

NASA Astrophysics Data System (ADS)

2004-06-01

JULY 2004 2nd World Congress of the Game Theory Society, Faculty of Luminy, Marseille, France 5-9 July 2004 Europa Organisation (europa@europa-organisation.com), +33 5 34 45 26 45, www.gts2004.org Budapest Workshop on Behavioral Economics, Central European University, Budapest, Hungary 5-10 July 2004 Eva Dotzi (behavecon@ceu.hu), www.iza.org/en/calls_conferences/CallCEU_04.pdf FDA'04. 1st IFAC Workshop on Fractional Differentiation and its Applications, Bordeaux, France 19-20 July 2004 IFAC secretariat (fda04@lap.u-bordeaux1.fr), www.lap.u-bordeaux.fr/fda04/ Bachelier Finance Society Third World Congress, InterContinental Hotel, Chicago, IL, USA 21-24 July 2004 bfs2004@uic.edu, www.uic.edu/orgs/bachelier/ BS/IMS 2004. 6th World Congress of the Bernoulli Society for Mathematical Statistics and Probability, Barcelona, Spain 26-31 July 2004 wc2004@pacifico-meetings.com, +34 93 402 13 85, www.imub.ub.es/events/wc2004 AUGUST 2004 Summer School in Econometrics. The Cointegrated VAR Model: Econometric Methodology and Macroeconomic Applications, Institute of Economics, University of Copenhagen, Denmark 2-22 August 2004 Summerschool@econ.ku.dk, www.econ.ku.dk/summerschool SEPTEMBER 2004 First Bonzenfreies Colloquium on Market Dynamics and Quantitative Economics, Alessandria, Palazzo Borsalino, Italy 9-10 September 2004 colloquium@unipmn.it, www.mfn.unipmn.it/~colloqui/ Risk Analysis 2004. 4th International Conference on Computer Simulation in Risk Analysis and Hazard Mitigation, Aldemar Paradise Royal Mare Hotel, Rhodes, Greece 27-29 September 2004 enquiries@wessex.ac.uk, +44 (0)238 029 3223, www.wessex.ac.uk/conferences/2004/risk04/ OCTOBER 2004 IRC Hedge 2004, InterContinental Hotel, London, UK 10, 11 October 2004 enquiries@irc-conferences.com, www.irc-conferences.com/show_conference.php?id=10 NOVEMBER 2004 IRC DICE 2004, InterContinental Hotel, London, UK 22, 23 November 2004 enquiries@irc-conferences.com, www.irc-conferences.com/show_conference.php?id=13 DECEMBER 2004

Cyber Operations and Cyber Terrorism

DTIC Science & Technology

2005-08-15

available from http://www.geocities.com/ Area51 /Shadowlands/6583/project395.html; Internet; accessed 14 April 2004. DCSINT Handbook 1.02, Cyber...www.geocities.com/ Area51 /Shadowlands/6583/project395.html; Internet; Accessed 14 April 2004. Raufer, Xavier. “New World Disorder, New

F-35B Joint Strike Fighter on the MEU: Innovation or Just New Techology?

DTIC Science & Technology

2013-04-11

Events, Dec 19, 2012. http://www.defenseindustrydaily.com/ f22 -raptor-procurement-events-updated- 02908/. 15 Jeremiah Gertler, V-22 Osprey Tilt...www.defenseindustrydaily.com/ f22 -raptor-procurement-events-updated- 02908/. —. AV-8B Harrier Finding Success in Iraq. March 30, 2005, http

Alternative Fuels Data Center: Virginia Transportation Data for Alternative

Science.gov Websites

://www.youtube.com/embed/1S7JJHQpc1w Video thumbnail for Propane Buses Save Money for Virginia Schools Propane Buses Save Money for Virginia Schools Feb. 25, 2010 https://www.youtube.com/embed/enxaQ_QooWE Chart Data

THE BINDING OF COCAINE TO CYCLODEXTRINS. (R826653)

EPA Science Inventory

Abstract

Cocaine binds into www.sciencedirect.com/scidirimg/entities/beta.gif" alt="small beta, Greek" border=0>-cyclodextrin, but not detectably into www.sciencedirect.com/scidirimg/entities/alpha.gif" alt="small alpha, Greek" border=...

Present and Future of the United States-Bolivia Relations

DTIC Science & Technology

2009-12-11

Programa de Gobierno-MAS-IPSP,” Archivo Chile , http://www.archivochile.com/Portada/bol_elecciones05/bolelecciones0009.pdf (accessed May 2, 2009...accessed November 9, 2009). Movimiento al Socialismo. “ Programa de Gobierno-MAS-IPSP.” Archivo Chile . http://www.archivochile.com/Portada/bol_elecciones05...partidos en Bolivia,” Futuros Revista Trimestral Latinoamericana y Caribeña de Desarrollo Sustentable, http://www.revistafuturos.info/ futuros_9

[Pain and analgesia : Mutations of voltage-gated sodium channels].

PubMed

Eberhardt, M J; Leffler, A

2017-02-01

Voltage-gated sodium channels (Navs) are crucial for the generation and propagation of action potentials in all excitable cells, and therefore for the function of sensory neurons as well. Preclinical research over the past 20 years identified three Nav-isoforms in sensory neurons, namely Nav1.7, Nav1.8 and Nav1.9. A specific role for the function of nociceptive neurons was postulated for each. Whereas no selective sodium channel inhibitors have been established in the clinic so far, the relevance of all three isoforms regarding the pain sensitivity in humans is currently undergoing a remarkable verification through the translation of preclinical data into clinically manifest pictures. For the last ten years, Nav1.7 has been the main focus of clinical interest, as a large number of hereditary mutants were identified. The so-called "gain-of-function" mutations of Nav1.7 cause the pain syndromes hereditary erythromelalgia and paroxysmal extreme pain disorder. In addition, several Nav1.7 mutants were shown to be associated with small-fiber neuropathies. On the contrary, "loss-of-function" Nav1.7 mutants lead to a congenital insensitivity to pain. Recently, several gain-of-function mutations in Nav1.8 and Nav1.9 have been identified in patients suffering from painful peripheral neuropathies. However, another gain-of-function Nav1.9 mutation is associated with congenital insensitivity to pain. This review offers an overview of published work on painful Nav mutations with clinical relevance, and proposes possible consequences for the therapy of different pain symptoms resulting from these findings.

Cyber Operations and Cyber Terrorism, Handbook Number 1.02

DTIC Science & Technology

2005-08-15

Quinn, “Teen Hackers Plead Guilty to Stunning Pentagon Attacks,” Reuters, 31 July 1998, 1; available from http://www.geocities.com/ Area51 ...Hackers Plead Guilty to Stunning Pentagon Attacks.” Reuters, 31 July 1998, 1. Available from http://www.geocities.com/ Area51 /Shadowlands/6583

76 FR 65756 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-24

... 600.400, Administrative Litigation Records; USPS 810.100, http://www.usps.com Registration; USPS 810... Records; USPS 870.200, Postage Meter and PC Postage Customer Data and Transaction Records; USPS 880.000....400 SYSTEM NAME: Administrative Litigation Records USPS 810.100 SYSTEM NAME: http://www.usps.com...

Defense Industrial Base Capabilities Study: Battlespace Awareness

DTIC Science & Technology

2004-01-01

not production capacity or workforce issues. It considers the best capabilities in both the domestic and foreign components of the industrial base...www.maliburesearch.com Ground Penetrating Radar MARIMATECH 1989 Aarhus, Denmark n.a. n.a. www.marimatech.com Sonar Maser Technology (NZ) Ltd. 1983 Auckland , New

200,000 Homes Weatherized under the Recovery Act

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

Zoi, Cathy

Today Vice President Biden announced that the Weatherization Assistance Program has weatherized 200,000 homes under the Recovery Act. We're taking your questions and comments right now on weatherization. Join in the conversation! *Facebook -- http://www.facebook.com/energygov *Twitter -- http://www.twitter.com/energy

Jet Fuel Hedging Strategies for the Department of Defense Through Use of Financial Derivatives

DTIC Science & Technology

2009-03-01

W. (n.d.). Warren Buffett Quotes. Retrieved November 2008, from Brainy Quote: http://www.brainyquote.com/quotes/authors/w/warren_buffett.html...Prices Tough to Swallow. Retrieved August 2008, from Washington Post: http://www.washingtonpost.com/wp- dyn/articles/A11303-2004Jun2.html Buffett

200,000 Homes Weatherized under the Recovery Act

ScienceCinema

Zoi, Cathy

2017-12-12

Today Vice President Biden announced that the Weatherization Assistance Program has weatherized 200,000 homes under the Recovery Act. We're taking your questions and comments right now on weatherization. Join in the conversation! *Facebook -- http://www.facebook.com/energygov *Twitter -- http://www.twitter.com/energy

Websites of Note

ERIC Educational Resources Information Center

Parslow, Graham R.

2011-01-01

This article features websites related to biochemistry and molecular biology education. They include: (1) Scitable (www.nature.com/scitable); (2) Educause (www.educause.edu); (3) The Journal of Computer Assisted Learning (onlinelibrary.wiley.com/journal/10.1111/(ISSN)1365-2729); (4) European Conference on eLearning…

RHODIUM CATALYZED CONJUGATED ADDITION OF UNSATURATED CARBONYL COMPOUNDS BY TRIPHENYLBISMUTH IN AQUEOUS MEDIA AND UNDER AN AIR ATMOSPHERE. (R822668)

EPA Science Inventory

Abstract

In the presence of a rhodium catalyst, www.sciencedirect.com/scidirimg/entities/alpha.gif" alt="small alpha, Greek" border=0>,www.sciencedirect.com/scidirimg/entities/beta.gif" alt="small beta, Greek" border=0>-unsaturated est...

77 FR 58991 - State-Level Guarantee Fee Pricing

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-25

.../relatedservicinginfo/pdf/foreclosuretimeframes.pdf and http://www.freddiemac.com/learn/pdfs/service/exhibit83.pdf . The... Relative to the National Average Estimated Cost per day Foreclosure average Total time to relative to Rank.../guides/ssg/relatedservicinginfo/pdf/foreclosuretimeframes.pdf and http://www.freddiemac.com/learn/pdfs...

Free-breathing cine DENSE MRI using phase cycling with matchmaking and stimulated-echo image-based navigators.

PubMed

Cai, Xiaoying; Epstein, Frederick H

2018-04-01

This study aimed to develop a self-navigated method for free-breathing spiral cine displacement encoding with stimulated echoes (DENSE), a myocardial strain imaging technique that uses phase-cycling for artifact suppression. The method needed to address 2 consequences of motion for DENSE: striping artifacts from incomplete suppression of the T 1 -relaxation echo and blurring. The method identifies phase-cycled spiral interleaves at matched respiratory phases by minimizing the residual signal due to T 1 relaxation after phase-cycling subtraction. Next, the method reconstructs image-based navigators from matched phase-cycled interleaves that are comprised of the stimulated echo (ste-iNAVs). Ste-iNAVs are used for motion estimation and compensation of k-space data. The method was demonstrated in phantoms and compared to diaphragm-based navigator (dNAV) and conventional iNAV (c-iNAV) methods for the reconstruction of free-breathing volunteer data sets (N = 10). Phantom experiments demonstrated that the proposed method removes striping artifacts and blurring due to motion. Volunteer results showed that respiratory motion measured by ste-iNAVs was better correlated than c-iNAVs to dNAV data (R 2  = 0.82 ± 0.03 vs. 0.70 ± 0.05, P < 0.05). Match-making reconstructions of free-breathing data sets achieved lower residual T 1 -relaxation echo energy (1.04 ± 0.01 vs. 1.18 ± 0.04 for dNAV and 1.18 ± 0.03 for c-iNAV, P < 0.05), higher apparent SNR (11.93 ± 1.05 vs. 10.68 ± 1.06 for dNAV and 10.66 ± 0.99 for c-iNAV, P < 0.05), and better phase quality (0.147 ± 0.012 vs. 0.166 ± 0.017 for dNAV, P = 0.06, and 0.168 ± 0.015 for c-iNAV, P < 0.05) than dNAV and c-iNAV methods. For free-breathing cine DENSE, the proposed method addresses both types of breathing-induced artifacts and provides better quality images than conventional dNAV and iNAV methods. © 2018 International Society for Magnetic

Effect of and satisfaction with www.elearnSCI.org for training of nurse students: a submodule pilot study.

PubMed

Liu, N; Li, X W; Zhou, M W; Krassioukov, A V; Biering-Sørensen, F

2014-10-01

Interventional training session. To investigate the effect and satisfaction with didactic training using printed text of a submodule of www.elearnSCI.org for nurse students and to assess the answers of each question. A Peking University teaching hospital. Twenty-eight nurse students in two groups (14 in each) were involved. Only group A received a translated print-out of the slides from the 'Nursing management' submodule in www.elearnSCI.org for 1-h self-study before the class. At the beginning of class, both groups were tested using the self assessment questions. Then, a lecture according to the content of this submodule was carried out and afterwards both groups answered the self assessment questions again. Finally, both groups filled in a training course satisfaction questionnaire. At the beginning of the class, the mean score (max 9) of the self assessment in group A was 7.1 ± 1.1, which was significantly higher than that in group B (4.9 ± 1.7, P = 0.001). After the lecture, the mean score of the self assessment in group A had insignificantly increased to 7.4 ± 1.3, whereas in group B it increased significantly to 6.9 ± 0.8 (P < 0.001). The mean score (max 50) of the training course satisfaction questionnaire was 42.8 ± 5.2. Sixty-four percentage of the students indicated that they were very satisfied (overall score ⩾ 42) with the training and no students were unsatisfied (overall score < 30). Self-study and lecture presentation are effective methods for training the content of www.elearnSCI.org to nurse students. The training satisfaction of this submodule within the www.elearnSCI.org is favorable.

VIS-IR transmitting BGG glass windows

NASA Astrophysics Data System (ADS)

Bayya, Shyam S.; Chin, Geoff D.; Sanghera, Jasbinder S.; Aggarwal, Ishwar D.

2003-09-01

BaO-Ga2O3-GeO2 (BGG) glasses have the desired properties for various window applications in the 0.5-5 μm wavelength region. These glasses are low cost alternatives to the currently used window materials. Fabrication of a high optical quality 18" diameter BGG glass window has been demonstrated with a transmitted wave front error of λ/10 at 632 nm. BGG substrates have also been successfully tested for environmental weatherability (MIL-F-48616) and rain erosion durability up to 300 mph. Preliminary EMI grids have been successfully applied on BGG glasses demonstrating attenuation of 20dB in X and Ku bands. Although the mechanical properties of BGG glasses are acceptable for various window applications, it is demonstrated here that the properties can be further improved significantly by the glassceramization process. The ceramization process does not add any significant cost to the final window material. The crystallite size in the present glass-ceramic limits its transmission to the 2-5 μm region.

News from Online: A Spectrum of Color

NASA Astrophysics Data System (ADS)

Sweeney Judd, Carolyn

1999-06-01

Thomas Chasteen's site ( http://www.shsu.edu/~chm_tgc/sounds/sound.html) shows how to separate colors using a tuneable monochromator. This graphic comes from his monochromator animation ( http://www.shsu.edu/~chemistry/monochromator/mono.gif). Science Media's site ( http://www.scimedia.com/index.html#scimedia) includes spectroscopy tutorials by Brian Tissue. This graphic can be found at http://www.scimedia.com/chem-ed/light/graphics/em-rad.gif (©1998 B. M. Tissue, www.scimedia.com). All the colors in the rainbow! Now that is a good place to start. Go to About Rainbows ( http://www.unidata.ucar.edu/staff/blynds/rnbw.html), a tutorial from astronomer Beverly Lynds, working with the University Corporation for Atmospheric Research. The tutorial begins with a historical perspective, complete with a sketch by René Descartes in 1637. The bibliography makes this tutorial a good starting point for color exploration. About Rainbows brings you questions to explorefor example, "What happens when you look at a rainbow through dark glasses?" Try the links to these other sites. Project SkyMath: Making Mathematical Connections ( http://www.unidata.ucar.edu/staff/blynds/Skymath.html) is especially for the middle school student. Reproducible masters of these teaching modules can be printed in English and Spanish. From Project SkyMath, you can go to Blue-Skies, a user-friendly graphical interface from The Weather Underground at the University of Michigan ( http://groundhog.sprl.umich.edu/BS.html). And speaking of blue skies, look at a great site, Why is the Sky Blue at http://acept.la.asu.edu/PiN/act/sky/sky.shtml. This is a super site from the Arizona Collaborative for Excellence in the Preparation of Teachers, by the Department of Physics and Astronomy at Arizona State University. If you go to Patterns in Nature: Light and Optics at http

Worldwide Emerging Environmental Issues Affecting the U.S. Military. January 2008 Report

DTIC Science & Technology

2008-01-01

around the San Juan Islands, the Strait of Juan de Fuca and all of Puget Sound . One of its aspects includes assessing and improving vessel traffic... Sound Orca Recovery Plan Released http://www.physorg.com/news120453628.html Salty shepherds. The Economist, Jan 24th 2008 http://www.economist.com...not want or cannot process in an environmentally sound way. The Revised Green List Regulation 1418/2007 AC/UNU Millennium Project www.millennium

Feeling the Heat

NASA Astrophysics Data System (ADS)

2004-05-01

Successful "First Light" for the Mid-Infrared VISIR Instrument on the VLT Summary Close to midnight on April 30, 2004, intriguing thermal infrared images of dust and gas heated by invisible stars in a distant region of our Milky Way appeared on a computer screen in the control room of the ESO Very Large Telescope (VLT). These images mark the successful "First Light" of the VLT Imager and Spectrometer in the InfraRed (VISIR), the latest instrument to be installed on this powerful telescope facility at the ESO Paranal Observatory in Chile. The event was greeted with a mixture of delight, satisfaction and some relief by the team of astronomers and engineers from the consortium of French and Dutch Institutes and ESO who have worked on the development of VISIR for around 10 years [1]. Pierre-Olivier Lagage (CEA, France), the Principal Investigator, is content : "This is a wonderful day! A result of many years of dedication by a team of engineers and technicians, who can today be proud of their work. With VISIR, astronomers will have at their disposal a great instrument on a marvellous telescope. And the gain is enormous; 20 minutes of observing with VISIR is equivalent to a whole night of observing on a 3-4m class telescope." Dutch astronomer and co-PI Jan-Willem Pel (Groningen, The Netherlands) adds: "What's more, VISIR features a unique observing mode in the mid-infrared: spectroscopy at a very high spectral resolution. This will open up new possibilities such as the study of warm molecular hydrogen most likely to be an important component of our galaxy." PR Photo 16a/04: VISIR under the Cassegrain focus of the Melipal telescope PR Photo 16b/04: VISIR mounted behind the mirror of the Melipal telescope PR Photo 16c/04: Colour composite of the star forming region G333.6-0.2 PR Photo 16d/04: Colour composite of the Galactic Centre PR Photo 16e/04: The Ant Planetary Nebula at 12.8 μm PR Photo 16f/04: The starburst galaxy He2-10 at 11.3μm PR Photo 16g/04: High

Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs.

PubMed

Tarvin, Rebecca D; Santos, Juan C; O'Connell, Lauren A; Zakon, Harold H; Cannatella, David C

2016-04-01

Complex phenotypes typically have a correspondingly multifaceted genetic component. However, the genotype-phenotype association between chemical defense and resistance is often simple: genetic changes in the binding site of a toxin alter how it affects its target. Some toxic organisms, such as poison frogs (Anura: Dendrobatidae), have defensive alkaloids that disrupt the function of ion channels, proteins that are crucial for nerve and muscle activity. Using protein-docking models, we predict that three major classes of poison frog alkaloids (histrionicotoxins, pumiliotoxins, and batrachotoxins) bind to similar sites in the highly conserved inner pore of the muscle voltage-gated sodium channel, Nav1.4. We predict that poison frogs are somewhat resistant to these compounds because they have six types of amino acid replacements in the Nav1.4 inner pore that are absent in all other frogs except for a distantly related alkaloid-defended frog from Madagascar, Mantella aurantiaca. Protein-docking models and comparative phylogenetics support the role of these replacements in alkaloid resistance. Taking into account the four independent origins of chemical defense in Dendrobatidae, phylogenetic patterns of the amino acid replacements suggest that 1) alkaloid resistance in Nav1.4 evolved independently at least seven times in these frogs, 2) variation in resistance-conferring replacements is likely a result of differences in alkaloid exposure across species, and 3) functional constraint shapes the evolution of the Nav1.4 inner pore. Our study is the first to demonstrate the genetic basis of autoresistance in frogs with alkaloid defenses. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Northern Command: A Relevant and Necessary Partner to Increase Security in Mexico

DTIC Science & Technology

2010-10-27

month.19 Drug cartels leverage low pay and offer “ plato o plomo” or “silver or lead” which forces policemen to choose between taking a bribe or a...Scott Stewart, Hezbollah, Radical but Rational , Stratfor Security Weekly, (12 August 2010), http://www.stratfor.com/weekly...34Hezbollah, Radical but Rational ." Stratfor.com. August 12, 2010. http://www.stratfor.com/weekly/20100811_hezbollah_radical_rational (accessed 28

Agricultural, Nutritional, and Physical Fitness Policies That Support National Security

DTIC Science & Technology

2011-03-24

high fructose corn syrup (HFCS) – could be made inexpensively from corn ...www.nytimes.com/2003/10/12/magazine/12WWLN.html?pagewanted=all (accessed October 9, 2010). 78 Kate McLaughlin, ―The Facts about High Fructose Corn Syrup ...August 24, 2010, linked from the Suite101.com Home Page at ―Health and Wellness,‖ http://www.suite101.com/content/the-facts-about- high - fructose - corn

Stardial -- an autonomous astronomical camera on the WWW

NASA Astrophysics Data System (ADS)

McCullough, P. R.; Thakkar, U.

1997-05-01

The use of an autonomous electronic camera, called ``Stardial,'' for undergraduate instruction is described. Stardial delivers images of the night sky nearly in real-time to the world wide web (www.astro.uiuc.edu/stardial/). The remote instrumentation of Stardial is robust, inexpensive, and accomodates many students asynchronously with respect to the instructor(s). The guiding philosophy of the curriculum is to provide students with authentic astronomical data so that they may learn about science by doing it themselves on the internet. Students respond favorably to the opportunity to learn from their own experiences with genuine data, complete with its irregularities and its surprises. Perhaps surprisingly, 9 of 10 self-selected student volunteers in our pilot project were female. Stardial's instrumentation is similar to that of Gaustad et al., and to that of Richmond, Droege, et al. (both at this same meeting). Stardial has benefitted from contributions from students, especially Lawrence Tan, Troy Klyber, Jim Pulokas, Jim Waldemer, and Diana Lopez, and from a number of professionals, especially G.T. Becker, Mike Newberry, John Dolby, Tom Droege, Bob Mutel, Mike Richmond, John Thorstensen, and Rick White. Stardial is funded by the University of Illinois, primarily from the office of the Vice President for Academic Affairs. We welcome participation from amateur astronomers and other educators.

Pursuit of Precision in the Field Artillery

DTIC Science & Technology

2010-05-21

convention banning cluster bombs will enter into force on Aug.,” Huffingtonpost , http://www.huffingtonpost.com/2010/02/17/un-ratifies-ban-on...banning cluster bombs will enter into force on Aug.” Huffingtonpost . http://www.huffingtonpost.com/2010/02/17/un-ratifies-ban-on- cluste_n_465022.html

SYNTHESIS OF ALPHA-AMINO GAMMA-LACTONE VIA A NOVEL TANDEM THREE-COMPONENT REACTION OF ALKENES, GLYOXYLATES AND AMINES. (R822668)

EPA Science Inventory

Abstract

www.sciencedirect.com/scidirimg/entities/alpha.gif" alt="small alpha, Greek" border=0>-Amino www.sciencedirect.com/scidirimg/entities/gamma.gif" alt="small gamma, Greek" border=0>-lactones were generated by an InCl₃...

An Empirical Research Study of the Efficacy of Two Plagiarism-Detection Applications

ERIC Educational Resources Information Center

Hill, Jacob D.; Page, Elaine Fetyko

2009-01-01

This article describes a study of the two most popular plagiarism-detection software platforms available on today's market--Turnitin (http://www.turnitin.com/static/index.html) and SafeAssign (http://www.safeassign.com/). After a brief discussion of plagiarism's relevance to librarians, the authors examine plagiarism-detection methodology and…

Acute Pancreatitis as a Model to Predict Transition of Systemic Inflammation to Organ Failure in Trauma and Critical Illiness

DTIC Science & Technology

2015-10-01

of the samples. Table 1. Characteristics of common filters suitable for use with the LIVE/DEAD® Viability Kit Omega Filters* Chroma Filters* Notes...www.omegafilters.com). Chroma filters are supplied by Chroma Technology Corp. (www.chroma.com). LIVE/DEAD® Viability/Cytotoxicity Kit 3 4.2 Incubate the cells

United States Coast Guard: Officer Corps Military Professional Development Program

DTIC Science & Technology

2011-06-10

captain relieved of command after viewing porn on computer,‖ 10 July 2010, http://www.thenewstribune.com/2010/07/ 10/1259108/portland-coast-guard...Coast Guard captain relieved of command after viewing porn on computer,‖ 10 July 2010. http://www.thenewstribune.com/2010/07/ 10/1259108/portland

Chemical engineering and structural and pharmacological characterization of the α-scorpion toxin OD1.

