Science.gov

Sample records for acoustic-to-seismic coupled signals

  1. On the location of frequencies of maximum acoustic-to-seismic coupling

    SciTech Connect

    Sabatier, J.M.; Bass, H.E.; Elliott, G.R.

    1986-10-01

    Measurements of the acoustic-to-seismic transfer function (ratio of the normal soil particle velocity at a depth d to the acoustic pressure at the surface) for outdoor ground surfaces quite typically reveal a series of maxima and minima. In a publication (Sabatier et al., J. Acoust. Soc. Am. 80, 646--649 (1986)), the location and magnitude of these maxima are measured and predicted for several outdoor ground surfaces using a layered poroelastic model of the ground surface. In this paper, the seismic transfer function for a desert site is compared to the seismic transfer function for holes dug in the desert floor which were filled with pumice (volcanic rock). The hole geometry was rectangular and the hole depths varied from 0.25--2.0 m. The p- and s-wave speeds, densities, porosities, and flow resistivities for the desert floor and pumice were all measured. By varying the hole depth and the fill material, the maxima in the seismic transfer function can be shifted in frequency and the locations of the maxima compare reasonably with that of a hard-backed layer calculation. The area or extent of the acoustic-to-seismic coupling for pumice was determined to be less than 1 m/sup 2/.

  2. In situ measurements of the fragipan acoustic to seismic coupling signature

    NASA Astrophysics Data System (ADS)

    Howard, Wheeler; Hickey, Craig J.

    2002-05-01

    The phenomena of acoustic to seismic (A/S) coupling, observed and studied since the 1950s, has most recently been used to detect shallow buried objects [Sabatier and Xiang, J. Acoust. Soc. Am. 105, 1383 (1999); 106, 2143 (1999)] and monitor detonation of nuclear weapons [Orcutt, J. Acoust. Soc. Am. 105, 1038 (1999)]. At an air-surface interface airborne acoustic energy is coupled into the ground as seismic energy. The ratio of the seismic and airborne waves constitutes the A/S coupling signature, which is distinctive to the underlying structure. Seismic energy received by a geophone at the interface contains information, via reflected waves, about the underlying subsurface layer, media, and boundaries. Of particular interest in the Mississippi River Valley is the fragipan layer. The fragipan is the layer that directly affects the growth of crops, rate of soil erosion, and rate of water absorption in underlying layers. In this presentation, the A/S coupling signature data taken at an agricultural field station and forward model are discussed.

  3. An experimental study on antipersonnel landmine detection using acoustic-to-seismic coupling.

    PubMed

    Xiang, Ning; Sabatier, James M

    2003-03-01

    An acoustic-to-seismic system to detect buried antipersonnel mines exploits airborne acoustic waves penetrating the surface of the ground. Acoustic waves radiating from a sound source above the ground excite Biot type I and II compressional waves in the porous soil. The type I wave and type II waves refract toward the normal and cause air and soil particle motion. If a landmine is buried below the surface of the insonified area, these waves are scattered or reflected by the target, resulting in distinct changes to the acoustically coupled ground motion. A scanning laser Doppler vibrometer measures the motion of the ground surface. In the past, this technique has been employed with remarkable success in locating antitank mines during blind field tests [Sabatier and Xiang, IEEE Trans. Geosci. Remote Sens. 39, 1146-1154 (2001)]. The humanitarian demining mission requires an ability to locate antipersonnel mines, requiring a surmounting of additional challenges due to a plethora of shapes and smaller sizes. This paper describes an experimental study on the methods used to locate antipersonnel landmines in recent field measurements.

  4. Air-ground interface: Surface waves, surface impedance and acoustic-to-seismic coupling coefficient

    NASA Technical Reports Server (NTRS)

    Daigle, Gilles; Embleton, Tony

    1990-01-01

    In atmospheric acoustics, the subject of surface waves has been an area of discussion for many years. The existence of an acoustic surface wave is now well established theoretically. The mathematical solution for spherical wave propagation above an impedance boundary includes the possibility of a contribution that possesses all the standard properties for a surface wave. Surface waves exist when the surface is sufficiently porous, relative to its acoustical resistance, that it can influence the airborne particle velocity near the surface and reduce the phase velocity of sound waves in air at the surface. This traps some of the sound energy in the air to remain near the surface as it propagates. Above porous grounds, the existence of surface waves has eluded direct experimental confirmation (pulse experiments have failed to show a separate arrival expected from the reduced phase speed) and indirect evidence for its existence has appeared contradictory. The experimental evidence for the existence of an acoustical surface wave above porous boundaries is reviewed. Recent measurements including pulse experiments are also described. A few years ago the acoustic impedance of a grass-covered surface was measured in the frequency range 30 to 300 Hz. Here, further measurements on the same site are discussed. These measurements include core samples, a shallow refractive survey to determine the seismic velocities, and measurements of the acoustic-to-seismic coupling coefficient.

  5. Accelerometer measurements of acoustic-to-seismic coupling above buried objects.

    PubMed

    Attenborough, Keith; Qin, Qin; Jefferis, Jonathan; Heald, Gary

    2007-12-01

    The surface velocity of sand inside a large PVC container, induced by the sound pressure from either a large loudspeaker radiating into an inverted cone and pipe or a Bruel and Kjaer point source loudspeaker mounted with its axis vertical, has been measured using accelerometers. Results of white noise and stepped frequency excitation are presented. Without any buried object the mass loading of an accelerometer creates resonances in the spectral ratio of sand surface velocity to incident acoustic pressure, i.e., the acoustic-to-seismic (A/S) admittance spectra. The A/S responses above a buried compliant object are larger and distinctive. The linear A/S admittance spectra in the presence of a buried electronic components box have been studied as a function of burial depth and sand state. The nonlinear responses above the buried box have been studied as a function of depth, sand state, and amplitude. Predictions of a modified one-dimensional lumped parameter model have been found to be consistent with the observed nonlinear responses. Also the modified model has been used to explain features of the A/S responses observed when using an accelerometer without any buried object.

  6. Investigation of the near subsurface using acoustic to seismic coupling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Agricultural, hydrological and civil engineering applications have realized a need for information of the near subsurface over large areas. In order to obtain this spatially distributed data over such scales, the measurement technique must be highly mobile with a short acquisition time. Therefore, s...

  7. Acoustic-to-Seismic Coupling Over Porous Ground Surfaces.

    DTIC Science & Technology

    1984-01-01

    predictions based on these values and assumed values of grain shape factor ratio. Figure 4.2 comparison of measurements and predictions for characteristic ...and prediction for characteristic impedance in sands. Key as in 4.3 L Figure 4.5 Microphone Probe system for soils and sands Figure 4.6 Measured and...porosity "" Figure 5.2 Predicted sensitivity of fast-wpe characteristics in water-filled sana to grain shape factor Figure 5.3 Predicted sensitivity of

  8. Direct coupling of haptic signals between hands

    PubMed Central

    Dupin, Lucile; Hayward, Vincent; Wexler, Mark

    2015-01-01

    Although motor actions can profoundly affect the perceptual interpretation of sensory inputs, it is not known whether the combination of sensory and movement signals occurs only for sensory surfaces undergoing movement or whether it is a more general phenomenon. In the haptic modality, the independent movement of multiple sensory surfaces poses a challenge to the nervous system when combining the tactile and kinesthetic signals into a coherent percept. When exploring a stationary object, the tactile and kinesthetic signals come from the same hand. Here we probe the internal structure of haptic combination by directing the two signal streams to separate hands: one hand moves but receives no tactile stimulation, while the other hand feels the consequences of the first hand’s movement but remains still. We find that both discrete and continuous tactile and kinesthetic signals are combined as if they came from the same hand. This combination proceeds by direct coupling or transfer of the kinesthetic signal from the moving to the feeling hand, rather than assuming the displacement of a mediating object. The combination of signals is due to perception rather than inference, because a small temporal offset between the signals significantly degrades performance. These results suggest that the brain simplifies the complex coordinate transformation task of remapping sensory inputs to take into account the movements of multiple body parts in haptic perception, and they show that the effects of action are not limited to moving sensors. PMID:25548179

  9. Direct coupling of haptic signals between hands.

    PubMed

    Dupin, Lucile; Hayward, Vincent; Wexler, Mark

    2015-01-13

    Although motor actions can profoundly affect the perceptual interpretation of sensory inputs, it is not known whether the combination of sensory and movement signals occurs only for sensory surfaces undergoing movement or whether it is a more general phenomenon. In the haptic modality, the independent movement of multiple sensory surfaces poses a challenge to the nervous system when combining the tactile and kinesthetic signals into a coherent percept. When exploring a stationary object, the tactile and kinesthetic signals come from the same hand. Here we probe the internal structure of haptic combination by directing the two signal streams to separate hands: one hand moves but receives no tactile stimulation, while the other hand feels the consequences of the first hand's movement but remains still. We find that both discrete and continuous tactile and kinesthetic signals are combined as if they came from the same hand. This combination proceeds by direct coupling or transfer of the kinesthetic signal from the moving to the feeling hand, rather than assuming the displacement of a mediating object. The combination of signals is due to perception rather than inference, because a small temporal offset between the signals significantly degrades performance. These results suggest that the brain simplifies the complex coordinate transformation task of remapping sensory inputs to take into account the movements of multiple body parts in haptic perception, and they show that the effects of action are not limited to moving sensors.

  10. Infrasound signals coupled from an underwater explosion

    NASA Astrophysics Data System (ADS)

    Che, I.-Y.; Kim, T. S.; Lee, H.-I.

    2012-04-01

    On 26 March 2010, a South Korean warship, Cheoanham, was sunken down offshore of an island, Bakryeong, in the Yellow Sea, South Korea. In the island that is near to the incident site, were a seismo-acoustic array and a broadband seismic station in operation. These stations recorded clear seismic and infrasonic signals associated with the warship-sinking. In addition, five infrasound arrays being operated in the inland of South Korea also detected the infrasound signals propagated up to 348 km from the source. We studied the seismic and infrasonic signatures from the event for the determination of exact source location and explanation of coupling phenomena among three different media; sea, solid earth and atmosphere. For the accurate source localization we fused all the available seismo-acoustic information of arrival time and azimuth estimates of coupled seismic and infrasonic signals. The calculated location is nearly coincident with the event location reported by the Civilian Military Joint Investigation Group, which shows seismo-acoustic location is much better than those calculated with just seismic or infrasonic dataset. The relationship between explosion depth and charge was constrained with the period of the observed infrasonic signals. The attenuated amplitude of infrasound signal was corrected to estimate the perturbed air pressure at source location.

  11. Polished Downhole Transducer Having Improved Signal Coupling

    DOEpatents

    Hall, David R.; Fox, Joe

    2006-03-28

    Apparatus and methods to improve signal coupling in downhole inductive transmission elements to reduce the dispersion of magnetic energy at the tool joints and to provide consistent impedance and contact between transmission elements located along the drill string. A transmission element for transmitting information between downhole tools is disclosed in one embodiment of the invention as including an annular core constructed of a magnetically conductive material. The annular core forms an open channel around its circumference and is configured to form a closed channel by mating with a corresponding annular core along an annular mating surface. The mating surface is polished to provide improved magnetic coupling with the corresponding annular core. An annular conductor is disposed within the open channel.

  12. Heterotrimeric G protein-coupled signaling in plants.

    PubMed

    Urano, Daisuke; Jones, Alan M

    2014-01-01

    Investigators studying G protein-coupled signaling--often called the best-understood pathway in the world owing to intense research in medical fields--have adopted plants as a new model to explore the plasticity and evolution of G signaling. Much research on plant G signaling has not disappointed. Although plant cells have most of the core elements found in animal G signaling, differences in network architecture and intrinsic properties of plant G protein elements make G signaling in plant cells distinct from the animal paradigm. In contrast to animal G proteins, plant G proteins are self-activating, and therefore regulation of G activation in plants occurs at the deactivation step. The self-activating property also means that plant G proteins do not need and therefore do not have typical animal G protein-coupled receptors. Targets of activated plant G proteins, also known as effectors, are unlike effectors in animal cells. The simpler repertoire of G signal elements in Arabidopsis makes G signaling easier to manipulate in a multicellular context.

  13. Signal bi-amplification in networks of unidirectionally coupled MEMS

    NASA Astrophysics Data System (ADS)

    Tchakui, Murielle Vanessa; Woafo, Paul; Colet, Pere

    2016-01-01

    The purpose of this paper is to analyze the propagation and the amplification of an input signal in networks of unidirectionally coupled micro-electro-mechanical systems (MEMS). Two types of external excitations are considered: sinusoidal and stochastic signals. We show that sinusoidal signals are amplified up to a saturation level which depends on the transmission rate and despite MEMS being nonlinear the sinusoidal shape is well preserved if the number of MEMS is not too large. However, increasing the number of MEMS, there is an instability that leads to chaotic behavior and which is triggered by the amplification of the harmonics generated by the nonlinearities. We also show that for stochastic input signals, the MEMS array acts as a band-pass filter and after just a few elements the signal has a narrow power spectra.

  14. G-protein—coupled receptors, hedgehog signaling and primary cilia

    PubMed Central

    Mukhopadhyay, Saikat; Rohatgi, Rajat

    2014-01-01

    The Hedgehog (Hh) pathway has become an important model to study diverse aspects of cell biology of the primary cilium, and reciprocally, the study of ciliary processes provides an opportunity to solve longstanding mysteries in the mechanism of vertebrate Hh signal transduction. The cilium is emerging as an unique compartment for G-protein—coupled receptor (GPCR) signaling in many systems. Two members of the GPCR family, Smoothened and Gpr161, play important roles in the Hh pathway. We review the current understanding of how these proteins may function to regulate Hh signaling and also highlight some of the critical unanswered questions being tackled by the field. Uncovering GPCR-regulated mechanisms important in Hh signaling may provide therapeutic strategies against the Hh pathway that plays important roles in development, regeneration and cancer. PMID:24845016

  15. G-protein-coupled receptors, Hedgehog signaling and primary cilia.

    PubMed

    Mukhopadhyay, Saikat; Rohatgi, Rajat

    2014-09-01

    The Hedgehog (Hh) pathway has become an important model to study the cell biology of primary cilia, and reciprocally, the study of ciliary processes provides an opportunity to solve longstanding mysteries in the mechanism of vertebrate Hh signal transduction. The cilium is emerging as an unique compartment for G-protein-coupled receptor (GPCR) signaling in many systems. Two members of the GPCR family, Smoothened and Gpr161, play important roles in the Hh pathway. We review the current understanding of how these proteins may function to regulate Hh signaling and also highlight some of the critical unanswered questions being tackled by the field. Uncovering GPCR-regulated mechanisms important in Hh signaling may provide therapeutic strategies against the Hh pathway that plays important roles in development, regeneration and cancer.

  16. Power coupling characteristics between FBG and back-scattering signals

    NASA Astrophysics Data System (ADS)

    Li, Jianzhi; Zhao, Desheng; Hou, Yuemin; Sun, Baochen

    2017-03-01

    The property and compatibility between fiber Bragg grating (FBG) and back-scattering signals are investigated by employing optical time domain reflectometry. We compare the power spectrums of spontaneous Brillouin scattering (SpBS), simultaneous Brillouin scattering (SBS) and Rayleigh scattering (RS), and coupling mechanism between FBG and back-scattering signal is explored. Experimental results show that the region of FBG contributes to the backscatter power and causes the desired reflection, and the power peak of FBG in SBS power spectrum is the sharpest among back-scattering light power spectrums and broadens with the decrease of spatial resolution. Moreover, the FBG-based method is used to find the location of temperature or stain event for scatter-based distributed sensors.

  17. Medium effect on the characteristics of the coupled seismic and electromagnetic signals.

    PubMed

    Huang, Qinghua; Ren, Hengxin; Zhang, Dan; Chen, Y John

    2015-01-01

    Recently developed numerical simulation technique can simulate the coupled seismic and electromagnetic signals for a double couple point source or a finite fault planar source. Besides the source effect, the simulation results showed that both medium structure and medium property could affect the coupled seismic and electromagnetic signals. The waveform of coupled signals for a layered structure is more complicated than that for a simple uniform structure. Different from the seismic signals, the electromagnetic signals are sensitive to the medium properties such as fluid salinity and fluid viscosity. Therefore, the co-seismic electromagnetic signals may be more informative than seismic signals.

  18. Signal coupling and signal integrity in multi-strip resistive plate chambers used for timing applications

    NASA Astrophysics Data System (ADS)

    Gonzalez-Diaz, Diego; Chen, Huangshan; Wang, Yi

    2011-08-01

    We have systematically studied the transmission of electrical signals along several 2-strip Resistive Plate Chambers (RPCs) in the frequency range f=0.1-3.5 GHz. Such a range was chosen to fully cover the bandwidth associated to the very short rise-times of signals originated in RPCs used for sub-100 ps timing applications. This work conveys experimental evidence of the dominant role of modal dispersion in counters built at the 1 m scale, a fact that results in large cross-talk levels and strong signal shaping. It is shown that modal dispersion appears in RPCs due to their inherent unbalance between capacitive and inductive coupling. A practical way to restore this symmetry has been introduced (hereafter 'electrostatic compensation'), allowing for a cross-talk suppression factor up to ×12 and a rise-time reduction by 200 ps. Under conditions of compensation the signal transmission is only limited by dielectric losses, yielding a length-dependent cutoff frequency of around 1 GHz for propagation along 2 m in typical float glass-based RPCs. It is further shown that 'electrostatic compensation' can be achieved for an arbitrary number of strips as long as the nature of the coupling is 'short-range', that is an almost exact assumption for typical strip-line RPCs. This work extends the bandwidth of previous studies by a factor of×20.

  19. Spatio-temporal coupling of EEG signals in epilepsy

    NASA Astrophysics Data System (ADS)

    Senger, Vanessa; Müller, Jens; Tetzlaff, Ronald

    2011-05-01

    Approximately 1% of the world's population suffer from epileptic seizures throughout their lives that mostly come without sign or warning. Thus, epilepsy is the most common chronical disorder of the neurological system. In the past decades, the problem of detecting a pre-seizure state in epilepsy using EEG signals has been addressed in many contributions by various authors over the past two decades. Up to now, the goal of identifying an impending epileptic seizure with sufficient specificity and reliability has not yet been achieved. Cellular Nonlinear Networks (CNN) are characterized by local couplings of dynamical systems of comparably low complexity. Thus, they are well suited for an implementation as highly parallel analogue processors. Programmable sensor-processor realizations of CNN combine high computational power comparable to tera ops of digital processors with low power consumption. An algorithm allowing an automated and reliable detection of epileptic seizure precursors would be a"huge step" towards the vision of an implantable seizure warning device that could provide information to patients and for a time/event specific treatment directly in the brain. Recent contributions have shown that modeling of brain electrical activity by solutions of Reaction-Diffusion-CNN as well as the application of a CNN predictor taking into account values of neighboring electrodes may contribute to the realization of a seizure warning device. In this paper, a CNN based predictor corresponding to a spatio-temporal filter is applied to multi channel EEG data in order to identify mutual couplings for different channels which lead to a enhanced prediction quality. Long term EEG recordings of different patients are considered. Results calculated for these recordings with inter-ictal phases as well as phases with seizures will be discussed in detail.

  20. Dynamic interactions mediated by nonredundant signaling mechanisms couple circadian clock neurons.

    PubMed

    Evans, Jennifer A; Leise, Tanya L; Castanon-Cervantes, Oscar; Davidson, Alec J

    2013-11-20

    Interactions among suprachiasmatic nucleus (SCN) neurons are required for robust circadian rhythms entrained to local time. To investigate these signaling mechanisms, we developed a functional coupling assay that uniquely captures the dynamic process by which SCN neurons interact. As a population, SCN neurons typically display synchronized rhythms with similar peak times, but will peak 6-12 hr apart after in vivo exposure to long days. Once they are removed from these conditions, SCN neurons resynchronize through a phase-dependent coupling process mediated by both vasoactive intestinal polypeptide (VIP) and GABAA signaling. Notably, GABAA signaling contributes to coupling when the SCN network is in an antiphase configuration, but opposes synchrony under steady-state conditions. Further, VIP acts together with GABAA signaling to couple the network in an antiphase configuration, but promotes synchrony under steady-state conditions by counteracting the actions of GABAA signaling. Thus, SCN neurons interact through nonredundant coupling mechanisms influenced by the state of the network.

  1. Early warning signals of regime shifts in coupled human-environment systems.

    PubMed

    Bauch, Chris T; Sigdel, Ram; Pharaon, Joe; Anand, Madhur

    2016-12-20

    In complex systems, a critical transition is a shift in a system's dynamical regime from its current state to a strongly contrasting state as external conditions move beyond a tipping point. These transitions are often preceded by characteristic early warning signals such as increased system variability. However, early warning signals in complex, coupled human-environment systems (HESs) remain little studied. Here, we compare critical transitions and their early warning signals in a coupled HES model to an equivalent environment model uncoupled from the human system. We parameterize the HES model, using social and ecological data from old-growth forests in Oregon. We find that the coupled HES exhibits a richer variety of dynamics and regime shifts than the uncoupled environment system. Moreover, the early warning signals in the coupled HES can be ambiguous, heralding either an era of ecosystem conservationism or collapse of both forest ecosystems and conservationism. The presence of human feedback in the coupled HES can also mitigate the early warning signal, making it more difficult to detect the oncoming regime shift. We furthermore show how the coupled HES can be "doomed to criticality": Strategic human interactions cause the system to remain perpetually in the vicinity of a collapse threshold, as humans become complacent when the resource seems protected but respond rapidly when it is under immediate threat. We conclude that the opportunities, benefits, and challenges of modeling regime shifts and early warning signals in coupled HESs merit further research.

  2. Early warning signals of regime shifts in coupled human–environment systems

    PubMed Central

    Bauch, Chris T.; Sigdel, Ram; Pharaon, Joe; Anand, Madhur

    2016-01-01

    In complex systems, a critical transition is a shift in a system’s dynamical regime from its current state to a strongly contrasting state as external conditions move beyond a tipping point. These transitions are often preceded by characteristic early warning signals such as increased system variability. However, early warning signals in complex, coupled human–environment systems (HESs) remain little studied. Here, we compare critical transitions and their early warning signals in a coupled HES model to an equivalent environment model uncoupled from the human system. We parameterize the HES model, using social and ecological data from old-growth forests in Oregon. We find that the coupled HES exhibits a richer variety of dynamics and regime shifts than the uncoupled environment system. Moreover, the early warning signals in the coupled HES can be ambiguous, heralding either an era of ecosystem conservationism or collapse of both forest ecosystems and conservationism. The presence of human feedback in the coupled HES can also mitigate the early warning signal, making it more difficult to detect the oncoming regime shift. We furthermore show how the coupled HES can be “doomed to criticality”: Strategic human interactions cause the system to remain perpetually in the vicinity of a collapse threshold, as humans become complacent when the resource seems protected but respond rapidly when it is under immediate threat. We conclude that the opportunities, benefits, and challenges of modeling regime shifts and early warning signals in coupled HESs merit further research. PMID:27815533

  3. Signal beating elimination using single-mode fiber to multimode fiber coupling.

    PubMed

    Fok, Mable P; Deng, Yanhua; Kravtsov, Konstantin; Prucnal, Paul R

    2011-12-01

    We experimentally demonstrate an all-passive fiber-based approach to prevent undesired beating during signal merging and detection. Beating occurs when optical signals of very close or the same wavelength are combined at a coupler and detected using a photodetector. Our approach is based on signal coupling from several single-mode fibers to a single piece of multimode fiber without interference, such that different signals propagate in different modes with different spatial positions inside the multimode fiber. We have investigated signal beating when the signals are coherent, partially coherent, or incoherent with each other. The measured results for single-mode to multimode coupling show signal beating is substantially reduced, resulting in widely opened eye diagrams and error-free bit error rate performance.