PubMed

Durek, Thomas; Vetter, Irina; Wang, Ching-I Anderson; Motin, Leonid; Knapp, Oliver; Adams, David J; Lewis, Richard J; Alewood, Paul F

2013-01-01

Scorpion α-toxins are invaluable pharmacological tools for studying voltage-gated sodium channels, but few structure-function studies have been undertaken due to their challenging synthesis. To address this deficiency, we report a chemical engineering strategy based upon native chemical ligation. The chemical synthesis of α-toxin OD1 was achieved by chemical ligation of three unprotected peptide segments. A high resolution X-ray structure (1.8 Å) of synthetic OD1 showed the typical βαββ α-toxin fold and revealed important conformational differences in the pharmacophore region when compared with other α-toxin structures. Pharmacological analysis of synthetic OD1 revealed potent α-toxin activity (inhibition of fast inactivation) at Nav1.7, as well as Nav1.4 and Nav1.6. In addition, OD1 also produced potent β-toxin activity at Nav1.4 and Nav1.6 (shift of channel activation in the hyperpolarizing direction), indicating that OD1 might interact at more than one site with Nav1.4 and Nav1.6. Investigation of nine OD1 mutants revealed that three residues in the reverse turn contributed significantly to selectivity, with the triple OD1 mutant (D9K, D10P, K11H) being 40-fold more selective for Nav1.7 over Nav1.6, while OD1 K11V was 5-fold more selective for Nav1.6 than Nav1.7. This switch in selectivity highlights the importance of the reverse turn for engineering α-toxins with altered selectivity at Nav subtypes.

Popularity of Russian information sources of medical education.

PubMed

Vasilyeva, Irina V; Arseniev, Sergey B

2014-01-01

The aim of the present study is to analyze the popularity of information sources of medical educational sites <webmedinfo.ru>, medical information portal <meduniver.com>, medical portal for students <6years.net>, electronic library of medical literature <booksmed.com>, <medliter.ru> and <medbook.net.ru>. Three sites (<www.webmedinfo.ru>, <meduniver.com> and <6years.net>) provide sources of medical literature, educational videos, medical histories, medical papers and medical popular literature. And three other sites (<www.booksmed.com>, <www.medliter.ru> and <www.medbook.net.ru>) provide sources for electronic medical books on various subjects. Using on-line programs Alexa and Cy-pr we have analyzed the website's rating and identified the main data and time-varying data of the sites. Calculated Alexa Rank rating was determined for each site. Our study has shown that the most popular information sources of medical education among the six studied sites for Russian users is <meduniver.com>; the site <booksmed.com> is at the second place referring to the Alexa Rank rating and the site <webmedinfo.ru> is at the second place referring to the citation index in Yandex. The most popular medical site of electronic medical books is <booksmed.com>.

Enhanced Cyberspace Defense through Covert Publish-Subscribe Broker Pattern Communications

DTIC Science & Technology

2008-06-01

http://www.cnn.com/TECH/computing/9902/26/t_t/internet.time/, accessed June 2008. [3] C. V. Clausewitz, On War, 1st ed.. London, England: Kegan ...34 2003. [17] T. Greene . (2008 , Apr.) Network World. [Online]. http://www.networkworld.com/news/2008/040908-rsa-hack-power-grid.html, accessed

Sustaining the Knowledge Base of the United States Air Force for Future Operations

DTIC Science & Technology

2015-12-10

Comptroller, 53, no. 1 (Winter 2008), 20. 30 “Lagan Web Self-Service: Knowledge Management,” 19 September 2015, http://www.kana.com/lagan- crm ...2015, http://www.kana.com/lagan- crm /knowledge-management. Madden, Leign. “U.S. Air Force Soaring to the Cloud with Office 365,” http

Laboratory Diagnosis of Lassa Fever

DTIC Science & Technology

2017-01-30

this type of document. You can upgrade to the latest version of Adobe Reader for Windows®, Mac, or Linux® by visiting http://www.adobe.com/ go ...reader_download. For more assistance with Adobe Reader visit http://www.adobe.com/ go /acrreader. Windows is either a registered trademark or a

Cigarette filter ventilation is a defective design because of misleading taste, bigger puffs, and blocked vents.

PubMed

Kozlowski, L T; O'Connor, R J

2002-03-01

To review tobacco industry documents on filter ventilation in light of published studies and to explore the role of filter ventilation in the design of cigarettes that deliver higher smoke yields to smokers than would be expected from standard machine smoked tests (Federal Trade Commission (FTC), International Organization for Standardization (ISO)). Searched from November 1999 to November 2000 internet databases of industry documents (www.pmdocs.com, www.rjrtdocs.com, www.lorillarddocs.com, www.bw.aalatg.com, www.cdc.gov/tobacco/industrydocs, www.tobaccodocuments.org, www.tobaccopapers.org, www.hlth.gov.bc.ca/Guildford, www.cctc.ca/ncth/Guildford, www.cctc.ca/ncth/Guildford2) for documents related to filter ventilation. Documents found dated from 1955 through 1994. Those documents judged to contain the most relevant information or data on filter ventilation related to cigarette taste and compensatory smoking, while also trying to avoid redundancy from various documents deriving from the same underlying data. Filter ventilation is a crucial design feature creating three main problems for lower tar cigarettes as measured by official smoking machine testing. Firstly, it misleadingly makes cigarettes taste lighter and milder, and, therefore, they appear less dangerous to smokers. Secondly, it promotes compensation mainly by facilitating the taking of larger puffs. Thirdly, for very heavily ventilated cigarettes (that is, > 65% filter air dilution), behavioural blocking of vents with lips or fingers is an additional contributor to compensatory smoking. These three effects are found in industry research as well as published research. Filter ventilation is a dangerous, defective technology that should be abandoned in less hazardous nicotine delivery systems. Health interested groups should test cigarettes in a way that reflects compensatory smoking. Lower tar (vented filter) cigarettes should be actively countermarketed.

Worldwide Emerging Environmental Issues Affecting the U.S. Military. November 2007 Report

DTIC Science & Technology

2007-11-01

Economist.com, Nov 19th 2007, DELHI http://www.economist.com/daily/news/displaystory.cfm?story_id=10163828&top_story=1 Andes water supply in peril...Economist.com, Nov 19th 2007, DELHI http://www.economist.com/daily/news/displaystory.cfm?story_id=10163828&top_story=1 Andes water supply in peril, scientists...Committee………………………………...3 Item 6. Reducing Military Footprint with Solar Energy at 30 Cents per Watt……………...4 Item 7. Updates on Previously Identified

Air Superiority And The Anti Access/Area Denial Environment In The Asia pacific In 2044

DTIC Science & Technology

2014-04-01

Ibid. 74 Ibid. 75 Ibid. 76 Ibid. 77 Lockheed Martin, “F-22 Raptor Specifications,” http://www.lockheedmartin.com/us/products/ f22 /f-22...Specifications.” http://www.lockheedmartin.com/us/products/ f22 /f-22-specifications.html (accessed 16 March 2014). Lockheed Martin. “F-35C Carrier Variant

Unmanned Bomber: The Effects It Will Bring to the Nuclear Triad

DTIC Science & Technology

2014-06-01

New York, NY: Avery Trade, 2011), 41. 16 Boeing, History of B-2 Spirit , http://www.boeing.com/boeing/history/boeing/ b2 .page retrieved on January...factsheets/start1 retrieved on February 23, 2014 Boeing, History of B-2 Spirit , http://www.boeing.com/boeing/history/boeing/ b2 .page retrieved on

78 FR 49579 - Self-Regulatory Organizations; EDGX Exchange, Inc.; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-14

...://www.lavatrading.com/solutions/pricing.php (July 1, 2013) (charging a fee of $0.0030 per share for..., available at https://www.lavatrading.com/solutions/pricing.php (July 1, 2013) (no longer charging a fee of... omitted'' from Footnote 7 and replace it with the exact content from Footnote 11. Conforming changes are...

78 FR 32676 - Changes in Flood Hazard Determinations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-31

... flood insurance premium rates for new buildings and the contents of those buildings. For rating purposes...://www.rampp-team.com/ September 23, 2013........ 050084 Springs (13-06- Ruth Carney, 111 Opera lomrs.htm... http://www.rampp-team.com/ July 25, 2013 340343 Hanover (12-02- Ronald F. Engineering lomrs.htm. 1077P...

78 FR 69168 - Self-Regulatory Organizations; Chicago Board Options Exchange, Incorporated; Notice of Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-18

... available on the Exchange's Web site ( http://www.cboe.com/AboutCBOE/CBOELegalRegulatoryHome.aspx ), at the... set forth on the Price List on the MDX Web site ( www.marketdataexpress.com ). MDX currently charges a.... Market participants would be able to purchase Historical COPS Data through the MDX Web site. The proposed...

Macromedia Flash as a Tool for Mathematics Teaching and Learning

ERIC Educational Resources Information Center

Garofalo, Joe; Summers, Tim

2004-01-01

Macromedia Flash is a powerful and robust development tool. Because of its graphical, sound, and animation capabilities (and ubiquitous browser plug-in), major companies employ it in their website development (see www.nike.com or www.espn.com). These same features also make Flash a valuable environment for building multi-representational "movies"…

Piracy and Maritime Terrorism; A Seamless Transition

DTIC Science & Technology

2004-05-18

1/.html>. [24 April 2004]. Cropley , Ed. “Asia eyes sea security after threats, US warning.” Reuters. 22 Apr 2004. <http://www.marketnewzealand.com...stm>. ii Ed Cropley , “Asia eyes sea security after threats, US warning,” Reuters, 22 Apr 2004. <http://www.marketnewzealand.com/mnz/News/Story.aspx

NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery

PubMed Central

Lehmann-Horn, Frank; Fan, Chunxiang; Wolf, Markus; Winston, Vern; Merlini, Luciano

2014-01-01

Hypokalaemic periodic paralysis is typically associated with mutations of voltage sensor residues in calcium or sodium channels of skeletal muscle. To date, causative sodium channel mutations have been studied only for the two outermost arginine residues in S4 voltage sensor segments of domains I to III. These mutations produce depolarization of skeletal muscle fibres in response to reduced extracellular potassium, owing to an inward cation-selective gating pore current activated by hyperpolarization. Here, we describe mutations of the third arginine, R3, in the domain III voltage sensor i.e. an R1135H mutation which was found in two patients in separate families and a novel R1135C mutation identified in a third patient in another family. Muscle fibres from a patient harbouring the R1135H mutation showed increased depolarization tendency at normal and reduced extracellular potassium compatible with the diagnosis. Additionally, amplitude and rise time of action potentials were reduced compared with controls, even for holding potentials at which all NaV1.4 are fully recovered from inactivation. These findings may be because of an outward omega current activated at positive potentials. Expression of R1135H/C in mammalian cells indicates further gating defects that include significantly enhanced entry into inactivation and prolonged recovery that may additionally contribute to action potential inhibition at the physiological resting potential. After S4 immobilization in the outward position, mutant channels produce an inward omega current that most likely depolarizes the resting potential and produces the hypokalaemia-induced weakness. Gating current recordings reveal that mutations at R3 inhibit S4 deactivation before recovery, and molecular dynamics simulations suggest that this defect is caused by disrupted interactions of domain III S2 countercharges with S4 arginines R2 to R4 during repolarization of the membrane. This work reveals a novel mechanism of disrupted S

Comparative study of the distribution of the alpha-subunits of voltage-gated sodium channels in normal and axotomized rat dorsal root ganglion neurons.

PubMed

Fukuoka, Tetsuo; Kobayashi, Kimiko; Yamanaka, Hiroki; Obata, Koichi; Dai, Yi; Noguchi, Koichi

2008-09-10

We compared the distribution of the alpha-subunit mRNAs of voltage-gated sodium channels Nav1.1-1.3 and Nav1.6-1.9 and a related channel, Nax, in histochemically identified neuronal subpopulations of the rat dorsal root ganglia (DRG). In the naïve DRG, the expression of Nav1.1 and Nav1.6 was restricted to A-fiber neurons, and they were preferentially expressed by TrkC neurons, suggesting that proprioceptive neurons possess these channels. Nav1.7, -1.8, and -1.9 mRNAs were more abundant in C-fiber neurons compared with A-fiber ones. Nax was evenly expressed in both populations. Although Nav1.8 and -1.9 were preferentially expressed by TrkA neurons, other alpha-subunits were expressed independently of TrkA expression. Actually, all IB4(+) neurons expressed both Nav1.8 and -1.9, and relatively limited subpopulations of IB4(+) neurons (3% and 12%, respectively) expressed Nav1.1 and/or Nav1.6. These findings provide useful information in interpreting the electrophysiological characteristics of some neuronal subpopulations of naïve DRG. After L5 spinal nerve ligation, Nav1.3 mRNA was up-regulated mainly in A-fiber neurons in the ipsilateral L5 DRG. Although previous studies demonstrated that nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF) reversed this up-regulation, the Nav1.3 induction was independent of either TrkA or GFRalpha1 expression, suggesting that the induction of Nav1.3 may be one of the common responses of axotomized DRG neurons without a direct relationship to NGF/GDNF supply. (c) 2008 Wiley-Liss, Inc.

A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a.

PubMed

Bende, Niraj S; Dziemborowicz, Sławomir; Mobli, Mehdi; Herzig, Volker; Gilchrist, John; Wagner, Jordan; Nicholson, Graham M; King, Glenn F; Bosmans, Frank

2014-07-11

β-Diguetoxin-Dc1a (Dc1a) is a toxin from the desert bush spider Diguetia canities that incapacitates insects at concentrations that are non-toxic to mammals. Dc1a promotes opening of German cockroach voltage-gated sodium (Nav) channels (BgNav1), whereas human Nav channels are insensitive. Here, by transplanting commonly targeted S3b-S4 paddle motifs within BgNav1 voltage sensors into Kv2.1, we find that Dc1a interacts with the domain II voltage sensor. In contrast, Dc1a has little effect on sodium currents mediated by PaNav1 channels from the American cockroach even though their domain II paddle motifs are identical. When exploring regions responsible for PaNav1 resistance to Dc1a, we identified two residues within the BgNav1 domain II S1-S2 loop that when mutated to their PaNav1 counterparts drastically reduce toxin susceptibility. Overall, our results reveal a distinct region within insect Nav channels that helps determine Dc1a sensitivity, a concept that will be valuable for the design of insect-selective insecticides.

30 CFR 47.71 - Access to HazCom materials.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Access to HazCom materials. 47.71 Section 47.71... COMMUNICATION (HazCom) Making HazCom Information Available § 47.71 Access to HazCom materials. Upon request, the operator must provide access to all HazCom materials required by this part to miners and designated...

Evaluation of Magnetostrictive Shunt Damper Performance Using Iron (Fe)-Gallium (Ga) Alloy

DTIC Science & Technology

2013-09-01

Technol. 2003, 11 (4), 482– 494 3. Manning, K. V.; Watanabe, K.; Drake, A. E.; Wright, A. Eddy Current. in AccessScience , ©McGraw-Hill Education...2012, http://www.accessscience.com. 4. Manning, K. V. Lenz’s Law in AccessScience , ©McGraw-Hill Education, 2012, http://www.accessscience.com 5

Fatigue Micromechanism Characterization in Carbon Fibre Reinforced Polymers Using Synchrotron Radiation Computed Tomography

DTIC Science & Technology

2014-12-18

Resources/DataSheets/ Prepreg -Data- Sheets/M21_global.pdf. [20] Hexcel HexPly 8552. http://www.hexcel.com/Resources/DataSheets/ Prepreg -Data- Sheets...8552_eu.pdf [21] 3501-6 Epoxy Matrix, Hexcel. http://www.hexcel.com/Resources/DataSheets/ Prepreg -Data- Sheets/3501-6_eu.pdf [22] B.A. Dowd, G.H

Will Technological Convergence Reverse Globalization (Strategic Forum, Number 297)

DTIC Science & Technology

2016-07-01

for counterfeiting high-value products they are contracted to produce. One technique is for the Chinese contractor to build a duplicate factory...www.meatinstitute.org/index. php? ht =d/sp/i/47465/pid/47465>. 66 “Soybean Meal Exports by Country in 1000 MT,” IndexMundi.com, available at <www.indexmundi.com

Construction and validation of a web-based epidemiological database for inflammatory bowel diseases in Europe An EpiCom study.

PubMed

Burisch, Johan; Cukovic-Cavka, Silvija; Kaimakliotis, Ioannis; Shonová, Olga; Andersen, Vibeke; Dahlerup, Jens F; Elkjaer, Margarita; Langholz, Ebbe; Pedersen, Natalia; Salupere, Riina; Kolho, Kaija-Leena; Manninen, Pia; Lakatos, Peter Laszlo; Shuhaibar, Mary; Odes, Selwyn; Martinato, Matteo; Mihu, Ion; Magro, Fernando; Belousova, Elena; Fernandez, Alberto; Almer, Sven; Halfvarson, Jonas; Hart, Ailsa; Munkholm, Pia

2011-08-01

The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration. To construct and validate a web-based inception cohort database available in both English and Russian language. The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments. The EpiCom database fulfills the requirements of the participating countries' local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database. A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu. Copyright © 2011 European Crohn's and Colitis Organisation. All rights reserved.

Instrumentation for Aim Point Determination in the Close-in Battle

DTIC Science & Technology

2007-12-01

Rugged camcorder with remote “ lipstick ” camera (http://www.samsung.com/Products/ Camcorder/DigitalMemory/files/scx210wl.pdf). ........ 5 Figure 5...target. One way of making a measurement is to mount a small “ lipstick ” camera to the rifle with a mount similar to the laser-tag transmitter mount...technology.com/contractors/surveillance/viotac-inc/viotac-inc1.html). Figure 4. Rugged camcorder with remote “ lipstick ” camera (http://www.samsung.com

Prioritizing Strategic Interests in South Asia

DTIC Science & Technology

2010-06-01

rolled out “Aghaz-e-Haqooq Balochistan ”—its by far the most serious fallout from the conflict in Afghanistan is the increasing radicalization of...Foreign Policy, August 2006, available at <www.foreignpolicy.com/ story/cms.php?story_id=3578>. 17 “Aghaz-e-Haqooq Balochistan Package,” Dawn. com...November 16, 2009, available at <www.dawn.com/ wps/wcm/connect/dawn-content-library/dawn/news/ pakistan/13+aghaz-e-haqooq+ balochistan +package- za-05

78 FR 38741 - Order Granting Limited Exemptions From Exchange Act Rule 10b-17 and Rules 101 and 102 of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-27

... value (``NAV'') and the secondary market price of the Shares should not vary substantially from the NAV... alignment between the market price of Shares and each Fund's NAV is expected. Regulation M While redeemable... alignment between the market price of Shares and the Funds' NAV is expected, the Commission finds that it is...

jsc2018m000189_ISS_As_Art-MP4

NASA Image and Video Library

2018-03-13

International Space Station as Art------- The International Space Station has been humanity’s outpost in space for nearly two decades, hosting astronauts from around the globe working on groundbreaking science to push the boundaries in a variety of fields. NASA astronaut Randy Bresnik sought to capture the beauty of the immense spacecraft amidst the endless tangle of cables and hardware in this series of photos taken during his most recent stay onboard. Follow Randy Bresnik on social media at: https://twitter.com/astrokomrade https://www.instagram.com/astrokomrade _______________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/

Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation.

PubMed

Peters, Colin H; Yu, Alec; Zhu, Wandi; Silva, Jonathan R; Ruben, Peter C

2017-01-01

E1784K is the most common mixed long QT syndrome/Brugada syndrome mutant in the cardiac voltage-gated sodium channel NaV1.5. E1784K shifts the midpoint of the channel conductance-voltage relationship to more depolarized membrane potentials and accelerates the rate of channel fast inactivation. The depolarizing shift in the midpoint of the conductance curve in E1784K is exacerbated by low extracellular pH. We tested whether the E1784K mutant shifts the channel conductance curve to more depolarized membrane potentials by affecting the channel voltage-sensors. We measured ionic currents and gating currents at pH 7.4 and pH 6.0 in Xenopus laevis oocytes. Contrary to our expectation, the movement of gating charges is shifted to more hyperpolarized membrane potentials by E1784K. Voltage-clamp fluorimetry experiments show that this gating charge shift is due to the movement of the DIVS4 voltage-sensor being shifted to more hyperpolarized membrane potentials. Using a model and experiments on fast inactivation-deficient channels, we show that changes to the rate and voltage-dependence of fast inactivation are sufficient to shift the conductance curve in E1784K. Our results localize the effects of E1784K to DIVS4, and provide novel insight into the role of the DIV-VSD in regulating the voltage-dependencies of activation and fast inactivation.

NOT Lost in Space

NASA Image and Video Library

2017-02-21

How hard would it be to keep track of your stuff if it could literally float away—which does happen on the International Space Station. Well, the crews in space have help, in the form of the Stowage team at NASA’s Marshall Space Flight Center in Huntsville, Alabama. From tools to trash, learn how the team keeps track of everything the astronauts need as they conduct groundbreaking science research on orbit. For more on ISS science, visit us online: https://www.nasa.gov/mission_pages/station/research/index.html www.twitter.com/iss_research HD download link: https://archive.org/details/TheSpaceProgram _______________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/ YouTube: https://youtu.be/arEf05Yf5IY

Functional Analysis of the ComK Protein of Bacillus coagulans

PubMed Central

Kovács, Ákos T.; Eckhardt, Tom H.; van Kranenburg, Richard; Kuipers, Oscar P.

2013-01-01

The genes for DNA uptake and recombination in Bacilli are commonly regulated by the transcriptional factor ComK. We have identified a ComK homologue in Bacillus coagulans, an industrial relevant organism that is recalcitrant for transformation. Introduction of B. coagulans comK gene under its own promoter region into Bacillus subtilis comK strain results in low transcriptional induction of the late competence gene comGA, but lacking bistable expression. The promoter regions of B. coagulans comK and the comGA genes are recognized in B. subtilis and expression from these promoters is activated by B. subtilis ComK. Purified ComK protein of B. coagulans showed DNA-binding ability in gel retardation assays with B. subtilis- and B. coagulans-derived probes. These experiments suggest that the function of B. coagulans ComK is similar to that of ComK of B. subtilis. When its own comK is overexpressed in B. coagulans the comGA gene expression increases 40-fold, while the expression of another late competence gene, comC is not elevated and no reproducible DNA-uptake could be observed under these conditions. Our results demonstrate that B. coagulans ComK can recognize several B. subtilis comK-responsive elements, and vice versa, but indicate that the activation of the transcription of complete sets of genes coding for a putative DNA uptake apparatus in B. coagulans might differ from that of B. subtilis. PMID:23301076

Functional analysis of the ComK protein of Bacillus coagulans.

PubMed

Kovács, Ákos T; Eckhardt, Tom H; van Hartskamp, Mariska; van Kranenburg, Richard; Kuipers, Oscar P

2013-01-01

The genes for DNA uptake and recombination in Bacilli are commonly regulated by the transcriptional factor ComK. We have identified a ComK homologue in Bacillus coagulans, an industrial relevant organism that is recalcitrant for transformation. Introduction of B. coagulans comK gene under its own promoter region into Bacillus subtilis comK strain results in low transcriptional induction of the late competence gene comGA, but lacking bistable expression. The promoter regions of B. coagulans comK and the comGA genes are recognized in B. subtilis and expression from these promoters is activated by B. subtilis ComK. Purified ComK protein of B. coagulans showed DNA-binding ability in gel retardation assays with B. subtilis- and B. coagulans-derived probes. These experiments suggest that the function of B. coagulans ComK is similar to that of ComK of B. subtilis. When its own comK is overexpressed in B. coagulans the comGA gene expression increases 40-fold, while the expression of another late competence gene, comC is not elevated and no reproducible DNA-uptake could be observed under these conditions. Our results demonstrate that B. coagulans ComK can recognize several B.subtilis comK-responsive elements, and vice versa, but indicate that the activation of the transcription of complete sets of genes coding for a putative DNA uptake apparatus in B. coagulans might differ from that of B. subtilis.

Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration.

PubMed

Xiao, Yucheng; Bingham, Jon-Paul; Zhu, Weiguo; Moczydlowski, Edward; Liang, Songping; Cummins, Theodore R

2008-10-03

Peptide toxins with high affinity, divergent pharmacological functions, and isoform-specific selectivity are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a number of interesting inhibitors have been reported from tarantula venoms, little is known about the mechanism for their interaction with VGSCs. We show that huwentoxin-IV (HWTX-IV), a 35-residue peptide from tarantula Ornithoctonus huwena venom, preferentially inhibits neuronal VGSC subtypes rNav1.2, rNav1.3, and hNav1.7 compared with muscle subtypes rNav1.4 and hNav1.5. Of the five VGSCs examined, hNav1.7 was most sensitive to HWTX-IV (IC(50) approximately 26 nM). Following application of 1 microm HWTX-IV, hNav1.7 currents could only be elicited with extreme depolarizations (>+100 mV). Recovery of hNav1.7 channels from HWTX-IV inhibition could be induced by extreme depolarizations or moderate depolarizations lasting several minutes. Site-directed mutagenesis analysis indicated that the toxin docked at neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II. Mutations E818Q and D816N in hNav1.7 decreased toxin affinity for hNav1.7 by approximately 300-fold, whereas the reverse mutations in rNav1.4 (N655D/Q657E) and the corresponding mutations in hNav1.5 (R812D/S814E) greatly increased the sensitivity of the muscle VGSCs to HWTX-IV. Our data identify a novel mechanism for sodium channel inhibition by tarantula toxins involving binding to neurotoxin receptor site 4. In contrast to scorpion beta-toxins that trap the IIS4 voltage sensor in an outward configuration, we propose that HWTX-IV traps the voltage sensor of domain II in the inward, closed configuration.

48 CFR 2901.603-1 - General.

Code of Federal Regulations, 2010 CFR

2010-10-01

... available at: http://www.arnet.gov/Library/OFPP/PolicyLetters/Letters/PL97-01.html, http://www.arnet.gov...: http://www.faionline.com/fai/campus/index4.htm. (b) The program must cover all contracting personnel in...

48 CFR 2901.603-1 - General.

Code of Federal Regulations, 2012 CFR

2012-10-01

... available at: http://www.arnet.gov/Library/OFPP/PolicyLetters/Letters/PL97-01.html, http://www.arnet.gov...: http://www.faionline.com/fai/campus/index4.htm. (b) The program must cover all contracting personnel in...

48 CFR 2901.603-1 - General.

Code of Federal Regulations, 2013 CFR

2013-10-01

... available at: http://www.arnet.gov/Library/OFPP/PolicyLetters/Letters/PL97-01.html, http://www.arnet.gov...: http://www.faionline.com/fai/campus/index4.htm. (b) The program must cover all contracting personnel in...

48 CFR 2901.603-1 - General.

Code of Federal Regulations, 2014 CFR

2014-10-01

... available at: http://www.arnet.gov/Library/OFPP/PolicyLetters/Letters/PL97-01.html, http://www.arnet.gov...: http://www.faionline.com/fai/campus/index4.htm. (b) The program must cover all contracting personnel in...

Mapping of voltage sensor positions in resting and inactivated mammalian sodium channels by LRET

PubMed Central

Kubota, Tomoya; Durek, Thomas; Dang, Bobo; Finol-Urdaneta, Rocio K.; Craik, David J.; Kent, Stephen B. H.; French, Robert J.; Bezanilla, Francisco; Correa, Ana M.

2017-01-01

Voltage-gated sodium channels (Navs) play crucial roles in excitable cells. Although vertebrate Nav function has been extensively studied, the detailed structural basis for voltage-dependent gating mechanisms remain obscure. We have assessed the structural changes of the Nav voltage sensor domain using lanthanide-based resonance energy transfer (LRET) between the rat skeletal muscle voltage-gated sodium channel (Nav1.4) and fluorescently labeled Nav1.4-targeting toxins. We generated donor constructs with genetically encoded lanthanide-binding tags (LBTs) inserted at the extracellular end of the S4 segment of each domain (with a single LBT per construct). Three different Bodipy-labeled, Nav1.4-targeting toxins were synthesized as acceptors: β-scorpion toxin (Ts1)-Bodipy, KIIIA-Bodipy, and GIIIA-Bodipy analogs. Functional Nav-LBT channels expressed in Xenopus oocytes were voltage-clamped, and distinct LRET signals were obtained in the resting and slow inactivated states. Intramolecular distances computed from the LRET signals define a geometrical map of Nav1.4 with the bound toxins, and reveal voltage-dependent structural changes related to channel gating. PMID:28202723

Mapping of voltage sensor positions in resting and inactivated mammalian sodium channels by LRET.

PubMed

Kubota, Tomoya; Durek, Thomas; Dang, Bobo; Finol-Urdaneta, Rocio K; Craik, David J; Kent, Stephen B H; French, Robert J; Bezanilla, Francisco; Correa, Ana M

2017-03-07

Voltage-gated sodium channels (Navs) play crucial roles in excitable cells. Although vertebrate Nav function has been extensively studied, the detailed structural basis for voltage-dependent gating mechanisms remain obscure. We have assessed the structural changes of the Nav voltage sensor domain using lanthanide-based resonance energy transfer (LRET) between the rat skeletal muscle voltage-gated sodium channel (Nav1.4) and fluorescently labeled Nav1.4-targeting toxins. We generated donor constructs with genetically encoded lanthanide-binding tags (LBTs) inserted at the extracellular end of the S4 segment of each domain (with a single LBT per construct). Three different Bodipy-labeled, Nav1.4-targeting toxins were synthesized as acceptors: β-scorpion toxin (Ts1)-Bodipy, KIIIA-Bodipy, and GIIIA-Bodipy analogs. Functional Nav-LBT channels expressed in Xenopus oocytes were voltage-clamped, and distinct LRET signals were obtained in the resting and slow inactivated states. Intramolecular distances computed from the LRET signals define a geometrical map of Nav1.4 with the bound toxins, and reveal voltage-dependent structural changes related to channel gating.

Global Horizons (Briefing Charts)

DTIC Science & Technology

2013-08-01

to Austere/Remote Bases • Precision airdrop (L) • Affordable wind profiling system (L) • Air to ground communications (L) • Efficient high power... bird www.youtube.com/watch?v=2QqTcQ1BxIs  Autonomy: Swarm of Nano quadrotors – fly in formation, navigate (1 min 42s) www.youtube.com/watch?v

Radical Islam in Latin America and the Caribbean: Implications for U.S. National Security

DTIC Science & Technology

2015-01-01

www.Newsmax.com/International/iran-missiles-venezu- ela/2008/12/22/id/327242/#ixzz3MfAmHOjT. 66. “Washington sanciona a Cavim for venta de tecnologia a Irán...El Universal, February 11, 2013, http://www.eluni- versal.com/nacional-y-politica/130211/washington-sanciona-a-cavim-por-venta-de- tecnologia -a-iran

The Need to Establish a Permanent Military Tribunal to Serve the Legal Needs of the Departments of Alta Verapaz, Baja Verapaz, and the Municipality of Ixcn in the Departamento de El Quich in the Republic of Guatemala

DTIC Science & Technology

2017-06-09

materia,” Monografías, 12 de diciembre de 2012, acceso 5 de marzo de 2017, http://www.monografias.com/ trabajos7/compro/compro.shtml# crm . 40...marzo de 2017. http://www.monografias.com/ trabajos7/compro/compro.shtml# crm . ———. “Temario derecho procesal penal.” Monografías. 18 de agosto de

Teach Students to Dig for Understanding Using an Unexpected Technological Shovel

ERIC Educational Resources Information Center

Lake, Susan E. L.

2004-01-01

Online genealogy tools is an unexpected resource as these tools not only serve valuable for genealogy research, but also can be used by students to learn about their country's past and learn to use primary materials to draw conclusions. Some of these Online sources like the 1880 census available at www.ancestry.com, www.thepastwhispers.com, which…

Making Dynamic Digital Maps Cross-Platform and WWW Capable

NASA Astrophysics Data System (ADS)

Condit, C. D.

2001-05-01

High-quality color geologic maps are an invaluable information resource for educators, students and researchers. However, maps with large datasets that include images, or various types of movies, in addition to site locations where analytical data has been collected, are difficult to publish in a format that facilitates their easy access, distribution and use. The development of capable desktop computers and object oriented graphical programming environments has facilitated publication of such data sets in an encapsulated form. The original Dynamic Digital Map (DDM) programs, developed using the Macintosh based SuperCard programming environment, exemplified this approach, in which all data are included in a single package designed so that display and access to the data did not depend on proprietary programs. These DDMs were aimed for ease of use, and allowed data to be displayed by several methods, including point-and-click at icons pin-pointing sample (or image) locations on maps, and from clicklists of sample or site numbers. Each of these DDMs included an overview and automated tour explaining the content organization and program use. This SuperCard development culminated in a "DDM Template", which is a SuperCard shell into which SuperCard users could insert their own content and thus create their own DDMs, following instructions in an accompanying "DDM Cookbook" (URL http://www.geo.umass.edu/faculty/condit/condit2.html). These original SuperCard-based DDMs suffered two critical limitations: a single user platform (Macintosh) and, although they can be downloaded from the web, their use lacked an integration into the WWW. Over the last eight months I have been porting the DDM technology to MetaCard, which is aggressively cross-platform (11 UNIX dialects, WIN32 and Macintosh). The new MetaCard DDM is redesigned to make the maps and images accessible either from CD or the web, using the "LoadNGo" concept. LoadNGo allows the user to download the stand-alone DDM

--No Title--

Science.gov Websites

.navbar-nav .open .dropdown-menu { float: none; width: auto; margin-top: 0; background-color: transparent ; border: 0; box-shadow: none; } #topnav .navbar-nav .open .dropdown-menu > li > a, #topnav .navbar -nav .open .dropdown-menu .dropdown-header { padding: 10px 15px 10px 25px; } #topnav .navbar-nav .open

Distribution of TTX-sensitive voltage-gated sodium channels in primary sensory endings of mammalian muscle spindles.

PubMed

Carrasco, Dario I; Vincent, Jacob A; Cope, Timothy C

2017-04-01

Knowledge of the molecular mechanisms underlying signaling of mechanical stimuli by muscle spindles remains incomplete. In particular, the ionic conductances that sustain tonic firing during static muscle stretch are unknown. We hypothesized that tonic firing by spindle afferents depends on sodium persistent inward current (INaP) and tested for the necessary presence of the appropriate voltage-gated sodium (NaV) channels in primary sensory endings. The NaV 1.6 isoform was selected for both its capacity to produce INaP and for its presence in other mechanosensors that fire tonically. The present study shows that NaV 1.6 immunoreactivity (IR) is concentrated in heminodes, presumably where tonic firing is generated, and we were surprised to find NaV 1.6 IR strongly expressed also in the sensory terminals, where mechanotransduction occurs. This spatial pattern of NaV 1.6 IR distribution was consistent for three mammalian species (rat, cat, and mouse), as was tonic firing by primary spindle afferents. These findings meet some of the conditions needed to establish participation of INaP in tonic firing by primary sensory endings. The study was extended to two additional NaV isoforms, selected for their sensitivity to TTX, excluding TTX-resistant NaV channels, which alone are insufficient to support firing by primary spindle endings. Positive immunoreactivity was found for NaV 1.1 , predominantly in sensory terminals together with NaV 1.6 and for NaV 1.7 , mainly in preterminal axons. Differential distribution in primary sensory endings suggests specialized roles for these three NaV isoforms in the process of mechanosensory signaling by muscle spindles. NEW & NOTEWORTHY The molecular mechanisms underlying mechanosensory signaling responsible for proprioceptive functions are not completely elucidated. This study provides the first evidence that voltage-gated sodium channels (NaVs) are expressed in the spindle primary sensory ending, where NaVs are found at every site

Biophysical Adaptations of Prokaryotic Voltage-Gated Sodium Channels.

PubMed

Vien, T N; DeCaen, P G

2016-01-01

This chapter describes the adaptive features found in voltage-gated sodium channels (NaVs) of prokaryotes and eukaryotes. These two families are distinct, having diverged early in evolutionary history but maintain a surprising degree of convergence in function. While prokaryotic NaVs are required for growth and motility, eukaryotic NaVs selectively conduct fast electrical currents for short- and long-range signaling across cell membranes in mammalian organs. Current interest in prokaryotic NaVs is stoked by their resolved high-resolution structures and functional features which are reminiscent of eukaryotic NaVs. In this chapter, comparisons between eukaryotic and prokaryotic NaVs are made to highlight the shared and unique aspects of ion selectivity, voltage sensitivity, and pharmacology. Examples of prokaryotic and eukaryotic NaV convergent evolution will be discussed within the context of their structural features. Copyright © 2016 Elsevier Inc. All rights reserved.

NASA Cribs: Human Exploration Research Analog

NASA Image and Video Library

2017-07-20

Follow along as interns at NASA’s Johnson Space Center show you around the Human Exploration Research Analog (HERA), a mission simulation environment located onsite at the Johnson Space Center in Houston. HERA is a unique three-story habitat designed to serve as an analog for isolation, confinement, and remote conditions in exploration scenarios. This video gives a tour of where crew members live, work, sleep, and eat during the analog missions. Find out more about HERA mission activities: https://www.nasa.gov/analogs/hera Find out how to be a HERA crew member: https://www.nasa.gov/analogs/hera/want-to-participate For more on NASA internships: https://intern.nasa.gov/ For Johnson Space Center specific internships: https://pathways.jsc.nasa.gov/ https://www.nasa.gov/centers/johnson/education/interns/index.html HD download link: https://archive.org/details/jsc2017m000730_NASA-Cribs-Human-Exploration-Research-Analog --------------------------------- FOLLOW JOHNSON SPACE CENTER INTERNS! Facebook: @NASA.JSC.Students https://www.facebook.com/NASA.JSC.Students/ Instagram: @nasajscstudents https://www.instagram.com/nasajscstudents/ Twitter: @NASAJSCStudents https://twitter.com/nasajscstudents

COM-BUS : A Southern California Subscription Bus Service

DOT National Transportation Integrated Search

1977-05-01

The evolution and operations of the COM-BUS Subscription Commuter Bus Service are documented. COM-BUS is a privately owned organization operating at a profit without any form of subsidy. COM-BUS serves approximately 2,000 commuters per day on 47 rout...

COMS normal operation for Earth Observation mission

NASA Astrophysics Data System (ADS)

Cho, Young-Min

2012-09-01

Communication Ocean Meteorological Satellite (COMS) for the hybrid mission of meteorological observation, ocean monitoring, and telecommunication service was launched onto Geostationary Earth Orbit on June 27, 2010 and it is currently under normal operation service since April 2011. The COMS is located on 128.2° East of the geostationary orbit. In order to perform the three missions, the COMS has 3 separate payloads, the meteorological imager (MI), the Geostationary Ocean Color Imager (GOCI), and the Ka-band antenna. Each payload is dedicated to one of the three missions, respectively. The MI and GOCI perform the Earth observation mission of meteorological observation and ocean monitoring, respectively. For this Earth observation mission the COMS requires daily mission commands from the satellite control ground station and daily mission is affected by the satellite control activities. For this reason daily mission planning is required. The Earth observation mission operation of COMS is described in aspects of mission operation characteristics and mission planning for the normal operation services of meteorological observation and ocean monitoring. And the first year normal operation results after the In-Orbit-Test (IOT) are investigated through statistical approach to provide the achieved COMS normal operation status for the Earth observation mission.

Navigator-3, a modulator of cell migration, may act as a suppressor of breast cancer progression

PubMed Central

Cohen-Dvashi, Hadas; Ben-Chetrit, Nir; Russell, Roslin; Carvalho, Silvia; Lauriola, Mattia; Nisani, Sophia; Mancini, Maicol; Nataraj, Nishanth; Kedmi, Merav; Roth, Lee; Köstler, Wolfgang; Zeisel, Amit; Yitzhaky, Assif; Zylberg, Jacques; Tarcic, Gabi; Eilam, Raya; Wigelman, Yoav; Will, Rainer; Lavi, Sara; Porat, Ziv; Wiemann, Stefan; Ricardo, Sara; Schmitt, Fernando; Caldas, Carlos; Yarden, Yosef

2015-01-01

Dissemination of primary tumor cells depends on migratory and invasive attributes. Here, we identify Navigator-3 (NAV3), a gene frequently mutated or deleted in human tumors, as a regulator of epithelial migration and invasion. Following induction by growth factors, NAV3 localizes to the plus ends of microtubules and enhances their polarized growth. Accordingly, NAV3 depletion trimmed microtubule growth, prolonged growth factor signaling, prevented apoptosis and enhanced random cell migration. Mathematical modeling suggested that NAV3-depleted cells acquire an advantage in terms of the way they explore their environment. In animal models, silencing NAV3 increased metastasis, whereas ectopic expression of the wild-type form, unlike expression of two, relatively unstable oncogenic mutants from human tumors, inhibited metastasis. Congruently, analyses of > 2,500 breast and lung cancer patients associated low NAV3 with shorter survival. We propose that NAV3 inhibits breast cancer progression by regulating microtubule dynamics, biasing directionally persistent rather than random migration, and inhibiting locomotion of initiated cells. PMID:25678558

In Situ Chemical Reduction for Organic Explosives in Soil

DTIC Science & Technology

2009-05-01

DARAMEND®  Implementation  Results  Degradation and Toxicity  Summary Presentation Outline www.AdventusGroup.com March 2008 © Copyright Adventus...2008 © Copyright Adventus Intellectual Property Inc. 9 DARAMEND ® Technology Applications Cycled Anaerobic/Aerobic • chlorinated pesticides and...Consistency • Fungus www.AdventusGroup.com March 2008 © Copyright Adventus Intellectual Property Inc. 17 Implementation - Full Scale • Conducted inside

Continuing Education for Department of Defense Health Professionals

DTIC Science & Technology

2015-11-24

American Pharmacists Association, 60 and American Nurses Association. 61 These associations and other health-focused organizations, including health...1298. Accessed May 29, 2014. 60. American Pharmacists Association. Learn [Web page]. 2014; http://www.pharmacist.com/node/26541. Accessed May 29...American Pharmacists Association. Learn [Web page]. 2014; http://www.pharmacist.com/node/26541. Accessed May 29, 2014. 61. American Nurses Association

Access Denied: Future Military Operations in an Anti-Access Environment

DTIC Science & Technology

2011-05-04

Naval War College 686 Cushing Road Newport, RI 02841-1207 9. SPONSORING/MONITORING AGENCY NAME( S ...Haddick, “This Week at War: Gates‟ s China Syndrome ,” Foreign Policy, http://www.foreignpolicy.com/articles/2011/01/07...accessed 23 February 2011). Haddick, Robert. “This Week at War: Gates‟ s China Syndrome .” Foreign Policy. http://www.foreignpolicy.com/articles/2011

Alternative Fuels Data Center: Fleet Application for School Transportation

Science.gov Websites

/_kZz_IxCsQA Video thumbnail for Natural Gas School Buses Help Kansas City Save Money Natural Gas School Buses Help Kansas City Save Money Nov. 12, 2011 https://www.youtube.com/embed/VYbBFQEKKCs Video thumbnail for , 2011 https://www.youtube.com/embed/ZJVXELFPywI Video thumbnail for Propane Buses Save Money for

Saving The Savable: Using Bystanders To Increase Survival From Out Of Hospital Cardiac Arrest (Ohca) In New York City

DTIC Science & Technology

2016-03-01

Howley, “What Is NFC, and Why Does it Matter for the iPhone 6?” Yahoo , September 3, 2014, https://www.yahoo.com/tech/what-is-nfc-and-why-does-it...www.wired.com/ 2006/06/crowds. Howley, Daniel. “What Is NFC, and Why Does it Matter for the iPhone 6?” Yahoo . September 3, 2014. https

How to Train a Dragon: How the Peoples Liberation Army Air Force (PLAAF) Modernizes to Fight and Win Wars

DTIC Science & Technology

2015-06-01

Initiative: Definition of Initiative in Oxford Dictionary (American English ) (US),” accessed March 19, 2015, http://www.oxforddictionaries.com/us...definition/american_english/initiative. 10 “Autonomy: Definition of Autonomy in Oxford Dictionary (American English ) (US),” accessed March 19, 2015, http...Definition of Autonomy in Oxford Dictionary (American English ) (US).” Accessed March 19, 2015. http://www.oxforddictionaries.com/us/definition

[An Experimental Set-Up for Navigated-Contrast-Agent and Radiation Sparing Endovascular Aortic Repair (Nav-CARS EVAR)].

PubMed

Horn, M; Nolde, J; Goltz, J P; Barkhausen, J; Schade, W; Waltermann, C; Modersitzki, J; Olesch, J; Papenberg, N; Keck, T; Kleemann, M

2015-10-01

Over the last decade endovascular stenting of aortic aneurysm (EVAR) has been developed from single centre experiences to a standard procedure. With increasing clinical expertise and medical technology advances treatment of even complex aneurysms are feasible by endovascular methods. One integral part for the success of this minimally invasive procedure is innovative and improved vascular imaging to generate exact measurements and correct placement of stent prosthesis. One of the greatest difficulty in learning and performing this endovascular therapy is the fact that the three-dimensional vascular tree has to be overlaid with the two-dimensional angiographic scene by the vascular surgeon. We report the development of real-time navigation software, which allows a three-dimensional endoluminal view of the vascular system during an EVAR procedure in patients with infrarenal aortic aneurysm. We used the preoperative planning CT angiography for three-dimensional reconstruction of aortic anatomy by volume-rendered segmentation. At the beginning of the intervention the relevant landmarks are matched in real-time with the two-dimensional angiographic scene. During the intervention the software continously registers the position of the guide-wire or the stent. An additional 3D-screen shows the generated endoluminal view during the whole intervention in real-time. We examined the combination of hardware and software components including complex image registration and fibre optic sensor technology (fibre-bragg navigation) with integration in stent graft introducer sheaths using patient-specific vascular phantoms in an experimental setting. From a technical point of view the feasibility of fibre-Bragg navigation has been proven in our experimental setting with patient-based vascular models. Three-dimensional preoperative planning including registration and simulation of virtual angioscopy in real time are realised. The aim of the Nav-CARS-EVAR concept is reduction of contrast

Pacemaker rate and depolarization block in nigral dopamine neurons: a somatic sodium channel balancing act

PubMed Central

Tucker, Kristal R.; Huertas, Marco A.; Horn, John P.; Canavier, Carmen C.; Levitan, Edwin S.

2012-01-01

Midbrain dopamine (DA) neurons are slow intrinsic pacemakers that undergo depolarization (DP) block upon moderate stimulation. Understanding DP block is important because it has been correlated with the clinical efficacy of chronic antipsychotic drug treatment. Here we describe how voltage-gated sodium (NaV) channels regulate DP block and pacemaker activity in DA neurons of the substantia nigra using rat brain slices. The distribution, density and gating of NaV currents were manipulated by blocking native channels with tetrodotoxin and by creating virtual channels and anti-channels with dynamic clamp. Although action potentials initiate in the axon initial segment (AIS) and NaV channels are distributed in multiple dendrites, selective reduction of NaV channel activity in the soma was sufficient to decrease pacemaker frequency and increase susceptibility to DP block. Conversely, increasing somatic NaV current density raised pacemaker frequency and lowered susceptibility to DP block. Finally, when NaV currents were restricted to the soma, pacemaker activity occurred at abnormally high rates due to excessive local subthreshold NaV current. Together with computational simulations, these data show that both the slow pacemaker rate and the sensitivity to DP block that characterizes DA neurons result from the low density of somatic NaV channels. More generally, we conclude that the somatodendritic distribution of NaV channels is a major determinant of repetitive spiking frequency. PMID:23077037

Where is the spike generator of the cochlear nerve? Voltage-gated sodium channels in the mouse cochlea.

PubMed

Hossain, Waheeda A; Antic, Srdjan D; Yang, Yang; Rasband, Matthew N; Morest, D Kent

2005-07-20

The origin of the action potential in the cochlea has been a long-standing puzzle. Because voltage-dependent Na+ (Nav) channels are essential for action potential generation, we investigated the detailed distribution of Nav1.6 and Nav1.2 in the cochlear ganglion, cochlear nerve, and organ of Corti, including the type I and type II ganglion cells. In most type I ganglion cells, Nav1.6 was present at the first nodes flanking the myelinated bipolar cell body and at subsequent nodes of Ranvier. In the other ganglion cells, including type II, Nav1.6 clustered in the initial segments of both of the axons that flank the unmyelinated bipolar ganglion cell bodies. In the organ of Corti, Nav1.6 was localized in the short segments of the afferent axons and their sensory endings beneath each inner hair cell. Surprisingly, the outer spiral fibers and their sensory endings were well labeled beneath the outer hair cells over their entire trajectory. In contrast, Nav1.2 in the organ of Corti was localized to the unmyelinated efferent axons and their endings on the inner and outer hair cells. We present a computational model illustrating the potential role of the Nav channel distribution described here. In the deaf mutant quivering mouse, the localization of Nav1.6 was disrupted in the sensory epithelium and ganglion. Together, these results suggest that distinct Nav channels generate and regenerate action potentials at multiple sites along the cochlear ganglion cells and nerve fibers, including the afferent endings, ganglionic initial segments, and nodes of Ranvier.

Block of human cardiac sodium channels by lacosamide: evidence for slow drug binding along the activation pathway.

PubMed

Wang, Ging Kuo; Wang, Sho-Ya

2014-05-01

Lacosamide is an anticonvulsant hypothesized to enhance slow inactivation of neuronal Na(+) channels for its therapeutic action. Cardiac Na(+) channels display less and incomplete slow inactivation, but their sensitivity toward lacosamide remains unknown. We therefore investigated the action of lacosamide in human cardiac Nav1.5 and Nav1.5-CW inactivation-deficient Na(+) channels. Lacosamide showed little effect on hNav1.5 Na(+) currents at 300 µM when cells were held at -140 mV. With 30-second conditioning pulses from -90 to -50 mV; however, hNav1.5 Na(+) channels became sensitive to lacosamide with IC50 (50% inhibitory concentration) around 70-80 µM. Higher IC50 values were found at -110 and -30 mV. The development of lacosamide block at -70 mV was slow in wild-type Na(+) channels (τ; 8.04 ± 0.39 seconds, n = 8). This time constant was significantly accelerated in hNav1.5-CW inactivation-deficient counterparts. The recovery from lacosamide block at -70 mV for 10 seconds was relatively rapid in wild-type Na(+) channels (τ; 639 ± 90 milliseconds, n = 8). This recovery was accelerated further in hNav1.5-CW counterparts. Unexpectedly, lacosamide elicited a time-dependent block of persistent hNav1.5-CW Na(+) currents with an IC50 of 242 ± 19 µM (n = 5). Furthermore, both hNav1.5-CW/F1760K mutant and batrachotoxin-activated hNav1.5 Na(+) channels became completely lacosamide resistant, indicating that the lacosamide receptor overlaps receptors for local anesthetics and batrachotoxin. Our results together suggest that lacosamide targets the intermediate preopen and open states of hNav1.5 Na(+) channels. Lacosamide may thus track closely the conformational changes at the hNav1.5-F1760 region along the activation pathway.