  4. The Acoustic Signal of a Helicopter can be Used to Track it With Seismic Arrays

    NASA Astrophysics Data System (ADS)

    Eibl, Eva P. S.; Lokmer, Ivan; Bean, Christopher J.; Akerlie, Eggert

    2016-04-01

    We apply traditional frequency domain methods usually applied to volcanic tremor on seismic recordings of a helicopter. On a volcano the source can be repeating, closely spaced earthquakes whereas for a helicopter the source are repeating pressure pulses from the rotor blades that are converted through acoustic-to-seismic coupling. In both cases the seismic signal is referred to as tremor. As frequency gliding is in this case merely caused by the Doppler effect, not a change in the source, we can use its shape to deduce properties of the helicopter. We show in this analysis that the amount of rotor blades, rotor revolutions per minute (RPM), flight direction, height and location can be deduced. The signal was recorded by a seven station broadband array with an aperture of 1.6 km. Our spacing is close enough to record the signal at all stations and far enough to observe traveltime differences. We perform a detailed spectral and location analysis of the signal, and compare our results with the known information on the helicopter's speed, location, height, the frequency of the blades rotation and the amount of blades. This analysis is based on the characteristic shape of the curve i.e. speed of the gliding, minimum and maximum fundamental frequency, amplitudes at the inflection points at different stations and traveltimes deduced from the inflection points at different stations. The helicopter GPS track gives us a robust way of testing the method. This observation has an educative value, because the same principles can be applied to signals in different disciplines.

  5. Coupling Oxidative Signals to Protein Phosphorylation via Methionine Oxidation in Arabidopsis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mechanisms involved in sensing oxidative signaling molecules such as H2O2 in plant and animal cells are not completely understood. In the present study, we tested the postulate that oxidation of methionine (Met) to Met sulfoxide (MetSO) can couple oxidative signals to changes in protein phosphor...

  6. Allosteric mechanisms of G protein coupled receptor signaling: a structural perspective

    PubMed Central

    Thaker, Tarjani M.; Kaya, Ali I.; Preininger, Anita M.; Hamm, Heidi E.; Iverson, T.M.

    2012-01-01

    G protein-Coupled Receptors (GPCRs) use a complex series of intramolecular conformational changes to couple agonist binding to the binding and activation of cognate heterotrimeric G protein (Gαβγ). The mechanisms underlying this long-range activation have been identified using a variety of biochemical and structural approaches and have primarily used visual signal transduction via the GPCR rhodopsin and cognate heterotrimeric G protein transducin (Gt) as a model system. In this chapter, we will review the methods that have revealed allosteric signaling through rhodopsin and transducin. These methods can be applied to a variety of GPCR-mediated signaling pathways. PMID:22052489

  7. Reservoir computing with a slowly modulated mask signal for preprocessing using a mutually coupled optoelectronic system

    NASA Astrophysics Data System (ADS)

    Tezuka, Miwa; Kanno, Kazutaka; Bunsen, Masatoshi

    2016-08-01

    Reservoir computing is a machine-learning paradigm based on information processing in the human brain. We numerically demonstrate reservoir computing with a slowly modulated mask signal for preprocessing by using a mutually coupled optoelectronic system. The performance of our system is quantitatively evaluated by a chaotic time series prediction task. Our system can produce comparable performance with reservoir computing with a single feedback system and a fast modulated mask signal. We showed that it is possible to slow down the modulation speed of the mask signal by using the mutually coupled system in reservoir computing.

  8. Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.

    PubMed

    García-Cáceres, Cristina; Quarta, Carmelo; Varela, Luis; Gao, Yuanqing; Gruber, Tim; Legutko, Beata; Jastroch, Martin; Johansson, Pia; Ninkovic, Jovica; Yi, Chun-Xia; Le Thuc, Ophelia; Szigeti-Buck, Klara; Cai, Weikang; Meyer, Carola W; Pfluger, Paul T; Fernandez, Ana M; Luquet, Serge; Woods, Stephen C; Torres-Alemán, Ignacio; Kahn, C Ronald; Götz, Magdalena; Horvath, Tamas L; Tschöp, Matthias H

    2016-08-11

    We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.

  9. New direction of arrival estimation of coherent signals based on reconstructing matrix under unknown mutual coupling

    NASA Astrophysics Data System (ADS)

    Guo, Rui; Li, Weixing; Zhang, Yue; Chen, Zengping

    2016-01-01

    A direction of arrival (DOA) estimation algorithm for coherent signals in the presence of unknown mutual coupling is proposed. A group of auxiliary sensors in a uniform linear array are applied to eliminate the effects on the orthogonality of subspaces brought by mutual coupling. Then, a Toeplitz matrix, whose rank is independent of the coherency between impinging signals, is reconstructed to eliminate the rank loss of the spatial covariance matrix. Therefore, the signal and noise subspaces can be estimated properly. This method can estimate the DOAs of coherent signals under unknown mutual coupling accurately without any iteration and calibration sources. It has a low computational burden and high accuracy. Simulation results demonstrate the effectiveness of the algorithm.

  10. Endogenous field feedback promotes the detectability for exogenous electric signal in the hybrid coupled population

    SciTech Connect

    Wei, Xile; Zhang, Danhong; Wang, Jiang; Yu, Haitao; Lu, Meili; Che, Yanqiu

    2015-01-15

    This paper presents the endogenous electric field in chemical or electrical synaptic coupled networks, aiming to study the role of endogenous field feedback in the signal propagation in neural systems. It shows that the feedback of endogenous fields to network activities can reduce the required energy of the noise and enhance the transmission of input signals in hybrid coupled populations. As a common and important nonsynaptic interactive method among neurons, particularly, the endogenous filed feedback can not only promote the detectability of exogenous weak signal in hybrid coupled neural population but also enhance the robustness of the detectability against noise. Furthermore, with the increasing of field coupling strengths, the endogenous field feedback is conductive to the stochastic resonance by facilitating the transition of cluster activities from the no spiking to spiking regions. Distinct from synaptic coupling, the endogenous field feedback can play a role as internal driving force to boost the population activities, which is similar to the noise. Thus, it can help to transmit exogenous weak signals within the network in the absence of noise drive via the stochastic-like resonance.

  11. Theoretical analysis of anharmonic coupling and cascading Raman signals observed with femtosecond stimulated Raman spectroscopy.

    PubMed

    Mehlenbacher, Randy D; Lyons, Brendon; Wilson, Kristina C; Du, Yong; McCamant, David W

    2009-12-28

    We present a classical theoretical treatment of a two-dimensional Raman spectroscopy based on the initiation of vibrational coherence with an impulsive Raman pump and subsequent probing by two-pulse femtosecond stimulated Raman spectroscopy (FSRS). The classical model offers an intuitive picture of the molecular dynamics initiated by each laser pulse and the generation of the signal field traveling along the probe wave vector. Previous reports have assigned the observed FSRS signals to anharmonic coupling between the impulsively driven vibration and the higher-frequency vibration observed with FSRS. However, we show that the observed signals are not due to anharmonic coupling, which is shown to be a fifth-order coherent Raman process, but instead due to cascades of coherent Raman signals. Specifically, the observed vibrational sidebands are generated by parallel cascades in which a coherent anti-Stokes or Stokes Raman spectroscopy (i.e., CARS or CSRS) field generated by the coherent coupling of the impulsive pump and the Raman pump pulses participates in a third-order FSRS transition. Additional sequential cascades are discussed that will give rise to cascade artifacts at the fundamental FSRS frequencies. It is shown that the intended fifth-order FSRS signals, generated by an anharmonic coupling mechanism, will produce signals of approximately 10(-4) DeltaOD (change in the optical density). The cascading signals, however, will produce stimulated Raman signal of approximately 10(-2) DeltaOD, as has been observed experimentally. Experiments probing deuterochloroform find significant sidebands of the CCl(3) bend, which has an E type symmetry, shifted from the A(1) type C-D and C-Cl stretching modes, despite the fact that third-order anharmonic coupling between these modes is forbidden by symmetry. Experiments probing a 50:50 mixture of chloroform and d-chloroform find equivalent intensity signals of low-frequency CDCl(3) modes as sidebands shifted from both the C

  12. G protein-coupled receptors provide survival signals in prostate cancer.

    PubMed

    Yowell, Charles W; Daaka, Yehia

    2002-12-01

    Prostate cancer is the leading cause for noncutaneous cancer-related deaths among men in the United States. The disease is biologically characterized as being either androgen dependent or androgen independent. Whereas androgen-dependent prostate cancer can be successfully treated with androgen ablative therapy, to date no cure exists for androgen-independent disease. Mechanisms involved in the progression of prostate cancer to androgen independence are not known. Here we present evidence that in addition to growth factor receptor tyrosine kinases, G protein- coupled receptors can mediate survival signals in prostate cancer cells. The G protein- coupled receptors exert their effects by activating multiple intracellular signal transduction networks that promote prostate cancer cell survival, including the activation of c-Jun N-terminal kinase, protein kinase B (Akt) and nuclear factor-kB. Prostate-expressed G protein- coupled receptors and their downstream effectors may prove to be effective targets in the treatment of advanced prostate cancer.

  13. G-protein-coupled receptor kinase 2 terminates G-protein-coupled receptor function in steroid hormone 20-hydroxyecdysone signaling

    PubMed Central

    Zhao, Wen-Li; Wang, Di; Liu, Chun-Yan; Zhao, Xiao-Fan

    2016-01-01

    G-protein-coupled receptors (GPCRs) transmit extracellular signals across the cell membrane. GPCR kinases (GRKs) desensitize GPCR signals in the cell membrane. However, the role and mechanism of GRKs in the desensitization of steroid hormone signaling are unclear. In this study, we propose that GRK2 is phosphorylated by protein kinase C (PKC) in response to induction by the steroid hormone 20-hydroxyecdysone (20E), which determines its translocation to the cell membrane of the lepidopteran Helicoverpa armigera. GRK2 protein expression is increased during the metamorphic stage because of induction by 20E. Knockdown of GRK2 in larvae causes accelerated pupation, an increase in 20E-response gene expression, and advanced apoptosis and metamorphosis. 20E induces translocation of GRK2 from the cytoplasm to the cell membrane via steroid hormone ecdysone-responsive GPCR (ErGPCR-2). GRK2 is phosphorylated by PKC on serine 680 after induction by 20E, which leads to the translocation of GRK2 to the cell membrane. GRK2 interacts with ErGPCR-2. These data indicate that GRK2 terminates the ErGPCR-2 function in 20E signaling in the cell membrane by a negative feedback mechanism. PMID:27412951

  14. Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca2+ signaling

    PubMed Central

    Muñoz, Manuel F.; Puebla, Mariela; Figueroa, Xavier F.

    2015-01-01

    Neuronal activity must be tightly coordinated with blood flow to keep proper brain function, which is achieved by a mechanism known as neurovascular coupling. Then, an increase in synaptic activity leads to a dilation of local parenchymal arterioles that matches the enhanced metabolic demand. Neurovascular coupling is orchestrated by astrocytes. These glial cells are located between neurons and the microvasculature, with the astrocytic endfeet ensheathing the vessels, which allows fine intercellular communication. The neurotransmitters released during neuronal activity reach astrocytic receptors and trigger a Ca2+ signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca2+ signaling is coordinated by gap junction channels and hemichannels formed by connexins (Cx43 and Cx30) and channels formed by pannexins (Panx-1). The neuronal activity-initiated Ca2+ waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca2+ entry via connexin hemichannels or pannexin channels may participate in the regulation of the astrocyte signaling-mediated neurovascular coupling. Interestingly, nitric oxide (NO) can activate connexin hemichannel by S-nitrosylation and the Ca2+-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca2+ signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca2+ influx through hemichannel activation. Furthermore, NO release from the hemichannels located at astrocytic endfeet may contribute to the vasodilation of parenchymal arterioles. In this review, we discuss the mechanisms involved in the regulation of the astrocytic Ca2+ signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in this process

  15. Control of the neurovascular coupling by nitric oxide-dependent regulation of astrocytic Ca(2+) signaling.

    PubMed

    Muñoz, Manuel F; Puebla, Mariela; Figueroa, Xavier F

    2015-01-01

    Neuronal activity must be tightly coordinated with blood flow to keep proper brain function, which is achieved by a mechanism known as neurovascular coupling. Then, an increase in synaptic activity leads to a dilation of local parenchymal arterioles that matches the enhanced metabolic demand. Neurovascular coupling is orchestrated by astrocytes. These glial cells are located between neurons and the microvasculature, with the astrocytic endfeet ensheathing the vessels, which allows fine intercellular communication. The neurotransmitters released during neuronal activity reach astrocytic receptors and trigger a Ca(2+) signaling that propagates to the endfeet, activating the release of vasoactive factors and arteriolar dilation. The astrocyte Ca(2+) signaling is coordinated by gap junction channels and hemichannels formed by connexins (Cx43 and Cx30) and channels formed by pannexins (Panx-1). The neuronal activity-initiated Ca(2+) waves are propagated among neighboring astrocytes directly via gap junctions or through ATP release via connexin hemichannels or pannexin channels. In addition, Ca(2+) entry via connexin hemichannels or pannexin channels may participate in the regulation of the astrocyte signaling-mediated neurovascular coupling. Interestingly, nitric oxide (NO) can activate connexin hemichannel by S-nitrosylation and the Ca(2+)-dependent NO-synthesizing enzymes endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are expressed in astrocytes. Therefore, the astrocytic Ca(2+) signaling triggered in neurovascular coupling may activate NO production, which, in turn, may lead to Ca(2+) influx through hemichannel activation. Furthermore, NO release from the hemichannels located at astrocytic endfeet may contribute to the vasodilation of parenchymal arterioles. In this review, we discuss the mechanisms involved in the regulation of the astrocytic Ca(2+) signaling that mediates neurovascular coupling, with a special emphasis in the possible participation of NO in

  16. A Coupled Phase-Temperature Model for Dynamics of Transient Neuronal Signal in Mammals Cold Receptor

    PubMed Central

    Kirana, Firman Ahmad; Husein, Irzaman Sulaiman

    2016-01-01

    We propose a theoretical model consisting of coupled differential equation of membrane potential phase and temperature for describing the neuronal signal in mammals cold receptor. Based on the results from previous work by Roper et al., we modified a nonstochastic phase model for cold receptor neuronal signaling dynamics in mammals. We introduce a new set of temperature adjusted functional parameters which allow saturation characteristic at high and low steady temperatures. The modified model also accommodates the transient neuronal signaling process from high to low temperature by introducing a nonlinear differential equation for the “effective temperature” changes which is coupled to the phase differential equation. This simple model can be considered as a candidate for describing qualitatively the physical mechanism of the corresponding transient process. PMID:27774102

  17. Signal enhancement of surface plasmon-coupled directional emission by a conical mirror.

    PubMed

    Smith, Derek S; Kostov, Yordan; Rao, Govind

    2008-10-01

    A simple strategy for increasing the collection efficiency of surface plasmon-coupled emission (SPCE) is demonstrated. SPCE is a near-field phenomenon occurring when excited fluorophores are in close proximity to a subwavelength metal film. The energy of the fluorophores induces surface plasmons that radiate the coupled energy at highly specific angles. In an attempt to maximize the collected emission, a conical mirror was placed around the coupling prism. The result was a nearly 500 fold enhancement over the free space signal as detected from a single point from a poly(vinyl alcohol) layer doped with ruthenium. Coupling this large enhancement with LED excitation could lead to the development of inexpensive, handheld fluorescent devices with high sensitivity.

  18. Loss of Gi G-Protein-Coupled Receptor Signaling in Osteoblasts Accelerates Bone Fracture Healing.

    PubMed

    Wang, Liping; Hsiao, Edward C; Lieu, Shirley; Scott, Mark; O'Carroll, Dylan; Urrutia, Ashley; Conklin, Bruce R; Colnot, Celine; Nissenson, Robert A

    2015-10-01

    G-protein-coupled receptors (GPCRs) are key regulators of skeletal homeostasis and are likely important in fracture healing. Because GPCRs can activate multiple signaling pathways simultaneously, we used targeted disruption of G(i) -GPCR or activation of G(s) -GPCR pathways to test how each pathway functions in the skeleton. We previously demonstrated that blockade of G(i) signaling by pertussis toxin (PTX) transgene expression in maturing osteoblastic cells enhanced cortical and trabecular bone formation and prevented age-related bone loss in female mice. In addition, activation of G(s) signaling by expressing the G(s) -coupled engineered receptor Rs1 in maturing osteoblastic cells induced massive trabecular bone formation but cortical bone loss. Here, we test our hypothesis that the G(i) and G(s) pathways also have distinct functions in fracture repair. We applied closed, nonstabilized tibial fractures to mice in which endogenous G(i) signaling was inhibited by PTX, or to mice with activated G(s) signaling mediated by Rs1. Blockade of endogenous G(i) resulted in a smaller callus but increased bone formation in both young and old mice. PTX treatment decreased expression of Dkk1 and increased Lef1 mRNAs during fracture healing, suggesting a role for endogenous G(i) signaling in maintaining Dkk1 expression and suppressing Wnt signaling. In contrast, adult mice with activated Gs signaling showed a slight increase in the initial callus size with increased callus bone formation. These results show that G(i) blockade and G(s) activation of the same osteoblastic lineage cell can induce different biological responses during fracture healing. Our findings also show that manipulating the GPCR/cAMP signaling pathway by selective timing of G(s) and G(i) -GPCR activation may be important for optimizing fracture repair.

  19. G-Protein–Coupled Receptors Signaling Pathways in New Antiplatelet Drug Development

    PubMed Central

    Gurbel, Paul A.; Kuliopulos, Athan; Tantry, Udaya S.

    2016-01-01

    Platelet G-protein–coupled receptors influence platelet function by mediating the response to various agonists, including ADP, thromboxane A2, and thrombin. Blockade of the ADP receptor, P2Y12, in combination with cyclooxygenase-1 inhibition by aspirin has been among the most widely used pharmacological strategies to reduce cardiovascular event occurrence in high-risk patients. The latter dual pathway blockade strategy is one of the greatest advances in the field of cardiovascular medicine. In addition to P2Y12, the platelet thrombin receptor, protease activated receptor-1, has also been recently targeted for inhibition. Blockade of protease activated receptor-1 has been associated with reduced thrombotic event occurrence when added to a strategy using P2Y12 and cyclooxygenase-1 inhibition. At this time, the relative contributions of these G-protein–coupled receptor signaling pathways to in vivo thrombosis remain incompletely defined. The observation of treatment failure in ≈10% of high-risk patients treated with aspirin and potent P2Y12 inhibitors provides the rationale for targeting novel pathways mediating platelet function. Targeting intracellular signaling downstream from G-protein–coupled receptor receptors with phosphotidylionisitol 3-kinase and Gq inhibitors are among the novel strategies under investigation to prevent arterial ischemic event occurrence. Greater understanding of the mechanisms of G-protein–coupled receptor–mediated signaling may allow the tailoring of antiplatelet therapy. PMID:25633316

  20. Higgs couplings and new signals from Flavon-Higgs mixing effects within multi-scalar models

    NASA Astrophysics Data System (ADS)

    Diaz-Cruz, J. Lorenzo; Saldaña-Salazar, Ulises J.

    2016-12-01

    Testing the properties of the Higgs particle discovered at the LHC and searching for new physics signals, are some of the most important tasks of Particle Physics today. Current measurements of the Higgs couplings to fermions and gauge bosons, seem consistent with the Standard Model, and when taken as a function of the particle mass, should lay on a single line. However, in models with an extended Higgs sector the diagonal Higgs couplings to up-quarks, down-quarks and charged leptons, could lay on different lines, while non-diagonal flavor-violating Higgs couplings could appear too. We describe these possibilities within the context of multi-Higgs doublet models that employ the Froggatt-Nielsen (FN) mechanism to generate the Yukawa hierarchies. Furthermore, one of the doublets can be chosen to be of the inert type, which provides a viable dark matter candidate. The mixing of the Higgs doublets with the flavon field, can provide plenty of interesting signals, including: i) small corrections to the couplings of the SM-like Higgs, ii) exotic signals from the flavon fields, iii) new signatures from the heavy Higgs bosons. These aspects are studied within a specific model with 3 + 1 Higgs doublets and a singlet FN field. Constraints on the model are derived from the study of K and D mixing and the Higgs search at the LHC. For last, the implications from the latter aforementioned constraints to the FCNC top decay t → ch are presented too.

  1. Succinate is a preferential metabolic stimulus-coupling signal for glucose-induced proinsulin biosynthesis translation.

    PubMed

    Alarcon, Cristina; Wicksteed, Barton; Prentki, Marc; Corkey, Barbara E; Rhodes, Christopher J

    2002-08-01

    The secondary signals emanating from increased glucose metabolism, which lead to specific increases in proinsulin biosynthesis translation, remain elusive. It is known that signals for glucose-stimulated insulin secretion and proinsulin biosynthesis diverge downstream of glycolysis. Consequently, the mitochondrial products ATP, Krebs cycle intermediates, glutamate, and acetoacetate were investigated as candidate stimulus-coupling signals specific for glucose-induced proinsulin biosynthesis in rat islets. Decreasing ATP levels by oxidative phosphorylation inhibitors showed comparable effects on proinsulin biosynthesis and total protein synthesis. Although it is a cofactor, ATP is unlikely to be a metabolic stimulus-coupling signal specific for glucose-induced proinsulin biosynthesis. Neither glutamic acid methyl ester nor acetoacetic acid methyl ester showed a specific effect on glucose-stimulated proinsulin biosynthesis. Interestingly, among Krebs cycle intermediates, only succinic acid monomethyl ester specifically stimulated proinsulin biosynthesis. Malonic acid methyl ester, an inhibitor of succinate dehydrogenase, also specifically increased glucose-induced proinsulin biosynthesis without affecting islet ATP levels or insulin secretion. Glucose caused a 40% increase in islet intracellular succinate levels, but malonic acid methyl ester showed no further effect, probably due to efficient conversion of succinate to succinyl-CoA. In this regard, a GTP-dependent succinyl-CoA synthetase activity was found in cytosolic fractions of pancreatic islets. Thus, succinate and/or succinyl-CoA appear to be preferential metabolic stimulus-coupling factors for glucose-induced proinsulin biosynthesis translation.