Mapping the interaction site for the tarantula toxin hainantoxin-IV (β-TRTX-Hn2a) in the voltage sensor module of domain II of voltage-gated sodium channels.

PubMed

Cai, Tianfu; Luo, Ji; Meng, Er; Ding, Jiuping; Liang, Songping; Wang, Sheng; Liu, Zhonghua

2015-06-01

Peptide toxins often have pharmacological applications and are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a group of potential VGSC inhibitors have been reported from tarantula venoms, little is known about the mechanism of their interaction with VGSCs. In this study, we showed that hainantoxin-IV (β-TRTX-Hn2a, HNTX-IV in brief), a 35-residue peptide from Ornithoctonus hainana venom, preferentially inhibited rNav1.2, rNav1.3 and hNav1.7 compared with rNav1.4 and hNav1.5. hNav1.7 was the most sensitive to HNTX-IV (IC50∼21nM). In contrast to many other tarantula toxins that affect VGSCs, HNTX-IV at subsaturating concentrations did not alter activation and inactivation kinetics in the physiological range of voltages, while very large depolarization above +70mV could partially activate toxin-bound hNav1.7 channel, indicating that HNTX-IV acts as a gating modifier rather than a pore blocker. Site-directed mutagenesis indicated that the toxin bound to site 4, which was located on the extracellular S3-S4 linker of hNav1.7 domain II. Mutants E753Q, D816N and E818Q of hNav1.7 decreased toxin affinity for hNav1.7 by 2.0-, 3.3- and 130-fold, respectively. In silico docking indicated that a three-toed claw substructure formed by residues with close contacts in the interface between HNTX-IV and hNav1.7 domain II stabilized the toxin-channel complex, impeding movement of the domain II voltage sensor and inhibiting hNav1.7 activation. Our data provide structural details for structure-based drug design and a useful template for the design of highly selective inhibitors of a specific subtype of VGSCs. Copyright © 2014 Elsevier Inc. All rights reserved.

30 CFR 47.31 - Requirement for a HazCom program.

Code of Federal Regulations, 2010 CFR

2010-07-01

... TRAINING HAZARD COMMUNICATION (HazCom) HazCom Program § 47.31 Requirement for a HazCom program. Each operator must— (a) Develop and implement a written HazCom program, (b) Maintain it for as long as a... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Requirement for a HazCom program. 47.31 Section...

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

Tomopy is a Python toolbox to perform x-ray data processing, image reconstruction and data exchange tasks at synchrotron facilities. The dependencies of the software are currently as follows: -Python related python standard library (http://docs.python.org/2/library/) numpy (http://www.numpy.org/) scipy (http://scipy.org/) matplotlib (http://matplotlip.org/) sphinx (http://sphinx-doc.org) pil (http://www.pythonware.com/products/pil/) pyhdf (http://pysclint.sourceforge.net/pyhdf/) h5py (http://www.h5py.org) pywt (http://www.pybytes.com/pywavelets/) file.py (https://pyspec.svn.sourceforge.net/svnroot/pyspec/trunk/pyspec/ccd/files.py) -C/C++ related: gridec (anonymous?? C-code written back in 1997 that uses standard C library) fftw (http://www.fftw.org/) tomoRecon (multi-threaded C++ verion of gridrec. Author: Mark Rivers from APS. http://cars9.uchicago.edu/software/epics/tomoRecon.html) epics (http://www.aps.anl.gov/epics/)

Matching Organs

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Organ Facts

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Getting on the List

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Types of Cancer Associated with Transplant Recipients

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Organ Facts: Pancreas

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Kidney Facts

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Liver Facts

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Diet and Exercise

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Organ Transplantation: Frequently Asked Questions

MedlinePlus

... to enews Follow Facebook Twitter LinkedIn YouTube Instagram Google+ Contact 700 N. 4th Street Richmond, VA 23219 ( ... com/UnitedNetworkForOrganSharing https://twitter.com/unosnews https://plus.google.com/+UnosOrg https://www.linkedin.com/company/unos

Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation

PubMed Central

Yu, Alec; Zhu, Wandi; Silva, Jonathan R.; Ruben, Peter C.

2017-01-01

E1784K is the most common mixed long QT syndrome/Brugada syndrome mutant in the cardiac voltage-gated sodium channel NaV1.5. E1784K shifts the midpoint of the channel conductance-voltage relationship to more depolarized membrane potentials and accelerates the rate of channel fast inactivation. The depolarizing shift in the midpoint of the conductance curve in E1784K is exacerbated by low extracellular pH. We tested whether the E1784K mutant shifts the channel conductance curve to more depolarized membrane potentials by affecting the channel voltage-sensors. We measured ionic currents and gating currents at pH 7.4 and pH 6.0 in Xenopus laevis oocytes. Contrary to our expectation, the movement of gating charges is shifted to more hyperpolarized membrane potentials by E1784K. Voltage-clamp fluorimetry experiments show that this gating charge shift is due to the movement of the DIVS4 voltage-sensor being shifted to more hyperpolarized membrane potentials. Using a model and experiments on fast inactivation-deficient channels, we show that changes to the rate and voltage-dependence of fast inactivation are sufficient to shift the conductance curve in E1784K. Our results localize the effects of E1784K to DIVS4, and provide novel insight into the role of the DIV-VSD in regulating the voltage-dependencies of activation and fast inactivation. PMID:28898267

Diagnosis and prediction of neuroendocrine liver metastases: a protocol of six systematic reviews.

PubMed

Arigoni, Stephan; Ignjatovic, Stefan; Sager, Patrizia; Betschart, Jonas; Buerge, Tobias; Wachtl, Josephine; Tschuor, Christoph; Limani, Perparim; Puhan, Milo A; Lesurtel, Mickael; Raptis, Dimitri A; Breitenstein, Stefan

2013-12-23

Patients with hepatic metastases from neuroendocrine tumors (NETs) benefit from an early diagnosis, which is crucial for the optimal therapy and management. Diagnostic procedures include morphological and functional imaging, identification of biomarkers, and biopsy. The aim of six systematic reviews discussed in this study is to assess the predictive value of Ki67 index and other biomarkers, to compare the diagnostic accuracy of morphological and functional imaging, and to define the role of biopsy in the diagnosis and prediction of neuroendocrine tumor liver metastases. An objective group of librarians will provide an electronic search strategy to examine the following databases: MEDLINE, EMBASE and The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects). There will be no restriction concerning language and publication date. The qualitative and quantitative synthesis of the systematic review will be conducted with randomized controlled trials (RCT), prospective and retrospective comparative cohort studies, and case-control studies. Case series will be collected in a separate database and only used for descriptive purposes. This study is ongoing and presents a protocol of six systematic reviews to elucidate the role of histopathological and biochemical markers, biopsies of the primary tumor and the metastases as well as morphological and functional imaging modalities for the diagnosis and prediction of neuroendocrine liver metastases. These systematic reviews will assess the value and accuracy of several diagnostic modalities in patients with NET liver metastases, and will provide a basis for the development of clinical practice guidelines. The systematic reviews have been prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42012002644; http://www.metaxis.com/prospero/full_doc.asp?RecordID=2644 (Archived

Top 16 Earth Images of 2016

NASA Image and Video Library

2017-02-12

Astronauts on the International Space Station take pictures of Earth out their windows nearly every day; over a year that adds up to thousands of photos. The people at the Earth Science and Remote Sensing Unit at NASA’s Johnson Space Center in Houston pored through this year’s crop to pick their top 16 photos of Earth for 2016—enjoy! Download the images: https://www.flickr.com/photos/nasa2explore/albums/72157674260752223 HD download link: https://archive.org/details/TheSpaceProgram _______________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/

Developing a WWW Resource Centre for Acquiring and Accessing Open Learning Materials on Research Methods (ReMOTE).

ERIC Educational Resources Information Center

Newton, Robert; Marcella, Rita; Middleton, Iain; McConnell, Michael

This paper reports on ReMOTE (Research Methods Online Teaching Environment), a Robert Gordon University (Scotland) project focusing on the development of a World Wide Web (WWW) site devoted to the teaching of research methods. The aim of ReMOTE is to provide an infrastructure that allows direct links to specialist sources in order to enable the…

Side Effects of Neem Oil on the Midgut Endocrine Cells of the Green Lacewing Ceraeochrysa claveri (Navás) (Neuroptera: Chrysopidae).

PubMed

Scudeler, E L; Santos, D C

2014-04-01

We described the ultrastructure of Ceraeochrysa claveri (Navás) midgut endocrine cells in larva, pupa, and adult, and evaluated the side effects of ingested neem oil, a botanical insecticide obtained from the seeds of the neem tree (Azadirachta indica), on these cells. During the larval period, C. claveri were fed (ad libitum) Diatraea saccharalis (F.) eggs treated with neem oil at concentrations of 0.5%, 1%, or 2%. Transmission electron microscopy showed that two subtypes of endocrine cells, namely granular and vesicular, occurred in the midgut epithelium during the three stages of the life cycle. Both cell types did not reach the midgut lumen and were positioned basally in the epithelium. The endocrine cells did not show extensive infoldings of the basal plasma membrane, and there were numerous secretory granules in the basal region of the cytoplasm. In the granular endocrine cells, the granules were completely filled with a dense matrix. In the vesicular endocrine cells, the main secretory products consisted of haloed vesicles. Ultrastructural examination indicated that only the granular endocrine cells exhibited signs of morphologic changes of cell injury present in all life cycle stages after the larvae were chronically exposed to neem oil by ingestion. The major cellular damage consisted of dilatation and vesiculation of the rough endoplasmic reticulum and the development of smooth endoplasmic reticulum and mitochondrial swelling. Our data suggest that cytotoxic effects on midgut endocrine cells can contribute to a generalized disruption of the physiological processes in this organ due to a general alteration of endocrine function.

Differential effects of five 'classical' scorpion {beta}-toxins on rNa{sub v}1.2a and DmNav1 provide clues on species-selectivity

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

Bosmans, Frank; Martin-Eauclaire, Marie-France; Tytgat, Jan

2007-01-01

In general, scorpion {beta}-toxins have been well examined. However, few in-depth studies have been devoted to species selectivity and affinity comparisons on the different voltage-activated Na{sup +} channels since they have become available as cloned channels that can be studied in heterologous expression systems. As a result, their classification is largely historical and dates from early in vivo experiments on mice and cockroach and fly larvae. In this study, we aimed to provide an updated overview of selectivity and affinity of scorpion {beta}-toxins towards voltage-activated Na{sup +} channels of vertebrates or invertebrates. As pharmacological tools, we used the classic {beta}-toxinsmore » AaHIT, Css II, Css IV, Css VI and Ts VII and tested them on the neuronal vertebrate voltage-activated Na{sup +} channel, rNa{sub v}1.2a. For comparison, its invertebrate counterpart, DmNav1, was also tested. Both these channels were expressed in Xenopus laevis oocytes and the currents measured with the two-electrode voltage-clamp technique. We supplemented this data with several binding displacement studies on rat brain synaptosomes. The results lead us to propose a general classification and a novel nomenclature of scorpion {beta}-toxins based on pharmacological activity.« less

Friending Brandeis: Privacy and Government Surveillance in the Era of Social Media

DTIC Science & Technology

2012-06-01

colonial postmaster, warned patrons of the service: 56 William Blackstone , “Commentaries on the Law of...England,” 1769, http://www.lonang.com/exlibris/ blackstone . 57 Joel P. Bishop, Bishop Commentaries on Criminal Law, 670, 1882. 58 United States Postal...Bishop, Joel P. Bishop Commentaries on Criminal Law. 670, 1882. Blackstone , William. “Commentaries on the Law of England.” 1769. http://www.lonang.com

Privacy-Enhancing Technologies for the Internet

DTIC Science & Technology

1997-01-01

http://www.communities.com/paper/swamp.html 7 David Chaum , ``Untraceable Electronic Mail, Return addresses, and Digital Pseudonyms,’’ Communications of...the ACM, February 1981, vol. 24 no. 2. http://www.eskimo.com/~weidai/mix-net.txt 8 David Chaum , ``Blind Signatures for Untraceable Payments...Privacy-enhancing technologies for the Internet Ian Goldberg David Wagner Eric Brewer University of California, Berkeley {iang,daw,brewer

SAGE-III Ready for Ozone Checkup

NASA Image and Video Library

2017-02-15

A third-generation investigation into the state of the ozone layer of Earth’s atmosphere is scheduled for launch to the International Space Station on the SpaceX-10 cargo ship. Marilee Roell of NASA’s Langley Research Center explains how the third iteration of the Stratospheric Aerosol and Gas Experiment will measure ozone, aerosols and other components of the atmosphere for scientists who hope to see an improvement in the atmosphere’s ability to protect the planet—and everyone and everything on it—from harmful ultraviolet radiation. For more on ISS science, visit us online: https://www.nasa.gov/mission_pages/station/research/index.html www.twitter.com/iss_research HD download link: https://archive.org/details/TheSpaceProgram _______________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/ YouTube: https://youtu.be/HQdMZ5OAU3U

MiR-21 promoted proliferation and migration in hepatocellular carcinoma through negative regulation of Navigator-3

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

Wang, Zhipeng, E-mail: dr_zpwang@163.com; Yang, Huan; Ren, Lei

2015-09-04

MicroRNA-21 (miR-21) has been well-established and found to be over-expressed in various human cancers and has been associated with hepatocellular carcinoma (HCC) progression. However, the underlying mechanism of miR-21 involvement in the development and progression of HCC remains to be understood. In the present study, we firstly identified that the Navigator-3 (NAV-3) gene as a novel direct target of miR-21. Knock-down of NAV-3 using shRNA can rescue the effects of anti-miR-21 inhibitor in HCC cell lines, whereas re-expression of miR-21 using transfection with miR-21 mimics phenocopied the NAV-3 knock-down model. Additionally, miR-21 levels inversely correlated with NAV-3 both in HCCmore » cells and tissues. Knock-down of NAV-3 promoted both the proliferation and migration in HCC cells. Together, our findings suggest an important role for miR-21 in the progression of HCC, which negatively regulated Navigator-3 in the migration of HCC. - Highlights: • Navigator-3 (NAV-3) suppresses proliferation, migration and tumorigenesis of HCC cells. • NAV-3 was a novel target of miR-21. • MiR-21 negatively regulates NAV-3 in HCC.« less

Biophysical costs associated with tetrodotoxin resistance in the sodium channel pore of the garter snake, Thamnophis sirtalis.

PubMed

Lee, Chong Hyun; Jones, David K; Ahern, Christopher; Sarhan, Maen F; Ruben, Peter C

2011-01-01

Tetrodotoxin (TTX) is a potent toxin that specifically binds to voltage-gated sodium channels (NaV). TTX binding physically blocks the flow of sodium ions through NaV, thereby preventing action potential generation and propagation. TTX has different binding affinities for different NaV isoforms. These differences are imparted by amino acid substitutions in positions within, or proximal to, the TTX-binding site in the channel pore. These substitutions confer TTX-resistance to a variety of species. The garter snake Thamnophis sirtalis has evolved TTX-resistance over the course of an arms race, allowing some populations of snakes to feed on tetrodotoxic newts, including Taricha granulosa. Different populations of the garter snake have different degrees of TTX-resistance, which is closely related to the number of amino acid substitutions. We tested the biophysical properties and ion selectivity of NaV of three garter snake populations from Bear Lake, Idaho; Warrenton, Oregon; and Willow Creek, California. We observed changes in gating properties of TTX-resistant (TTXr) NaV. In addition, ion selectivity of TTXr NaV was significantly different from that of TTX-sensitive NaV. These results suggest TTX-resistance comes at a cost to performance caused by changes in the biophysical properties and ion selectivity of TTXr NaV.

Using PIDs to Support the Full Research Data Publishing Lifecycle

NASA Astrophysics Data System (ADS)

Waard, A. D.

2016-12-01

Persistent identifiers can help support scientific research, track scientific impact and let researchers achieve recognition for their work. We discuss a number of ways in which Elsevier utilizes PIDs to support the scholarly lifecycle: To improve the process of storing and sharing data, Mendeley Data (http://data.mendeley.com) makes use of persistent identifiers to support the dynamic nature of data and software, by tracking and recording the provenance and versioning of datasets. This system now allows the comparison of different versions of a dataset, to see precisely what was changed during a versioning update. To present research data in context for the reader, we include PIDs in research articles as hyperlinks: https://www.elsevier.com/books-and-journals/content-innovation/data-base-linking. In some cases, PIDs fetch data files from the repositories provide that allow the embedding of visualizations, e.g. with PANGAEA and PubChem: https://www.elsevier.com/books-and-journals/content-innovation/protein-viewer; https://www.elsevier.com/books-and-journals/content-innovation/pubchem. To normalize referenced data elements, the Resource Identification Initiative - which we developed together with members of the Force11 RRID group - introduces a unified standard for resource identifiers (RRIDs) that can easily be interpreted by both humans and text mining tools. https://www.force11.org/group/resource-identification-initiative/update-resource-identification-initiative, as can be seen in our Antibody Data app: https://www.elsevier.com/books-and-journals/content-innovation/antibody-data To enable better citation practices and support robust metrics system for sharing research data, we have helped develop, and are early adopters of the Force11 Data Citation Principles and Implementation groups (https://www.force11.org/group/dcip) Lastly, through our work with the Research Data Alliance Publishing Data Services group, we helped create a set of guidelines (http://www

First International Conference between West and East—Leonardo and Lao-Tze. Western Science Meets Eastern Wisdom. Experiences of Scientists and Intellectuals for the Creation of a New Paradigm of Modern Science

PubMed Central

2008-01-01

The Conference was organized and supported by: Nei Dan School (European School of Internal Martial Arts), NIB (Laboratory of Molecular Biology and Stem Cell Bioengineering, National Institute of Biostructures and Biosystems, Institute of Cardiology, S.Orsola-Malpighi Hospital, Bologna), WACIMA (Worldwide Association Chinese Internal Martial Arts), Arti D’Oriente (Magazine of Eastern culture and traditions), Nuovo Orizzonte (Taiji Quan School in Florence), Samurai (Journal on Martial Arts), and Pinus (First National Institute for the Unification of Medical Strategies). Nei Dan School (www.taichineidan.com, neidan@libero.it) was in charge of the organization. Future meetings of the Centro studi ‘Tao and Science’ will take place in spring 2007 in Firenze and in October 2007 in Bologna. For information: E-mail: neidan@libero.it; web site: www.taichineidan.com, www.taoandscience.com PMID:18317548

Epilepsy - resources

MedlinePlus

Resources - epilepsy ... The following organizations are good resources for information on epilepsy : Epilepsy Foundation -- www.epilepsy.com National Institute of Neurological Disorders and Stroke -- www.ninds.nih.gov/disorders/ ...

Breastfeeding - resources

MedlinePlus

Resources - breastfeeding ... The following organizations are good resources for information on breastfeeding and breastfeeding problems : La Leche League International -- www.llli.org March of Dimes -- www.marchofdimes.com Centers ...

Trends in free WWW-based E-learning Modules seen from the Learning Resource Server Medicine (LRSMed).

PubMed

Stausberg, Jürgen; Geueke, Martin; Bludßat, Kevin

2005-01-01

Despite the lost enthusiasm concerning E-learning a lot of material is available on the World Wide Web (WWW) free of charge. This material is collected and systematically described by services like the Learning Resource Server Medicine (LRSMed) at http://mmedia.medizin.uni-essen.de/portal/. With the LRSMed E-learning modules are made available for medical students by means of a metadata description that can be used for a catalogue search. The number of resources included has risen enormously from 100 in 1999 up to 805 today. Especially in 2004 there was an exponential increase in the LRSMed's content. Anatomy is still the field with the highest amount of available material, but general medicine has improved its position over the years and is now the second one. Technically and didactically simple material as scripts, textbooks, and link lists (called info services) is still dominating. Similar to 1999, there is not one module which could be truly referred to as tutorial dialogue. Simple material can not replace face-to-face-teaching. But it could be combined with conventional courses to establish some kind of blending learning. The scene of free E-learning modules on the WWW is ready to meet current challenges for efficient training of students and continuing education in medicine.

Methods of editing cloud and atmospheric layer affected pixels from satellite data

NASA Technical Reports Server (NTRS)

Nixon, P. R. (Principal Investigator); Wiegand, C. L.; Richardson, A. J.; Johnson, M. P.

1981-01-01

Plotted transects made from south Texas daytime HCMM data show the effect of subvisible cirrus (SCI) clouds in the emissive (IR) band but the effect is unnoticable in the reflective (VIS) band. The depression of satellite indicated temperatures ws greatest in the center of SCi streamers and tapered off at the edges. Pixels of uncontaminated land and water features in the HCMM test area shared identical VIS and IR digital count combinations with other pixels representing similar features. A minimum of 0.015 percent repeats of identical VIS-IR combinations are characteristic of land and water features in a scene of 30 percent cloud cover. This increases to 0.021 percent of more when the scene is clear. Pixels having shared VIS-IR combinations less than these amounts are considered to be cloud contaminated in the cluster screening method. About twenty percent of SCi was machine indistinguishable from land features in two dimensional spectral space (VIS vs IR).

Low-loss VIS/IR-XUV beam splitter for high-power applications.

PubMed

Pupeza, Ioachim; Fill, Ernst E; Krausz, Ferenc

2011-06-20

We present a low-loss VIS/IR-XUV beam splitter, suitable for high-power operation. The spatial separation of the VIS/IR and XUV components of a beam is achieved by the wedged top layer of a dielectric multilayer structure, onto which the beam is impinging under Brewster's angle (for VIS/IR). With a fused silica wedge with an angle of 0.5° we achieve a separation angle of 2.2° and an IR reflectivity of 0.9995. Typical XUV reflectivities amount to 0.1-0.2. The novel element is mechanically robust, exhibiting two major advantages over free-standing Brewster plates: (i) a significant improvement of heat conduction and (ii) easier handling, in particular for high-optical-quality fabrication. The beam splitter could be used as an output coupler for intracavity-generated XUV radiation, promising a boost of the power regime of current MHz-HHG experiments. It is also suited for single-pass experiments and as a beam combiner for pump-probe experiments.

Medical pioneers in cyberspace: German practice owners advertising on the WWW.

PubMed

Schuh, C

1999-01-01

In the last few years, the number of Internet users has increased explosively. In the same way the number of Internet users has exploded, the costs in the public health sector have also increased. This resulted cost saving efforts by those responsible people in politics and medical administration. These economy measures have impacted in particular the established physicians. The current German practice owners are faced with an unknown economic situation and are forced to think and act like businessmen. Doubts arise concerning the age-old tradition of the advertising prohibition. Now advertisement is recognized as an important necessity. This study was conducted to answer the following questions: Who are the pioneers among the German practice owners presenting themselves to the public with their own website? How do they differ from their colleagues not advertising on the WWW? What motives and expectations do they associate with their website? Built on a detailed analysis of the relevant German and international literature, hypotheses were developed which were empirically checked in the further course of the work. For this purpose, an online survey was conducted on the WWW among established German physicians with their own websites. 194 physicians participated and 159 valid questionnaires were included in the analysis. The study revealed the following results: The age and sex distribution as well as the distribution of medical specialties in the examined group correspond to the expectations. A high percentage of the respondents participated in a medical professional organization. The median time in practice for practice age of the respondents was a little more than ten years. Many of the websites have been online less than one year. The following hypotheses could only partly be confirmed by the results of the survey: Physicians from different specialties deal with their own website differently. The Internet Familiarity of the physicians is responsible for the

Calcium Supplements: Do They Interfere with Blood Pressure Drugs?

MedlinePlus

... www.micromedexsolutions.com. Accessed July 8, 2015. Calcium. Natural Medicines. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=781#adverseEvents. Accessed ...

The WWW as a research medium: an illustrative survey on paranormal belief.

PubMed

Göritz, A S; Schumacher, J

2000-06-01

Data collected with a short World Wide Web (WWW) survey on paranormal belief, age, sex, locus of control, extraversion, emotional and physical well-being, and mood were compared with findings from recent literature while controlling for effects of self-selection. Each variable was measured with one item. The sample comprised 342 women, 648 men, and 8 participants of unknown sex, of whom 76.7% were self-selected and 23.3% did not select themselves. There was a weak but, given the large sample, significant effect of self-selection regarding paranormal belief (rpb 932 = .08) but no relationships for paranormal belief and the examined variables. In the entire sample, statistically significant correlations ranging from .13 to .07 between paranormal belief and female sex, scores on external locus of control, good mood, extraversion, and emotional well-being corresponded with previous offline results.

Health information for young people where and when they most want it: a case study of www.teenagehealthfreak.org.