  2. Bidirectional coupling of splicing and ATM signaling in response to transcription-blocking DNA damage

    PubMed Central

    Tresini, Maria; Marteijn, Jurgen A.; Vermeulen, Wim

    2016-01-01

    ABSTRACT In response to DNA damage cells activate intricate protein networks to ensure genomic fidelity and tissue homeostasis. DNA damage response signaling pathways coordinate these networks and determine cellular fates, in part, by modulating RNA metabolism. Here we discuss a replication-independent pathway activated by transcription-blocking DNA lesions, which utilizes the ATM signaling kinase to regulate spliceosome function in a reciprocal manner. We present a model according to which, displacement of co-transcriptional spliceosomes from lesion-arrested RNA polymerases, culminates in R-loop formation and non-canonical ATM activation. ATM signals in a feed-forward fashion to further impede spliceosome organization and regulates UV-induced gene expression and alternative splicing genome-wide. This reciprocal coupling between ATM and the spliceosome highlights the importance of ATM signaling in the cellular response to transcription-blocking lesions and supports a key role of the splicing machinery in this process. PMID:26913497

  3. Astrocyte sodium signaling and neuro-metabolic coupling in the brain.

    PubMed

    Rose, C R; Chatton, J-Y

    2016-05-26

    At tripartite synapses, astrocytes undergo calcium signaling in response to release of neurotransmitters and this calcium signaling has been proposed to play a critical role in neuron-glia interaction. Recent work has now firmly established that, in addition, neuronal activity also evokes sodium transients in astrocytes, which can be local or global depending on the number of activated synapses and the duration of activity. Furthermore, astrocyte sodium signals can be transmitted to adjacent cells through gap junctions and following release of gliotransmitters. A main pathway for activity-related sodium influx into astrocytes is via high-affinity sodium-dependent glutamate transporters. Astrocyte sodium signals differ in many respects from the well-described glial calcium signals both in terms of their temporal as well as spatial distribution. There are no known buffering systems for sodium ions, nor is there store-mediated release of sodium. Sodium signals thus seem to represent rather direct and unbiased indicators of the site and strength of neuronal inputs. As such they have an immediate influence on the activity of sodium-dependent transporters which may even reverse in response to sodium signaling, as has been shown for GABA transporters for example. Furthermore, recovery from sodium transients through Na(+)/K(+)-ATPase requires a measurable amount of ATP, resulting in an activation of glial metabolism. In this review, we present basic principles of sodium regulation and the current state of knowledge concerning the occurrence and properties of activity-related sodium transients in astrocytes. We then discuss different aspects of the relationship between sodium changes in astrocytes and neuro-metabolic coupling, putting forward the idea that indeed sodium might serve as a new type of intracellular ion signal playing an important role in neuron-glia interaction and neuro-metabolic coupling in the healthy and diseased brain.

  4. G Protein-Coupled Receptor Signaling in Stem Cells and Cancer

    PubMed Central

    Lynch, Jennifer R.; Wang, Jenny Yingzi

    2016-01-01

    G protein-coupled receptors (GPCRs) are a large superfamily of cell-surface signaling proteins that bind extracellular ligands and transduce signals into cells via heterotrimeric G proteins. GPCRs are highly tractable drug targets. Aberrant expression of GPCRs and G proteins has been observed in various cancers and their importance in cancer stem cells has begun to be appreciated. We have recently reported essential roles for G protein-coupled receptor 84 (GPR84) and G protein subunit Gαq in the maintenance of cancer stem cells in acute myeloid leukemia. This review will discuss how GPCRs and G proteins regulate stem cells with a focus on cancer stem cells, as well as their implications for the development of novel targeted cancer therapies. PMID:27187360

  5. G Protein-Coupled Receptor Signaling in Stem Cells and Cancer.

    PubMed

    Lynch, Jennifer R; Wang, Jenny Yingzi

    2016-05-11

    G protein-coupled receptors (GPCRs) are a large superfamily of cell-surface signaling proteins that bind extracellular ligands and transduce signals into cells via heterotrimeric G proteins. GPCRs are highly tractable drug targets. Aberrant expression of GPCRs and G proteins has been observed in various cancers and their importance in cancer stem cells has begun to be appreciated. We have recently reported essential roles for G protein-coupled receptor 84 (GPR84) and G protein subunit Gαq in the maintenance of cancer stem cells in acute myeloid leukemia. This review will discuss how GPCRs and G proteins regulate stem cells with a focus on cancer stem cells, as well as their implications for the development of novel targeted cancer therapies.

  6. Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

    PubMed Central

    Bologna, Zuzana; Teoh, Jian-peng; Bayoumi, Ahmed S.; Tang, Yaoliang; Kim, Il-man

    2017-01-01

    G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of β-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or β-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation. PMID:28035079

  7. G protein-coupled receptors: signalling and regulation by lipid agonists for improved glucose homoeostasis.

    PubMed

    Moran, Brian M; Flatt, Peter R; McKillop, Aine M

    2016-04-01

    G protein-coupled receptors (GPCRs) play a pivotal role in cell signalling, controlling many processes such as immunity, growth, cellular differentiation, neurological pathways and hormone secretions. Fatty acid agonists are increasingly recognised as having a key role in the regulation of glucose homoeostasis via stimulation of islet and gastrointestinal GPCRs. Downstream cell signalling results in modulation of the biosynthesis, secretion, proliferation and anti-apoptotic pathways of islet and enteroendocrine cells. GPR40 and GPR120 are activated by long-chain fatty acids (>C12) with both receptors coupling to the Gαq subunit that activates the Ca(2+)-dependent pathway. GPR41 and GPR43 are stimulated by short-chain fatty acids (C2-C5), and activation results in binding to Gαi that inhibits the adenylyl cyclase pathway attenuating cAMP production. In addition, GPR43 also couples to the Gαq subunit augmenting intracellular Ca(2+) and activating phospholipase C. GPR55 is specific for cannabinoid endogenous agonists (endocannabinoids) and non-cannabinoid fatty acids, which couples to Gα12/13 and Gαq proteins, leading to enhancing intracellular Ca(2+), extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and Rho kinase. GPR119 is activated by fatty acid ethanolamides and binds to Gαs utilising the adenylate cyclase pathway, which is dependent upon protein kinase A. Current research indicates that GPCR therapies may be approved for clinical use in the near future. This review focuses on the recent advances in preclinical diabetes research in the signalling and regulation of GPCRs on islet and enteroendocrine cells involved in glucose homoeostasis.

  8. Coupling Condition In A Hololens - Optical Fiber System : Output Signal Optimization

    NASA Astrophysics Data System (ADS)

    Calvo, M. L.; De Pedraza, L.

    1988-04-01

    Based upon the scalar diffraction theory we have derived a very simple condition to control the optimization in the coupling phenomenon in a holocoupler - optical fiber system. A systematic numerical procedure allows a scanning simulation at the output plane of the system. The influence of the physical optimization parameters can be easily obtained giving an interesting criterium for the optimization of the output signal in a suitable experimental set up.

  9. Heterotrimeric G Protein-coupled Receptor Signaling in Yeast Mating Pheromone Response.

    PubMed

    Alvaro, Christopher G; Thorner, Jeremy

    2016-04-08

    The DNAs encoding the receptors that respond to the peptide mating pheromones of the budding yeastSaccharomyces cerevisiaewere isolated in 1985, and were the very first genes for agonist-binding heterotrimeric G protein-coupled receptors (GPCRs) to be cloned in any organism. Now, over 30 years later, this yeast and its receptors continue to provide a pathfinding experimental paradigm for investigating GPCR-initiated signaling and its regulation, as described in this retrospective overview.

  10. Note: automatic laser-to-optical-fiber coupling system based on monitoring of Raman scattering signal.

    PubMed

    Park, Kyoung-Duck; Kim, Yong Hwan; Park, Jin-Ho; Yim, Sang-Youp; Jeong, Mun Seok

    2012-09-01

    We developed an automatic laser-to-optical-fiber coupling (ALOC) system that is based on the difference in the Raman scattering signals of the core and cladding of the optical fiber. This system can be easily applied to all fields of fiber optics since it can perform automatic optical coupling within a few seconds regardless of the core size or the condition of the output end of the optical fiber. The coupling time for a commercial single-mode fiber for a wavelength of 632.8 nm (core diameter: 9 μm, cladding diameter: 125 μm) is ~1.5 s. The ALOC system was successfully applied to single-mode-fiber Raman endoscopy for the measurement of the Raman spectrum of carbon nanotubes.

  11. Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake

    PubMed Central

    Nakajima, Ken-ichiro; Cui, Zhenzhong; Li, Chia; Meister, Jaroslawna; Cui, Yinghong; Fu, Ou; Smith, Adam S.; Jain, Shalini; Lowell, Bradford B.; Krashes, Michael J.; Wess, Jürgen

    2016-01-01

    Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity. PMID:26743492

  12. Motivational salience signal in the basal forebrain is coupled with faster and more precise decision speed.

    PubMed

    Avila, Irene; Lin, Shih-Chieh

    2014-03-01

    The survival of animals depends critically on prioritizing responses to motivationally salient stimuli. While it is generally believed that motivational salience increases decision speed, the quantitative relationship between motivational salience and decision speed, measured by reaction time (RT), remains unclear. Here we show that the neural correlate of motivational salience in the basal forebrain (BF), defined independently of RT, is coupled with faster and also more precise decision speed. In rats performing a reward-biased simple RT task, motivational salience was encoded by BF bursting response that occurred before RT. We found that faster RTs were tightly coupled with stronger BF motivational salience signals. Furthermore, the fraction of RT variability reflecting the contribution of intrinsic noise in the decision-making process was actively suppressed in faster RT distributions with stronger BF motivational salience signals. Artificially augmenting the BF motivational salience signal via electrical stimulation led to faster and more precise RTs and supports a causal relationship. Together, these results not only describe for the first time, to our knowledge, the quantitative relationship between motivational salience and faster decision speed, they also reveal the quantitative coupling relationship between motivational salience and more precise RT. Our results further establish the existence of an early and previously unrecognized step in the decision-making process that determines both the RT speed and variability of the entire decision-making process and suggest that this novel decision step is dictated largely by the BF motivational salience signal. Finally, our study raises the hypothesis that the dysregulation of decision speed in conditions such as depression, schizophrenia, and cognitive aging may result from the functional impairment of the motivational salience signal encoded by the poorly understood noncholinergic BF neurons.

  13. Sorting nexin 27 couples PTHR trafficking to retromer for signal regulation in osteoblasts during bone growth

    PubMed Central

    Chan, Audrey S. M.; Clairfeuille, Thomas; Landao-Bassonga, Euphemie; Kinna, Genevieve; Ng, Pei Ying; Loo, Li Shen; Cheng, Tak Sum; Zheng, Minghao; Hong, Wanjin; Teasdale, Rohan D.; Collins, Brett M.; Pavlos, Nathan J.

    2016-01-01

    The parathyroid hormone 1 receptor (PTHR) is central to the process of bone formation and remodeling. PTHR signaling requires receptor internalization into endosomes, which is then terminated by recycling or degradation. Here we show that sorting nexin 27 (SNX27) functions as an adaptor that couples PTHR to the retromer trafficking complex. SNX27 binds directly to the C-terminal PDZ-binding motif of PTHR, wiring it to retromer for endosomal sorting. The structure of SNX27 bound to the PTHR motif reveals a high-affinity interface involving conserved electrostatic interactions. Mechanistically, depletion of SNX27 or retromer augments intracellular PTHR signaling in endosomes. Osteoblasts genetically lacking SNX27 show similar disruptions in PTHR signaling and greatly reduced capacity for bone mineralization, contributing to profound skeletal deficits in SNX27-knockout mice. Taken together, our data support a critical role for SNX27-retromer mediated transport of PTHR in normal bone development. PMID:26912788

  14. Implication of Two-Coupled Differential Van der Pol Duffing Oscillator in Weak Signal Detection

    NASA Astrophysics Data System (ADS)

    Peng, Hang-hang; Xu, Xue-mei; Yang, Bing-chu; Yin, Lin-zi

    2016-04-01

    The principle of the Van der Pol Duffing oscillator for state transition and for determining critical value is described, which has been studied to indicate that the application of the Van der Pol Duffing oscillator in weak signal detection is feasible. On the basis of this principle, an improved two-coupled differential Van der Pol Duffing oscillator is proposed which can identify signals under any frequency and ameliorate signal-to-noise ratio (SNR). The analytical methods of the proposed model and the construction of the proposed oscillator are introduced in detail. Numerical experiments on the properties of the proposed oscillator compared with those of the Van der Pol Duffing oscillator are carried out. Our numerical simulations have confirmed the analytical treatment. The results demonstrate that this novel oscillator has better detection performance than the Van der Pol Duffing oscillator.

  15. Early warning signals of Atlantic Meridional Overturning Circulation collapse in a fully coupled climate model.

    PubMed

    Boulton, Chris A; Allison, Lesley C; Lenton, Timothy M

    2014-12-08

    The Atlantic Meridional Overturning Circulation (AMOC) exhibits two stable states in models of varying complexity. Shifts between alternative AMOC states are thought to have played a role in past abrupt climate changes, but the proximity of the climate system to a threshold for future AMOC collapse is unknown. Generic early warning signals of critical slowing down before AMOC collapse have been found in climate models of low and intermediate complexity. Here we show that early warning signals of AMOC collapse are present in a fully coupled atmosphere-ocean general circulation model, subject to a freshwater hosing experiment. The statistical significance of signals of increasing lag-1 autocorrelation and variance vary with latitude. They give up to 250 years warning before AMOC collapse, after ~550 years of monitoring. Future work is needed to clarify suggested dynamical mechanisms driving critical slowing down as the AMOC collapse is approached.

  16. Novel insights into G protein and G protein-coupled receptor signaling in cancer.

    PubMed

    O'Hayre, Morgan; Degese, Maria S; Gutkind, J Silvio

    2014-04-01

    G protein-coupled receptors (GPCRs) play a central role in signal transmission, thereby controlling many facets of cellular function. Overwhelming evidence now implicates GPCRs, G proteins and their downstream signaling targets in cancer initiation and progression, where they can influence aberrant cell growth and survival, largely through activation of AKT/mTOR, MAPKs, and Hippo signaling pathways. GPCRs also play critical roles in the invasion and metastasis of cancer cells via activation of Rho GTPases and cytoskeletal changes, and angiogenesis to supply the tumor with nutrients and provide routes for metastasis. Lastly, GPCRs contribute to the establishment and maintenance of a permissive tumor microenvironment. Understanding GPCR involvement in cancer malignancy may help identify novel therapeutic opportunities for cancer prevention and treatment.

  17. Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory

    PubMed Central

    Orr, Anna G.; Hsiao, Edward C.; Wang, Max M.; Ho, Kaitlyn; Kim, Daniel H.; Wang, Xin; Guo, Weikun; Kang, Jing; Yu, Gui-Qiu; Adame, Anthony; Devidze, Nino; Dubal, Dena B.; Masliah, Eliezer; Conklin, Bruce R.; Mucke, Lennart

    2014-01-01

    Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer’s disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice, and increased the levels of Arc/Arg3.1, an immediate-early gene required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Similar to humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss. PMID:25622143

  18. Coupling Mechanism and Significance of the BOLD Signal: A Status Report

    PubMed Central

    Hillman, Elizabeth M.C.

    2014-01-01

    Functional magnetic resonance imaging (fMRI) provides a unique view of the working human mind. The blood-oxygen-level-dependent (BOLD) signal, detected in fMRI, reflects changes in deoxyhemoglobin driven by localized changes in brain blood flow and blood oxygenation, which are coupled to underlying neuronal activity by a process termed neurovascular coupling. Over the past 10 years, a range of cellular mechanisms, including astrocytes, pericytes, and interneurons, have been proposed to play a role in functional neurovascular coupling. However, the field remains conflicted over the relative importance of each process, while key spatiotemporal features of BOLD response remain unexplained. Here, we review current candidate neurovascular coupling mechanisms and propose that previously overlooked involvement of the vascular endothelium may provide a more complete picture of how blood flow is controlled in the brain. We also explore the possibility and consequences of conditions in which neurovascular coupling may be altered, including during postnatal development, pathological states, and aging, noting relevance to both stimulus-evoked and resting-state fMRI studies. PMID:25032494

  19. Characteristics of receptor- and transducer-coupled activation of the intracellular signalling in sensory neuron revealed by atomic force microscopy

    NASA Astrophysics Data System (ADS)

    Khalisov, M. M.; Penniyaynen, V. A.; Esikova, N. A.; Ankudinov, A. V.; Krylov, B. V.

    2017-01-01

    The mechanical properties of sensory neurons upon activation of intracellular cascade processes by comenic acid binding to a membrane opioid-like receptor (receptor-coupled), as well as a very low (endogenous) concentration of ouabain (transducer-coupled), have been investigated. Using atomic force microscopy, it is established that exposure to ouabain, in contrast to the impact of comenic acid, leads to a hardening of the neuron soma. This suggests that the receptor-coupled signal transmission to the cell genome is carried out through mechanisms that are different from the transducer-coupled signal pathways.

  20. Neurophysiological, metabolic and cellular compartments that drive neurovascular coupling and neuroimaging signals

    PubMed Central

    Moreno, Andrea; Jego, Pierrick; de la Cruz, Feliberto; Canals, Santiago

    2013-01-01

    Complete understanding of the mechanisms that coordinate work and energy supply of the brain, the so called neurovascular coupling, is fundamental to interpreting brain energetics and their influence on neuronal coding strategies, but also to interpreting signals obtained from brain imaging techniques such as functional magnetic resonance imaging. Interactions between neuronal activity and cerebral blood flow regulation are largely compartmentalized. First, there exists a functional compartmentalization in which glutamatergic peri-synaptic activity and its electrophysiological events occur in close proximity to vascular responses. Second, the metabolic processes that fuel peri-synaptic activity are partially segregated between glycolytic and oxidative compartments. Finally, there is cellular segregation between astrocytic and neuronal compartments, which has potentially important implications on neurovascular coupling. Experimental data is progressively showing a tight interaction between the products of energy consumption and neurotransmission-driven signaling molecules that regulate blood flow. Here, we review some of these issues in light of recent findings with special attention to the neuron-glia interplay on the generation of neuroimaging signals. PMID:23543907

  1. Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling.

    PubMed

    Lappano, Rosamaria; Rigiracciolo, Damiano; De Marco, Paola; Avino, Silvia; Cappello, Anna Rita; Rosano, Camillo; Maggiolini, Marcello; De Francesco, Ernestina Marianna

    2016-03-01

    G protein-coupled receptors (GPCRs) are cell surface proteins mainly involved in signal transmission; however, they play a role also in several pathophysiological conditions. Chemically heterogeneous molecules like peptides, hormones, lipids, and neurotransmitters activate second messengers and induce several biological responses by binding to these seven transmembrane receptors, which are coupled to heterotrimeric G proteins. Recently, additional molecular mechanisms have been involved in GPCR-mediated signaling, leading to an intricate network of transduction pathways. In this regard, it should be mentioned that diverse GPCR family members contribute to the adaptive cell responses to low oxygen tension, which is a distinguishing feature of several illnesses like neoplastic and cardiovascular diseases. For instance, the G protein estrogen receptor, namely G protein estrogen receptor (GPER)/GPR30, has been shown to contribute to relevant biological effects induced by hypoxia via the hypoxia-inducible factor (HIF)-1α in diverse cell contexts, including cancer. Likewise, GPER has been found to modulate the biological outcome of hypoxic/ischemic stress in both cardiovascular and central nervous systems. Here, we describe the role exerted by GPCR-mediated signaling in low oxygen conditions, discussing, in particular, the involvement of GPER by a hypoxic microenvironment.

  2. A theory of synchrony by coupling through a diffusive chemical signal

    NASA Astrophysics Data System (ADS)

    Gou, Jia; Chiang, Wei-Yin; Lai, Pik-Yin; Ward, Michael J.; Li, Yue-Xian

    2017-01-01

    We formulate and analyze oscillatory dynamics associated with a model of dynamically active, but spatially segregated, compartments that are coupled through a chemical signal that diffuses in the bulk medium between the compartments. The coupling between each compartment and the bulk is due to both feedback terms to the compartmental dynamics and flux boundary conditions at the interface between the compartment and the bulk. Our coupled model consists of dynamically active compartments located at the two ends of a 1-D bulk region of spatial extent 2 L. The dynamics in the two compartments is modeled by Sel'kov kinetics, and the signaling molecule between the two-compartments is assumed to undergo both diffusion, with diffusivity D, and first-order, linear, bulk degradation. For the resulting PDE-ODE system, we construct a symmetric steady-state solution and analyze the stability of this solution to either in-phase synchronous or anti-phase synchronous perturbations about the midline x = L. The conditions for the onset of oscillatory dynamics, as obtained from a linearization of the steady-state solution, are studied using a winding number approach. Global branches of either in-phase or anti-phase periodic solutions, and their associated stability properties, are determined numerically. For the case of a linear coupling between the compartments and the bulk, with coupling strength β, a phase diagram, in the parameter space D versus β is constructed that shows the existence of a rather wide parameter regime where stable in-phase synchronized oscillations can occur between the two compartments. By using a Floquet-based approach, this analysis with linear coupling is then extended to determine Hopf bifurcation thresholds for a periodic chain of evenly-spaced dynamically active units. Finally, we consider one particular case of a nonlinear coupling between two active compartments and the bulk. It is shown that stable in-phase and anti-phase synchronous oscillations

  3. Spurious cross-frequency amplitude-amplitude coupling in nonstationary, nonlinear signals

    NASA Astrophysics Data System (ADS)

    Yeh, Chien-Hung; Lo, Men-Tzung; Hu, Kun

    2016-07-01

    Recent studies of brain activities show that cross-frequency coupling (CFC) plays an important role in memory and learning. Many measures have been proposed to investigate the CFC phenomenon, including the correlation between the amplitude envelopes of two brain waves at different frequencies - cross-frequency amplitude-amplitude coupling (AAC). In this short communication, we describe how nonstationary, nonlinear oscillatory signals may produce spurious cross-frequency AAC. Utilizing the empirical mode decomposition, we also propose a new method for assessment of AAC that can potentially reduce the effects of nonlinearity and nonstationarity and, thus, help to avoid the detection of artificial AACs. We compare the performances of this new method and the traditional Fourier-based AAC method. We also discuss the strategies to identify potential spurious AACs.

  4. Receptor component protein (RCP): a member of a multi-protein complex required for G-protein-coupled signal transduction.

    PubMed

    Prado, M A; Evans-Bain, B; Dickerson, I M

    2002-08-01

    The calcitonin-gene-related peptide (CGRP) receptor component protein (RCP) is a 148-amino-acid intracellular protein that is required for G-protein-coupled signal transduction at receptors for the neuropeptide CGRP. RCP works in conjunction with two other proteins to constitute a functional CGRP receptor: calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying protein 1 (RAMP1). CRLR has the stereotypical seven-transmembrane topology of a G-protein-coupled receptor; it requires RAMP1 for trafficking to the cell surface and for ligand specificity, and requires RCP for coupling to the cellular signal transduction pathway. We have made cell lines that expressed an antisense construct of RCP and determined that CGRP-mediated signal transduction was reduced, while CGRP binding was unaffected. Furthermore, signalling at two other endogenous G-protein-coupled receptors was unaffected, suggesting that RCP was specific for a limited subset of receptors.