PubMed

McPherson, Ann; Macfarlane, Aidan

2007-08-01

The Internet is an exciting resource for providing immediately available, evidence-based, health information for young people in an age-appropriate form on a 24 hours/day, 7 days/week basis. www.teenagehealthfreak.org is a United Kingdom-based Web site designed to take advantage of this. The content of the site, which is the leading teenage health Web site on a Google search, contains both the diary of a hypochondriac 15-year-old boy and a virtual doctor's surgery. It also allows for young people to e-mail health-related questions and receive relevant answers from a health expert. Analysis of the content of these e-mails indicates the unmet health needs and concerns of young people. Future developments of the site include linking the site www.youthhealthtalk.org, a Web site that contains videotaped interviews with young people who have a variety other health concerns.

[Effect of polychromatic visible light combined with infrared radiation on tumorigenicity of murine hepatoma cells and their sensitivity to lytic activity of natural killers].

PubMed

Filatova, N A; Kniazev, N A; Kosheverova, V V; Shatrova, A N; Samoĭlova, K A

2013-01-01

Tumorigenicity of murine hepatoma cells (MH22a) and their sensitivity to lysis by natural killers (NKs) have been studied after exposure to polychromatic visible and infrared light (VIS-IR, 480-3400 nm, 40 mW/cm2), similar to the terrestrial solar spectrum without its minor UV component, in order to elucidate the involvement of this important environmental and physiotherapeutic factor in regulation of the anti-tumor defense system. The MH22 cells were in vitro exposed to VIS-IR light and their sensitivity to lytic activity of NKs was evaluated. We found that sensitivity of MH22a cells to lysis by NKs after exposure to VIS-IR light at a dose of 4.8 J/cm2 increased 1.5-2 times, while it did not change after exposure to a dose of 9.6 J/cm2 at all ratios (1 : 5-1 : 50) of the number of NKs (effectors) to that of hepatoma cells (targets). The increase in the sensitivity of hepatoma cells to NKs was accompanied by structural changes of cell surface: the capability of supramembraneous glycoproteins (glycocalix) to sorb the vital dye alcian blue (AB) was significantly lower as compared with the unexposed cells of control group. However, no changes in AB sorption was revealed in hepatoma cells exposed to the light at a dose 9.6 J/cm2. Tumorigenicity of photo-irradiated MH22a cells has been studied in the in vivo experiments. Light-exposed (4.8 and 9.6 J/cm2) and intact hepatoma cells were transplanted into syngenic mice C3HA. Tumor volumes 25 days after transplantation proved to be smaller after exposure to the light at both doses than in the control group (4-4.5 times and 2.5-4 times, respectively), which correlated with the increase in the sensitivity to lisys by NKs and decrease in the AB sorption only after light exposure at dose 4.8 J/cm2. Using the flow cytometry method we could show that VIS-IR light at the applied doses did not interfere with the distribution of hepatoma cells over the cycle phases and thus deceleration of the tumor growth was not associated with

Chronic lithium treatment up-regulates cell surface Na(V)1.7 sodium channels via inhibition of glycogen synthase kinase-3 in adrenal chromaffin cells: enhancement of Na(+) influx, Ca(2+) influx and catecholamine secretion after lithium withdrawal.

PubMed

Yanagita, Toshihiko; Maruta, Toyoaki; Nemoto, Takayuki; Uezono, Yasuhito; Matsuo, Kiyotaka; Satoh, Shinya; Yoshikawa, Norie; Kanai, Tasuku; Kobayashi, Hideyuki; Wada, Akihiko

2009-09-01

In cultured bovine adrenal chromaffin cells expressing Na(V)1.7 isoform of voltage-dependent Na(+) channels, we have previously reported that lithium chloride (LiCl) inhibits function of Na(+) channels independent of glycogen synthase kinase-3 (GSK-3) (Yanagita et al., 2007). Here, we further examined the effects of chronic lithium treatment on Na(+) channels. LiCl treatment (1-30 mM, > or = 12 h) increased cell surface [(3)H]saxitoxin ([(3)H]STX) binding by approximately 32% without altering the affinity of [(3)H]STX binding. This increase was prevented by cycloheximide and actinomycin D. SB216763 and SB415286 (GSK-3 inhibitors) also increased cell surface [(3)H]STX binding by approximately 31%. Simultaneous treatment with LiCl and SB216763 or SB415286 did not produce an increased effect on [(3)H]STX binding compared with either treatment alone. LiCl increased Na(+) channel alpha-subunit mRNA level by 32% at 24 h. LiCl accelerated alpha-subunit gene transcription by 35% without altering alpha-subunit mRNA stability. In LiCl-treated cells, LiCl inhibited veratridine-induced (22)Na(+) influx as in untreated cells. However, washout of LiCl after chronic treatment enhanced veratridine-induced (22)Na(+) influx, (45)Ca(2+) influx and catecholamine secretion by approximately 30%. Washout of LiCl after 24 h treatment shifted concentration-response curve of veratridine upon (22)Na(+) influx upward, without altering its EC(50) value. Ptychodiscus brevis toxin-3 allosterically enhanced veratridine-induced (22)Na(+) influx by two-fold in untreated and LiCl-treated cells. Whole-cell patch-clamp analysis indicated that I-V curve and steady-state inactivation/activation curves were comparable between untreated and LiCl-treated cells. Thus, GSK-3 inhibition by LiCl up-regulated cell surface Na(V)1.7 via acceleration of alpha-subunit gene transcription, enhancing veratridine-induced Na(+) influx, Ca(2+) influx and catecholamine secretion.

Block of Human Cardiac Sodium Channels by Lacosamide: Evidence for Slow Drug Binding along the Activation Pathway

PubMed Central

Wang, Sho-Ya

2014-01-01

Lacosamide is an anticonvulsant hypothesized to enhance slow inactivation of neuronal Na+ channels for its therapeutic action. Cardiac Na+ channels display less and incomplete slow inactivation, but their sensitivity toward lacosamide remains unknown. We therefore investigated the action of lacosamide in human cardiac Nav1.5 and Nav1.5-CW inactivation-deficient Na+ channels. Lacosamide showed little effect on hNav1.5 Na+ currents at 300 µM when cells were held at −140 mV. With 30-second conditioning pulses from −90 to −50 mV; however, hNav1.5 Na+ channels became sensitive to lacosamide with IC50 (50% inhibitory concentration) around 70–80 µM. Higher IC50 values were found at −110 and −30 mV. The development of lacosamide block at −70 mV was slow in wild-type Na+ channels (τ; 8.04 ± 0.39 seconds, n = 8). This time constant was significantly accelerated in hNav1.5-CW inactivation-deficient counterparts. The recovery from lacosamide block at −70 mV for 10 seconds was relatively rapid in wild-type Na+ channels (τ; 639 ± 90 milliseconds, n = 8). This recovery was accelerated further in hNav1.5-CW counterparts. Unexpectedly, lacosamide elicited a time-dependent block of persistent hNav1.5-CW Na+ currents with an IC50 of 242 ± 19 µM (n = 5). Furthermore, both hNav1.5-CW/F1760K mutant and batrachotoxin-activated hNav1.5 Na+ channels became completely lacosamide resistant, indicating that the lacosamide receptor overlaps receptors for local anesthetics and batrachotoxin. Our results together suggest that lacosamide targets the intermediate preopen and open states of hNav1.5 Na+ channels. Lacosamide may thus track closely the conformational changes at the hNav1.5-F1760 region along the activation pathway. PMID:24563546

Shaping Strategic Defense: The Air Force Nuclear Mission

DTIC Science & Technology

2009-01-01

Strike Command. Washington DC: Department of the Air Force. Kall , Rob. June 20, 2008. “Pentagon: Over 1000 Nuclear Weapons Parts Missing?” http...www.huffingtonpost.com/rob- kall /pentagon-over-1000-nuclea_b_108225.html (accessed December 16, 2008). Rolfsen, B. November 6, 2007. http...16, 2008). 6 Schlesinger. 7 Kall , Rob. June 20, 2008. “Pentagon: Over 1000 Nuclear Weapons Parts Missing?” http://www.huffingtonpost.com/rob- kall

Development and Application of a Wireless, Networked Raspberry Pi Controlled Head Mounted Tactile Display (HMTD)

DTIC Science & Technology

2016-09-01

10 Fig. 8 Lithium ion polymer battery .................................................................. 11 Fig. 9 PowerBoost 1000C (right) and...7]. http://www.adafruit.com/products/1552. 7. Lithium Ion Polymer Battery –3.7v 2500mAh. [accessed Jul 7]. https://www.adafruit.com/products/328. 8...port directly) RealTek RT5370 Wi-Fi USB adapter 1 Wire-wrapping wires . . . Wire-wrap hand tool . . . Soldering kit . . . alipo: lithium - ion

Finding Lawrence: Recruiting Talent for Unconventional Warfare

DTIC Science & Technology

2011-06-01

SEAL Recruiters toward Athletes,‖ San Diego Union Tribune, March 15, 2010, http://www.signonsandiego.com/news/2010/mar/15/navys-seriously-sports/; U.S... rugby , swimming, and wrestling Alternative sports: skiing, snowboarding, mountain biking, climbing, rappelling, martial arts Height: At least 5... Union Tribune, March 15, 2010, http://www.signonsandiego.com/news/2010/mar/15/navys-seriously-sports/. 120 Ibid. 121 Ibid. 122 Dave Hecht, ―Naval

Structure and function of μ-conotoxins, peptide-based sodium channel blockers with analgesic activity

PubMed Central

Green, Brad R; Bulaj, Grzegorz; Norton, Raymond S

2015-01-01

μ-Conotoxins block voltage-gated sodium channels (VGSCs) and compete with tetrodotoxin for binding to the sodium conductance pore. Early efforts identified μ-conotoxins that preferentially blocked the skeletal muscle subtype (NaV1.4). However, the last decade witnessed a significant increase in the number of μ-conotoxins and the range of VGSC subtypes inhibited (NaV1.2, NaV1.3 or NaV1.7). Twenty μ-conotoxin sequences have been identified to date and structure–activity relationship studies of several of these identified key residues responsible for interactions with VGSC subtypes. Efforts to engineer-in subtype specificity are driven by in vivo analgesic and neuromuscular blocking activities. This review summarizes structural and pharmacological studies of μ-conotoxins, which show promise for development of selective blockers of NaV1.2, and perhaps also NaV1.1,1.3 or 1.7. PMID:25406007

Bioluminescence methodology for the detection of protein-protein interactions within the voltage-gated sodium channel macromolecular complex.

PubMed

Shavkunov, Alexander; Panova, Neli; Prasai, Anesh; Veselenak, Ron; Bourne, Nigel; Stoilova-McPhie, Svetla; Laezza, Fernanda

2012-04-01

Protein-protein interactions are critical molecular determinants of ion channel function and emerging targets for pharmacological interventions. Yet, current methodologies for the rapid detection of ion channel macromolecular complexes are still lacking. In this study we have adapted a split-luciferase complementation assay (LCA) for detecting the assembly of the voltage-gated Na+ (Nav) channel C-tail and the intracellular fibroblast growth factor 14 (FGF14), a functionally relevant component of the Nav channelosome that controls gating and targeting of Nav channels through direct interaction with the channel C-tail. In the LCA, two complementary N-terminus and C-terminus fragments of the firefly luciferase were fused, respectively, to a chimera of the CD4 transmembrane segment and the C-tail of Nav1.6 channel (CD4-Nav1.6-NLuc) or FGF14 (CLuc-FGF14). Co-expression of CLuc-FGF14 and CD4-Nav1.6-NLuc in live cells led to a robust assembly of the FGF14:Nav1.6 C-tail complex, which was attenuated by introducing single-point mutations at the predicted FGF14:Nav channel interface. To evaluate the dynamic regulation of the FGF14:Nav1.6 C-tail complex by signaling pathways, we investigated the effect of kinase inhibitors on the complex formation. Through a platform of counter screenings, we show that the p38/MAPK inhibitor, PD169316, and the IκB kinase inhibitor, BAY 11-7082, reduce the FGF14:Nav1.6 C-tail complementation, highlighting a potential role of the p38MAPK and the IκB/NFκB pathways in controlling neuronal excitability through protein-protein interactions. We envision the methodology presented here as a new valuable tool to allow functional evaluations of protein-channel complexes toward probe development and drug discovery targeting ion channels implicated in human disorders.

Business as Usual: Amazon.com and the Academic Library

ERIC Educational Resources Information Center

Van Ullen, Mary K.; Germain, Carol Anne

2002-01-01

In 1999, Steve Coffman proposed that libraries form a single interlibrary loan based entity patterned after Amazon.com. This study examined the suitability of Amazon.com's Web interface and record enhancements for academic libraries. Amazon.com could not deliver circulating monographs in the University at Albany Libraries' collection quickly…

Voltage-gated sodium channels: pharmaceutical targets via anticonvulsants to treat epileptic syndromes.

PubMed

Abdelsayed, Mena; Sokolov, Stanislav

2013-01-01

Epilepsy is a brain disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels, Nav1.1 and Nav1.2. The effects of antiepileptic drugs (AEDs) as effective therapies for epilepsy have been characterized by extensive research. Most of the classic AEDs targeting Nav share a common mechanism of action by stabilizing the channel's fast-inactivated state. In contrast, novel AEDs, such as lacosamide, stabilize the slow-inactivated state in neuronal Nav1.1 and Nav1.7 isoforms. This paper reviews the different mechanisms by which this stabilization occurs to determine new methods for treatment.

n-Alcohols Inhibit Voltage-Gated Na+ Channels Expressed in Xenopus Oocytes

PubMed Central

Horishita, Takafumi; Harris, R. Adron

2008-01-01

Voltage-gated sodium channels are essential for the initiation and propagation of action potentials in excitable cells and are known as a target of local anesthetics. In addition, inhibition of sodium channels by volatile anesthetics has been proposed as a mechanism of general anesthesia. The n-alcohols produce anesthesia, and their potency increases with carbon number until a “cut-off” is reached. In this study, we examined effects of a range of n-alcohols on Nav1.2 subunits to determine the alcohol cut-off for this channel. We also studied the effect of a short-chain alcohol (ethanol) and a long-chain alcohol (octanol) on Nav1.2, Nav1.4, Nav1.6, and Nav1.8 subunits, and we investigated the effects of alcohol on channel kinetics. Ethanol and octanol inhibited sodium currents of all subunits, and the inhibition of the Nav1.2 channel by n-alcohols indicated a cut-off at nonanol. Ethanol and octanol produced open-channel block, which was more pronounced for Nav1.8 than for the other sodium channels. Inhibition of Nav1.2 was due to decreased activation and increased inactivation. These results suggest that sodium channels may have a hydrophobic binding site for n-alcohols and demonstrate the differences in the kinetic mechanisms of inhibition for n-alcohols and inhaled anesthetics. PMID:18434586

Human Growth Hormone (HGH): Does It Slow Aging?

MedlinePlus

... Pediatric. 7th ed. Philadelphia, Pa.; Saunders Elsevier; 2016. http://www.clinicalkey.com. Accessed Sept. 4, 2016. Anti-aging products. Federal Trade Commission. https://www.consumer.ftc.gov/articles/0118-anti-aging- ...

78 FR 48795 - Airworthiness Directives; BRP-Powertrain GmbH & Co KG Rotax Reciprocating Engines

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-12

..., contact BRP- Powertrain GmbH & Co KG, Welser Strasse 32, A-4623 Gunskirchen, Austria; Internet: http://www..., A-4623 Gunskirchen, Austria; Internet: http://www.FLYROTAX.com . (4) You may view this service...

Antidepressant Withdrawal

MedlinePlus

... www.uptodate.com/home. Accessed Dec. 11, 2015. Definition of addiction. American Society of Addiction Medicine. http://www.asam.org/for-the-public/definition-of-addiction. Accessed Dec. 11, 2015. Harvey BH, ...

COM-GEOM Interactive Display Debugger (CIDD)

DTIC Science & Technology

1984-08-01

necessery and Identify by block nlum.ber) Target Description GIFT interactive Computer Graphics SolIi d Geone t ry Combintatorial Gecometry * COM-GLOM 120...program was written to speed up the process of formulating the Com-Geom data used by the Geometric Information for Targets ( GIFT ) 1,2 computer code...Polyhedron Lawrence W. Bain, Mathew J. Reisinger, "The GIFT Code User Manual; Volume I, Introduction and Input Requirements (u)," BRL Report No. 1802

Pheromone Recognition and Selectivity by ComR Proteins among Streptococcus Species

PubMed Central

Morrison, Donald A.; Talagas, Antoine; Nessler, Sylvie; Federle, Michael J.; Prehna, Gerd

2016-01-01

Natural transformation, or competence, is an ability inherent to bacteria for the uptake of extracellular DNA. This process is central to bacterial evolution and allows for the rapid acquirement of new traits, such as antibiotic resistance in pathogenic microorganisms. For the Gram-positive bacteria genus Streptococcus, genes required for competence are under the regulation of quorum sensing (QS) mediated by peptide pheromones. One such system, ComRS, consists of a peptide (ComS) that is processed (XIP), secreted, and later imported into the cytoplasm, where it binds and activates the transcription factor ComR. ComR then engages in a positive feedback loop for the expression of ComS and the alternative sigma-factor SigX. Although ComRS are present in the majority of Streptococcus species, the sequence of both ComS/XIP and ComR diverge significantly, suggesting a mechanism for species-specific communication. To study possible cross-talk between streptococcal species in the regulation of competence, and to explore in detail the molecular interaction between ComR and XIP we undertook an interdisciplinary approach. We developed a ‘test-bed’ assay to measure the activity of different ComR proteins in response to cognate and heterologous XIP peptides in vivo, revealing distinct ComR classes of strict, intermediate, and promiscuous specificity among species. We then solved an X-ray crystal structure of ComR from S. suis to further understand the interaction with XIP and to search for structural features in ComR proteins that may explain XIP recognition. Using the structure as a guide, we probed the apo conformation of the XIP-binding pocket by site-directed mutagenesis, both in test-bed cultures and biochemically in vitro. In alignments with ComR proteins from other species, we find that the pocket is lined by a variable and a conserved face, where residues of the conserved face contribute to ligand binding and the variable face discriminate among XIP peptides

2 CFR 176.50 - Award term-Reporting and registration requirements under section 1512 of the Recovery Act.

Code of Federal Regulations, 2010 CFR

2010-01-01

... registrations in the Central Contractor Registration (http://www.ccr.gov) at all times during which they have... System (DUNS) Number (http://www.dnb.com) is one of the requirements for registration in the Central... Recovery Act using the reporting instructions and data elements that will be provided online at http://www...

Understanding and using organizational politics, Part Two.

PubMed

Pickett, Ronald B; Kennedy, Marilyn Moats

2004-01-01

Politics is a fact of life in industry, academia, the military, religion, and even health care. Remember these five major ideas: 1. Politics exists in organizations. 2. Politics can be understood. 3. Politics can be managed. 4. Denial won't make politics go away. 5. You can become a better and more ethical organizational politician. Try these web sites for more information: http://www.bredemeyer.com/pdf_files/PoliticsCompetency.PDF. The political competency model presented here is for architects; however, it provides some interesting insights that you may find helpful. http://www.andersonconsulting.com/doopinto.htm. This web site has "The Dysfunctional Office and Organizational Politics Scale" that you can take online. http://www.politicalsavvy.com/. In addition to a newsletter, this web site lets you test your political savvy IQ and allows you to read further about politics in organizations.

A Worldwide Web-portal for Aquatic Mesocosm Facilities: WWW.MESOCOSM.EU

NASA Astrophysics Data System (ADS)

Berger, S. A.; Nejstgaard, J. C.

2016-02-01

Experimental mesocosms are valuable tools to fill the gap between highly controlled/replicated lab experiments and uncontrolled/non-replicated natural environments such as rivers, lakes and oceans. WWW.MESOCOSM.EU is an open web-portal for leading aquatic mesocosm facilities around the world. It was created within the FP7 EU-project MESOAQUA (A network of leading MESOcosm facilities to advance the studies of future AQUAtic ecosystems from the Arctic to the Mediterranean). The goal of the portal is to increase international knowledge about existing mesocosm facilities, including information on locations, environment, equipment, contacts, research opportunities and mesocosm-based publications. MESOCOSM.EU specifically aims to be a tool to enhance the quality of research by facilitating international cooperative network building, announcement of new research initiatives, transfer of best practice, and dissemination of knowledge, public information and press releases. As an open platform for all aquatic ecosystem scale science (marine and freshwater), MESOCOSM.EU aims to fill the lack of a centralized, coordinating virtual infrastructure for international aquatic mesocosm research, from the mountains to the ocean and from polar to tropical regions.

Nonsurgical Strategies in Patients With NET Liver Metastases: A Protocol of Four Systematic Reviews.

PubMed

Limani, Perparim; Tschuor, Christoph; Gort, Laura; Balmer, Bettina; Gu, Alexander; Ceresa, Christos; Raptis, Dimitri Aristotle; Lesurtel, Mickael; Puhan, Milo; Breitenstein, Stefan

2014-03-07

Patients diagnosed with neuroendocrine tumors (NETs) with hepatic metastases generally have a worse prognosis as compared with patients with nonmetastasized NETs. Due to tumor location and distant metastases, a surgical approach is often not possible and nonsurgical therapeutic strategies may apply. The aim of these systematic reviews is to evaluate the role of nonsurgical therapy options for patients with nonresectable liver metastases of NETs. An objective group of librarians will provide an electronic search strategy to examine the MEDLINE, EMBASE, and The Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials [CENTRAL]) databases. There will be no restriction concerning language and publication date. The qualitative and quantitative synthesis of the systematic review will be conducted with randomized controlled trials (RCT), prospective, and retrospective comparative cohort, and case-control studies. Case series will be collected in a separate database and only used for descriptive purposes. This study is ongoing and presents a protocol of four systematic reviews to assess the role of nonsurgical treatment options in patients with neuroendocrine liver metastases. These systematic reviews, performed according to this protocol, will assess the value of noninvasive therapy options for patients with nonresectable liver metastases of NETs in combination with invasive techniques, such as percutaneous liver-directed techniques and local ablation techniques. International Prospective Register of Systematic Reviews (PROSPERO): CRD42012002657; http://www.metaxis.com/PROSPERO/full_doc.asp?RecordID=2657 (Archived by WebCite at http://www.webcitation.org/6NDlYi37O); CRD42012002658; http://www.metaxis.com/PROSPERO/full_doc.asp?RecordID=2658 (Archived by WebCite at http://www.webcitation.org/6NDlfWSuD); CRD42012002659; www.metaxis.com/PROSPERO/full_doc.asp?RecordID=2659 (Arichived

Reducing the Footprint: Post Combat Operations, Budget Cuts, and Modern Day Sequestration

DTIC Science & Technology

2013-05-02

That Scary , in One Graph”; The Washington Post; November, 2012; http://www.washingtonpost.com/blogs/wonkblog/wp/2012/11/20/the- sequesters-defense-cuts...arent-that- scary -in-one-graph Figure 1 highlights the ebbs and flows of the DOD budget since the post World War II timeframe. Although the 2011...defense cuts aren’t that scary , in one graph”. The Washington Post, Washington: November, 2012, http://www.washingtonpost.com/blogs/wonkblog/wp

An Estimate and Score Algorithm for Simultaneous Parameter Estimation and Reconstruction of Incomplete Data on Social Networks

DTIC Science & Technology

2013-01-12

www.security-informatics.com/content/2/1/1 References 1. SM Radilm, C Flint, GE Tita , Spatializing Social Networks: Using Social Network Analysis to...http://www.tandfonline.com/doi/ abs/10.1080/00045600903550428 2. G Tita , S Radil, Spatializing the social networks of gangs to explore patterns of...violence. Journal of Quantitative Criminology. 27, 1–25 (2011) 3. G Tita , JK Riley, G Ridgeway, AF Abrahamse, P Greenwood, Reducing Gun Violence

CAS - A Turboprop Solution for the COIN Fight

DTIC Science & Technology

2009-01-01

Worlds First Civilian Tiltrotor. http://www.bellagusta.com/air ba main.cfm. Accessed 13 Jan 2009. Blake, Brett R , AT-6-The Best Investmentfor the Long War...Terroism and Counterinsurgency, CRS for Congress RL32737, Washington DC: Congressional Research Service, 24 Jan. 2005. Blake, Brett R Major USAF. AT-6...www.aviationweek.com/aw/generic/channel .jsp?channel= awst # (accessed 15 Jan 2009). 7 Bolkcom and Katzman, 24. 8 U.S. Congress, Office ofTechnology

Implementation and Evaluation of an INS System Using a Three Degrees of Freedom MEMS Accelerometer

DTIC Science & Technology

2008-12-01

122 123 124 125 LIST OF REFERENCES [1] Robert C. Michelson, “Autonomous navigation,” in AccessScience @McGraw-Hil, DOI... AccessScience @McGraw-Hil, DOI 10.1036/1097-8542.342700 at http://www.accesssicence.com (accessed October 13, 2008). [4] T. Logsdon, The Navstar Global... AccessScience @McGraw-Hill,http://www.accessscience.com (accessed October 15, 2008). [13] Z-World Inc., BL2000 User’s Manual, 2001. 126 [14

Emerging DoD Role in the Interagency Counter Threat Finance Mission

DTIC Science & Technology

2012-03-14

Policy magazine article entitled “ Follow the Money ,” by Stuart Levey and Christy Clark, suggests that the FATF should branch out beyond establishing...February 2008), 2. 23 Ibid. 24 Stuart Levey and Christy Clark, “ Follow the Money ,” Foreign Policy online, www.foreignpolicy.com/articles/2011/10/3...PA, November 29, 2011. 28 Stuart Levey and Christy Clark, “ Follow the Money ,” Foreign Policy online, www.foreignpolicy.com/articles/2011/10/3

Architectural Patterns for Self-Organizing Systems-of-Systems

DTIC Science & Technology

2011-05-01

show that they are necessary for self-organization to occur. Common Purpose Abraham Maslow proposed a theory on human motivation based on a hierarchy...http://www.hole-in-the-wall.com/abouthiwel.html (accessed October 28, 2010). 21. Maslow , Abraham . 1943. A theory of human motivation. In Psychological...in-the-wall Education Ltd. http://www.hole- in-the-wall.com/abouthiwel.html (accessed October 28, 2010). 22. Maslow , Abraham . 1943. A theory of human

Practical Measurement of Complexity In Dynamic Systems

DTIC Science & Technology

2012-01-01

policies that produce highly complex behaviors , yet yield no benefit. 21Jason B. Clark and David R. Jacques / Procedia Computer Science 8 (2012) 14... Procedia Computer Science 8 (2012) 14 – 21 1877-0509 © 2012 Published by Elsevier B.V. doi:10.1016/j.procs.2012.01.008 Available online at...www.sciencedirect.com Procedia Computer Science Procedia Computer Science 00 (2012) 000–000 www.elsevier.com/locate/ procedia Available online at

Open Component Portability Infrastructure (OPENCPI)

DTIC Science & Technology

2009-11-01

Disk Drive 7 1 www.antec.com P182 $120. ATX Mid Tower Computer Case 8 1 www.xilinx.com HW-V5-ML555-G $2200. Xilinx ML555 V5 Dev Kit Notes: Cost...s/ GEORGE RAMSEYER EDWARD J. JONES, Deputy Chief Work Unit Manager Advanced Computing ...uniquely positioned to meet the goals of the Software Systems Stockroom (S3) since in some sense component-based systems are computer -science’s

The Human Proteome Project: Unlocking the Mysteries of Human Life and Unleashing Its Potential

DTIC Science & Technology

2011-02-16

Australasian Genetics Resource Book. June 2007. Accessed September 27, 2010. www.genetics.com.au/pdf/factsheets/fs24.pdf. 2 White House, Office of...Project and Beyond." The Australasian Genetics Resource Book. June 2007. Accessed September 27, 2010. www.genetics.com.au/pdf/factsheets/fs24.pdf...9 Centre for Genetics Education. "The Human Genetic Code – The Human Genome Project and Beyond." The Australasian Genetics Resource Book. June

Next-Generation Strategic Communication: Building Influence through Online Social Networking

DTIC Science & Technology

2009-06-01

Millon de  Voces  Marchan en Contra de las FARC,” http://www.eltiempo.com, (accessed April 21, 2009).  11 The Washington Post, “Young Voters Find Voice...Millon de Voces Marchan en Contra de las FARC,” http://www.eltiempo.com, (accessed April 21 2009). Facebook, “Barack Obama,” Facebook, https

How Does Hamas End: A Historical Overview And Where The Future Leads

DTIC Science & Technology

2014-04-10

26 September 2013, http://www.jpost.com/ Middle - East /Hamas-Islamic-Jihad-call-for-a-third-intifada-327202 (accessed 6 April 2014). 37 Interview with a...www.jpost.com/ Middle - East /Hamas-Islamic-Jihad-call-for-a- third-intifada-327202 (accessed 6 April 2014). University of Maryland. Global Terrorism Database...religious standpoint all three monotheistic religions, Judaism, Christianity, and Islam claim a common patriarch in Abraham, who settled in what is modern

What Drives Pakistan’s Interest in Afghanistan?