  5. Activity-dependent signal changes in neurons by fiber-coupled microscopy

    NASA Astrophysics Data System (ADS)

    Sakurai, Takashi; Koida, Kowa

    2014-03-01

    To study neuronal functions in brain, we developed a higher resolution type fiber-coupled microscope (FCM), and measured the activity-dependent fluorescence intensity of the excitable cells over time. FCM was constructed by combining a fluorescence microscope with the high density type of fiber bundle, which consisted of 1.5 x 104 unit fiber in the assemble less than 0.5 mm tip. The spatial resolution was calculated to be 2.4 mm with the 5 mm focal depth. The activity-dependent Ca signals were detectable in each cell of either the pancreatic spheroids or the brain slices. The present FCM is very promising for detailed studies with the live imaging of signal molecules in the body at a single cell level.

  6. Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors

    PubMed Central

    de Munnik, Sabrina M.; Smit, Martine J.; Leurs, Rob; Vischer, Henry F.

    2015-01-01

    Human herpesviruses (HHVs) are widespread infectious pathogens that have been associated with proliferative and inflammatory diseases. During viral evolution, HHVs have pirated genes encoding viral G protein-coupled receptors (vGPCRs), which are expressed on infected host cells. These vGPCRs show highest homology to human chemokine receptors, which play a key role in the immune system. Importantly, vGPCRs have acquired unique properties such as constitutive activity and the ability to bind a broad range of human chemokines. This allows vGPCRs to hijack human proteins and modulate cellular signaling for the benefit of the virus, ultimately resulting in immune evasion and viral dissemination to establish a widespread and lifelong infection. Knowledge on the mechanisms by which herpesviruses reprogram cellular signaling might provide insight in the contribution of vGPCRs to viral survival and herpesvirus-associated pathologies. PMID:25805993

  7. Immobilized Metal Affinity Chromatography Coupled to Multiple Reaction Monitoring Enables Reproducible Quantification of Phospho-signaling*

    PubMed Central

    Kennedy, Jacob J.; Yan, Ping; Zhao, Lei; Ivey, Richard G.; Voytovich, Uliana J.; Moore, Heather D.; Lin, Chenwei; Pogosova-Agadjanyan, Era L.; Stirewalt, Derek L.; Reding, Kerryn W.; Whiteaker, Jeffrey R.; Paulovich, Amanda G.

    2016-01-01

    A major goal in cell signaling research is the quantification of phosphorylation pharmacodynamics following perturbations. Traditional methods of studying cellular phospho-signaling measure one analyte at a time with poor standardization, rendering them inadequate for interrogating network biology and contributing to the irreproducibility of preclinical research. In this study, we test the feasibility of circumventing these issues by coupling immobilized metal affinity chromatography (IMAC)-based enrichment of phosphopeptides with targeted, multiple reaction monitoring (MRM) mass spectrometry to achieve precise, specific, standardized, multiplex quantification of phospho-signaling responses. A multiplex immobilized metal affinity chromatography- multiple reaction monitoring assay targeting phospho-analytes responsive to DNA damage was configured, analytically characterized, and deployed to generate phospho-pharmacodynamic curves from primary and immortalized human cells experiencing genotoxic stress. The multiplexed assays demonstrated linear ranges of ≥3 orders of magnitude, median lower limit of quantification of 0.64 fmol on column, median intra-assay variability of 9.3%, median inter-assay variability of 12.7%, and median total CV of 16.0%. The multiplex immobilized metal affinity chromatography- multiple reaction monitoring assay enabled robust quantification of 107 DNA damage-responsive phosphosites from human cells following DNA damage. The assays have been made publicly available as a resource to the community. The approach is generally applicable, enabling wide interrogation of signaling networks. PMID:26621847

  8. Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling

    PubMed Central

    Luchetti, Giovanni; Sircar, Ria; Kong, Jennifer H; Nachtergaele, Sigrid; Sagner, Andreas; Byrne, Eamon FX; Covey, Douglas F; Siebold, Christian; Rohatgi, Rajat

    2016-01-01

    Cholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike many GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility. DOI: http://dx.doi.org/10.7554/eLife.20304.001 PMID:27705744

  9. A pseudokinase couples signaling pathways to enable asymmetric cell division in a bacterium

    PubMed Central

    Childers, W. S.; Shapiro, Lucy

    2014-01-01

    Bacteria face complex decisions when initiating developmental events such as sporulation, nodulation, virulence, and asymmetric cell division. These developmental decisions require global changes in genomic readout, and bacteria typically employ intricate (yet poorly understood) signaling networks that enable changes in cell function. The bacterium Caulobacter crescentus divides asymmetrically to yield two functionally distinct cells: a motile, chemotactic swarmer cell, and a sessile stalked cell with replication and division capabilities. Work from several Caulobacter labs has revealed that differentiation requires concerted regulation by several two-component system (TCS) signaling pathways that are differentially positioned at the poles of the predivisional cell (Figure 1). The strict unidirectional flow from histidine kinase (HK) to the response regulator (RR), observed in most studied TCS, is difficult to reconcile with the notion that information can be transmitted between two or more TCS signaling pathways. In this study, we uncovered a mechanism by which daughter cell fate, which is specified by the DivJ-DivK-PleC system and effectively encoded in the phosphorylation state of the single-domain RR DivK, is communicated to the CckA-ChpT-CtrA signaling pathway that regulates more than 100 genes for polar differentiation, replication initiation and cell division. Using structural biology and biochemical findings we proposed a mechanistic basis for TCS pathway coupling in which the DivL pseudokinase is repurposed as a sensor rather than participant in phosphotransduction.

  10. G-protein-coupled receptor controls steroid hormone signaling in cell membrane

    PubMed Central

    Wang, Di; Zhao, Wen-Li; Cai, Mei-Juan; Wang, Jin-Xing; Zhao, Xiao-Fan

    2015-01-01

    G-protein-coupled receptors (GPCRs) are involved in animal steroid hormone signaling, but their mechanism is unclear. In this research, we report that a GPCR called ErGPCR-2 controls steroid hormone 20-hydroxyecdysone (20E) signaling in the cell membrane of the lepidopteran insect Helicoverpa armigera. ErGPCR-2 was highly expressed during molting and metamorphosis. 20E, via ErGPCR-2, regulated rapid intracellular calcium increase, protein phosphorylation, gene transcription, and insect metamorphosis. ErGPCR-2 was located in the cell surface and was internalized by 20E induction. GPCR kinase 2 participated in 20E-induced ErGPCR-2 phosphorylation and internalization. The internalized ErGPCR-2 was degraded by proteases to desensitize 20E signaling. ErGPCR-2 knockdown suppressed the entrance of 20E analog [3H] ponasterone A ([3H]Pon A) into the cells. ErGPCR-2 overexpression or blocking of ErGPCR-2 internalization increased the entrance of [3H]Pon A into the cells. However, ErGPCR-2 did not bind to [3H]Pon A. Results suggest that ErGPCR-2 transmits steroid hormone 20E signaling and controls 20E entrance into cells in the cell membrane. PMID:25728569

  11. Chemical biology methods for investigating G protein-coupled receptor signaling.

    PubMed

    Huber, Thomas; Sakmar, Thomas P

    2014-09-18

    G protein-coupled receptors (GPCRs) are targets for a quarter of prescription drugs. Despite recent progress in structural biology of GPCRs, only few key conformational states in the signal transduction process have been elucidated. Agonist ligands frequently display functional selectivity where activated receptors are biased to either G protein- or arrestin-mediated downstream signaling pathways. Selective manipulation of individual steps in the GPCR activation scheme requires precise information about the kinetics of ligand binding and the dynamics of downstream signaling. One approach is to obtain time-resolved information using receptors tagged with fluorescent or structural probes. Recent advances allow for site-specific introduction of genetically encoded unnatural amino acids into expressed GPCRs. We describe how bioorthogonal functional groups on GPCRs enable the mapping of receptor-ligand interactions and how bioorthogonal chemical reactions can be used to introduce fluorescent labels for single-molecule fluorescence applications to study the kinetics and conformational dynamics of GPCR signaling complexes ("signalosomes").

  12. Transmembrane signal transduction by peptide hormones via family B G protein-coupled receptors

    PubMed Central

    Culhane, Kelly J.; Liu, Yuting; Cai, Yingying; Yan, Elsa C. Y.

    2015-01-01

    Although family B G protein-coupled receptors (GPCRs) contain only 15 members, they play key roles in transmembrane signal transduction of hormones. Family B GPCRs are drug targets for developing therapeutics for diseases ranging from metabolic to neurological disorders. Despite their importance, the molecular mechanism of activation of family B GPCRs remains largely unexplored due to the challenges in expression and purification of functional receptors to the quantity for biophysical characterization. Currently, there is no crystal structure available of a full-length family B GPCR. However, structures of key domains, including the extracellular ligand binding regions and seven-helical transmembrane regions, have been solved by X-ray crystallography and NMR, providing insights into the mechanisms of ligand recognition and selectivity, and helical arrangements within the cell membrane. Moreover, biophysical and biochemical methods have been used to explore functions, key residues for signaling, and the kinetics and dynamics of signaling processes. This review summarizes the current knowledge of the signal transduction mechanism of family B GPCRs at the molecular level and comments on the challenges and outlook for mechanistic studies of family B GPCRs. PMID:26594176

  13. Digital DC-Reconstruction of AC-Coupled Electrophysiological Signals with a Single Inverting Filter.

    PubMed

    Abächerli, Roger; Isaksen, Jonas; Schmid, Ramun; Leber, Remo; Schmid, Hans-Jakob; Generali, Gianluca

    2016-01-01

    Since the introduction of digital electrocardiographs, high-pass filters have been necessary for successful analog-to-digital conversion with a reasonable amplitude resolution. On the other hand, such high-pass filters may distort the diagnostically significant ST-segment of the ECG, which can result in a misleading diagnosis. We present an inverting filter that successfully undoes the effects of a 0.05 Hz single pole high-pass filter. The inverting filter has been tested on more than 1600 clinical ECGs with one-minute durations and produces a negligible mean RMS-error of 3.1*10(-8) LSB. Alternative, less strong inverting filters have also been tested, as have different applications of the filters with respect to rounding of the signals after filtering. A design scheme for the alternative inverting filters has been suggested, based on the maximum strength of the filter. With the use of the suggested filters, it is possible to recover the original DC-coupled ECGs from AC-coupled ECGs, at least when a 0.05 Hz first order digital single pole high-pass filter is used for the AC-coupling.

  14. Astrocyte Ca2+ Signaling Drives Inversion of Neurovascular Coupling after Subarachnoid Hemorrhage.

    PubMed

    Pappas, Anthony C; Koide, Masayo; Wellman, George C

    2015-09-30

    Physiologically, neurovascular coupling (NVC) matches focal increases in neuronal activity with local arteriolar dilation. Astrocytes participate in NVC by sensing increased neurotransmission and releasing vasoactive agents (e.g., K(+)) from perivascular endfeet surrounding parenchymal arterioles. Previously, we demonstrated an increase in the amplitude of spontaneous Ca(2+) events in astrocyte endfeet and inversion of NVC from vasodilation to vasoconstriction in brain slices obtained from subarachnoid hemorrhage (SAH) model rats. However, the role of spontaneous astrocyte Ca(2+) signaling in determining the polarity of the NVC response remains unclear. Here, we used two-photon imaging of Fluo-4-loaded rat brain slices to determine whether altered endfoot Ca(2+) signaling underlies SAH-induced inversion of NVC. We report a time-dependent emergence of endfoot high-amplitude Ca(2+) signals (eHACSs) after SAH that were not observed in endfeet from unoperated animals. Furthermore, the percentage of endfeet with eHACSs varied with time and paralleled the development of inversion of NVC. Endfeet with eHACSs were present only around arterioles exhibiting inversion of NVC. Importantly, depletion of intracellular Ca(2+) stores using cyclopiazonic acid abolished SAH-induced eHACSs and restored arteriolar dilation in SAH brain slices to two mediators of NVC (a rise in endfoot Ca(2+) and elevation of extracellular K(+)). These data indicate a causal link between SAH-induced eHACSs and inversion of NVC. Ultrastructural examination using transmission electron microscopy indicated that a similar proportion of endfeet exhibiting eHACSs also exhibited asymmetrical enlargement. Our results demonstrate that subarachnoid blood causes a delayed increase in the amplitude of spontaneous intracellular Ca(2+) release events leading to inversion of NVC. Significance statement: Aneurysmal subarachnoid hemorrhage (SAH)--strokes involving cerebral aneurysm rupture and release of blood onto the

  15. G protein-coupled receptors as oncogenic signals in glioma: emerging therapeutic avenues

    PubMed Central

    Cherry, Allison E; Stella, Nephi

    2014-01-01

    Gliomas are the most common malignant intracranial tumors. Newly developed targeted therapies for these cancers aim to inhibit oncogenic signals, many of which emanate from receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR). Unfortunately, the first generation treatments targeting these oncogenic signals provide little survival benefit in both mouse xenograft models and human patients. The search for new treatment options has uncovered several G protein-coupled receptor (GPCR) candidates and generated a growing interest in this class of proteins as alternative therapeutic targets for the treatment of various cancers, including GBM. GPCRs constitute a large family of membrane receptors that influence oncogenic pathways through canonical and non-canonical signaling. Accordingly, evidence indicates that GPCRs display a unique ability to crosstalk with receptor tyrosine kinases, making them important molecular components controlling tumorigenesis. This review summarizes the current research on GPCR functionality in gliomas and explores the potential of modulating these receptors to treat this devastating disease. PMID:25158675

  16. An algebra of dimerization and its implications for G-protein coupled receptor signaling.

    PubMed

    Woolf, Peter J; Linderman, Jennifer J

    2004-07-21

    Many species of receptors form dimers, but how can we use this information to make predictions about signal transduction? This problem is particularly difficult when receptors dimerize with many different species, leading to a combinatoric increase in the possible number of dimer pairs. As an example system, we focus on receptors in the G-protein coupled receptor (GPCR) family. GPCRs have been shown to reversibly form dimers, but this dimerization does not directly affect signal transduction. Here we present a new theoretical framework called a dimerization algebra. This algebra provides a systematic and rational way to represent, manipulate, and in some cases simplify large and often complicated networks of dimerization interactions. To compliment this algebra, Monte Carlo simulations are used to predict dimerization's effect on receptor organization on the membrane, signal transduction, and internalization. These simulation results are directly comparable to various experimental measures such as fluorescence resonance energy transfer (FRET), and as such provide a link between the dimerization algebra and experimental data. As an example, we show how the algebra and computational results can be used to predict the effects of dimerization on the dopamine D2 and somatastatin SSTR1 receptors. When these predictions were compared to experimental findings from the literature, good agreement was found, demonstrating the utility of our approach. Applications of this work to the development of a novel class of dimerization-modulating drugs are also discussed.

  17. Antibody fragments for stabilization and crystallization of G protein-coupled receptors and their signaling complexes.

    PubMed

    Shukla, Arun K; Gupta, Charu; Srivastava, Ashish; Jaiman, Deepika

    2015-01-01

    G protein-coupled receptors (GPCRs) are one of the key players in extracellular signal recognition and their subsequent communications with cellular signaling machinery. Crystallization and high-resolution structure determination of GPCRs has been one of the major advances in the area of GPCR biology over the last 7-8 years. There have primarily been three approaches to GPCR crystallization till date. These are fusion protein strategy, thermostabilization, and antibody fragment-mediated crystallization. Of these, antibody fragment-mediated crystallization has not only provided the first breakthrough in structure determination of a non-rhodopsin GPCR but it has also assisted in obtaining structures of fully active conformations of GPCRs. Antibody fragment approach has also been crucial in obtaining structural information on GPCR signaling complexes. Here, we highlight the specific examples of GPCR crystal structures that have utilized antibody fragments for promoting crystallogenesis and structure solution. We also discuss emerging powerful technologies such as the nanobody technology and the synthetic phage display libraries in the context of GPCR crystallization and underline how these tools are likely to propel key GPCR structural studies in future.

  18. G protein-coupled receptors as oncogenic signals in glioma: emerging therapeutic avenues.

    PubMed

    Cherry, A E; Stella, N

    2014-10-10

    Gliomas are the most common malignant intracranial tumors. Newly developed targeted therapies for these cancers aim to inhibit oncogenic signals, many of which emanate from receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR). Unfortunately, the first-generation treatments targeting these oncogenic signals provide little survival benefit in both mouse xenograft models and human patients. The search for new treatment options has uncovered several G protein-coupled receptor (GPCR) candidates and generated a growing interest in this class of proteins as alternative therapeutic targets for the treatment of various cancers, including glioblastoma multiforme (GBM). GPCRs constitute a large family of membrane receptors that influence oncogenic pathways through canonical and non-canonical signaling. Accordingly, evidence indicates that GPCRs display a unique ability to crosstalk with receptor tyrosine kinases, making them important molecular components controlling tumorigenesis. This review summarizes the current research on GPCR functionality in gliomas and explores the potential of modulating these receptors to treat this devastating disease.

  19. G-protein-coupled receptor signaling and neural tube closure defects.

    PubMed

    Shimada, Issei S; Mukhopadhyay, Saikat

    2017-01-30

    Disruption of the normal mechanisms that mediate neural tube closure can result in neural tube defects (NTDs) with devastating consequences in affected patients. With the advent of next-generation sequencing, we are increasingly detecting mutations in multiple genes in NTD cases. However, our ability to determine which of these genes contribute to the malformation is limited by our understanding of the pathways controlling neural tube closure. G-protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors in humans and have been historically favored as drug targets. Recent studies implicate several GPCRs and downstream signaling pathways in neural tube development and closure. In this review, we will discuss our current understanding of GPCR signaling pathways in pathogenesis of NTDs. Notable examples include the orphan primary cilia-localized GPCR, Gpr161 that regulates the basal suppression machinery of sonic hedgehog pathway by means of activation of cAMP-protein kinase A signaling in the neural tube, and protease-activated receptors that are activated by a local network of membrane-tethered proteases during neural tube closure involving the surface ectoderm. Understanding the role of these GPCR-regulated pathways in neural tube development and closure is essential toward identification of underlying genetic causes to prevent NTDs. Birth Defects Research 109:129-139, 2017. © 2016 Wiley Periodicals, Inc.

  20. Glucocorticoids regulate arrestin gene expression and redirect the signaling profile of G protein-coupled receptors.

    PubMed

    Oakley, Robert H; Revollo, Javier; Cidlowski, John A

    2012-10-23

    G protein-coupled receptors (GPCRs) compose the largest family of cell surface receptors and are the most common target of therapeutic drugs. The nonvisual arrestins, β-arrestin-1 and β-arrestin-2, are multifunctional scaffolding proteins that play critical roles in GPCR signaling. On binding of activated GPCRs at the plasma membrane, β-arrestins terminate G protein-dependent responses (desensitization) and stimulate β-arrestin-dependent signaling pathways. Alterations in the cellular complement of β-arrestin-1 and β-arrestin-2 occur in many human diseases, and their genetic ablation in mice has severe consequences. Surprisingly, however, the factors that control β-arrestin gene expression are poorly understood. We demonstrate that glucocorticoids differentially regulate β-arrestin-1 and β-arrestin-2 gene expression in multiple cell types. Glucocorticoids act via the glucocorticoid receptor (GR) to induce the synthesis of β-arrestin-1 and repress the expression of β-arrestin-2. Glucocorticoid-dependent regulation involves the recruitment of ligand-activated glucocorticoid receptors to conserved and functional glucocorticoid response elements in intron-1 of the β-arrestin-1 gene and intron-11 of the β-arrestin-2 gene. In human lung adenocarcinoma cells, the increased expression of β-arrestin-1 after glucocorticoid treatment impairs G protein-dependent activation of inositol phosphate signaling while enhancing β-arrestin-1-dependent stimulation of the MAPK pathway by protease activated receptor 1. These studies demonstrate that glucocorticoids redirect the signaling profile of GPCRs via alterations in β-arrestin gene expression, revealing a paradigm for cross-talk between nuclear and cell surface receptors and a mechanism by which glucocorticoids alter the clinical efficacy of GPCR-based drugs.

  1. SLO BK Potassium Channels Couple Gap Junctions to Inhibition of Calcium Signaling in Olfactory Neuron Diversification

    PubMed Central

    Schumacher, Jennifer A.; Wang, Xiaohong; Merrill, Sean A.; Millington, Grethel; Bayne, Brittany; Jorgensen, Erik M.; Chuang, Chiou-Fen

    2016-01-01

    The C. elegans AWC olfactory neuron pair communicates to specify asymmetric subtypes AWCOFF and AWCON in a stochastic manner. Intercellular communication between AWC and other neurons in a transient NSY-5 gap junction network antagonizes voltage-activated calcium channels, UNC-2 (CaV2) and EGL-19 (CaV1), in the AWCON cell, but how calcium signaling is downregulated by NSY-5 is only partly understood. Here, we show that voltage- and calcium-activated SLO BK potassium channels mediate gap junction signaling to inhibit calcium pathways for asymmetric AWC differentiation. Activation of vertebrate SLO-1 channels causes transient membrane hyperpolarization, which makes it an important negative feedback system for calcium entry through voltage-activated calcium channels. Consistent with the physiological roles of SLO-1, our genetic results suggest that slo-1 BK channels act downstream of NSY-5 gap junctions to inhibit calcium channel-mediated signaling in the specification of AWCON. We also show for the first time that slo-2 BK channels are important for AWC asymmetry and act redundantly with slo-1 to inhibit calcium signaling. In addition, nsy-5-dependent asymmetric expression of slo-1 and slo-2 in the AWCON neuron is necessary and sufficient for AWC asymmetry. SLO-1 and SLO-2 localize close to UNC-2 and EGL-19 in AWC, suggesting a role of possible functional coupling between SLO BK channels and voltage-activated calcium channels in AWC asymmetry. Furthermore, slo-1 and slo-2 regulate the localization of synaptic markers, UNC-2 and RAB-3, in AWC neurons to control AWC asymmetry. We also identify the requirement of bkip-1, which encodes a previously identified auxiliary subunit of SLO-1, for slo-1 and slo-2 function in AWC asymmetry. Together, these results provide an unprecedented molecular link between gap junctions and calcium pathways for terminal differentiation of olfactory neurons. PMID:26771544

  2. Lipid modulation of early G protein-coupled receptor signalling events.

    PubMed

    Dijkman, Patricia M; Watts, Anthony

    2015-11-01

    Upon binding of extracellular ligands, G protein coupled-receptors (GPCRs) initiate signalling cascades by activating heterotrimeric G proteins through direct interactions with the α subunit. While the lipid dependence of ligand binding has previously been studied for one class A GPCR, the neurotensin receptor 1 (NTS1), the role the lipid environment plays in the interaction of activated GPCRs with G proteins is less well understood. It is therefore of interest to understand the balance of lipid interactions required to support both ligand binding and G protein activation, not least since some receptors have multiple locations, and may experience different membrane environments when signalling in the plasma membrane or during endocytosis. Here, using the sensitive biophysical technique of microscale thermophoresis in conjunction with nanodisc lipid bilayer reconstitution, we show that in more native lipid environments rich in phosphatidyl ethanolamine (PE), the Gαi1 subunit has a ~4-fold higher affinity for NTS1 than in the absence of native lipids. The G protein-receptor affinity was further shown to be dependent on the ligand-binding state of the receptor, with potential indication of biased signalling for the known antagonist SR142948A. Gαi1 also showed preferential interaction with empty nanodiscs of native lipid mixtures rich in PE by around 2- to 4-fold over phosphatidyl choline (PC)/phosphatidyl glycerol (PG) lipid mixtures. The lipid environment may therefore play a role in creating favourable micro-environments for efficient GPCR signalling. Our approach combining nanodiscs with microscale thermophoresis will be useful in future studies to elucidate further the complexity of the GPCR interactome.

  3. Identification of G protein-coupled receptor signaling pathway proteins in marine diatoms using comparative genomics

    PubMed Central

    2013-01-01

    Background The G protein-coupled receptor (GPCR) signaling pathway plays an essential role in signal transmission and response to external stimuli in mammalian cells. Protein components of this pathway have been characterized in plants and simpler eukaryotes such as yeast, but their presence and role in unicellular photosynthetic eukaryotes have not been determined. We use a comparative genomics approach using whole genome sequences and gene expression libraries of four diatoms (Pseudo-nitzschia multiseries, Thalassiosira pseudonana, Phaeodactylum tricornutum and Fragilariopsis cylindrus) to search for evidence of GPCR signaling pathway proteins that share sequence conservation to known GPCR pathway proteins. Results The majority of the core components of GPCR signaling were well conserved in all four diatoms, with protein sequence similarity to GPCRs, human G protein α- and β-subunits and downstream effectors. There was evidence for the Gγ-subunit and thus a full heterotrimeric G protein only in T. pseudonana. Phylogenetic analysis of putative diatom GPCRs indicated similarity but deep divergence to the class C GPCRs, with branches basal to the GABAB receptor subfamily. The extracellular and intracellular regions of these putative diatom GPCR sequences exhibited large variation in sequence length, and seven of these sequences contained the necessary ligand binding domain for class C GPCR activation. Transcriptional data indicated that a number of the putative GPCR sequences are expressed in diatoms under various stress conditions in culture, and that many of the GPCR-activated signaling proteins, including the G protein, are also expressed. Conclusions The presence of sequences in all four diatoms that code for the proteins required for a functional mammalian GPCR pathway highlights the highly conserved nature of this pathway and suggests a complex signaling machinery related to environmental perception and response in these unicellular organisms. The lack of

  4. Coupling mechanical forces to electrical signaling: molecular motors and the intracellular transport of ion channels.

    PubMed

    Barry, Joshua; Gu, Chen

    2013-04-01

    Proper localization of various ion channels is fundamental to neuronal functions, including postsynaptic potential plasticity, dendritic integration, action potential initiation and propagation, and neurotransmitter release. Microtubule-based forward transport mediated by kinesin motors plays a key role in placing ion channel proteins to correct subcellular compartments. PDZ- and coiled-coil-domain proteins function as adaptor proteins linking ionotropic glutamate and GABA receptors to various kinesin motors, respectively. Recent studies show that several voltage-gated ion channel/transporter proteins directly bind to kinesins during forward transport. Three major regulatory mechanisms underlying intracellular transport of ion channels are also revealed. These studies contribute to understanding how mechanical forces are coupled to electrical signaling and illuminating pathogenic mechanisms in neurodegenerative diseases.

  5. A biosignal instrumentation system using capacitive coupling for power and signal isolation.

    PubMed

    Piipponen, Kari Väinö Tapio; Sepponen, Raimo; Eskelinen, Pekka

    2007-10-01

    Requirements for patient safety and a high interference rejection ratio in medical equipment create a demand for effective isolation devices. A system scale approach that uses capacitive coupling for power and signal isolation is presented. In addition, we describe the development of an instrumentation system prototype that applies microwaves for power exchange and bidirectional data transfer across the isolation barrier. The system consists of an isolated transducer unit, a central unit, and a single coaxial cable between the units. The isolation capacitance is as low as 1.6 pF, inclusive of the digital data transfer and power exchange up to 600 mW of isolated direct current (dc) power. The system is suitable for line-powered biopotential measurements and it is shown that reducing the isolation capacitance from 180 to 1.6 pF improves the power line rejection by 30 dB in a typical electrocardiogram (ECG) measurement setup.

  6. Signal-Coupled Subthreshold Hopf-Type Systems Show a Sharpened Collective Response

    NASA Astrophysics Data System (ADS)

    Gomez, Florian; Lorimer, Tom; Stoop, Ruedi

    2016-03-01

    Astounding properties of biological sensors can often be mapped onto a dynamical system below the occurrence of a bifurcation. For mammalian hearing, a Hopf bifurcation description has been shown to work across a whole range of scales, from individual hair bundles to whole regions of the cochlea. We reveal here the origin of this scale invariance, from a general level, applicable to all dynamics in the vicinity of a Hopf bifurcation (embracing, e.g., neuronal Hodgkin-Huxley equations). When subject to natural "signal coupling," ensembles of Hopf systems below the bifurcation threshold exhibit a collective Hopf bifurcation. This collective Hopf bifurcation occurs at parameter values substantially below where the average of the individual systems would bifurcate, with a frequency profile that is sharpened if compared to the individual systems.

  7. G protein-coupled receptors: bridging the gap from the extracellular signals to the Hippo pathway.

    PubMed

    Zhou, Xin; Wang, Zhen; Huang, Wei; Lei, Qun-Ying

    2015-01-01

    The Hippo pathway is crucial in organ size control, whereas its dysregulation contributes to organ degeneration or tumorigenesis. The kinase cascade of MST1/2 and LATS1/2 and the coupling transcription co-activators YAP/TAZ represent the core components of the Hippo pathway. Extensive studies have identified a number of upstream regulators of the Hippo pathway, including contact inhibition, mechanic stress, extracellular matrix stiffness, cytoskeletal rearrangement, and some molecules of cell polarity and cell junction. However, how the diffuse extracellular signals regulate the Hippo pathway puzzles the researchers for a long time. Unexpectedly, recent elegant studies demonstrated that stimulation of some G protein-coupled receptors (GPCRs), such as lysophosphatidic acid receptor, sphingosine-1-phosphate receptor, and the protease activated receptor PAR1, causes potent YAP/TAZ dephosphorylation and activation by promoting actin cytoskeleton assemble. In this review, we briefly describe the components of the Hippo pathway and focus on the recent progress with respect to the regulation of the Hippo pathway by GPCRs and G proteins in cancer cells. In addition, we also discuss the potential therapeutic roles targeting the Hippo pathway in human cancers.

  8. Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease

    PubMed Central

    Haas, Laura T.; Salazar, Santiago V.; Kostylev, Mikhail A.; Um, Ji Won; Kaufman, Adam C.

    2016-01-01

    Alzheimer’s disease-related phenotypes in mice can be rescued by blockade of either cellular prion protein or metabotropic glutamate receptor 5. We sought genetic and biochemical evidence that these proteins function cooperatively as an obligate complex in the brain. We show that cellular prion protein associates via transmembrane metabotropic glutamate receptor 5 with the intracellular protein mediators Homer1b/c, calcium/calmodulin-dependent protein kinase II, and the Alzheimer’s disease risk gene product protein tyrosine kinase 2 beta. Coupling of cellular prion protein to these intracellular proteins is modified by soluble amyloid-β oligomers, by mouse brain Alzheimer’s disease transgenes or by human Alzheimer’s disease pathology. Amyloid-β oligomer-triggered phosphorylation of intracellular protein mediators and impairment of synaptic plasticity in vitro requires Prnp–Grm5 genetic interaction, being absent in transheterozygous loss-of-function, but present in either single heterozygote. Importantly, genetic coupling between Prnp and Grm5 is also responsible for signalling, for survival and for synapse loss in Alzheimer’s disease transgenic model mice. Thus, the interaction between metabotropic glutamate receptor 5 and cellular prion protein has a central role in Alzheimer’s disease pathogenesis, and the complex is a potential target for disease-modifying intervention. PMID:26667279

  9. Simulation and Measurement of Medium-Frequency Signals Coupling From a Line to a Loop Antenna

    PubMed Central

    Damiano, Nicholas W.; Li, Jingcheng; Zhou, Chenming; Brocker, Donovan E.; Qin, Yifeng; Werner, Douglas H.; Werner, Pingjuan L.

    2016-01-01

    The underground-mining environment can affect radio-signal propagation in various ways. Understanding these effects is especially critical in evaluating communications systems used during normal mining operations and during mine emergencies. One of these types of communications systems relies on medium-frequency (MF) radio frequencies. This paper presents the simulation and measurement results of recent National Institute for Occupational Safety and Health (NIOSH) research aimed at investigating MF coupling between a transmission line (TL) and a loop antenna in an underground coal mine. Two different types of measurements were completed: 1) line-current distribution and 2) line-to-antenna coupling. Measurements were taken underground in an experimental coal mine and on a specially designed surface test area. The results of these tests are characterized by current along a TL and voltage induced in the loop from a line. This paper concludes with a discussion of issues for MF TLs. These include electromagnetic fields at the ends of the TL, connection of the ends of the TL, the effect of other conductors underground, and the proximity of coal or earth. These results could help operators by providing examples of these challenges that may be experienced underground and a method by which to measure voltage induced by a line. PMID:27784954

  10. Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease.

    PubMed

    Haas, Laura T; Salazar, Santiago V; Kostylev, Mikhail A; Um, Ji Won; Kaufman, Adam C; Strittmatter, Stephen M

    2016-02-01

    Alzheimer's disease-related phenotypes in mice can be rescued by blockade of either cellular prion protein or metabotropic glutamate receptor 5. We sought genetic and biochemical evidence that these proteins function cooperatively as an obligate complex in the brain. We show that cellular prion protein associates via transmembrane metabotropic glutamate receptor 5 with the intracellular protein mediators Homer1b/c, calcium/calmodulin-dependent protein kinase II, and the Alzheimer's disease risk gene product protein tyrosine kinase 2 beta. Coupling of cellular prion protein to these intracellular proteins is modified by soluble amyloid-β oligomers, by mouse brain Alzheimer's disease transgenes or by human Alzheimer's disease pathology. Amyloid-β oligomer-triggered phosphorylation of intracellular protein mediators and impairment of synaptic plasticity in vitro requires Prnp-Grm5 genetic interaction, being absent in transheterozygous loss-of-function, but present in either single heterozygote. Importantly, genetic coupling between Prnp and Grm5 is also responsible for signalling, for survival and for synapse loss in Alzheimer's disease transgenic model mice. Thus, the interaction between metabotropic glutamate receptor 5 and cellular prion protein has a central role in Alzheimer's disease pathogenesis, and the complex is a potential target for disease-modifying intervention.

  11. Minireview: Ubiquitination-regulated G Protein-Coupled Receptor Signaling and Trafficking

    PubMed Central

    Alonso, Verónica

    2013-01-01

    G protein-coupled receptors (GPCRs) are the largest and most diverse superfamily of membrane proteins and mediate most cellular responses to hormones and neurotransmitters. Posttranslational modifications are considered the main regulators of all GPCRs. In addition to phosphorylation, glycosylation, and palmitoylation, increasing evidence as reviewed here reveals that ubiquitination also regulates the magnitude and temporospatial aspects of GPCR signaling. Posttranslational protein modification by ubiquitin is a key molecular mechanism governing proteins degradation. Ubiquitination mediates the covalent conjugation of ubiquitin, a highly conserved polypeptide of 76 amino acids, to protein substrates. This process is catalyzed by 3 enzymes acting in tandem: an E1, ubiquitin-activating enzyme; an E2, ubiquitin-carrying enzyme; and an E3, ubiquitin ligase. Ubiquitination is counteracted by deubiquitinating enzymes that deconjugate ubiquitin-modified proteins and rescue the substrate from proteasomal degradation. Although ubiquitination is known to target many GPCRs for lysosomal or proteasomal degradation, emerging findings define novel roles for the basal status of ubiquitination and for rapid deubiquitination and transubiquitination controlling cell surface expression and cellular responsiveness of some GPCRs. In this review, we highlight the classical and novel roles of ubiquitin in the regulation of GPCR function, signaling, and trafficking. PMID:23471539

  12. Optical biosensors based on direct coupling of recognition, signal transduction, and amplification

    NASA Astrophysics Data System (ADS)

    Song, Xuedong; Swanson, Basil I.

    1999-02-01

    Highly sensitive, specific and reagent-free optical signal transduction methods for detection of polyvalent proteins have been developed by directly coupling distance-dependent fluorescence self-quenching and/or resonant energy transfer to the protein receptor binding events. The ganglioside GM1 as recognition unit for cholera toxin (CT) was covalently labeled with fluorophores, and then incorporated into a biomimetic membrane surface. In the case using fluorescence self-quenching as a signal transduction mechanism, the fluorescence intensity drops significantly due to aggregation of the fluorophore-labeled GM1 on a biomimetic surface. By labeling GM1 with a fluorescence energy transfer pair, aggregation of the labeled-GM1 results in a decrease in donor and an increase in acceptor fluorescence, providing a unique signature for specific protein-receptor binding. The detection systems can reliably detect less than 0.05 nM CT with fast response (less than five minutes). This approach can easily be adapted to any biosensor scheme that relies on multiple receptors or coreceptors. The methods can also be applied to investigate the kinetics and thermodynamics of the multivalent interactions.

  13. Negative Coupling as a Mechanism for Signal Propagation between C2 Domains of Synaptotagmin I

    PubMed Central

    Fealey, Michael E.; Gauer, Jacob W.; Kempka, Sarah C.; Miller, Katie; Nayak, Kamakshi; Sutton, R. Bryan; Hinderliter, Anne

    2012-01-01

    Synaptotagmin I (Syt I) is a vesicle-localized protein implicated in sensing the calcium influx that triggers fast synchronous release of neurotransmitter. How Syt I utilizes its two C2 domains to integrate signals and mediate neurotransmission has continued to be a controversial area of research, though prevalent hypotheses favor independent function. Using differential scanning calorimetry and fluorescence lifetime spectroscopy in a thermodynamic denaturation approach, we tested an alternative hypothesis in which both domains interact to cooperatively disseminate binding information. The free energy of stability was determined for C2A, C2B, and C2AB constructs by globally fitting both methods to a two-state model of unfolding. By comparing the additive free energies of C2A and C2B with C2AB, we identified a negative coupling interaction between the C2 domains of Syt I. This interaction not only provides a mechanistic means for propagating signals, but also a possible means for coordinating the molecular events of neurotransmission. PMID:23071627

  14. Signal enhancement in cantilever magnetometry based on a co-resonantly coupled sensor

    PubMed Central

    Körner, Julia; Reiche, Christopher F; Gemming, Thomas; Büchner, Bernd; Gerlach, Gerald

    2016-01-01

    Summary Cantilever magnetometry is a measurement technique used to study magnetic nanoparticles. With decreasing sample size, the signal strength is significantly reduced, requiring advances of the technique. Ultrathin and slender cantilevers can address this challenge but lead to increased complexity of detection. We present an approach based on the co-resonant coupling of a micro- and a nanometer-sized cantilever. Via matching of the resonance frequencies of the two subsystems we induce a strong interplay between the oscillations of the two cantilevers, allowing for a detection of interactions between the sensitive nanocantilever and external influences in the amplitude response curve of the microcantilever. In our magnetometry experiment we used an iron-filled carbon nanotube acting simultaneously as nanocantilever and magnetic sample. Measurements revealed an enhancement of the commonly used frequency shift signal by five orders of magnitude compared to conventional cantilever magnetometry experiments with similar nanomagnets. With this experiment we do not only demonstrate the functionality of our sensor design but also its potential for very sensitive magnetometry measurements while maintaining a facile oscillation detection with a conventional microcantilever setup. PMID:27547621

  15. Gαi/o-coupled receptor signaling restricts pancreatic β-cell expansion.

    PubMed

    Berger, Miles; Scheel, David W; Macias, Hector; Miyatsuka, Takeshi; Kim, Hail; Hoang, Phuong; Ku, Greg M; Honig, Gerard; Liou, Angela; Tang, Yunshuo; Regard, Jean B; Sharifnia, Panid; Yu, Lisa; Wang, Juehu; Coughlin, Shaun R; Conklin, Bruce R; Deneris, Evan S; Tecott, Laurence H; German, Michael S

    2015-03-03

    Gi-GPCRs, G protein-coupled receptors that signal via Gα proteins of the i/o class (Gαi/o), acutely regulate cellular behaviors widely in mammalian tissues, but their impact on the development and growth of these tissues is less clear. For example, Gi-GPCRs acutely regulate insulin release from pancreatic β cells, and variants in genes encoding several Gi-GPCRs--including the α-2a adrenergic receptor, ADRA2A--increase the risk of type 2 diabetes mellitus. However, type 2 diabetes also is associated with reduced total β-cell mass, and the role of Gi-GPCRs in establishing β-cell mass is unknown. Therefore, we asked whether Gi-GPCR signaling regulates β-cell mass. Here we show that Gi-GPCRs limit the proliferation of the insulin-producing pancreatic β cells and especially their expansion during the critical perinatal period. Increased Gi-GPCR activity in perinatal β cells decreased β-cell proliferation, reduced adult β-cell mass, and impaired glucose homeostasis. In contrast, Gi-GPCR inhibition enhanced perinatal β-cell proliferation, increased adult β-cell mass, and improved glucose homeostasis. Transcriptome analysis detected the expression of multiple Gi-GPCRs in developing and adult β cells, and gene-deletion experiments identified ADRA2A as a key Gi-GPCR regulator of β-cell replication. These studies link Gi-GPCR signaling to β-cell mass and diabetes risk and identify it as a potential target for therapies to protect and increase β-cell mass in patients with diabetes.

  16. Inverse coupling in leak and voltage-activated K+ channel gates underlies distinct roles in electrical signaling.

    PubMed

    Ben-Abu, Yuval; Zhou, Yufeng; Zilberberg, Noam; Yifrach, Ofer

    2009-01-01

    Voltage-activated (Kv) and leak (K(2P)) K(+) channels have key, yet distinct, roles in electrical signaling in the nervous system. Here we examine how differences in the operation of the activation and slow inactivation pore gates of Kv and K(2P) channels underlie their unique roles in electrical signaling. We report that (i) leak K(+) channels possess a lower activation gate, (ii) the activation gate is an important determinant controlling the conformational stability of the K(+) channel pore, (iii) the lower activation and upper slow inactivation gates of leak channels cross-talk and (iv) unlike Kv channels, where the two gates are negatively coupled, these two gates are positively coupled in K(2P) channels. Our results demonstrate how basic thermodynamic properties of the K(+) channel pore, particularly conformational stability and coupling between gates, underlie the specialized roles of Kv and K(2P) channel families in electrical signaling.

  17. The influence of the sample introduction system on signals of different tin compounds in inductively coupled plasma-based techniques

    NASA Astrophysics Data System (ADS)

    Montiel, Javier; Grindlay, Guillermo; Gras, Luis; de Loos-Vollebregt, Margaretha T. C.; Mora, Juan

    2013-03-01

    The influence of the sample introduction system on the signals obtained with different tin compounds in inductively coupled plasma (ICP) based techniques, i.e., ICP atomic emission spectrometry (ICP-AES) and ICP mass spectrometry (ICP-MS) has been studied. Signals for test solutions prepared from four different tin compounds (i.e., tin tetrachloride, monobutyltin, dibutyltin and di-tert-butyltin) in different solvents (methanol 0.8% (w/w), i-propanol 0.8% (w/w) and various acid matrices) have been measured by ICP-AES and ICP-MS. The results demonstrate a noticeable influence of the volatility of the tin compounds on their signals measured with both techniques. Thus, in agreement with the compound volatility, the highest signals are obtained for tin tetrachloride followed by di-tert-butyltin/monobutyltin and dibutyltin. The sample introduction system exerts an important effect on the amount of solution loading the plasma and, hence, on the relative signals afforded by the tin compounds in ICP-based techniques. Thus, when working with a pneumatic concentric nebulizer, the use of spray chambers affording high solvent transport efficiency to the plasma (such as cyclonic and single pass) or high spray chamber temperatures is recommended to minimize the influence of the tin chemical compound. Nevertheless, even when using the conventional pneumatic nebulizer coupled to the best spray chamber design (i.e., a single pass spray chamber), signals obtained for di-tert-butyltin/monobutyltin and dibutyltin are still around 10% and 30% lower than the corresponding signal for tin tetrachloride, respectively. When operating with a pneumatic microconcentric nebulizer coupled to a 50 °C-thermostated cinnabar spray chamber, all studied organotin compounds provided similar emission signals although about 60% lower than those obtained for tin tetrachloride. The use of an ultrasonic nebulizer coupled to a desolvation device provides the largest differences in the emission signals

  18. Mitigating Oscillator Pulling Due To Magnetic Coupling in Monolithic Mixed-Signal Radio-Frequency Integrated Circuits

    SciTech Connect

    Sobering, Ian David

    2014-01-01

    An analysis of frequency pulling in a varactor-tuned LC VCO under coupling from an on-chip PA is presented. The large-signal behavior of the VCO's inversion-mode MOS varactors is outlined, and the susceptibility of the VCO to frequency pulling from PA aggressor signals with various modulation schemes is discussed. We show that if the aggressor signal is aperiodic, band-limited, or amplitude-modulated, the varactor-tuned LC VCO will experience frequency pulling due to time-modulation of the varactor capacitance. However, if the aggressor signal has constant-envelope phase modulation, VCO pulling can be eliminated, even in the presence of coupling, through careful choice of VCO frequency and divider ratio. Additional mitigation strategies, including new inductor topologies and system-level architectural choices, are also examined.

  19. Signalling-Dependent Interactions Between the Kinase-Coupling Protein CheW and Chemoreceptors in Living Cells

    PubMed Central

    Pedetta, Andrea; Parkinson, John S.; Studdert, Claudia A.