DTIC Science & Technology

2011-05-19

2010), 13. 172 Kamran Shafi, “Putting on a Brave Face and Standing Tall,” http://www.dawn.com/wps/wcm/connect/dawn-content-library/dawn/the-newspaper...columnists/ kamran -shafi- putting-on-a-brave-face-and-standing-tall-480 (accessed September 10, 2010). 59 include sanctuary, to militant...Shafi, Kamran . “Putting on a Brave Face and Standing Tall.” http://www.dawn.com/wps/wcm/connect/dawn-content-library/dawn/the- newspaper

Vasodilators

MedlinePlus

... directly on the vessel walls are hydralazine and minoxidil. Doctors prescribe vasodilators to prevent, treat or improve ... http://www.micromedexsolutions.com. Accessed May 23, 2016. Minoxidil. Micromedex 2.0 Healthcare Series. http://www.micromedexsolutions. ...

www.mydrugdealer.com: Ethics and legal implications of Internet-based access to substances of abuse.

PubMed

Klein, Carolina A; Kandel, Surendra

2011-01-01

The Internet has increasingly become an intrinsic part of everyday life, offering countless possibilities for education, services, recreation, and more. In fact, an entire virtual life within the digitalized World Wide Web is possible and common among many Internet users. Today's psychiatrists must therefore incorporate this dimension of human life into clinical practice, to achieve an adequate assessment of the tools and risks available to the patient. We focus on the Internet as a portal for the trade of and access to substances of abuse. We review the legal regulations that may inform care and standards of practice and analyze the difficulties that arise in assessment and monitoring of the current situation. We consider the potential impact of Internet-based narcotics trade on addiction morbidities and the practice of clinical psychiatry, as well as on the potential legal implications that the forensic expert may face.

Voltage-gated sodium channels

PubMed Central

Abdelsayed, Mena; Sokolov, Stanislav

2013-01-01

Epilepsy is a brain disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels, Nav1.1 and Nav1.2. The effects of antiepileptic drugs (AEDs) as effective therapies for epilepsy have been characterized by extensive research. Most of the classic AEDs targeting Nav share a common mechanism of action by stabilizing the channel’s fast-inactivated state. In contrast, novel AEDs, such as lacosamide, stabilize the slow-inactivated state in neuronal Nav1.1 and Nav1.7 isoforms. This paper reviews the different mechanisms by which this stabilization occurs to determine new methods for treatment. PMID:23531742

State-dependent compound inhibition of Nav1.2 sodium channels using the FLIPR Vm dye: on-target and off-target effects of diverse pharmacological agents.

PubMed

Benjamin, Elfrida R; Pruthi, Farhana; Olanrewaju, Shakira; Ilyin, Victor I; Crumley, Gregg; Kutlina, Elena; Valenzano, Kenneth J; Woodward, Richard M

2006-02-01

Voltage-gated sodium channels (NaChs) are relevant targets for pain, epilepsy, and a variety of neurological and cardiac disorders. Traditionally, it has been difficult to develop structure-activity relationships for NaCh inhibitors due to rapid channel kinetics and state-dependent compound interactions. Membrane potential (Vm) dyes in conjunction with a high-throughput fluorescence imaging plate reader (FLIPR) offer a satisfactory 1st-tier solution. Thus, the authors have developed a FLIPR Vm assay of rat Nav1.2 NaCh. Channels were opened by addition of veratridine, and Vm dye responses were measured. The IC50 values from various structural classes of compounds were compared to the resting state binding constant (Kr)and inactivated state binding constant (Ki)obtained using patch-clamp electrophysiology (EP). The FLIPR values correlated with Ki but not Kr. FLIPRIC50 values fell within 0.1-to 1.5-fold of EP Ki values, indicating that the assay generally reports use-dependent inhibition rather than resting state block. The Library of Pharmacologically Active Compounds (LOPAC, Sigma) was screened. Confirmed hits arose from diverse classes such as dopamine receptor antagonists, serotonin transport inhibitors, and kinase inhibitors. These data suggest that NaCh inhibition is inherent in a diverse set of biologically active molecules and may warrant counterscreening NaChs to avoid unwanted secondary pharmacology.

Research and Design of the Three-tier Distributed Network Management System Based on COM / COM + and DNA

NASA Astrophysics Data System (ADS)

Liang, Likai; Bi, Yushen

Considered on the distributed network management system's demand of high distributives, extensibility and reusability, a framework model of Three-tier distributed network management system based on COM/COM+ and DNA is proposed, which adopts software component technology and N-tier application software framework design idea. We also give the concrete design plan of each layer of this model. Finally, we discuss the internal running process of each layer in the distributed network management system's framework model.

Prednisone and Other Corticosteroids: Balance the Risks and Benefits

MedlinePlus

... Drug reactions. In: Dermatology Essentials. Philadelphia, Pa.: Saunders Elsevier; 2014. http://www.clinicalkey.com. Accessed Oct. 6, ... Principles and Practice. 8th ed. Philadelphia, Pa.: Saunders Elsevier; 2014. Nieman LK. Pharmacologic use of glucocorticoids. www. ...

Eosinophilia

MedlinePlus

... Version. https://www.merckmanuals.com/professional/hematology-and-oncology/eosinophilic-disorders/eosinophilia. Accessed July 22, 2016. Kliegman RM, et al. Eosinophils. In: Nelson Textbook of Pediatrics. 20th ed. Philadelphia, Pa.: Elsevier; 2016. http://www. ...

Integration of Live Video and WWW Delivery Systems To Teach University Level Science, Technology, and Society in High Schools.

ERIC Educational Resources Information Center

Urven, Lance E.; Yin, L. Roger; Bak, John D.

In fall 1997, the University of Wisconsin-Whitewater (UWW) provided Science and Technology in Society, a university general studies science literacy course, to advanced placement high school students at three local high schools, using a combination of live video presentations and World Wide Web (WWW) courseware. A total of 26 high school students…

Characteristics of international websites with information on developmental disabilities.

PubMed

Reichow, Brian; Gelbar, Nicholas W; Mouradjian, Keri; Shefcyk, Allison; Smith, Isaac C

2014-10-01

The Internet often serves as a primary resource for individuals seeking health-related information, and a large and growing number of websites contain information related to developmental disabilities. This paper presents the results of an international evaluation of the characteristics and content of the top 10 ranked results (i.e., not including sponsored results - pay-per-click) returned when one of five terms related to developmental disabilities (i.e., ADHD, autism, down syndrome, learning disability, intellectual disability) was entered into one of six country specific Google online search engines (i.e., Australia (https://www.google.com.au), Canada (https://www.google.ca), Ireland (https://www.google.ie), New Zealand (https://www.google.co.nz), the United Kingdom (https://www.google.co.uk), and the United States (https://www.google.com)) on October 22, 2013. Collectively, we found that international consumers of websites related to developmental disabilities will encounter different websites with differing content and terminology, and should be critical consumers to ensure they locate the information they are seeking. Copyright © 2014 Elsevier Ltd. All rights reserved.

ComSciCon: The Communicating Science Workshop for Graduate Students

NASA Astrophysics Data System (ADS)

Sanders, Nathan; Drout, Maria; Kohler, Susanna; Cook, Ben; ComSciCon Leadership Team

2018-01-01

ComSciCon (comscicon.com) is a national workshop series organized by graduate students, for graduate students, focused on leadership and training in science communication. Our goal is to empower young scientists to become leaders in their field, propagating appreciation and understanding of research results to broad and diverse audiences. ComSciCon attendees meet and interact with professional communicators, build lasting networks with graduate students in all fields of science and engineering from around the country, and write and publish original works. ComSciCon consists of both a flagship national conference series run annually for future leaders in science communication, and a series of regional and specialized workshops organized by ComSciCon alumni nationwide. We routinely receive over 1000 applications for 50 spots in our national workshop. Since its founding in 2012, over 300 STEM graduate students have participated in the national workshop, and 23 local spin-off workshops have been organized in 10 different locations throughout the country. This year, ComSciCon is working to grow as a self-sustaining organization by launching as an independent 501(c)(3) non-profit. In this poster we will discuss the ComSciCon program and methods, our results to date, potential future collaborations between ComSciCon and AAS, and how you can become involved.

Army Communicator. Volume 35, Number 4, Winter 2010

DTIC Science & Technology

2010-12-01

Students and cadre at the Signal Center of Excellence have written and published nearly 30 applications on the Android Market and iTunes Store in just...Android Market or the iTunes Store: http:// www.android.com/market/or www.apple.com/ iTunes . Our aggressive move into application development...family members, this Army would have collapsed like a deck of cards .” I agree. I would also like to thank our Army families for their sacrifice and

The Fate of Saudi Arabia: Regime Evolution in the Saudi Monarchy

DTIC Science & Technology

2008-12-01

on women drivers by pointing out advantages to economy if women drove,141 and “Shattering Glass Ceilings at Lingerie Shops,” which criticized a law to...http://www.arabnews.com/?page=1§ion=0&article=108366&d=29&m=3&y=2008 (accessed November 30, 2008) 142 Najah Alosaimi, “Shattering Glass Ceilings at...accessed December 4, 2008). Alosaimi, Najah. “Shattering Glass Ceilings at Lingerie Shops.” Arab News, October 15, 2008. http://www.arabnews.com

Building Peace in a Post-ASSAD Syria

DTIC Science & Technology

2013-03-01

Robert F. Worth, “Earth is Parched Where Syrian Farms Thrived,” New York Times, October 14, 2010. Accessed December 8, 2012. http://www.nytimes.com/2010...education.261 The Tutsi people became the scape goat to any shock to the state. This included increased poverty that resulted after the international...Worth, Robert F. “Earth is Parched Where Syrian Farms Thrived.” New York Timess, October 14, 2010. Accessed. December 8, 2012. http://www.nytimes.com

CAS -- A Turboprop Solution for the COIN Fight

DTIC Science & Technology

2009-04-14

Civilian Tiltrotor. http://www.bellagusta.com/air ba main.cfm. Accessed 13 Jan 2009. Blake, Brett R , AT-6-The Best Investmentfor the Long War, Air...Counterinsurgency, CRS for Congress RL32737, Washington DC: Congressional Research Service, 24 Jan. 2005. Blake, Brett R Major USAF. AT-6-The Best...www.aviationweek.com/aw/generic/channel .jsp?channel= awst # (accessed 15 Jan 2009). 7 Bolkcom and Katzman, 24. 8 U.S. Congress, Office ofTechnology Assessment, Global

Nonalignment To Balance Chinas Influence On Sri Lanka: Negotiating Chinas String Of Pearls Strategy For The Pearl Of The Indian Ocean

DTIC Science & Technology

2017-12-01

crisis-is-so-bad-the-government- doesnt-even-know-how-much- money -it-owes/#c6eb6a946082. 3 Ibid. 4 Ibid. 5 Iromi Dharmawardana, Sri Lanka Foreign...Annie Gowen, “Can Sri Lanka’s New Government Break Free from China,” Washington Post, August 16, 2015, http://www.washingtonpost.com/world...55 Wade Shepard, “China Tells Sri Lanka: We Want Our Money , Not Your Empty Port,” Forbes, July 31, 2016, http://www.forbes.com

A Generic Fusion Tool on Command Control of C4ISR Simulations

DTIC Science & Technology

2006-12-01

Sarı, Şeref Paşalıoğlu TUBITAK , Marmara Research Center, Information Technologies Research Institute Gebze, Kocaeli TURKEY {name.surname...bte.mam.gov.tr; www.mam.gov.tr Cüneyd Fırat C2Tech A.Ş., TUBITAK , TEKSEB, C 210, Gebze, Kocaeli TURKEY firat@ctech.com.tr; www.ctech.com.tr ABSTRACT We...NAME(S) AND ADDRESS(ES) TUBITAK , Marmara Research Center, Information Technologies Research Institute Gebze, Kocaeli TURKEY 8. PERFORMING

Refined Orbital Architecture for Targets of Naval Interest

DTIC Science & Technology

2015-03-01

45° 30° 34 now likely to cost less than $20 million.34 A commercial launch from SpaceX currently costs $61.2 million to place 13,000 kg into...2015. 35 SpaceX , “Capabilities & Services,” http://www.spacex.com/about/capabilities, accessed January 2015. 35 VI. CONCLUSION The takeaway is that... SpaceX . “Capabilities & Services.” Accessed January 2015. http://www.spacex.com/about/capabilities. Tomme, Edward B. “The Myth of the Tactical

Time-cumulated visible and infrared histograms used as descriptor of cloud cover

NASA Technical Reports Server (NTRS)

Seze, G.; Rossow, W.

1987-01-01

To study the statistical behavior of clouds for different climate regimes, the spatial and temporal stability of VIS-IR bidimensional histograms is tested. Also, the effect of data sampling and averaging on the histogram shapes is considered; in particular the sampling strategy used by the International Satellite Cloud Climatology Project is tested.

"MTA"-an Hydraulic Silicate Cement: review update and setting reaction.

PubMed

Darvell, B W; Wu, R C T

2011-05-01

To review the current status and understanding of Portland cement-like endodontic materials commonly referred to by the trade designation "MTA" (alias "Mineral Trioxide Aggregate"), and to present an outline setting reaction scheme, hitherto unattempted. The literature was searched using on-line tools, overlapping an earlier substantial review to pick up any omissions, including that in respect of ordinary Portland cement (OPC), with which MTA shares much. The search was conducted for the period January 2005 to December 2009 using 'MTA', 'GMTA', 'WMTA', and 'mineral AND trioxide AND aggregate' as keywords, with various on-line search engines including ScienceDirect (http://www.sciencedirect.com), SAGE Journals Online (http://online.sagepub.com), Wiley Online Library (http://onlinelibrary.wiley.com), SciELO Scientific electronic library online (http://www.scielo.br/scielo.php), JSTOR (http://www.jstor.org), and Scopus (http://www.scopus.com). References of articles found were cross-checked where appropriate for missed publications. Manufacturers' and related websites were searched with Google Search (http://www.google.com.hk). A generic name for this class of materials, Hydraulic Silicate Cement (HSC), is proposed, and an outline reaction scheme has been deduced. HSC has distinct advantages apparent, including sealing, sterilizing, mineralizing, dentinogenic and osteogenic capacities, which research continues to demonstrate. However, ad hoc modifications have little supporting justification. While HSC has a definite place in dentistry, with few of the drawbacks associated with other materials, some improvements in handling and other properties are highly desirable, as are studies of the mechanisms of the several beneficial physiological effects. Reference to the extensive, but complex, literature on OPC may provide the necessary insight. Copyright © 2011 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

The hitchhiker’s guide to the voltage-gated sodium channel galaxy

PubMed Central

2016-01-01

Eukaryotic voltage-gated sodium (Nav) channels contribute to the rising phase of action potentials and served as an early muse for biophysicists laying the foundation for our current understanding of electrical signaling. Given their central role in electrical excitability, it is not surprising that (a) inherited mutations in genes encoding for Nav channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Nav channels are targeted by various drugs and naturally occurring toxins. Although the overall architecture and behavior of these channels are likely to be similar to the more well-studied voltage-gated potassium channels, eukaryotic Nav channels lack structural and functional symmetry, a notable difference that has implications for gating and selectivity. Activation of voltage-sensing modules of the first three domains in Nav channels is sufficient to open the channel pore, whereas movement of the domain IV voltage sensor is correlated with inactivation. Also, structure–function studies of eukaryotic Nav channels show that a set of amino acids in the selectivity filter, referred to as DEKA locus, is essential for Na+ selectivity. Structures of prokaryotic Nav channels have also shed new light on mechanisms of drug block. These structures exhibit lateral fenestrations that are large enough to allow drugs or lipophilic molecules to gain access into the inner vestibule, suggesting that this might be the passage for drug entry into a closed channel. In this Review, we will synthesize our current understanding of Nav channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Nav channels that, for the time being, serve as structural models of their eukaryotic counterparts. PMID:26712848

Mu-opioid receptors in nociceptive afferents produce a sustained suppression of hyperalgesia in chronic pain.

PubMed

Severino, Amie; Chen, Wenling; Hakimian, Joshua K; Kieffer, Brigitte L; Gaveriaux-Ruff, Claire; Walwyn, Wendy; Marvizon, Juan Carlos

2018-04-17

The latent sensitization model of chronic pain reveals that recovery from some types of long-term hyperalgesia is an altered state in which nociceptive sensitization persists but is suppressed by the ongoing activity of analgesic receptors such as µ-opioid receptors (MORs). To determine whether these MORs are the ones present in nociceptive afferents, we bred mice expressing Cre-recombinase under the Nav1.8 channel promoter (Nav1.8cre) with MOR-floxed mice (flMOR). These Nav1.8cre/flMOR mice had reduced MOR expression in primary afferents, as revealed by quantitative PCR, in situ hybridization and immunofluorescence colocalization with the neuropeptide CGRP. We then studied the recovery from chronic pain of these mice and their flMOR littermates. When Nav1.8cre/flMOR mice were injected in the paw with complete Freund's adjuvant they developed mechanical hyperalgesia that persisted for over two months, whereas the responses of flMOR mice returned to baseline after three weeks. We then used the inverse agonist naltrexone to assess ongoing MOR activity. Naltrexone produced a robust reinstatement of hyperalgesia in control flMOR mice, but produced no effect in the Nav1.8/flMOR males and a weak reinstatement of hyperalgesia in Nav1.8/flMOR females. Naltrexone also reinstated swelling of the hind paw in flMOR mice and female Nav1.8cre/flMOR mice, but not male Nav1.8cre/flMOR mice. The MOR agonist DAMGO inhibited substance P release in flMOR mice but not Nav1.8cre/flMOR mice, demonstrating a loss of MOR function at the central terminals of primary afferents. We conclude that MORs in nociceptive afferents mediate an ongoing suppression of hyperalgesia to produce remission from chronic pain.

78 FR 51239 - Self-Regulatory Organizations; NYSE Arca, Inc.; Order Approving a Proposed Rule Change To List...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-20

... the NAV as of the time the NAV is calculated (``Bid/Ask Price''), and a calculation of the premium or... discounts and premiums of the Bid/Ask Price against the NAV, within appropriate ranges, for each of the four... participants at the same time.\\19\\ Moreover, investors may obtain gold pricing information from a variety of...

78 FR 14376 - Order Granting Limited Exemptions From Exchange Act Rule 10b-17 and Rules 101 and 102 of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-05

... market price of the Shares should not vary substantially from the NAV of such Shares; Shares of the Fund... the Fund and that a close alignment between the market price of Shares and the Fund's NAV is expected... alignment between the market price of Shares and the Fund's NAV is expected, the Commission finds that it is...

--No Title--

Science.gov Websites

: "\\f106"; /* open - switch to fa-angle-up */ } @media(min-width:768px) { /* top level open */ } } /* top level open hover */ .navbar-dark .navbar-nav > li.open > a:hover, .navbar-dark .navbar-nav :768px) { /* top level open hover desktop*/ .navbar-dark .navbar-nav > li.open > a:hover, .navbar

--No Title--

Science.gov Websites

{ background-color:#fff; padding-bottom:20px; } .navbar-default ul li { background-color:#1E8728; margin: 0 , .navbar-default .navbar-nav > .active > a:focus { background-color: #004C09; color: #fff; } .navbar -default .navbar-nav > li > a { color:#fff; } .navbar-default .navbar-nav > li > a:hover

Total Navigation in Spine Surgery; A Concise Guide to Eliminate Fluoroscopy Using a Portable Intraoperative Computed Tomography 3-Dimensional Navigation System.

PubMed

Navarro-Ramirez, Rodrigo; Lang, Gernot; Lian, Xiaofeng; Berlin, Connor; Janssen, Insa; Jada, Ajit; Alimi, Marjan; Härtl, Roger

2017-04-01

Portable intraoperative computed tomography (iCT) with integrated 3-dimensional navigation (NAV) offers new opportunities for more precise navigation in spinal surgery, eliminates radiation exposure for the surgical team, and accelerates surgical workflows. We present the concept of "total navigation" using iCT NAV in spinal surgery. Therefore, we propose a step-by-step guideline demonstrating how total navigation can eliminate fluoroscopy with time-efficient workflows integrating iCT NAV into daily practice. A prospective study was conducted on collected data from patients undergoing iCT NAV-guided spine surgery. Number of scans, radiation exposure, and workflow of iCT NAV (e.g., instrumentation, cage placement, localization) were documented. Finally, the accuracy of pedicle screws and time for instrumentation were determined. iCT NAV was successfully performed in 117 cases for various indications and in all regions of the spine. More than half (61%) of cases were performed in a minimally invasive manner. Navigation was used for skin incision, localization of index level, and verification of implant position. iCT NAV was used to evaluate neural decompression achieved in spinal fusion surgeries. Total navigation eliminates fluoroscopy in 75%, thus reducing staff radiation exposure entirely. The average times for iCT NAV setup and pedicle screw insertion were 12.1 and 3.1 minutes, respectively, achieving a pedicle screw accuracy of 99%. Total navigation makes spine surgery safer and more accurate, and it enhances efficient and reproducible workflows. Fluoroscopy and radiation exposure for the surgical staff can be eliminated in the majority of cases. Copyright © 2017 Elsevier Inc. All rights reserved.

Glial interleukin-1β upregulates neuronal sodium channel 1.7 in trigeminal ganglion contributing to temporomandibular joint inflammatory hypernociception in rats.