    2014-01-01

    Summary Chemical signals sensed on the periplasmic side of bacterial cells by transmembrane chemoreceptors are transmitted to the flagellar motors via the histidine kinase CheA, which controls the phosphorylation level of the effector protein CheY. Chemoreceptor arrays comprise remarkably stable supramolecular structures in which thousands of chemoreceptors are networked through interactions between their cytoplasmic tips, CheA, and the small coupling protein CheW. To explore the conformational changes that occur within this protein assembly during signalling, we used in vivo crosslinking methods to detect close interactions between the coupling protein CheW and the serine receptor Tsr in intact E. coli cells. We identified two signal-sensitive contacts between CheW and the cytoplasmic tip of Tsr. Our results suggest that ligand binding triggers changes in the receptor that alter its signalling contacts with CheW (and/or CheA). PMID:25060668

  20. Coupled Research in Ocean Acoustics and Signal Processing for the Next Generation of Underwater Acoustic Communication Systems

    DTIC Science & Technology

    2015-08-09

    Coupled Research in Ocean Acoustics and Signal Processing for the Next Generation of Underwater Acoustic Communication Systems 5a. CONTRACT NUMBER 5b...Processing for the Next Generation of Underwater Acoustic Communication Systems Principal Investigator’s Name: Dr. James Preisig Period Covered By...correlation structure of received communications signals after they have been converted to the frequency domain via Fourier Transforms as de- scribed in

  1. Coupled Research in Ocean Acoustics and Signal Processing for the Next Generation of Underwater Acoustic Communication Systems

    DTIC Science & Technology

    2016-08-05

    JPAnalytics LLC CC: DCMA Boston DTIC Director, NRL Progress Report #9 Coupled Research in Ocean Acoustics and Signal Processing for the Next Generation...of Underwater Acoustic Communication Systems Principal Investigator’s Name: Dr. James Preisig Period Covered By Report: 4/20/2016 to 7/19/2016 Report...lower dimensional structures in acoustic communications data, specifically fre- quency domain transformations of received communications signals, to

  2. G protein-coupled receptor signaling through Gq and JNK negatively regulates neural progenitor cell migration

    PubMed Central

    Mizuno, Norikazu; Kokubu, Hiroshi; Sato, Maiko; Nishimura, Akiyuki; Yamauchi, Junji; Kurose, Hitoshi; Itoh, Hiroshi

    2005-01-01

    In the early development of the central nervous system, neural progenitor cells divide in an asymmetric manner and migrate along the radial glia cells. The radial migration is an important process for the proper lamination of the cerebral cortex. Recently, a new mode of the radial migration was found at the intermediate zone where the neural progenitor cells become multipolar and reduce the migration rate. However, the regulatory signals for the radial migration are unknown. Using the migration assay in vitro, we examined how neural progenitor cell migration is regulated. Neural progenitor cells derived from embryonic mouse telencephalon migrated on laminin-coated dishes. Endothelin (ET)-1 inhibited the neural progenitor cell migration. This ET-1 effect was blocked by BQ788, a specific inhibitor of the ETB receptor, and by the expression of a carboxyl-terminal peptide of Gαq but not Gαi. The expression of constitutively active mutant of Gαq, GαqR183C, inhibited the migration of neural progenitor cells. Moreover, the inhibitory effect of ET-1 was suppressed by the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the expression of the JNK-binding domain of JNK-interacting protein-1, a specific inhibitor of the JNK pathway. Using the slice culture system of embryonic brain, we demonstrated that ET-1 and the constitutively active mutant of Gαq caused the retention of the neural progenitor cells in the intermediate zone and JNK-binding domain of JNK-interacting protein-1 abrogated the effect of ET-1. These results indicated that G protein-coupled receptor signaling negatively regulates neural progenitor cell migration through Gq and JNK. PMID:16116085

  3. The emerging anthropogenic signal in land-atmosphere carbon-cycle coupling

    NASA Astrophysics Data System (ADS)

    Lombardozzi, Danica; Bonan, Gordon B.; Nychka, Douglas W.

    2014-09-01

    Earth system models simulate prominent terrestrial carbon-cycle responses to anthropogenically forced changes in climate and atmospheric composition over the twenty-first century. The rate and magnitude of the forced climate change is routinely evaluated relative to unforced, or natural, variability using a multi-member ensemble of simulations. However, Earth system model carbon-cycle analyses do not account for unforced variability. To investigate unforced terrestrial carbon-cycle variability, we analyse ensembles from the Coupled Model Intercomparison Project (CMIP5), focusing on the Community Climate System Model (CCSM4). The unforced variability of CCSM4 is comparable to that observed at the Harvard Forest eddy covariance flux tower site. Over the twenty-first century, unforced variability in land-atmosphere CO2 flux is larger than the forced response at decadal timescales in many areas of the world, precluding detection of the forced carbon-cycle change. Only after several decades does the forced carbon signal consistently emerge in CCSM4 and other models for the business-as-usual radiative forcing scenario (RCP8.5). Grid-cell variability in time of emergence is large, but decreases at regional scales. To attribute changes in the terrestrial carbon cycle to anthropogenic forcings, monitoring networks and model projections must consider the timescale at which the forced biogeochemical response emerges from the natural variability.

  4. G protein coupled receptor 18: A potential role for endocannabinoid signaling in metabolic dysfunction.

    PubMed

    Rajaraman, Gayathri; Simcocks, Anna; Hryciw, Deanne H; Hutchinson, Dana S; McAinch, Andrew J

    2016-01-01

    Endocannabinoids are products of dietary fatty acids that are modulated by an alteration in food intake levels. Overweight and obese individuals have substantially higher circulating levels of the arachidonic acid derived endocannabinoids, anandamide and 2-arachidonoyl glycerol, and show an altered pattern of cannabinoid receptor expression. These cannabinoid receptors are part of a large family of G protein coupled receptors (GPCRs). GPCRs are major therapeutic targets for various diseases within the cardiovascular, neurological, gastrointestinal, and endocrine systems, as well as metabolic disorders such as obesity and type 2 diabetes mellitus. Obesity is considered a state of chronic low-grade inflammation elicited by an immunological response. Interestingly, the newly deorphanized GPCR (GPR18), which is considered to be a putative cannabinoid receptor, is proposed to have an immunological function. In this review, the current scientific knowledge on GPR18 is explored including its localization, signaling pathways, and pharmacology. Importantly, the involvement of nutritional factors and potential dietary regulation of GPR18 and its (patho)physiological roles are described. Further research on this receptor and its regulation will enable a better understanding of the complex mechanisms of GPR18 and its potential as a novel therapeutic target for treating metabolic disorders.

  5. New functions and signaling mechanisms for the class of adhesion G protein–coupled receptors

    PubMed Central

    Liebscher, Ines; Ackley, Brian; Araç, Demet; Ariestanti, Donna M.; Aust, Gabriela; Bae, Byoung-il; Bista, Bigyan R.; Bridges, James P.; Duman, Joseph G.; Engel, Felix B.; Giera, Stefanie; Goffinet, André M.; Hall, Randy A.; Hamann, Jörg; Hartmann, Nicole; Lin, Hsi-Hsien; Liu, Mingyao; Luo, Rong; Mogha, Amit; Monk, Kelly R.; Peeters, Miriam C.; Prömel, Simone; Ressl, Susanne; Schiöth, Helgi B.; Sigoillot, Séverine M.; Song, Helen; Talbot, William S.; Tall, Gregory G.; White, James P.; Wolfrum, Uwe; Xu, Lei; Piao, Xianhua

    2014-01-01

    The class of adhesion G protein–coupled receptors (aGPCRs), with 33 human homologs, is the second largest family of GPCRs. In addition to a seven-transmembrane α-helix—a structural feature of all GPCRs—the class of aGPCRs is characterized by the presence of a large N-terminal extracellular region. In addition, all aGPCRs but one (GPR123) contain a GPCR autoproteolysis–inducing (GAIN) domain that mediates autoproteolytic cleavage at the GPCR autoproteolysis site (GPS) motif to generate N- and a C-terminal fragments (NTF and CTF, respectively) during protein maturation. Subsequently, the NTF and CTF are associated non-covalently as a heterodimer at the plasma membrane. While the biological function of the GAIN domain–mediated autocleavage is not fully understood, mounting evidence suggests that the NTF and CTF possess distinct biological activities in addition to their function as a receptor unit. We discuss recent advances in understanding the biological functions, signaling mechanisms, and disease associations of the aGPCRs. PMID:25424900

  6. Ectopic vesicular neurotransmitter release along sensory axons mediates neurovascular coupling via glial calcium signaling.

    PubMed

    Thyssen, Anne; Hirnet, Daniela; Wolburg, Hartwig; Schmalzing, Günther; Deitmer, Joachim W; Lohr, Christian

    2010-08-24

    Neurotransmitter release generally is considered to occur at active zones of synapses, and ectopic release of neurotransmitters has been demonstrated in a few instances. However, the mechanism of ectopic neurotransmitter release is poorly understood. We took advantage of the intimate morphological and functional proximity of olfactory receptor axons and specialized glial cells, olfactory ensheathing cells (OECs), to study ectopic neurotransmitter release. Axonal stimulation evoked purinergic and glutamatergic Ca(2+) responses in OECs, indicating ATP and glutamate release. In axons expressing synapto-pHluorin, stimulation evoked an increase in synapto-pHluorin fluorescence, indicative of vesicle fusion. Transmitter release was dependent on Ca(2+) and could be inhibited by bafilomycin A1 and botulinum toxin A. Ca(2+) transients in OECs evoked by ATP, axonal stimulation, and laser photolysis of NP-EGTA resulted in constriction of adjacent blood vessels. Our results indicate that ATP and glutamate are released ectopically by vesicles along axons and mediate neurovascular coupling via glial Ca(2+) signaling.

  7. Characterization of signaling pathways coupled to melatonin receptors in gastrointestinal smooth muscle.

    PubMed

    Ahmed, Rashad; Mahavadi, Sunila; Al-Shboul, Othman; Bhattacharya, Sayak; Grider, John R; Murthy, Karnam S

    2013-06-10

    Melatonin, a close derivative of serotonin, is involved in physiological regulation of circadian rhythms. In the gastrointestinal (GI) system, melatonin exhibits endocrine, paracrine and autocrine actions and is implicated in the regulation of GI motility. However, it is not known whether melatonin can also act directly on GI smooth muscle cells. The aim of the present study was to determine the expression of melatonin receptors in smooth muscle and identify their signaling pathways. MT1, but not MT2 receptors are expressed in freshly dispersed and cultured gastric smooth muscle cells. Melatonin selectively activated Gq and stimulated phosphoinositide (PI) hydrolysis in freshly dispersed and cultured muscle cells. PI hydrolysis was blocked by the expression of Gq, but not Gi minigene in cultured muscle cells. Melatonin also caused rapid increase in cytosolic Ca(2+) as determined by epifluorescence microscopy in fura-2 loaded single smooth muscle cells, and induced rapid contraction. Melatonin-induced PI hydrolysis and contraction were blocked by a non-selective MT1/MT2 antagonist luzindole (1 μM), but not by a selective MT2 antagonist 4P-PDOT (100 nM), and by the PLC inhibitor U73122. MT2 selective agonist IIK7 (100 nM) had no effect on PI hydrolysis and contraction. We conclude that rabbit gastric smooth muscle cells express melatonin MT1 receptors coupled to Gq. Activation of these receptors causes stimulation of PI hydrolysis and increase in cytosolic Ca(2+), and elicits muscle contraction.

  8. New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors.

    PubMed

    Liebscher, Ines; Ackley, Brian; Araç, Demet; Ariestanti, Donna M; Aust, Gabriela; Bae, Byoung-il; Bista, Bigyan R; Bridges, James P; Duman, Joseph G; Engel, Felix B; Giera, Stefanie; Goffinet, André M; Hall, Randy A; Hamann, Jörg; Hartmann, Nicole; Lin, Hsi-Hsien; Liu, Mingyao; Luo, Rong; Mogha, Amit; Monk, Kelly R; Peeters, Miriam C; Prömel, Simone; Ressl, Susanne; Schiöth, Helgi B; Sigoillot, Séverine M; Song, Helen; Talbot, William S; Tall, Gregory G; White, James P; Wolfrum, Uwe; Xu, Lei; Piao, Xianhua

    2014-12-01

    The class of adhesion G protein-coupled receptors (aGPCRs), with 33 human homologs, is the second largest family of GPCRs. In addition to a seven-transmembrane α-helix-a structural feature of all GPCRs-the class of aGPCRs is characterized by the presence of a large N-terminal extracellular region. In addition, all aGPCRs but one (GPR123) contain a GPCR autoproteolysis-inducing (GAIN) domain that mediates autoproteolytic cleavage at the GPCR autoproteolysis site motif to generate N- and a C-terminal fragments (NTF and CTF, respectively) during protein maturation. Subsequently, the NTF and CTF are associated noncovalently as a heterodimer at the plasma membrane. While the biological function of the GAIN domain-mediated autocleavage is not fully understood, mounting evidence suggests that the NTF and CTF possess distinct biological activities in addition to their function as a receptor unit. We discuss recent advances in understanding the biological functions, signaling mechanisms, and disease associations of the aGPCRs.

  9. COUPLING

    DOEpatents

    Frisch, E.; Johnson, C.G.

    1962-05-15

    A detachable coupling arrangement is described which provides for varying the length of the handle of a tool used in relatively narrow channels. The arrangement consists of mating the key and keyhole formations in the cooperating handle sections. (AEC)

  10. A historical perspective on the lateral diffusion model of GTPase activation and related coupling of membrane signaling proteins

    PubMed Central

    Liebman, Paul A

    2014-01-01

    Aspects of our discovery of lateral diffusion of the G protein coupled receptor (GPCR) rhodopsin and that a single activated rhodopsin can non-covalently catalyze GTP binding to thousands of GTPases per second on rod disk membranes via this diffusion are summarized herein. Rapid GTPase coupling to membrane-bound phosphodiesterase (PDE) further amplifies the signal via cGMP hydrolysis, essential to visual transduction. Important generalizations from this work are that biomembranes can uniquely concentrate, orient for reaction and provide a solvent appropriate to rapid, powerful and appropriately controlled sequential interaction of signaling proteins. Of equal importance to function is timely control and termination of such powerful amplification via receptor phosphorylation (quenching) and arrestin binding. Downstream kinetic modulation by GTPase activating proteins (GAPs) and regulators of G protein signaling (RGS) and related mechanisms as well as limitations set by membrane domain fencing, structural protein binding etc. can be essential in relevant systems. PMID:25279248

  11. The Orphan G Protein-coupled Receptor Gpr175 (Tpra40) Enhances Hedgehog Signaling by Modulating cAMP Levels*

    PubMed Central

    Singh, Jaskirat; Wen, Xiaohui; Scales, Suzie J.

    2015-01-01

    The Hedgehog (Hh) signaling pathway plays an essential role in vertebrate embryonic tissue patterning of many developing organs. Signaling occurs predominantly in primary cilia and is initiated by the entry of the G protein-coupled receptor (GPCR)-like protein Smoothened into cilia and culminates in gene transcription via the Gli family of transcription factors upon their nuclear entry. Here we identify an orphan GPCR, Gpr175 (also known as Tpra1 or Tpra40: transmembrane protein, adipocyte associated 1 or of 40 kDa), which also localizes to primary cilia upon Hh stimulation and positively regulates Hh signaling. Interaction experiments place Gpr175 at the level of PKA and upstream of the Gαi component of heterotrimeric G proteins, which itself localizes to cilia and can modulate Hh signaling. Gpr175 or Gαi1 depletion leads to increases in cellular cAMP levels and in Gli3 processing into its repressor form. Thus we propose that Gpr175 coupled to Gαi1 normally functions to inhibit the production of cAMP by adenylyl cyclase upon Hh stimulation, thus maximizing signaling by turning off PKA activity and hence Gli3 repressor formation. Taken together our data suggest that Gpr175 is a novel positive regulator of the Hh signaling pathway. PMID:26451044

  12. Effects of nonylphenol on the calcium signal and catecholamine secretion coupled with nicotinic acetylcholine receptors in bovine adrenal chromaffin cells.

    PubMed

    Liu, Pei-Shan; Liu, Ging-Hui; Chao, Wei-Liang

    2008-02-03

    Nonylphenol (NP) is the most critical metabolite of alkylphenol polyethoxylate detergents. NP is known as an endocrine disruptor with estrogenic activities and as an inhibitor of endoplasmic reticulum Ca(2+)-ATPase. Estrogen has modulatory roles on ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). Ca(2+)-ATPase inhibitors can modulate the cytosolic calcium concentration ([Ca(2+)](c)]) and thus can affect the calcium signaling coupled with nAChRs. Therefore, NP is predicted to have complex effects on the Ca(2+) signaling and secretion coupled with nAChRs. This study investigated these effects using bovine adrenal chromaffin cells. The results show that NP suppressed the Ca(2+) signaling coupled with nAChRs and voltage-operated Ca(2+) channels in a dose-dependent manner, with IC(50)s of 1 and 5.9 microM, respectively. Estradiol exhibits similar suppression but much lower inhibitory potencies. NP alone induced a transient rise in [Ca(2+)](c) in the presence or absence of extracellular calcium. Thapsigargin, an endoplasmic reticulum Ca(2+)-ATPase inhibitor, partially suppressed the [Ca(2+)](c) rise induced by NP, but NP totally blocked the [Ca(2+)](c) rise induced by thapsigargin. This illustrates that NP can cause Ca(2+) release from thapsigargin-insensitive pools. Thapsigargin suppressed the Ca(2+) signaling coupled with nAChRs but increased that coupled with voltage-operated Ca(2+) channels. We propose that three routes are responsible for the effects of NP on nAChRs: named receptor channels, voltage-gated Ca(2+) channels, and Ca(2+)-induced Ca(2+) release. Three routes are related to the characteristics of NP as steroid-like compounds and Ca(2+)-ATPase inhibitor.

  13. Clustering and Functional Coupling of Diverse Ion Channels and Signaling Proteins Revealed by Super-resolution STORM Microscopy in Neurons.

    PubMed

    Zhang, Jie; Carver, Chase M; Choveau, Frank S; Shapiro, Mark S

    2016-10-19

    The fidelity of neuronal signaling requires organization of signaling molecules into macromolecular complexes, whose components are in intimate proximity. The intrinsic diffraction limit of light makes visualization of individual signaling complexes using visible light extremely difficult. However, using super-resolution stochastic optical reconstruction microscopy (STORM), we observed intimate association of individual molecules within signaling complexes containing ion channels (M-type K(+), L-type Ca(2+), or TRPV1 channels) and G protein-coupled receptors coupled by the scaffolding protein A-kinase-anchoring protein (AKAP)79/150. Some channels assembled as multi-channel supercomplexes. Surprisingly, we identified novel layers of interplay within macromolecular complexes containing diverse channel types at the single-complex level in sensory neurons, dependent on AKAP79/150. Electrophysiological studies revealed that such ion channels are functionally coupled as well. Our findings illustrate the novel role of AKAP79/150 as a molecular coupler of different channels that conveys crosstalk between channel activities within single microdomains in tuning the physiological response of neurons.

  14. Genetic analysis, structural modeling, and direct coupling analysis suggest a mechanism for phosphate signaling in Escherichia coli

    PubMed Central

    2015-01-01

    Background Proper phosphate signaling is essential for robust growth of Escherichia coli and many other bacteria. The phosphate signal is mediated by a classic two component signal system composed of PhoR and PhoB. The PhoR histidine kinase is responsible for phosphorylating/dephosphorylating the response regulator, PhoB, which controls the expression of genes that aid growth in low phosphate conditions. The mechanism by which PhoR receives a signal of environmental phosphate levels has remained elusive. A transporter complex composed of the PstS, PstC, PstA, and PstB proteins as well as a negative regulator, PhoU, have been implicated in signaling environmental phosphate to PhoR. Results This work confirms that PhoU and the PstSCAB complex are necessary for proper signaling of high environmental phosphate. Also, we identify residues important in PhoU/PhoR interaction with genetic analysis. Using protein modeling and docking methods, we show an interaction model that points to a potential mechanism for PhoU mediated signaling to PhoR to modify its activity. This model is tested with direct coupling analysis. Conclusions These bioinformatics tools, in combination with genetic and biochemical analysis, help to identify and test a model for phosphate signaling and may be applicable to several other systems. PMID:25953406

  15. Elevated levels of alpha-synuclein blunt cellular signal transduction downstream of Gq protein-coupled receptors.

    PubMed

    Volta, Mattia; Lavdas, Alexandros A; Obergasteiger, Julia; Überbacher, Christa; Picard, Anne; Pramstaller, Peter P; Hicks, Andrew A; Corti, Corrado

    2017-01-01

    Alpha-synuclein is central to Parkinson's disease pathogenesis and pathology, however its precise functions are still unclear. It has been shown to bind both PLCβ1 and MAPKs, but how this property influences the downstream signaling of Gq protein-coupled receptors has not been elucidated. Here we show that recombinant expression of alpha-synuclein in human neuroblastoma cells enhances cellular levels of PLCβ1 but blunts its signaling pathway, preventing the agonist-dependent rise of cytoplasmic Ca(2+). In addition, overexpressing alpha-synuclein abolishes the activation of ERK1/2 upon agonist stimulation, indicating an upstream action in the signal transduction pathway. This data demonstrates that alpha-synuclein, when recombinantly expressed, interferes with the normal signaling of Gq-protein coupled receptors, which are then dysfunctional. Since many neurotransmitter systems utilize these receptor signaling pathways to mediate different abilities affected in Parkinson's disease, we argue this novel perspective might be helpful in designing treatment strategies for some of the non-motor symptoms in Parkinson's disease and synucleinopathies.

  16. p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling.

    PubMed

    Sheffler, Douglas J; Kroeze, Wesley K; Garcia, Bonnie G; Deutch, Ariel Y; Hufeisen, Sandra J; Leahy, Patrick; Brüning, Jens C; Roth, Bryan L

    2006-03-21

    G protein-coupled receptors (GPCRs) are essential for normal central CNS function and represent the proximal site(s) of action for most neurotransmitters and many therapeutic drugs, including typical and atypical antipsychotic drugs. Similarly, protein kinases mediate many of the downstream actions for both ionotropic and metabotropic receptors. We report here that genetic deletion of p90 ribosomal S6 kinase 2 (RSK2) potentiates GPCR signaling. Initial studies of 5-hydroxytryptamine (5-HT)(2A) receptor signaling in fibroblasts obtained from RSK2 wild-type (+/+) and knockout (-/-) mice showed that 5-HT(2A) receptor-mediated phosphoinositide hydrolysis and both basal and 5-HT-stimulated extracellular signal-regulated kinase 1/2 phosphorylation are augmented in RSK2 knockout fibroblasts. Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, beta1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts. Importantly, reintroduction of RSK2 into RSK2-/- fibroblasts normalized signaling, thus demonstrating that RSK2 apparently modulates GPCR signaling by exerting a "tonic brake" on GPCR signal transduction. Our results imply the existence of a novel pathway regulating GPCR signaling, modulated by downstream members of the extracellular signal-related kinase/mitogen-activated protein kinase cascade. The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis. Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations.

  17. Frontal top-down signals increase coupling of auditory low-frequency oscillations to continuous speech in human listeners.

    PubMed

    Park, Hyojin; Ince, Robin A A; Schyns, Philippe G; Thut, Gregor; Gross, Joachim

    2015-06-15

    Humans show a remarkable ability to understand continuous speech even under adverse listening conditions. This ability critically relies on dynamically updated predictions of incoming sensory information, but exactly how top-down predictions improve speech processing is still unclear. Brain oscillations are a likely mechanism for these top-down predictions [1, 2]. Quasi-rhythmic components in speech are known to entrain low-frequency oscillations in auditory areas [3, 4], and this entrainment increases with intelligibility [5]. We hypothesize that top-down signals from frontal brain areas causally modulate the phase of brain oscillations in auditory cortex. We use magnetoencephalography (MEG) to monitor brain oscillations in 22 participants during continuous speech perception. We characterize prominent spectral components of speech-brain coupling in auditory cortex and use causal connectivity analysis (transfer entropy) to identify the top-down signals driving this coupling more strongly during intelligible speech than during unintelligible speech. We report three main findings. First, frontal and motor cortices significantly modulate the phase of speech-coupled low-frequency oscillations in auditory cortex, and this effect depends on intelligibility of speech. Second, top-down signals are significantly stronger for left auditory cortex than for right auditory cortex. Third, speech-auditory cortex coupling is enhanced as a function of stronger top-down signals. Together, our results suggest that low-frequency brain oscillations play a role in implementing predictive top-down control during continuous speech perception and that top-down control is largely directed at left auditory cortex. This suggests a close relationship between (left-lateralized) speech production areas and the implementation of top-down control in continuous speech perception.