PubMed

Zhang, Peng; Bi, Rui-Yun; Gan, Ye-Hua

2018-04-20

The proinflammatory cytokine interleukin-1β (IL-1β) drives pain by inducing the expression of inflammatory mediators; however, its ability to regulate sodium channel 1.7 (Nav1.7), a key driver of temporomandibular joint (TMJ) hypernociception, remains unknown. IL-1β induces cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). We previously showed that PGE2 upregulated trigeminal ganglionic Nav1.7 expression. Satellite glial cells (SGCs) involve in inflammatory pain through glial cytokines. Therefore, we explored here in the trigeminal ganglion (TG) whether IL-1β upregulated Nav1.7 expression and whether the IL-1β located in the SGCs upregulated Nav1.7 expression in the neurons contributing to TMJ inflammatory hypernociception. We treated rat TG explants with IL-1β with or without inhibitors, including NS398 for COX-2, PF-04418948 for EP2, and H89 and PKI-(6-22)-amide for protein kinase A (PKA), or with adenylate cyclase agonist forskolin, and used real-time PCR, Western blot, and immunohistofluorescence to determine the expressions or locations of Nav1.7, COX-2, cAMP response element-binding protein (CREB) phosphorylation, and IL-1β. We used chromatin immunoprecipitation to examine CREB binding to the Nav1.7 promoter. Finally, we microinjected IL-1β into the TGs or injected complete Freund's adjuvant into TMJs with or without previous microinjection of fluorocitrate, an inhibitor of SGCs activation, into the TGs, and evaluated nociception and gene expressions. Differences between groups were examined by one-way analysis of variance (ANOVA) or independent samples t test. IL-1β upregulated Nav1.7 mRNA and protein expressions in the TG explants, whereas NS398, PF-04418948, H89, or PKI-(6-22)-amide could all block this upregulation, and forskolin could also upregulate Nav1.7 mRNA and protein expressions. IL-1β enhanced CREB binding to the Nav1.7 promoter. Microinjection of IL-1β into the TGs or TMJ inflammation both induced hypernociception of TMJ region

Magnesium/Lithium-Ion Hybrid Battery with High Reversibility by Employing NaV3O8·1.69H2O Nanobelts as a Positive Electrode.

PubMed

Rashad, Muhammad; Li, Xianfeng; Zhang, Huamin

2018-06-27

Recently, magnesium-ion batteries (MIBs) have been under remarkable research focus owing to their appealingly high energy density and natural abundance of magnesium. Nevertheless, MIBs exhibit a very limited performance because of sluggish solid-state Mg 2+ ion diffusion and high polarizability, which hinder their progress toward commercialization. Herein, we report a Mg 2+ /Li + hybrid-ion battery (MLIB) with NaV 3 O 8 ·1.69H 2 O (NVO) nanobelts synthesized at room temperature working as the positive electrode. In the hybrid-ion system, Li + intercalates/deintercalates along with a small amount of Mg 2+ adsorption at the NVO cathode, whereas the anode side of the cell is dominated by Mg 2+ deposition/dissolution. As a result, the MLIB exhibits a much higher rate capability (i.e., 446 mA h g -1 at 20 mA g -1 ) than the previously reported MLIBs. MLIB maintains a high specific capacity of 200 mA h g -1 at 80 mA g -1 for 150 cycles, showing excellent stability. Moreover, the effect of different Li-ion concentrations (i.e., 0.5-2.0 M) in the electrolyte and cutoff voltage (ranging from 2 to 2.6 V) on the specific capacities are investigated. The current study highlights a strategy to exploit the Mg 2+ /Li + hybrid electrolyte system with various electrode materials for high-performance MIBs.

30 CFR 47.91 - Exemptions from the HazCom standard.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Exemptions from the HazCom standard. 47.91... TRAINING HAZARD COMMUNICATION (HazCom) Exemptions § 47.91 Exemptions from the HazCom standard. A hazardous chemical is exempt from this part under the conditions described in Table 47.91 as follows: Table 47.91...

The influence of question design on the response to self-assessment in www.elearnSCI.org: a submodule pilot study.

PubMed

Liu, N; Li, X-W; Zhou, M-W; Biering-Sørensen, F

2015-08-01

This is an interventional training session. The objective of this study was to investigate the difference in response to self-assessment questions in the original and an adjusted version for a submodule of www.elearnSCI.org for student nurses. The study was conducted in a teaching hospital affiliated to Peking University, China. In all, 28 student nurses divided into two groups (groups A and B; 14 in each) received a print-out of a Chinese translation of the slides from the 'Maintaining skin integrity following spinal cord injury' submodule in www.elearnSCI.org for self-study. Both groups were then tested using the 10 self-assessment multiple-choice questions (MCQs) related to the same submodule. Group A used the original questions, whereas group B received an adjusted questionnaire. The responses to four conventional single-answer MCQs were nearly all correct in both groups. However, in three questions, group A, with the option 'All of the above', had a higher number of correct answers than group B, with multiple-answer MCQs. In addition, in another three questions, group A, using the original multiple-answer MCQs, had fewer correct answers than group B, where it was only necessary to tick a single incorrect answer. Variations in design influence the response to questions. The use of conventional single-answer MCQs should be reconsidered, as they only examine the recall of isolated knowledge facts. The 'All of the above' option should be avoided because it would increase the number of correct answers arrived at by guessing. When using multiple-answer MCQs, it is recommended that the questions asked should be in accordance with the content within the www.elearnSCI.org.

Patient information on breast reconstruction in the era of the world wide web. A snapshot analysis of information available on youtube.com.

PubMed

Tan, M L H; Kok, K; Ganesh, V; Thomas, S S

2014-02-01

Breast cancer patient's expectation and choice of reconstruction is increasing and patients often satisfy their information needs outside clinic time by searching the world wide web. The aim of our study was to analyse the quality of content and extent of information regarding breast reconstruction available on YouTube videos and whether this is an appropriate additional source of information for patients. A snapshot qualitative and quantitative analysis of the first 100 videos was performed after the term 'breast reconstruction' was input into the search window of the video sharing website www.youtube.com on the 1st of September 2011. Qualitative categorical analysis included patient, oncological and reconstruction factors. It was concluded that although videos uploaded onto YouTube do not provide comprehensive information, it is a useful resource that can be utilised in patient education provided comprehensive and validated videos are made available. Copyright © 2013 Elsevier Ltd. All rights reserved.

Airpower’s Emasculation? -- Non-lethal Weapons in Joint Urban Operations

DTIC Science & Technology

2005-02-14

Lethal, Subdue the Enemy Without Killing,” 14, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 /Shadowlands/6583...37 “Non-Lethal, Subdue the Enemy Without Killing,” 10-11, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 ... Area51 /Shadowlands/6583/project035.html> [15 December 2004]. 42 “US Plans for Use of Gas in Iraq,” The Sunshine Project, 7 February 2003, <http

Anbar Awake: What Now?

DTIC Science & Technology

2009-04-01

enough local support in the area to prevent the AM from taking root.64 The rapid expansion of the AM was both stunning and game -changing. By...in between. 40 Oppel, “Iraq Takes Aim.” 41 Wong, al-Ansary, and Cooper, and Anna Badkhen, “We Were basically Hiring Terrorists,” Salon , August 29...www.worldthreats.com/?p=533 (accessed January 20, 2008). Badkhen, Anna. “We Were Basically Hiring Terrorists.” Salon , August 29, 2008. http://www.salon.com/news

SeisComP 3 - Where are we now?

NASA Astrophysics Data System (ADS)

Saul, Joachim; Becker, Jan; Hanka, Winfried; Heinloo, Andres; Weber, Bernd

2010-05-01

The seismological software SeisComP has evolved within the last approximately 10 years from a pure acquisition modules to a fully featured real-time earthquake monitoring software. The now very popular SeedLink protocol for seismic data transmission has been the core of SeisComP from the very beginning. Later additions included simple, purely automatic event detection, location and magnitude determination capabilities. Especially within the development of the 3rd-generation SeisComP, also known as "SeisComP 3", automatic processing capabilities have been augmented by graphical user interfaces for vizualization, rapid event review and quality control. Communication between the modules is achieved using a a TCP/IP infrastructure that allows distributed computing and remote review. For seismological metadata exchange export/import to/from QuakeML is avalable, which also provides a convenient interface with 3rd-party software. SeisComP is the primary seismological processing software at the GFZ Potsdam. It has also been in use for years in numerous seismic networks in Europe and, more recently, has been adopted as primary monitoring software by several tsunami warning centers around the Indian Ocean. In our presentation we describe the current status of development as well as future plans. We illustrate its possibilities by discussing different use cases for global and regional real-time earthquake monitoring and tsunami warning.

Space to Ground: A Fleet of CUBESATS: 05/19/2017

NASA Image and Video Library

2017-05-18

NASA's Space to Ground is your weekly update on what's happening aboard the International Space Station. Got a question or comment? Use #spacetoground to talk to us. ________________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/

Space-to-Ground_171_170407

NASA Image and Video Library

2017-04-07

NASA's Space to Ground is your weekly update on what's happening aboard the International Space Station. Got a question or comment? Use #spacetoground to talk to us. ________________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/

Space to Ground: Who Doesn't Enjoy a Good View of Planet Earth?: 02/10/2017

NASA Image and Video Library

2017-02-10

NASA's Space to Ground is your weekly update on what's happening aboard the International Space Station. Got a question or comment? Use #spacetoground to talk to us. ________________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/

GERD: Can Certain Medications Increase Severity?

MedlinePlus

... com/home. Accessed Dec. 31, 2014. Bisphosphonates. Facts & Comparisons. http://www.factsandcomparisons.com. Accessed Dec. 31, 2014. ... Healthy Living," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education ...

Securing Voice over IP Conferencing with Decentralized Group Encryption

DTIC Science & Technology

2007-09-04

media stream. Call data can then be encrypted and decrypted. Zfone is available as a plug-in for a number of VoIP programs, including Gizmo [13...Terminal. http://www.l- 3com.com/csw/product/specs/Airborne/TCDLAir.asp. [13] The Gizmo Project. http://gizmoproject.com. [14] The OpenSSL

Democratic Security and Defense Policy: A Successful Counterinsurgency Model

DTIC Science & Technology

2012-06-08

Nueva Colombia, “ Programa Agrario de los Guerrilleros de las FARC,” Mbolivariano.blogspot.com, http://mbolivariano.blogspot. com/2007/12/ programa ...Conferencias de FARC.” Archivo Chile . http://www. Archivochile. Com/america_latina/doc_paises_al/co/farc/ al_farc0003. Pdf (accessed 24 September 2011... Programa Agrario de los Guerrilleros de las FARC.” Mbolivariano.blogspot.com, http://mbolivariano.blogspot. com/2007/12/ programa -agrario- de -los

10 CFR 431.75 - Materials incorporated by reference.

Code of Federal Regulations, 2010 CFR

2010-01-01

...-Conditioning Engineers, Inc., 1971 Tullie Circle, NE., Atlanta, GA 30329, or http://www.ashrae.org/book..., CO 80112, or http://global.ihs.com/, or http://webstore.ansi.org/ansidocstore/. (iii) The UL Standard... 07922, or http://www.gamanet.org/publist/hydroordr.htm. ...

Validation of a patch clamp screening protocol that simultaneously measures compound activity in multiple states of the voltage-gated sodium channel Nav1.2.

PubMed

Liu, Yi; Beck, Edward J; Flores, Christopher M

2011-12-01

Hyperactivity of voltage-gated sodium channels underlies, at least in part, a range of pathological states, including pain and epilepsy. Selective blockers of these channels may offer effective treatment of such disorders. Currently employed methods to screen for sodium channel blockers, however, are inadequate to rationally identify mechanistically diverse blockers, limiting the potential range of indications that may be treated by such agents. Here, we describe an improved patch clamp screening assay that increases the mechanistic diversity of sodium channel blockers being identified. Using QPatch HT, a medium-throughput, automated patch clamp system, we tested three common sodium channel blockers (phenytoin, lidocaine, and tetrodotoxin) with distinct mechanistic profiles at Nav1.2. The single-voltage protocol employed in this assay simultaneously measured the compound activity in multiple states, including the slow inactivated state, of the channel. A long compound incubation period (10 s) was introduced during channel inactivation to increase the probability of identifying "slow binders." As such, phenytoin, which preferentially binds with slow kinetics to the fast inactivated state, exhibited significantly higher potency than that obtained from a brief exposure (100 ms) used in typical assays. This assay also successfully detected the use-dependent block of tetrodotoxin, a well-documented property of this molecule yet unobserved in typical patch clamp protocols. These results indicate that the assay described here can increase the likelihood of identification and mechanistic diversity of sodium channel blockers from a primary screen. It can also be used to efficiently guide the in vitro optimization of leads that retain the desired mechanistic properties. © MARY ANN LIEBERT, INC.

PTSD and Suicide Risk Association: A Look at Data

DTIC Science & Technology

2013-04-01

centers and in outreach programs, arguably the word is not getting to the entire population. One can also view videos of senior DoD officials...29 13 Lolita C. Baldor, “Army Suicides for 2012 Surpass Last Year’s Numbers,” November 15, 2012, http://www.military.com/daily-news/2012/11/16...February 13, 2012. 46 United States Navy, “A Global Force for Good,” YouTube, video file, http://www.youtube.com/watch?v=EEtZ5r0CIYI, (accessed on

Sony’s Nightmare before Christmas: The 2014 North Korean Cyber Attack on Sony and Lessons for US Government Actions in Cyberspace

DTIC Science & Technology

2018-02-01

4,  2014), http://www.businessinsider.com/ experts-the-sony-hack-looks-a-lot-like-previous-attacks-on- south-korea-2014-12. 39 Kim Zetter, “Logic Bomb ...Set Off South Korea Cyberattack,” Wired (March 21, 2013), https://www.wired.com/2013/03/logic- bomb -south-korea-attack/. 40 Brian Krebs, “The Case...Agency (March  21,  2013), http://english.yonhapnews.co.kr/ national/2013/03/21/55/0302000000AEN20130321003552315F. HTML. 47 Kim Zetter, “Logic Bomb

America’s Air Force, The Future Calls: An Evidentiary and Theoretical Analysis Of The Roles And Missions Of A USAF Astronaut Corps

DTIC Science & Technology

2016-06-01

wT0S8qQLCOqh. ; Keith Wagstaff, “ Elon Musk Says SpaceX Will Send People to Mars By 2025,” NBC News, 29 January 2016, Accessed 22 February 2016...http://www.nbcnews.com/tech/tech-news/ elon - musk -says-spacex-will-send-people- mars-2025-n506891. 76. “About Mars One,” Mars-One.com, 2016, Accessed 22...January 2014. Accessed 22 February 2016. https://www.stratcom.mil/factsheets/11/Space_Control_and_Space_Surveillan ce/. Wagstaff, Keith. “ Elon Musk Says

"ComPost": A Writing Program Newsletter and Its Rationale.

ERIC Educational Resources Information Center

Hall, Dennis R.

1993-01-01

Discusses the development and rationale of "ComPost," a weekly newsletter of the Composition Program at the University of Louisville. Suggests that a vehicle like ComPost can promote the communications that contribute to accomplishing collegiality and genuine program consensus. (RS)

Combined VIS-IR spectrometer with vertical probe beam

NASA Astrophysics Data System (ADS)

Protopopov, V.

2017-12-01

A prototype of a combined visible-infrared spectrometer with a vertical probe beam is designed and tested. The combined spectral range is 0.4-20 μ with spatial resolution 1 mm. Basic features include the ability to measure both visibly transparent and opaque substances, as well as buried structures, such as in semiconductor industry; horizontal orientation of a sample, including semiconductor wafers; and reflection mode of operation, delivering twice the sensitivity compared to the transmission mode.

Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

PubMed

Hedrich, Ulrike B S; Liautard, Camille; Kirschenbaum, Daniel; Pofahl, Martin; Lavigne, Jennifer; Liu, Yuanyuan; Theiss, Stephan; Slotta, Johannes; Escayg, Andrew; Dihné, Marcel; Beck, Heinz; Mantegazza, Massimo; Lerche, Holger

2014-11-05

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation. Copyright © 2014 the authors 0270-6474/14/3414874-16$15.00/0.

CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability

PubMed Central

Hsu, Wei-Chun J.; Scala, Federico; Nenov, Miroslav N.; Wildburger, Norelle C.; Elferink, Hannah; Singh, Aditya K.; Chesson, Charles B.; Buzhdygan, Tetyana; Sohail, Maveen; Shavkunov, Alexander S.; Panova, Neli I.; Nilsson, Carol L.; Rudra, Jai S.; Lichti, Cheryl F.; Laezza, Fernanda

2016-01-01

Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14−/− mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7-tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. In 1 d in vitro hippocampal neurons, TBB induced a reduction in FGF14 expression, a decrease in transient Na+ current amplitude, and a hyperpolarizing shift in the voltage dependence of Nav channel steady-state inactivation. In mature neurons, TBB reduces the axodendritic polarity of FGF14. In cornu ammonis area 1 hippocampal slices from wild-type mice, TBB impairs neuronal excitability by increasing action potential threshold and lowering firing frequency. Importantly, these changes in excitability are recapitulated in Fgf14−/− mice, and deletion of Fgf14 occludes TBB-dependent phenotypes observed in wild-type mice. These results suggest that a CK2-FGF14 axis may regulate Nav channels and neuronal excitability.—Hsu, W.-C. J., Scala, F., Nenov, M. N., Wildburger, N. C., Elferink, H., Singh, A. K., Chesson, C. B., Buzhdygan, T., Sohail, M., Shavkunov, A. S., Panova, N. I., Nilsson, C. L., Rudra, J. S., Lichti, C. F., Laezza, F. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal

Internet (WWW) based system of ultrasonic image processing tools for remote image analysis.

PubMed

Zeng, Hong; Fei, Ding-Yu; Fu, Cai-Ting; Kraft, Kenneth A

2003-07-01

Ultrasonic Doppler color imaging can provide anatomic information and simultaneously render flow information within blood vessels for diagnostic purpose. Many researchers are currently developing ultrasound image processing algorithms in order to provide physicians with accurate clinical parameters from the images. Because researchers use a variety of computer languages and work on different computer platforms to implement their algorithms, it is difficult for other researchers and physicians to access those programs. A system has been developed using World Wide Web (WWW) technologies and HTTP communication protocols to publish our ultrasonic Angle Independent Doppler Color Image (AIDCI) processing algorithm and several general measurement tools on the Internet, where authorized researchers and physicians can easily access the program using web browsers to carry out remote analysis of their local ultrasonic images or images provided from the database. In order to overcome potential incompatibility between programs and users' computer platforms, ActiveX technology was used in this project. The technique developed may also be used for other research fields.

Evolutionary diversification of Mesobuthus α-scorpion toxins affecting sodium channels.

PubMed

Zhu, Shunyi; Peigneur, Steve; Gao, Bin; Lu, Xiuxiu; Cao, Chunyang; Tytgat, Jan

2012-01-01

α-Scorpion toxins constitute a family of peptide modulators that induce a prolongation of the action potential of excitable cells by inhibiting voltage-gated sodium channel inactivation. Although they all adopt a conserved structural scaffold, the potency and phylogentic preference of these toxins largely vary, which render them an intriguing model for studying evolutionary diversification among family members. Here, we report molecular characterization of a new multigene family of α-toxins comprising 13 members (named MeuNaTxα-1 to MeuNaTxα-13) from the scorpion Mesobuthus eupeus. Of them, five native toxins (MeuNaTxα-1 to -5) were purified to homogeneity from the venom and the solution structure of MeuNaTxα-5 was solved by nuclear magnetic resonance. A systematic functional evaluation of MeuNaTxα-1, -2, -4, and -5 was conducted by two-electrode voltage-clamp recordings on seven cloned mammalian voltage-gated sodium channels (Na(v)1.2 to Na(v)1.8) and the insect counterpart DmNa(v)1 expressed in Xenopus oocytes. Results show that all these four peptides slow inactivation of DmNa(v)1 and are inactive on Na(v)1.8 at micromolar concentrations. However, they exhibit differential specificity for the other six channel isoforms (Na(v)1.2 to Na(v)1.7), in which MeuNaTxα-4 shows no activity on these isoforms and thus represents the first Mesobuthus-derived insect-selective α-toxin identified so far with a half maximal effective concentration of 130 ± 2 nm on DmNa(v)1 and a half maximal lethal dose of about 200 pmol g(-1) on the insect Musca domestica; MeuNaTxα-2 only affects Na(v)1.4; MeuNaTxα-1 and MeuNaTxα-5 have a wider range of channel spectrum, the former active on Na(v)1.2, Na(v)1.3, Na(v)1.6, and Na(v)1.7, whereas the latter acting on Na(v)1.3-Na(v)1.7. Remarkably, MeuNaTxα-4 and MeuNaTxα-5 are two nearly identical peptides differing by only one point mutation at site 50 (A50V) but exhibit rather different channel subtype selectivity, highlighting a

77 FR 52702 - Notice of Availability of Record of Decision for the Silver Strand Training Complex, California

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-30

... of Decision is available for public viewing on the project Web site at http://www... Decision are available by contacting: Ms. Amy P. Kelley, Naval Facilities Engineering Command Southwest... project Web site is found at http://www.silverstrandtrainingcomplexeis.com . Dated: August 24, 2012. C. K...

48 CFR 2909.105 - Procedures.

Code of Federal Regulations, 2010 CFR

2010-10-01

...'s responsibility in accordance with FAR 9.105. In addition to past performance information, the...” (available on the Internet at www.epls.gov). In addition, contracting officers should base their... & Bradstreet (available on the Internet for a fee at http://www.dnb.com/). ...

Changing the Department of Defense’s Policy on Homosexuals

DTIC Science & Technology

2008-02-19

2007 from http://www.hrc.org/alva/dadt.html 18. Ottosson, D (2006, November), LGBT World Legal Wrap Up Survey, International Lesbian Gay...from http://www.gaywired.com/article.cfm?section=66&id=16683 Ottosson, D (2006, November), LGBT World Legal Wrap Up Survey, International

75 FR 4375 - Transmission Loading Relief Reliability Standard and Curtailment Priorities

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-27

... Site: http://www.ferc.gov . Documents created electronically using word processing software should be... ensure operation within acceptable reliability criteria. NERC Glossary of Terms Used in Reliability Standards at 19, available at http://www.nerc.com/files/Glossary_12Feb08.pdf (NERC Glossary). An...

30 CFR 47.1 - Purpose of a HazCom standard; applicability.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Purpose of a HazCom standard; applicability. 47... EDUCATION AND TRAINING HAZARD COMMUNICATION (HazCom) Purpose, Scope, Applicability, and Initial Miner Training § 47.1 Purpose of a HazCom standard; applicability. The purpose of this part is to reduce injuries...

WWW.KASSERINEPASS.COM: Determining the U.S. Army’s Readiness for Tactical Operations in Cyberspace

DTIC Science & Technology

2008-06-01

PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) André Bernard Abadie 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING...ORGANIZATION NAME( S ) AND ADDRESS(ES) U.S. Army Command and General Staff College ATTN: ATZL-SWD-GD Fort Leavenworth, KS 66027-2301 8. PERFORMING ORG...REPORT NUMBER 9. SPONSORING / MONITORING AGENCY NAME( S ) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM( S ) 11. SPONSOR/MONITOR’S REPORT NUMBER( S

Lysine and the Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels.

PubMed

Li, Yang; Liu, Huihui; Xia, Mengdie; Gong, Haipeng

2016-01-01

Voltage-gated sodium (Nav) channels are critical in the generation and transmission of neuronal signals in mammals. The crystal structures of several prokaryotic Nav channels determined in recent years inspire the mechanistic studies on their selection upon the permeable cations (especially between Na+ and K+ ions), a property that is proposed to be mainly determined by residues in the selectivity filter. However, the mechanism of cation selection in mammalian Nav channels lacks direct explanation at atomic level due to the difference in amino acid sequences between mammalian and prokaryotic Nav homologues, especially at the constriction site where the DEKA motif has been identified to determine the Na+/K+ selectivity in mammalian Nav channels but is completely absent in the prokaryotic counterparts. Among the DEKA residues, Lys is of the most importance since its mutation to Arg abolishes the Na+/K+ selectivity. In this work, we modeled the pore domain of mammalian Nav channels by mutating the four residues at the constriction site of a prokaryotic Nav channel (NavRh) to DEKA, and then mechanistically investigated the contribution of Lys in cation selection using molecular dynamics simulations. The DERA mutant was generated as a comparison to understand the loss of ion selectivity caused by the K-to-R mutation. Simulations and free energy calculations on the mutants indicate that Lys facilitates Na+/K+ selection by electrostatically repelling the cation to a highly Na+-selective location sandwiched by the carboxylate groups of Asp and Glu at the constriction site. In contrast, the electrostatic repulsion is substantially weakened when Lys is mutated to Arg, because of two intrinsic properties of the Arg side chain: the planar geometric design and the sparse charge distribution of the guanidine group.

Parallel evolution of tetrodotoxin resistance in three voltage-gated sodium channel genes in the garter snake Thamnophis sirtalis.

PubMed

McGlothlin, Joel W; Chuckalovcak, John P; Janes, Daniel E; Edwards, Scott V; Feldman, Chris R; Brodie, Edmund D; Pfrender, Michael E; Brodie, Edmund D

2014-11-01

Members of a gene family expressed in a single species often experience common selection pressures. Consequently, the molecular basis of complex adaptations may be expected to involve parallel evolutionary changes in multiple paralogs. Here, we use bacterial artificial chromosome library scans to investigate the evolution of the voltage-gated sodium channel (Nav) family in the garter snake Thamnophis sirtalis, a predator of highly toxic Taricha newts. Newts possess tetrodotoxin (TTX), which blocks Nav's, arresting action potentials in nerves and muscle. Some Thamnophis populations have evolved resistance to extremely high levels of TTX. Previous work has identified amino acid sites in the skeletal muscle sodium channel Nav1.4 that confer resistance to TTX and vary across populations. We identify parallel evolution of TTX resistance in two additional Nav paralogs, Nav1.6 and 1.7, which are known to be expressed in the peripheral nervous system and should thus be exposed to ingested TTX. Each paralog contains at least one TTX-resistant substitution identical to a substitution previously identified in Nav1.4. These sites are fixed across populations, suggesting that the resistant peripheral nerves antedate resistant muscle. In contrast, three sodium channels expressed solely in the central nervous system (Nav1.1-1.3) showed no evidence of TTX resistance, consistent with protection from toxins by the blood-brain barrier. We also report the exon-intron structure of six Nav paralogs, the first such analysis for snake genes. Our results demonstrate that the molecular basis of adaptation may be both repeatable across members of a gene family and predictable based on functional considerations. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Properties of human brain sodium channel α-subunits expressed in HEK293 cells and their modulation by carbamazepine, phenytoin and lamotrigine

PubMed Central

Qiao, Xin; Sun, Guangchun; Clare, Jeffrey J; Werkman, Taco R; Wadman, Wytse J

2014-01-01

Background and purpose Voltage-activated Na+ channels contain one distinct α-subunit. In the brain NaV1.1, NaV1.2, NaV1.3 and NaV1.6 are the four most abundantly expressed α-subunits. The antiepileptic drugs (AEDs) carbamazepine, phenytoin and lamotrigine have voltage-gated Na+ channels as their primary therapeutic targets. This study provides a systematic comparison of the biophysical properties of these four α-subunits and characterizes their interaction with carbamazepine, phenytoin and lamotrigine. Experimental approach Na+ currents were recorded in voltage-clamp mode in HEK293 cells stably expressing one of the four α-subunits. Key results NaV1.2 and NaV1.3 subunits have a relatively slow recovery from inactivation, compared with the other subunits and NaV1.1 subunits generate the largest window current. Lamotrigine evokes a larger maximal shift of the steady-state inactivation relationship than carbamazepine or phenytoin. Carbamazepine shows the highest binding rate to the α-subunits. Lamotrigine binding to NaV1.1 subunits is faster than to the other α-subunits. Lamotrigine unbinding from the α-subunits is slower than that of carbamazepine and phenytoin. Conclusions and implications The four Na+ channel α-subunits show subtle differences in their biophysical properties, which, in combination with their (sub)cellular expression patterns in the brain, could contribute to differences in neuronal excitability. We also observed differences in the parameters that characterize AED binding to the Na+ channel subunits. Particularly, lamotrigine binding to the four α-subunits suggests a subunit-specific response. Such differences will have consequences for the clinical efficacy of AEDs. Knowledge of the biophysical and binding parameters could be employed to optimize therapeutic strategies and drug development. PMID:24283699

Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra

PubMed Central

Ding, Shengyuan; Wei, Wei

2011-01-01

GABA projection neurons (GABA neurons) in the substantia nigra pars reticulata (SNr) and dopamine projection neurons (DA neurons) in substantia nigra pars compacta (SNc) have strikingly different firing properties. SNc DA neurons fire low-frequency, long-duration spikes, whereas SNr GABA neurons fire high-frequency, short-duration spikes. Since voltage-activated sodium (NaV) channels are critical to spike generation, the different firing properties raise the possibility that, compared with DA neurons, NaV channels in SNr GABA neurons have higher density, faster kinetics, and less cumulative inactivation. Our quantitative RT-PCR analysis on immunohistochemically identified nigral neurons indicated that mRNAs for pore-forming NaV1.1 and NaV1.6 subunits and regulatory NaVβ1 and Navβ4 subunits are more abundant in SNr GABA neurons than SNc DA neurons. These α-subunits and β-subunits are key subunits for forming NaV channels conducting the transient NaV current (INaT), persistent Na current (INaP), and resurgent Na current (INaR). Nucleated patch-clamp recordings showed that INaT had a higher density, a steeper voltage-dependent activation, and a faster deactivation in SNr GABA neurons than in SNc DA neurons. INaT also recovered more quickly from inactivation and had less cumulative inactivation in SNr GABA neurons than in SNc DA neurons. Furthermore, compared with nigral DA neurons, SNr GABA neurons had a larger INaR and INaP. Blockade of INaP induced a larger hyperpolarization in SNr GABA neurons than in SNc DA neurons. Taken together, these results indicate that NaV channels expressed in fast-spiking SNr GABA neurons and slow-spiking SNc DA neurons are tailored to support their different spiking capabilities. PMID:21880943

The Maharaja’s New AVTAAR: Air-Refuelling Strategy for the Indian Air Force

DTIC Science & Technology

2013-06-01

and Lolita C Baldor, "Boeing gets $35 Billion Air Force Tanker Order," Aviation on NBC News.com. Feruary 24, 2011. http://www.nbcnews.com/id/41766812...rakshak.com/NAVY/Ships/Active/156-Nicobar-Class.html (accessed March 23, 2013). Cassata, Donna, and Lolita C Baldor. "Boeing gets $35 Billion Air Force

Islamic Radicalization in the United States. New Trends and a Proposed Methodology for Disruption

DTIC Science & Technology

2010-09-01

education system of our country somewhat promisingly," said Sen. Richard G. Lugar (R-Ind.). "I’ve always felt that this was the future in America for...www.youtube.com/watch?v=Q8S_0RFq4Nw&feature=related Al-Qaida Calls on U.S. Muslims to Attack America http://www.youtube.com/watch?v=BBmhKutfJ48 The...intelligence services in 10 countries in North America , Europe, Asia and Africa were investigating a plot apparently conceived, planned, and brought down on the

Hiperplasia angiolinfoide com eosinofilia: um caso raro em cavidade oral

PubMed Central

Tenório, Jefferson da Rocha; Gonzaga, Amanda Katarinny Goes; Gonçalves, Patrícia Guerra Peixe; de Oliveira, Denise Hélen Imaculada Pereira; Queiroz, Lélia Maria Guedes

2016-01-01

Resumo A hiperplasia angiolinfoide com eosinofilia (HALE) é considerada uma lesão vascular benigna rara que acomete, principalmente, o tecido cutâneo e subcutâneo da região de cabeça e pescoço, mas incomum na cavidade oral. Sua etiopatogenia permanece indefinida, sendo descrita como proliferação vascular reacional, malformação vascular ou neoplasia. Tem como principal diagnóstico diferencial a doença de Kimura. Este trabalho relata um caso de um paciente do sexo masculino, de 50 anos, que exibia aumento de volume nodular na mucosa do lábio superior, com 3 cm de dimensão e 7 anos de evolução. Após a biópsia excisional, o exame histopatológico mostrou lesão bem encapsulada multilobulada com proliferação de capilares sanguíneos com células endoteliais de aspecto epitelioide, infiltrado inflamatório difuso com linfócitos, plasmócitos, inúmeros eosinófilos e presença de folículos linfoides. A análise imuno-histoquímica revelou positividade para CD34 e Ki-67, o que, juntamente com o exame morfológico, direcionou o diagnóstico para HALE. PMID:29930611

U.S. Democracy Promotion and Al Jazeera: A View into Arab Reactions and Opposing Movements

DTIC Science & Technology

2005-09-01

New York Time, 13 April, 2000, http://www.stanford.edu/~wacziarg/articles/nytdemoc/nytdemoc.html (accessed 11 December 2004). 9. Amartya Sen ...February 12, 2005, 106 http://www.jsonline.com/news/editorials/feb05/301034.asp (accessed August 22, 2005). Sen , Amartya . “Democracy as a

Adaptive online self-gating (ADIOS) for free-breathing noncontrast renal MR angiography.

PubMed

Xie, Yibin; Fan, Zhaoyang; Saouaf, Rola; Natsuaki, Yutaka; Laub, Gerhard; Li, Debiao

2015-01-01

To develop a respiratory self-gating method, adaptive online self-gating (ADIOS), for noncontrast MR angiography (NC MRA) of renal arteries to overcome some limitations of current free-breathing methods. A NC MRA pulse sequence for online respiratory self-gating was developed based on three-dimensional balanced steady-state free precession (bSSFP) and slab-selective inversion-recovery. Motion information was derived directly from the slab being imaged for online gating. Scan efficiency was maintained by an automatic adaptive online algorithm. Qualitative and quantitative assessments of image quality were performed and results were compared with conventional diaphragm navigator (NAV). NC MRA imaging was successfully completed in all subjects (n = 15). Similarly good image quality was observed in the proximal-middle renal arteries with ADIOS compared with NAV. Superior image quality was observed in the middle-distal renal arteries in the right kidneys with no NAV-induced artifacts. Maximal visible artery length was significantly longer with ADIOS versus NAV in the right kidneys. NAV setup was completely eliminated and scan time was significantly shorter with ADIOS on average compared with NAV. The proposed ADIOS technique for noncontrast MRA provides high-quality visualization of renal arteries with no diaphragm navigator-induced artifacts, simplified setup, and shorter scan time. © 2014 Wiley Periodicals, Inc.

Environmental Enrichment and Social Isolation Mediate Neuroplasticity of Medium Spiny Neurons through the GSK3 Pathway.

PubMed

Scala, Federico; Nenov, Miroslav N; Crofton, Elizabeth J; Singh, Aditya K; Folorunso, Oluwarotimi; Zhang, Yafang; Chesson, Brent C; Wildburger, Norelle C; James, Thomas F; Alshammari, Musaad A; Alshammari, Tahani K; Elfrink, Hannah; Grassi, Claudio; Kasper, James M; Smith, Ashley E; Hommel, Jonathan D; Lichti, Cheryl F; Rudra, Jai S; D'Ascenzo, Marcello; Green, Thomas A; Laezza, Fernanda

2018-04-10

Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3β (GSK3β) and voltage-gated Na + channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions-models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3β and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6 T1936 by GSK3β. A GSK3β-Nav1.6 T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Sinus Infection and Toothache: Any Connection?

MedlinePlus

... Internal Medicine. 19th ed. New York, N.Y.: McGraw-Hill Education; 2015. http://accessmedicine.com. Accessed Jan. 8, ... Medicine. 7th ed. New York, N.Y.: The McGraw-Hill Companies; 2011. http://www.accessmedicine.com. Accessed Jan. ...

Realigning the Focus of Plagiarism Detection Using "Plagiarismdetect.com"

ERIC Educational Resources Information Center

Sabapathy, Elangkeeran A/L; Rahim, Rozlan Abd; Jusoff, Kamaruzaman

2009-01-01

The purpose of this article is to examine the extent to which "plagiarismdetect.com," an internet help/tool to detect plagiarism helps academicians tackle the ever-growing problem of plagiarism. Concerned with term papers, essays and most of the time with full-blown research reports, a tool like "plagiarismdetect.com" may…

SPECTRE (www.noveltis.fr/spectre): a web Service for Ionospheric Products

NASA Astrophysics Data System (ADS)

Jeansou, E.; Crespon, F.; Garcia, R.; Helbert, J.; Moreaux, G.; Lognonne, P.

2005-12-01

The dense GPS networks developed for geodesic applications appear to be very efficient ionospheric sensors because of interaction between plasma and electromagnetic waves. Indeed, the dual frequency receivers provide data from which the Slant Total Electron Content (STEC) can be easily extracted to compute Vertical Total Electron Content (VTEC) maps. The SPECTRE project, Service and Products for ionospheric Electron Content and Tropospheric Refractivity over Europe, is currently a pre-operational service providing VTEC maps with high time and space resolution after 3 days time delay (http://www.noveltis.fr/spectre and http://ganymede.ipgp.jussieu.fr/spectre). This project is a part of SWENET, SpaceWeather European Network, initiated by the European Space Agency. The SPECTRE data products are useful for many applications. We will present these applications in term of interest for the scientific community with a special focus on spaceweather and transient ionospheric perturbations related to Earthquakes. Moreover, the pre-operational extensions of SPECTRE to the californian (SCIGN/BARD) and japanese (GEONET) dense GPS networks will be presented. Then the method of 3D tomography of the electron density from GPS data will be presented and its resolution discussed. The expected improvements of the 3D tomographic images by new tomographic reconstruction algorithms and by the advent of the Galileo system will conclude the presentation.

Comments from physicsworld.com

NASA Astrophysics Data System (ADS)

Hamill, Harry; de Podesta, Michael; Weidig, Tom; Evanson, Nick; Thomas, Glen

2009-03-01

A new UK government campaign - dubbed "Science: [So What? So Everything]" - aims to boost public interest in science by countering impressions that science is "remote, elitist and irrelevant". An article on the physicsworld.com blog discussing the campaign ("Is science elitist?" 28 January) prompted several readers to share their opinions on what it means to be "elite", and whether elitism really is bad for science.

COM: Decisions and Applications in a Small University Library.

ERIC Educational Resources Information Center

Schwarz, Philip J.

Computer-output microfilm (COM) is used at the University of Wisconsin-Stout Library to generate reports from its major machine readable data bases. Conditions indicating the need to convert to COM include existence of a machine readable data base and high cost of report production. Advantages and disadvantages must also be considered before…

Index of Non-Government Standards on Human Engineering Design Criteria and Program Requirements/Guidelines. Version 3

DTIC Science & Technology

2002-10-01

the Seated Operator of Off-Highway Work Machines ♦ SAE J1013 1992 http://www.sae.org/servlets/ index http://standards.nasa.gov/NPTS/login.taf...Public Access permits users to view the NASA Preferred Technical Standards index , with the capability to download free of charge the NASA- Developed ...www.sae.org/servlets/ index http://www.techstreet.com/ Design of Ergonomic Requirements for the Design of Displays and Control Actuators -

Factors Related to Spatial Patterns of Rural Land Fragmentation in Texas

NASA Astrophysics Data System (ADS)

Kjelland, Michael E.; Kreuter, Urs P.; Clendenin, George A.; Wilkins, R. Neal; Wu, X. Ben; Afanador, Edith Gonzalez; Grant, William E.

2007-08-01

Fragmentation of family-owned farms and ranches has been identified as the greatest single threat to wildlife habitat, water supply, and the long-term viability of agriculture in Texas. However, an integrative framework for insights into the pathways of land use change has been lacking. The specific objectives of the study are to test the hypotheses that the nonagricultural value (NAV) of rural land is a reliable indicator of trends in land fragmentation and that NAV in Texas is spatially correlated with population density, and to explore the idea that recent changes in property size patterns are better represented by a categorical model than by one that reflects incremental changes. We propose that the State-and-Transition model, developed to describe the dynamics of semi-arid ecosystems, provides an appropriate conceptual framework for characterizing categorical shifts in rural property patterns. Results suggest that changes in population density are spatially correlated with NAV and farm size, and that rural property size is spatially correlated with changes in NAV. With increasing NAV, the proportion of large properties tends to decrease while the area represented by small properties tends to increase. Although a correlation exists between NAV and population density, it is the trend in NAV that appears to be a stronger predictor of land fragmentation. The empirical relationships established herein, viewed within the conceptual framework of the State-and-Transition model, can provide a useful tool for evaluating land use policies for maintaining critical ecosystem services delivered from privately owned land in private land states, such as Texas.

Putting the Brakes on Muscle Breakdown

NASA Image and Video Library

2018-01-15

Rodent Research-6 is a two-fold investigation aboard the International Space Station into the treatment of muscle loss in spaceflight, which may have implications for patients on Earth with muscle-wasting diseases. The experiment will study the effectiveness of a drug compound as well as the nano-channel drug delivery implant, a device implanted beneath the skin of the patient allowing for a constant, steady delivery of the drug. Rodent Research: https://www.nasa.gov/mission_pages/station/research/experiments/explorer/Investigation.html?#id=7423 HD Download: https://archive.org/details/jsc2018m000072_Putting_the_Brakes_on_Muscle_Breakdown_MXF _______________________________________ FOLLOW THE SPACE STATION! Twitter: https://twitter.com/Space_Station Facebook: https://www.facebook.com/ISS Instagram: https://instagram.com/iss/

jsc2018m000130_Orion Crew Module for Ascent Abort-2 Arrives in Houston

NASA Image and Video Library

2018-03-08

Ascent Abort-2 Module Arrives in Houston---------------------------------------------------------- NASA’s Johnson Space Center is the center of activity leading the design and build up for a critical safety test of America’s new exploration spacecraft. An Orion crew module was delivered to Houston last week for assembly and outfitting for the April 2019 Ascent Abort-2 test, to demonstrate the ability of the spacecraft’s Launch Abort System to pull the crew module to safety if an emergency ever arises during ascent to space. Doing this work at JSC is part of a lean approach to development, to minimize cost and schedule risks associated with the test. _______________________________________ FOLLOW ORION! Twitter: https://twitter.com/NASA_Orion/ Facebook: https://www.facebook.com/NASAOrion/ Instagram: https://www.instagram.com/explorenasa/

cyNeo4j: connecting Neo4j and Cytoscape

PubMed Central

Summer, Georg; Kelder, Thomas; Ono, Keiichiro; Radonjic, Marijana; Heymans, Stephane; Demchak, Barry

2015-01-01

Summary: We developed cyNeo4j, a Cytoscape App to link Cytoscape and Neo4j databases to utilize the performance and storage capacities Neo4j offers. We implemented a Neo4j NetworkAnalyzer, ForceAtlas2 layout and Cypher component to demonstrate the possibilities a distributed setup of Cytoscape and Neo4j have. Availability and implementation: The app is available from the Cytoscape App Store at http://apps.cytoscape.org/apps/cyneo4j, the Neo4j plugins at www.github.com/gsummer/cyneo4j-parent and the community and commercial editions of Neo4j can be found at http://www.neo4j.com. Contact: georg.summer@gmail.com PMID:26272981

Economic feasibility of manufacturing COM-PLY studs in the South

Treesearch

Gerald A. Koenigshof

1978-01-01

The investment and production cost required to manufacture COM-PLY studs in the South are presented. It is possible to obtain a 20 percent or greater internal rate of return on an investment in manufacturing COM-PLY.

SteadyCom: Predicting microbial abundances while ensuring community stability

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

Chan, Siu Hung Joshua; Simons, Margaret N.; Maranas, Costas D.

Genome-scale metabolic modeling has become widespread for analyzing microbial metabolism. Extending this established paradigm to more complex microbial communities is emerging as a promising way to unravel the interactions and biochemical repertoire of these omnipresent systems. While several modeling techniques have been developed for microbial communities, little emphasis has been placed on the need to impose a time-averaged constant growth rate across all members for a community to ensure co-existence and stability. In the absence of this constraint, the faster growing organism will ultimately displace all other microbes in the community. This is particularly important for predicting steady-state microbiota compositionmore » as it imposes significant restrictions on the allowable community membership, composition and phenotypes. In this study, we introduce the SteadyCom optimization framework for predicting metabolic flux distributions consistent with the steady-state requirement. SteadyCom can be rapidly converged by iteratively solving linear programming (LP) problem and the number of iterations is independent of the number of organisms. A significant advantage of SteadyCom is compatibility with flux variability analysis. SteadyCom is first demonstrated for a community of four E. coli double auxotrophic mutants and is then applied to a gut microbiota model consisting of nine species, with representatives from the phyla Bacteroidetes, Firmicutes, Actinobacteria and Proteobacteria. In contrast to the direct use of FBA, SteadyCom is able to predict the change in species abundance in response to changes in diets with minimal additional imposed constraints on the model. Furthermore, by randomizing the uptake rates of microbes, an abundance profile with a good agreement to experimental gut microbiota is inferred. SteadyCom provides an important step towards the cross-cutting task of predicting the composition of a microbial community in a given environment.« less

SteadyCom: Predicting microbial abundances while ensuring community stability

DOE PAGES

Chan, Siu Hung Joshua; Simons, Margaret N.; Maranas, Costas D.; ...

2017-05-15

Genome-scale metabolic modeling has become widespread for analyzing microbial metabolism. Extending this established paradigm to more complex microbial communities is emerging as a promising way to unravel the interactions and biochemical repertoire of these omnipresent systems. While several modeling techniques have been developed for microbial communities, little emphasis has been placed on the need to impose a time-averaged constant growth rate across all members for a community to ensure co-existence and stability. In the absence of this constraint, the faster growing organism will ultimately displace all other microbes in the community. This is particularly important for predicting steady-state microbiota compositionmore » as it imposes significant restrictions on the allowable community membership, composition and phenotypes. In this study, we introduce the SteadyCom optimization framework for predicting metabolic flux distributions consistent with the steady-state requirement. SteadyCom can be rapidly converged by iteratively solving linear programming (LP) problem and the number of iterations is independent of the number of organisms. A significant advantage of SteadyCom is compatibility with flux variability analysis. SteadyCom is first demonstrated for a community of four E. coli double auxotrophic mutants and is then applied to a gut microbiota model consisting of nine species, with representatives from the phyla Bacteroidetes, Firmicutes, Actinobacteria and Proteobacteria. In contrast to the direct use of FBA, SteadyCom is able to predict the change in species abundance in response to changes in diets with minimal additional imposed constraints on the model. Furthermore, by randomizing the uptake rates of microbes, an abundance profile with a good agreement to experimental gut microbiota is inferred. SteadyCom provides an important step towards the cross-cutting task of predicting the composition of a microbial community in a given environment.« less

Spatially extended polycyclic aromatic hydrocarbons in circumstellar disks around T Tauri and Herbig Ae stars

NASA Astrophysics Data System (ADS)

Geers, V. C.; van Dishoeck, E. F.; Visser, R.; Pontoppidan, K. M.; Augereau, J.-C.; Habart, E.; Lagrange, A. M.

2007-12-01

(ISAAC August 2005), 077.C-0668 (VISIR/ISAAC April/May 2006). Appendix A is only available in electronic form at http://www.aanda.org

Amorphous carbon in the disk around the post-AGB binary HR 4049. Discerning dust species with featureless opacity curves

NASA Astrophysics Data System (ADS)

Acke, B.; Degroote, P.; Lombaert, R.; de Vries, B. L.; Smolders, K.; Verhoelst, T.; Lagadec, E.; Gielen, C.; Van Winckel, H.; Waelkens, C.

2013-03-01

Context. Infrared spectroscopy has been extensively used to determine the mineralogy of circumstellar dust. The identification of dust species with featureless opacities, however, is still ambiguous. Here we present a method to lift the degeneracy using the combination of infrared spectroscopy and interferometry. Aims: The binary post-AGB star HR 4049 is surrounded by a circumbinary disk viewed at a high inclination angle. Apart from gaseous emission lines and molecular emission bands of polycyclic aromatic hydrocarbons (PAH), diamonds, and fullerenes, the 2-25 μm infrared spectrum is featureless. The goal of the paper is to identify the dust species responsible for the smooth spectrum. Methods: We gathered high-angular-resolution measurements in the near- and mid-infrared with the VLTI interferometric instruments AMBER and MIDI. The data set is expanded with archival Geneva optical photometry, ISO-SWS and Spitzer-IRS infrared spectroscopy, and VISIR N-band images and spectroscopy. We computed a grid of radiative-transfer models of the circumbinary disk of HR 4049 using the radiative-transfer code MCMax. We searched for models that provide good fits simultaneously to all available observations. Results: We find that the variable optical extinction towards the primary star is consistent with the presence of very small (0.01 μm) iron-bearing dust grains or amorphous carbon grains. The combination of the interferometric constraint on the disk extent and the shape of the infrared spectrum points to amorphous carbon as the dominant source of opacity in the circumbinary disk of HR 4049. The disk is optically thick to the stellar radiation in the radial direction. At infrared wavelengths it is optically thin. The PAH emission is spatially resolved in the VISIR data and emanates from a region with an extent of several hundreds of AU, with a projected photocenter displacement of several tens of AU from the disk center. The PAHs most likely reside in a bipolar outflow

75 FR 57090 - Self-Regulatory Organizations; Notice of Filing of Proposed Rule Change by NASDAQ OMX PHLX, Inc...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-17

... website at http://www.nasdaqtrader.com/micro.aspx?id=PHLXRulefilings , at the principal office of the Exchange, on the Commission's website at http://www.sec.gov/ , and at the Commission's Public Reference... designed to promote just and equitable principles of trade, to remove impediments to and perfect the...

Risk Quantified Structural Design and Evaluation

DTIC Science & Technology

2009-09-01

www.nessus.swri.org/, 2009. 4. Prediction Probe, Inc., “UNIPASS”, www.predictionprobe.com/prod_unipass.htm, 2008. 5. Smith, L., Millwater , H...Dynamics and Materials Conference, 7-10 April 2008, Schaumburg, IL, AIAA 2008- 6. Domyancic, L., Sparkman, D., Millwater , H., Smith, L., and Wieland, D

78 FR 76349 - Self-Regulatory Organizations; Topaz Exchange LLC; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-17

... change is available on the Exchange's Internet Web site at http://www.ise.com , at the principal office... immediately effective rule filing that, among other things, amended its Schedule of Fees to permit the... following methods: Electronic Comments Use the Commission's Internet comment form ( http://www.sec.gov/rules...

VMLO: The Strategic, Operational and Tactical imperative for a Light Observation Squadron with the USMC

DTIC Science & Technology

2012-06-01

15 Bob Cox, “Is the F-35 Flying High or Stuttering ?,” Star-Telegram, January 21, 2012, http://www.star...Washington, DC: HQMC, September 2011. Cox, Bob. “Is the F-35 Flying High or Stuttering ?.” Star-Telegram, January 21, 2012. http://www.star-telegram.com