  18. Signal-transduction pathways that regulate visceral smooth muscle function. III. Coupling of muscarinic receptors to signaling kinases and effector proteins in gastrointestinal smooth muscles.

    PubMed

    Gerthoffer, William T

    2005-05-01

    Stimulation of muscarinic M3 and M2 receptors on gastrointestinal smooth muscle elicits contraction via activation of G proteins that are coupled to a diverse set of downstream signaling pathways and effector proteins. Many studies suggest a canonical excitation-contraction coupling pathway that includes activation of phospholipases, production of inositol 1,4,5-trisphosphate and diacylglycerol, release of calcium from the sarcoplasmic reticulum, activation of L-type calcium channels, and activation of nonselective cation channels. These events lead to elevated intracellular calcium concentration, which activates myosin light chain kinase to phosphorylate and activate myosin II thus causing contraction. In addition, muscarinic receptors are coupled to signaling pathways that modulate the effect of activator calcium. The Rho/Rho kinase pathway inhibits myosin light chain phosphatase, one of the key steps in sensitization of the contractile proteins to calcium. Phosphatidylinositol 3-kinases and Src family tyrosine kinases are also activated by muscarinic agonists. Src family tyrosine kinases regulate L-type calcium and nonselective cation channels. Src activation also leads to activation of ERK and p38 MAPKs. ERK MAPKs phosphorylate caldesmon, an actin filament binding protein. P38 MAPKs activate phospholipases and MAPKAP kinase 2/3, which phosphorylate HSP27. HSP27 may regulate cross-bridge function, actin filament formation, and actin filament attachment to the cell membrane. In addition to the well-known role of M3 muscarinic receptors to regulate myoplasmic calcium levels, the integrated effect of muscarinic activation probably also includes signaling pathways that modulate phospholipases, cyclic nucleotides, contractile protein function, and cytoskeletal protein function.

  19. The G protein-coupled receptor N-terminus and receptor signalling: N-tering a new era.

    PubMed

    Coleman, James L J; Ngo, Tony; Smith, Nicola J

    2017-05-01

    G protein-coupled receptors (GPCRs) are a vast family of membrane-traversing proteins, essential to the ability of eukaryotic life to detect, and mount an intracellular response to, a diverse range of extracellular stimuli. GPCRs have evolved with archetypal features including an extracellular N-terminus and intracellular C-terminus that flank a transmembrane structure of seven sequential helices joined by intracellular and extracellular loops. These structural domains contribute to the ability of a GPCR to be correctly synthesised and inserted into the cell membrane, to interact with its cognate ligand(s) and to couple with signal-transducing heterotrimeric G proteins, allowing the activated receptor to selectively modulate a number of signalling cascades. Whilst well known for its importance in receptor translation and trafficking, the GPCR N-terminus is underexplored as a participant in receptor signalling. This review aims to discuss and integrate recent advances in knowledge of the vital roles of the GPCR N-terminus in receptor signalling.

  20. G-protein-coupled receptors and localized signaling in the primary cilium during ventral neural tube patterning.

    PubMed

    Hwang, Sun-Hee; Mukhopadhyay, Saikat

    2015-01-01

    The primary cilium is critical in sonic hedgehog (Shh)-dependent ventral patterning of the vertebrate neural tube. Most mutants that cause disruption of the cilium result in decreased Shh signaling in the neural tube. In contrast, mutations in the intraflagellar complex A (IFT-A) and the tubby family protein, Tulp3, result in increased Shh signaling in the neural tube. Proteomic analysis of Tulp3-binding proteins first pointed to the role of the IFT-A complex in trafficking Tulp3 into the cilia. Tulp3 directs trafficking of rhodopsin family G-protein-coupled receptors (GPCRs) to the cilia, suggesting the role of a GPCR in mediating the paradoxical effects of the Tulp3/IFT-A complex in causing increased Shh signaling. Gpr161 has recently been identified as a Tulp3/IFT-A-regulated GPCR that localizes to the primary cilium. A null knock-out mouse model of Gpr161 phenocopies Tulp3 and IFT-A mutants, and causes increased Shh signaling throughout the neural tube. In the absence of Shh, the bifunctional Gli transcription factors are proteolytically processed into repressor forms in a protein kinase A (PKA) -dependent and cilium-dependent manner. Gpr161 activity results in increased cAMP levels in a Gαs -coupled manner, and determines processing of Gli3. Shh signaling also results in removal of Gpr161 from the cilia, suggesting that Gpr161 functions in a positive feedback loop in the Shh pathway. As PKA-null and Gαs mutant embryos also exhibit increased Shh signaling in the neural tube, Gpr161 is a strong candidate for a GPCR that regulates ciliary cAMP levels, and activates PKA in close proximity to the cilia.

  1. The evolving role of lipid rafts and caveolae in G protein-coupled receptor signaling: implications for molecular pharmacology.

    PubMed

    Ostrom, Rennolds S; Insel, Paul A

    2004-09-01

    The many components of G-protein-coupled receptor (GPCR) signal transduction provide cells with numerous combinations with which to customize their responses to hormones, neurotransmitters, and pharmacologic agonists. GPCRs function as guanine nucleotide exchange factors for heterotrimeric (alpha, beta, gamma) G proteins, thereby promoting exchange of GTP for GDP and, in turn, the activation of 'downstream' signaling components. Recent data indicate that individual cells express mRNA for perhaps over 100 different GPCRs (out of a total of nearly a thousand GPCR genes), several different combinations of G-protein subunits, multiple regulators of G-protein signaling proteins (which function as GTPase activating proteins), and various isoforms of downstream effector molecules. The differential expression of such protein combinations allows for modulation of signals that are customized for a specific cell type, perhaps at different states of maturation or differentiation. In addition, in the linear arrangement of molecular interactions involved in a given GPCR-G-protein-effector pathway, one needs to consider the localization of receptors and post-receptor components in subcellular compartments, microdomains, and molecular complexes, and to understand the movement of proteins between these compartments. Co-localization of signaling components, many of which are expressed at low overall concentrations, allows cells to tailor their responses by arranging, or spatially organizing in unique and kinetically favorable ways, the molecules involved in GPCR signal transduction. This review focuses on the role of lipid rafts and a subpopulation of such rafts, caveolae, as a key spatial compartment enriched in components of GPCR signal transduction. Recent data suggest cell-specific patterns for expression of those components in lipid rafts and caveolae. Such domains likely define functionally important, cell-specific regions of signaling by GPCRs and drugs active at those GPCRs.

  2. Functional coupling of acoustic and chemical signals in the courtship behaviour of the male Drosophila melanogaster.

    PubMed Central

    Rybak, F; Sureau, G; Aubin, T

    2002-01-01

    During courtship, the male Drosophila melanogaster sends signals to the female through two major sensory channels: chemical and acoustic. These signals are involved in the stimulation of the female to accept copulation. In order to determine the respective importance in the courtship of these signals, their production was controlled using genetical and surgical techniques. Males deprived of the ability to emit both signals are unable to mate, demonstrating that other (e.g. visual or tactile) signals are not sufficient to stimulate the female. If either acoustic or chemical signals are lacking, the courtship success is strongly reduced, the lack of the former having significantly more drastic effects. However, the accelerated matings of males observed with males bearing wild-type hydrocarbons compared with defective ones, whichever the modality of acoustic performance (wing vibration or playback), strongly support the role of cuticular compounds to stimulate females. We can conclude that among the possible factors involved in communication during courtship, acoustic and chemical signals may act in a synergistic way and not separately in D. melanogaster. PMID:11934360

  3. Preferences of rhodamine coupled (aminoalkyl)-piperazine probes towards Hg(II) ion and their FRET mediated signaling.

    PubMed

    Biswal, Biswonath; Bag, Bamaprasad

    2013-08-14

    The metal ion induced absorption and emission signaling pattern of rhodamine coupled bis-(aminopropyl)-piperazine (1-3) and (aminoethyl)-piperazine (4) based probes evaluated in MeCN as well as in an MeCN-H2O binary mixture medium revealed that these probes exhibit optical signaling perturbations to a varying extent in MeCN, however, their complexation induced signaling could be tuned selectively towards Hg(II) in the presence of an aqueous component in the solvent medium where competitive interactions such as metal-probe interactions and hydration of metal ions play the determining factor to induce aqueous promoted Hg(II) selectivity. Attachment of another fluorophore (anthracene and nitrobenzofurazan moieties in 2 and 3 respectively) at the other end of the rhodamine coupled bis-(aminopropyl)-piperazine receptor enabled these probes to facilitate a complexation induced fluorescence resonance energy transfer (FRET) from the excited fluorophore to the ring-opened rhodamine along with contributions through operative PET inhibition and rhodamine delactonization processes. The enhancement in absorption transition of these probes at ~557 nm upon selective Hg(II)-complexation and consequent colourless to pink colour change in the solution imply a chromogenic signaling pattern whereas simultaneous fluorescence amplification and/or FRET initiation lead to fluorogenic signaling to facilitate detection at lower concentration. The Hg(II)-selective photo-physical spectral modulation in the presence of other competitive metal ions, and their reversible dual channel signaling pattern under the action of counter anions or chelating agents such as EDTA or ethylenediamine establish the potential of these probes for highly selective, sensitive and reversible 'OFF-ON-OFF' detection of Hg(II). The complexation induced optical signaling pattern of probes with a propyl-linker in their receptor (1-3) in comparison with that of 4 consisting of an ethyl-spacer indicate that signaling

  4. Semi-real-time monitoring of cracking on couplings by neural network analysis of acoustic emission signals

    NASA Astrophysics Data System (ADS)

    Godinez-Azcuaga, Valery F.; Shu, Fong; Finlayson, Richard D.; O'Donnell, Bruce W.

    2004-07-01

    This paper presents the results obtained during the development of a semi-real-time monitoring methodology based on Neural Network Pattern Recognition of Acoustic Emission (AE) signals for early detection of cracks in couplings used in aircraft and engine drive systems. AE signals were collected in order to establish a baseline of a gear-testing fixture background noise and its variations due to rotational speed and torque. Also, simulated cracking signals immersed in background noise were collected. EDM notches were machined in the driving gear and the load on the gearbox was increased until damaged was induced. Using these data, a Neural Network Signal Classifier (NNSC) was implemented and tested. The testing showed that the NNSC was capable of correctly identifying six different classes of AE signals corresponding to different gearbox operation conditions. Also, a semi-real-time classification software was implemented. This software includes functions that allow the user to view and classify AE data from a dynamic process as they are recorded at programmable time intervals. The software is capable of monitoring periodic statistics of AE data, which can be used as an indicator of damage presence and severity in a dynamic system. The semi-real-time classification software was successfully tested in situations where a delay of 10 seconds between data acquisition and classification was achieved with a hit rate of 50 hits/second per channel on eight active AE channels.

  5. Insights into Basal Signaling Regulation, Oligomerization, and Structural Organization of the Human G-Protein Coupled Receptor 83

    PubMed Central

    Scheerer, Patrick; Biebermann, Heike; Kleinau, Gunnar

    2016-01-01

    The murine G-protein coupled receptor 83 (mGPR83) is expressed in the hypothalamus and was previously suggested to be involved in the regulation of metabolism. The neuropeptide PEN has been recently identified as a potent GPR83 ligand. Moreover, GPR83 constitutes functionally relevant hetero-oligomers with other G-protein coupled receptors (GPCR) such as the ghrelin receptor (GHSR) or GPR171. Previous deletion studies also revealed that the long N-terminal extracellular receptor domain (eNDo) of mGPR83 may act as an intra-molecular ligand, which participates in the regulation of basal signaling activity, which is a key feature of GPCR function. Here, we investigated particular amino acids at the eNDo of human GPR83 (hGPR83) by side-directed mutagenesis to identify determinants of the internal ligand. These studies were accompanied by structure homology modeling to combine functional insights with structural information. The capacity for hetero-oligomer formation of hGPR83 with diverse family A GPCRs such as the melanocortin-4 receptor (MC4R) was also investigated, with a specific emphasis on the impact of the eNDo on oligomerization and basal signaling properties. Finally, we demonstrate that hGPR83 exhibits an unusual basal signaling for different effectors, which also supports signaling promiscuity. hGPR83 interacts with a variety of hypothalamic GPCRs such as the MC4R or GHSR. These interactions are not dependent on the ectodomain and most likely occur at interfaces constituted in the transmembrane regions. Moreover, several amino acids at the transition between the eNDo and transmembrane helix 1 were identified, where mutations lead also to biased basal signaling modulation. PMID:27936173

  6. Endocannabinoid-mediated modulation of Gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension.

    PubMed

    Szekeres, Mária; Nádasy, György L; Turu, Gábor; Soltész-Katona, Eszter; Benyó, Zoltán; Offermanns, Stefan; Ruisanchez, Éva; Szabó, Eszter; Takáts, Zoltán; Bátkai, Sándor; Tóth, Zsuzsanna E; Hunyady, László

    2015-03-05

    Activation of G protein-coupled receptors (GPCRs) can induce vasoconstriction via calcium signal-mediated and Rho-dependent pathways. Earlier reports have shown that diacylglycerol produced during calcium signal generation can be converted to an endocannabinoid, 2-arachidonoylglycerol (2-AG). Our aim was to provide evidence that GPCR signaling-induced 2-AG production and activation of vascular type1 cannabinoid receptors (CB1R) is capable of reducing agonist-induced vasoconstriction and hypertension. Rat and mouse aortic rings were examined by myography. Vascular expression of CB1R was demonstrated with immunohistochemistry. Rat aortic vascular smooth muscle cells (VSMCs) were cultured for calcium measurements and 2-AG-determination. Inhibition or genetic loss of CB1Rs enhanced vasoconstriction induced by angiotensin II (AngII) or phenylephrine (Phe), but not by prostaglandin(PG)F2α. AngII-induced vasoconstriction was augmented by inhibition of diacylglycerol lipase (tetrahydrolipstatin) and was attenuated by inhibition of monoacylglycerol lipase (JZL184) suggesting a functionally relevant role for endogenously produced 2-AG. In Gαq/11-deficient mice vasoconstriction was absent to AngII or Phe, which activate Gq/11-coupled receptors, but was maintained in response to PGF2α. In VSMCs, AngII-stimulated 2-AG-formation was inhibited by tetrahydrolipstatin and potentiated by JZL184. CB1R inhibition increased the sustained phase of AngII-induced calcium signal. Pharmacological or genetic loss of CB1R function augmented AngII-induced blood pressure rise in mice. These data demonstrate that vasoconstrictor effect of GPCR agonists is attenuated via Gq/11-mediated vascular endocannabinoid formation. Agonist-induced endocannabinoid-mediated CB1R activation is a significant physiological modulator of vascular tone. Thus, the selective modulation of GPCR signaling-induced endocannabinoid release has a therapeutic potential in case of increased vascular tone and hypertension.

  7. The Novel Functions of the PLC/PKC/PKD Signaling Axis in G Protein-Coupled Receptor-Mediated Chemotaxis of Neutrophils

    PubMed Central

    Xu, Xuehua; Jin, Tian

    2015-01-01

    Chemotaxis, a directional cell migration guided by extracellular chemoattractant gradients, plays an essential role in the recruitment of neutrophils to sites of inflammation. Chemotaxis is mediated by the G protein-coupled receptor (GPCR) signaling pathway. Extracellular stimuli trigger activation of the PLC/PKC/PKD signaling axis, which controls several signaling pathways. Here, we concentrate on the novel functions of PLC/PKC/PKD signaling in GPCR-mediated chemotaxis of neutrophils. PMID:26605346

  8. Phosphoinositides in Ca(2+) signaling and excitation-contraction coupling in skeletal muscle: an old player and newcomers.

    PubMed

    Csernoch, Laszlo; Jacquemond, Vincent

    2015-12-01

    Since the postulate, 30 years ago, that phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2) as the precursor of inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3) would be critical for skeletal muscle excitation-contraction (EC) coupling, the issue of whether phosphoinositides (PtdInsPs) may have something to do with Ca(2+) signaling in muscle raised limited interest, if any. In recent years however, the PtdInsP world has expanded considerably with new functions for PtdIns(4,5)P 2 but also with functions for the other members of the PtdInsP family. In this context, the discovery that genetic deficiency in a PtdInsP phosphatase has dramatic consequences on Ca(2+) homeostasis in skeletal muscle came unanticipated and opened up new perspectives in regards to how PtdInsPs modulate muscle Ca(2+) signaling under normal and disease conditions. This review intends to make an update of the established, the questioned, and the unknown regarding the role of PtdInsPs in skeletal muscle Ca(2+) homeostasis and EC coupling, with very specific emphasis given to Ca(2+) signals in differentiated skeletal muscle fibers.

  9. Stress and glucocorticoids impair memory retrieval via β2-adrenergic, Gi/o-coupled suppression of cAMP signaling.

    PubMed

    Schutsky, Keith; Ouyang, Ming; Castelino, Christina B; Zhang, Lei; Thomas, Steven A

    2011-10-05

    Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/or blocking the reuptake of norepinephrine (NE), a stress-responsive neurotransmitter. It has also been proposed that this enhanced NE signaling impairs memory retrieval by stimulating β(1)-adrenergic receptors and elevating levels of cAMP. In contrast, other evidence indicates that NE, β(1), and cAMP signaling is transiently required for the retrieval of hippocampus-dependent memory. To resolve this discrepancy, wild-type rats and mice with and without gene-targeted mutations were stressed or treated with glucocorticoids and/or adrenergic receptor drugs before testing memory for inhibitory avoidance or fear conditioning. Here we report that glucocorticoids do not require NE to impair retrieval. However, stress- and glucocorticoid-induced impairments of retrieval depend on the activation of β(2) (but not β(1))-adrenergic receptors. Offering an explanation for the opposing functions of these two receptors, the impairing effects of stress, glucocorticoids and β(2) agonists on retrieval are blocked by pertussis toxin, which inactivates signaling by G(i/o)-coupled receptors. In hippocampal slices, β(2) signaling decreases cAMP levels and greatly reduces the increase in cAMP mediated by β(1) signaling. Finally, augmenting cAMP signaling in the hippocampus prevents the impairment of retrieval by systemic β(2) agonists or glucocorticoids. These results demonstrate that the β(2) receptor can be a critical effector of acute stress, and that β(1) and β(2) receptors can have quite distinct roles in CNS signaling and cognition.

  10. FGFR4 signaling couples to Bim and not Bmf to discriminate subsets of alveolar rhabdomyosarcoma cells.

    PubMed

    Wachtel, Marco; Rakic, Jelena; Okoniewski, Michal; Bode, Peter; Niggli, Felix; Schäfer, Beat W

    2014-10-01

    Biological heterogeneity represents a major obstacle for cancer treatment. Therefore, characterization of treatment-relevant tumor heterogeneity is necessary to develop more effective therapies in the future. Here, we uncovered population heterogeneity among PAX/FOXO1-positive alveolar rhabdomyosarcoma by characterizing prosurvival networks initiated by FGFR4 signaling. We found that FGFR4 signaling rescues only subgroups of alveolar rhabdomyosarcoma cells from apoptosis induced by compounds targeting the IGF1R-PI3K-mTOR pathway. Differences in both proapoptotic machinery and FGFR4-activated signaling are involved in the different behavior of the phenotypes. Proapoptotic stress induced by the kinase inhibitors is sensed by Bim/Bad in rescue cells and by Bmf in nonrescue cells. Anti-apoptotic ERK1/2 signaling downstream of FGFR4 is long-lasting in rescue and short-termed in most non-rescue cells. Gene expression analysis detected signatures specific for these two groups also in biopsy samples. The different cell phenotypes are present in different ratios in alveolar rhabdomyosarcoma tumors and can be identified by AP2β expression levels. Hence, inhibiting FGFR signaling might represent an important strategy to enhance efficacy of current RMS treatments.

  11. Interaction of structure-specific and promiscuous G-protein-coupled receptors mediates small-molecule signaling in Caenorhabditis elegans.

    PubMed

    Park, Donha; O'Doherty, Inish; Somvanshi, Rishi K; Bethke, Axel; Schroeder, Frank C; Kumar, Ujendra; Riddle, Donald L

    2012-06-19

    A chemically diverse family of small-molecule signals, the ascarosides, control developmental diapause (dauer), olfactory learning, and social behaviors of the nematode model organism, Caenorhabditis elegans. The ascarosides act upstream of conserved signaling pathways, including the insulin, TGF-β, serotonin, and guanylyl cyclase pathways; however, the sensory processes underlying ascaroside function are poorly understood. Because ascarosides often are multifunctional and show strongly synergistic effects, characterization of their receptors will be essential for understanding ascaroside biology and may provide insight into molecular mechanisms that produce synergistic outcomes in small-molecule sensing. Based on DAF-8 immunoprecipitation, we here identify two G-protein-coupled receptors, DAF-37 and DAF-38, which cooperatively mediate ascaroside perception. daf-37 mutants are defective in all responses to ascr#2, one of the most potent dauer-inducing ascarosides, although this mutant responds normally to other ascarosides. In contrast, daf-38 mutants are partially defective in responses to several different ascarosides. Through cell-specific overexpression, we show that DAF-37 regulates dauer when expressed in ASI neurons and adult behavior when expressed in ASK neurons. Using a photoaffinity-labeled ascr#2 probe and amplified luminescence assays (AlphaScreen), we demonstrate that ascr#2 binds to DAF-37. Photobleaching fluorescent energy transfer assays revealed that DAF-37 and DAF-38 form heterodimers, and we show that heterodimerization strongly increases cAMP inhibition in response to ascr#2. These results suggest that that the ascarosides' intricate signaling properties result in part from the interaction of highly structure-specific G-protein-coupled receptors such as DAF-37 with more promiscuous G-protein-coupled receptors such as DAF-38.

  12. Interaction of structure-specific and promiscuous G-protein–coupled receptors mediates small-molecule signaling in Caenorhabditis elegans

    PubMed Central

    Park, Donha; O'Doherty, Inish; Somvanshi, Rishi K.; Bethke, Axel; Schroeder, Frank C.; Kumar, Ujendra; Riddle, Donald L.

    2012-01-01

    A chemically diverse family of small-molecule signals, the ascarosides, control developmental diapause (dauer), olfactory learning, and social behaviors of the nematode model organism, Caenorhabditis elegans. The ascarosides act upstream of conserved signaling pathways, including the insulin, TGF-β, serotonin, and guanylyl cyclase pathways; however, the sensory processes underlying ascaroside function are poorly understood. Because ascarosides often are multifunctional and show strongly synergistic effects, characterization of their receptors will be essential for understanding ascaroside biology and may provide insight into molecular mechanisms that produce synergistic outcomes in small-molecule sensing. Based on DAF-8 immunoprecipitation, we here identify two G-protein–coupled receptors, DAF-37 and DAF-38, which cooperatively mediate ascaroside perception. daf-37 mutants are defective in all responses to ascr#2, one of the most potent dauer-inducing ascarosides, although this mutant responds normally to other ascarosides. In contrast, daf-38 mutants are partially defective in responses to several different ascarosides. Through cell-specific overexpression, we show that DAF-37 regulates dauer when expressed in ASI neurons and adult behavior when expressed in ASK neurons. Using a photoaffinity-labeled ascr#2 probe and amplified luminescence assays (AlphaScreen), we demonstrate that ascr#2 binds to DAF-37. Photobleaching fluorescent energy transfer assays revealed that DAF-37 and DAF-38 form heterodimers, and we show that heterodimerization strongly increases cAMP inhibition in response to ascr#2. These results suggest that that the ascarosides' intricate signaling properties result in part from the interaction of highly structure-specific G-protein–coupled receptors such as DAF-37 with more promiscuous G-protein–coupled receptors such as DAF-38. PMID:22665789

  13. Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria.

    PubMed

    Hernandez, Lidia; Roux, Kyle J; Wong, Esther Sook Miin; Mounkes, Leslie C; Mutalif, Rafidah; Navasankari, Raju; Rai, Bina; Cool, Simon; Jeong, Jae-Wook; Wang, Honghe; Lee, Hyun-Shik; Kozlov, Serguei; Grunert, Martin; Keeble, Thomas; Jones, C Michael; Meta, Margarita D; Young, Stephen G; Daar, Ira O; Burke, Brian; Perantoni, Alan O; Stewart, Colin L

    2010-09-14

    The segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation. The defects are associated with inhibition of canonical Wnt signaling, due to reduced nuclear localization and transcriptional activity of Lef1, but not Tcf4, in both mouse and human progeric cells. Defective Wnt signaling, affecting ECM synthesis, may be critical to the etiology of HGPS because mice exhibit skeletal defects and apoptosis in major blood vessels proximal to the heart. These results establish a functional link between the nuclear envelope/lamina and the cell surface/ECM and may provide insights into the role of Wnt signaling and the ECM in aging.

  14. A Probe of Magnetosphere-Ionosphere Coupling using the Propagation Characteristics of Very Low Frequency Signal

    NASA Astrophysics Data System (ADS)

    Nwankwo, V. U. J.; Chakrabarti, S. K.; Ogunmodimu, O. A.

    2015-12-01

    The amplitude and phase of VLF/LF radio signal are sensitive to changes in the electrical conductivity of the lower ionosphere when propagated in the Earth-ionosphere waveguide. This unique characteristic makes it useful in studying sudden ionospheric disturbances and/or anomaly especially those related to prompt X-ray flux output from solar flares and gamma ray bursts (GRBs). However, strong geomagnetic disturbances and/or storm conditions are known to produce large and global ionospheric disturbances, which can significantly affect VLF radio propagation in the D region ionosphere. Other than X-ray flux enhancement of amplitude and phase, diurnal VLF signature may convey other important information especially those related to geomagnetic disturbance/storm induced ionospheric changes. In this paper, using the data of three propagation paths (at latitudes 40-54), we performed detail analysis of the trend of variations of aspects VLF diurnal signal under varying solar and/or geomagnetic space environmental conditions for identification of possible geomagnetic footprint on the ionosphere. We found that trend of variations significantly reflected the prevailing space weather conditions of various time scales. The `dipping' of the signal diurnal amplitude have shown noteworthy consistency with significantly geomagnetic perturbed and/or storm conditions in the time scale of 1-2 days. We also found that dipping of most MDP signal occurred irrespective of the time (of the day), which an event happened, while those of MBSR, MASS, SRT and SST appear to largely depend on event occurrence time and/or duration. Pre-sunset event had more influence on the SST and MASS (dusk signal), while pre-sunrise event had more influence on the SRT and MBSR (dawn signal), and depending on the duration of the event, impact could be extended to the neighbouring point/component in succession. The induced dipping varied with geomagnetic activity/event intensity and/or duration, as well as the

  15. Excitation of sidebands due to nonlinear coupling between a VLF transmitter signal and a natural ELF emission

    SciTech Connect

    Sotnikov, V.I.; Fiala, V.; Lefeuvre, F.; Lagoutte, D. ); Mogilevsky, M. )

    1991-07-01

    Symmetric sidebands are observed in the ionosphere by the AUREOL 3 satellite when it passes at a height of 1,200 km above the VLF transmitter at the Komsomolsk-on-Amur Alpha station (50{degree}5 N, 135{degree} E, frequency 11.90 and 12.65 kHz). The sidebands are about 500 Hz off the carrier frequency of Alpha pulses. They are approximately 20 dB lower than the transmitter signal, and they appear only when ELF natural emission above the local proton gyrofrequency is observed. The data are presented and analyzed. The nonlinear coupling of the VLF transmitter signal to natural ELF emission is invoked to explain the symmetric sidebands. It is shown that the nonlinear current excited by the beats of VLF and ELF waves is strong enough to explain the sideband amplitude.

  16. G-protein Coupled Receptor Signaling in Pluripotent Stem Cell-derived Cardiovascular Cells: Implications for Disease Modeling

    PubMed Central

    Dolatshad, Nazanin F.; Hellen, Nicola; Jabbour, Richard J.; Harding, Sian E.; Földes, Gabor

    2015-01-01

    Human pluripotent stem cell derivatives show promise as an in vitro platform to study a range of human cardiovascular diseases. A better understanding of the biology of stem cells and their cardiovascular derivatives will help to understand the strengths and limitations of this new model system. G-protein coupled receptors (GPCRs) are key regulators of stem cell maintenance and differentiation and have an important role in cardiovascular cell signaling. In this review, we will therefore describe the state of knowledge concerning the regulatory role of GPCRs in both the generation and function of pluripotent stem cell derived-cardiomyocytes, -endothelial, and -vascular smooth muscle cells. We will consider how far the in vitro disease models recapitulate authentic GPCR signaling and provide a useful basis for discovery of disease mechanisms or design of therapeutic strategies. PMID:26697426

  17. Functional MRI during Hyperbaric Oxygen: Effects of Oxygen on Neurovascular Coupling and BOLD fMRI signals

    PubMed Central

    Cardenas, Damon P.; Muir, Eric R.; Huang, Shiliang; Boley, Angela; Lodge, Daniel; Duong, Timothy Q.

    2015-01-01

    Hyperbaric oxygen (HBO) therapy is used to treat a number of ailments. Improved understanding of how HBO affects neuronal activity, cerebral blood flow (CBF) and blood-oxygenation-level dependent (BOLD) changes could shed light on the role of oxygen in neurovascular coupling and help guide HBO treatments. The goal of this study was to test two hypotheses: i) activation-induced CBF fMRI response is not dependent on hemoglobin deoxygenation, and ii) activation-induced BOLD fMRI is markedly attenuated under HBO. CBF and BOLD fMRI of forepaw stimulation in anesthetized rats under HBO at 3 atmospheres absolute (ATA) was compared with normobaric air. Robust BOLD and CBF fMRI were detected under HBO. Inflow effects and spin-density changes did not contribute significantly to the BOLD fMRI signal under HBO. Analysis of the T2*-weighted signal at normobaric air and 1, 2 and 3ATA oxygen in the tissue and the superior sagittal sinus showed a strong dependence on increasing inhaled [O2]. Spontaneous electrophysiological activity and evoked local-field potentials were reduced under HBO. The differences between normobaric air and HBO in basal and evoked electrical activity could not fully account for the strong BOLD responses under HBO. We concluded that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism and that stimulus-evoked BOLD responses and the venous T2*-weighted signals still have room to increase under 3ATA HBO. To our knowledge, this is the first fMRI study under HBO, providing insights into the effects of HBO on neural activity, neurovascular coupling, tissue oxygenation, and the BOLD signal. PMID:26143203

  18. Realization of synchronization of nonlinear oscillators under intermittent coupling controlled by pulse signal

    NASA Astrophysics Data System (ADS)

    Yuan, L. H.; Wang, C. N.; Zhang, Z. Z.

    2016-10-01

    Based on the Lyapunov stability theory, an improved Lyapunov function scheme is used to understand the complete synchronization of hyperchaotic systems by imposing pulse linear coupling on the response system. According to this scheme, the controller begins to control the response system in a period when the output error variables are increasing; otherwise, the controller turns off. The distribution of conditional Lyapunov exponent versus coupling intensity, and the synchronization cost (averaged power consumption of controller) is calculated, respectively. By designing an exponential type of Lyapunov function, it is found that complete synchronization could be realized between two Chen hyperchaotic systems and two 4-dimensional LC hyperchaotic systems. Our numerical results are consistent with the previous theoretical discussion.

  19. Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction

    PubMed Central

    Bradley, Sophie J.; Iglesias, Max Maza; Kong, Kok Choi; Butcher, Adrian J.; Plouffe, Bianca; Goupil, Eugénie; Bourgognon, Julie-Myrtille; Macedo-Hatch, Timothy; LeGouill, Christian; Russell, Kirsty; Laporte, Stéphane A.; König, Gabriele M.; Kostenis, Evi; Bouvier, Michel; Chung, Kian Fan; Amrani, Yassine; Tobin, Andrew B.

    2016-01-01

    G protein-coupled receptors (GPCRs) are known to initiate a plethora of signaling pathways in vitro. However, it is unclear which of these pathways are engaged to mediate physiological responses. Here, we examine the distinct roles of Gq/11-dependent signaling and receptor phosphorylation-dependent signaling in bronchial airway contraction and lung function regulated through the M3-muscarinic acetylcholine receptor (M3-mAChR). By using a genetically engineered mouse expressing a G protein-biased M3-mAChR mutant, we reveal the first evidence, to our knowledge, of a role for M3-mAChR phosphorylation in bronchial smooth muscle contraction in health and in a disease state with relevance to human asthma. Furthermore, this mouse model can be used to distinguish the physiological responses that are regulated by M3-mAChR phosphorylation (which include control of lung function) from those responses that are downstream of G protein signaling. In this way, we present an approach by which to predict the physiological/therapeutic outcome of M3-mAChR–biased ligands with important implications for drug discovery. PMID:27071102

  20. Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction.

    PubMed

    Bradley, Sophie J; Wiegman, Coen H; Iglesias, Max Maza; Kong, Kok Choi; Butcher, Adrian J; Plouffe, Bianca; Goupil, Eugénie; Bourgognon, Julie-Myrtille; Macedo-Hatch, Timothy; LeGouill, Christian; Russell, Kirsty; Laporte, Stéphane A; König, Gabriele M; Kostenis, Evi; Bouvier, Michel; Chung, Kian Fan; Amrani, Yassine; Tobin, Andrew B

    2016-04-19

    G protein-coupled receptors (GPCRs) are known to initiate a plethora of signaling pathways in vitro. However, it is unclear which of these pathways are engaged to mediate physiological responses. Here, we examine the distinct roles of Gq/11-dependent signaling and receptor phosphorylation-dependent signaling in bronchial airway contraction and lung function regulated through the M3-muscarinic acetylcholine receptor (M3-mAChR). By using a genetically engineered mouse expressing a G protein-biased M3-mAChR mutant, we reveal the first evidence, to our knowledge, of a role for M3-mAChR phosphorylation in bronchial smooth muscle contraction in health and in a disease state with relevance to human asthma. Furthermore, this mouse model can be used to distinguish the physiological responses that are regulated by M3-mAChR phosphorylation (which include control of lung function) from those responses that are downstream of G protein signaling. In this way, we present an approach by which to predict the physiological/therapeutic outcome of M3-mAChR-biased ligands with important implications for drug discovery.

  1. Limb joint effects on signal transmission in capacitive coupled intra-body communication systems.

    PubMed

    Seyedi, MirHojjat; Lai, Daniel T H; Faulkner, Michael

    2012-01-01

    This paper contributes empirical measurements towards an understanding of signal attenuation in intra-body communication (IBC) systems due to limb posture effects. Recent studies have shown a degradation of transmission signals for IBC transmissions between limb segments, but these degradations have yet to be quantified with respect to relative limb position and within the transmission frequency range from 300 KHz to 200 MHz. We examine the impact of limb position specifically the effect of elbow joint flexion and extension into account using a portable vector network analyzer. The results presented indicate that the signal attenuation is larger in the case of extension, i.e., when the angle between forearm and upper arm increases. The minimum attenuation was 20.64 dB and 24.81 dB for the fix distance of 15 cm between transmitter and receiver electrodes and the joint angle of 45 and 180 degree respectively. It was found that attenuation decreased at an approximately linear rate over 300 KHz to 100 MHz and increased over the frequency range from 100 MHz to 200 MHz for the input signal frequency range from 300 KHz to 200 MHz. It was concluded that the minimum attenuation for the range of flexions and extensions occurred in the range 80-100 MHz. Future work will explore theoretical models to explain the observed results.

  2. Detection and Correction of Under-/Overexposed Optical Soundtracks by Coupling Image and Audio Signal Processing

    NASA Astrophysics Data System (ADS)

    Taquet, Jonathan; Besserer, Bernard; Hassaine, Abdelali; Decenciere, Etienne

    2008-12-01

    Film restoration using image processing, has been an active research field during the last years. However, the restoration of the soundtrack has been mainly performed in the sound domain, using signal processing methods, despite the fact that it is recorded as a continuous image between the images of the film and the perforations. While the very few published approaches focus on removing dust particles or concealing larger corrupted areas, no published works are devoted to the restoration of soundtracks degraded by substantial underexposure or overexposure. Digital restoration of optical soundtracks is an unexploited application field and, besides, scientifically rich, because it allows mixing both image and signal processing approaches. After introducing the principles of optical soundtrack recording and playback, this contribution focuses on our first approaches to detect and cancel the effects of under and overexposure. We intentionally choose to get a quantification of the effect of bad exposure in the 1D audio signal domain instead of 2D image domain. Our measurement is sent as feedback value to an image processing stage where the correction takes place, building up a "digital image and audio signal" closed loop processing. The approach is validated on both simulated alterations and real data.

  3. Self-repair in a bidirectionally coupled astrocyte-neuron (AN) system based on retrograde signaling

    PubMed Central

    Wade, John; McDaid, Liam; Harkin, Jim; Crunelli, Vincenzo; Kelso, Scott

    2012-01-01

    In this paper we demonstrate that retrograde signaling via astrocytes may underpin self-repair in the brain. Faults manifest themselves in silent or near silent neurons caused by low transmission probability (PR) synapses; the enhancement of the transmission PR of a healthy neighboring synapse by retrograde signaling can enhance the transmission PR of the “faulty” synapse (repair). Our model of self-repair is based on recent research showing that retrograde signaling via astrocytes can increase the PR of neurotransmitter release at damaged or low transmission PR synapses. The model demonstrates that astrocytes are capable of bidirectional communication with neurons which leads to modulation of synaptic activity, and that indirect signaling through retrograde messengers such as endocannabinoids leads to modulation of synaptic transmission PR. Although our model operates at the level of cells, it provides a new research direction on brain-like self-repair which can be extended to networks of astrocytes and neurons. It also provides a biologically inspired basis for developing highly adaptive, distributed computing systems that can, at fine levels of granularity, fault detect, diagnose and self-repair autonomously, without the traditional constraint of a central fault detect/repair unit. PMID:23055965

  4. Coupled blind signal separation and spectroscopic database fitting of the mid infrared PAH features

    NASA Astrophysics Data System (ADS)

    Rosenberg, M. J. F.; Berné, O.; Boersma, C.; Allamandola, L. J.; Tielens, A. G. G. M.

    2011-08-01

    Context. The aromatic infrared bands (AIBs) observed in the mid infrared spectrum of galactic and extragalactic sources are attributed to polycyclic aromatic hydrocarbons (PAHs). Recently, two new approaches have been developed to analyze the variations of AIBs in terms of chemical evolution of PAH species: blind signal separation (BSS) and the NASA Ames PAH IR Spectroscopic Database fitting tool. Aims: We aim to study AIBs in a photo-dissociation region (PDR) since in these regions, as the radiation environment changes, the evolution of AIBs are observed. Methods: We observe the NGC 7023-north west (NW) PDR in the mid-infrared (10-19.5 μm) using the InfraRed Spectrometer (IRS), on board Spitzer, in the high-resolution, short wavelength mode. Clear variations are observed in the spectra, most notably the ratio of the 11.0 to 11.2 μm bands, the peak position of the 11.2 and 12.0 μm bands, and the degree of asymmetry of the 11.2 μm band. The observed variations appear to change as a function of position within the PDR. We aim to explain these variations by a change in the abundances of the emitting components of the PDR. A blind signal separation (BSS) method, i.e. a Non-Negative Matrix Factorization algorithm is applied to separate the observed spectrum into components. Using the NASA Ames PAH IR Spectroscopic Database, these extracted signals are fit. The observed signals alone were also fit using the database and these components are compared to the BSS components. Results: Three component signals were extracted from the observation using BSS. We attribute the three signals to ionized PAHs, neutral PAHs, and very small grains (VSGs). The fit of the BSS extracted spectra with the PAH database further confirms the attribution to PAH+ and PAH0 and provides confidence in both methods for producing reliable results. Conclusions: The 11.0 μm feature is attributed to PAH+ while the 11.2 μm band is attributed to PAH0. The VSG signal shows a characteristically

  5. Fractional dynamical model for the generation of ECG like signals from filtered coupled Van-der Pol oscillators.

    PubMed

    Das, Saptarshi; Maharatna, Koushik

    2013-12-01

    In this paper, an incommensurate fractional order (FO) model has been proposed to generate ECG like waveforms. Earlier investigation of ECG like waveform generation is based on two identical Van-der Pol (VdP) family of oscillators, which are coupled by time delays and gains. In this paper, we suitably modify the three state equations corresponding to the nonlinear cross-product of states, time delay coupling of the two oscillators and low-pass filtering, using the concept of fractional derivatives. Our results show that a wide variety of ECG like waveforms can be simulated from the proposed generalized models, characterizing heart conditions under different physiological conditions. Such generalization of the modelling of ECG waveforms may be useful to understand the physiological process behind ECG signal generation in normal and abnormal heart conditions. Along with the proposed FO models, an optimization based approach is also presented to estimate the VdP oscillator parameters for representing a realistic ECG like signal.

  6. Coupled Sensing of Hunger and Thirst Signals Balances Sugar and Water Consumption.

    PubMed

    Jourjine, Nicholas; Mullaney, Brendan C; Mann, Kevin; Scott, Kristin

    2016-08-11

    Hunger and thirst are ancient homeostatic drives for food and water consumption. Although molecular and neural mechanisms underlying these drives are currently being uncovered, less is known about how hunger and thirst interact. Here, we use molecular genetic, behavioral, and anatomical studies in Drosophila to identify four neurons that modulate food and water consumption. Activation of these neurons promotes sugar consumption and restricts water consumption, whereas inactivation promotes water consumption and restricts sugar consumption. By calcium imaging studies, we show that these neurons are directly regulated by a hormone signal of nutrient levels and by osmolality. Finally, we identify a hormone receptor and an osmolality-sensitive ion channel that underlie this regulation. Thus, a small population of neurons senses internal signals of nutrient and water availability to balance sugar and water consumption. Our results suggest an elegant mechanism by which interoceptive neurons oppositely regulate homeostatic drives to eat and drink.

  7. Charge Coupled Devices in Signal Processing Systems. Volume V. Final Report.

    DTIC Science & Technology

    1979-12-01

    the inability to directly interconnect two physically separated signal points by means of a metal conductor. The immense difficulty posed by the lack of... physical location to another involves interconnecting these locations through a series of gateb. This method of interconnect has several major...visual check cycle. Prior to this, only the design engineer could effectively check the layouts. A technique for interconnecting physically separated

  8. Convergence of glucose- and fatty acid-induced abnormal myocardial excitation-contraction coupling and insulin signalling.

    PubMed

    Davidoff, Amy J

    2006-01-01

    1. Myocardial insulin resistance and abnormal Ca(2+) regulation are hallmarks of hypertrophic and diabetic hearts, but deprivation of energetic substrates does not tell the whole story. Is there a link between the aetiology of these dysfunctions? 2. Diabetic cardiomyopathy is defined as phenotypic changes in the heart muscle cell independent of associated coronary vascular disease. The cellular consequences of diabetes on excitation-contraction (E-C) coupling and insulin signalling are presented in various models of diabetes in order to set the stage for exploring the pathogenesis of heart disease. 3. Excess glucose or fatty acids can lead to augmented flux through the hexosamine biosynthesis pathway (HBP). The formation of uridine 5 cent-diphosphate-hexosamines has been shown to be involved in abnormal E-C coupling and myocardial insulin resistance. 4. There is growing evidence that O-linked glycosylation (downstream of HBP) may regulate the function of cytosolic and nuclear proteins in a dynamic manner, similar to phosphorylation and perhaps involving reciprocal or synergistic modification of serine/threonine sites. 5. This review focuses on the question of whether there is a role for HBP and dynamic O-linked glycosylation in the development of myocardial insulin resistance and abnormal E-C coupling. The emerging concept that O-linked glycosylation is a regulatory, post-translational modification of cytosolic/nuclear proteins that interacts with phosphorylation in the heart is explored.

  9. Photorefractive two-beam coupling optimal thresholding filter for additive signal-dependent noise reduction

    NASA Astrophysics Data System (ADS)

    Fu, Jack; Khoury, Jehad; Cronin-Golomb, Mark; Woods, Charles L.

    1995-01-01

    Computer simulations of photorefractive thresholding filters for the reduction of artifact or dust noise demonstrate an increase in signal-to-noise ratio (SNR) of 70% to 95%, respectively, of that provided by the Wiener filter for inputs with a SNR of approximately 3. These simple, nearly optimal filters use a spectral thresholding profile that is proportional to the envelope of the noise spectrum. Alternative nonlinear filters with either 1/ nu or constant thresholding profiles increase the SNR almost as much as the noise-envelope thresholding filter.

  10. Modeling of coupled differential equations for cellular chemical signaling pathways: Implications for assay protocols utilized in cellular engineering.

    PubMed

    O'Clock, George D

    2016-08-01

    Cellular engineering involves modification and control of cell properties, and requires an understanding of fundamentals and mechanisms of action for cellular derived product development. One of the keys to success in cellular engineering involves the quality and validity of results obtained from cell chemical signaling pathway assays. The accuracy of the assay data cannot be verified or assured if the effect of positive feedback, nonlinearities, and interrelationships between cell chemical signaling pathway elements are not understood, modeled, and simulated. Nonlinearities and positive feedback in the cell chemical signaling pathway can produce significant aberrations in assay data collection. Simulating the pathway can reveal potential instability problems that will affect assay results. A simulation, using an electrical analog for the coupled differential equations representing each segment of the pathway, provides an excellent tool for assay validation purposes. With this approach, voltages represent pathway enzyme concentrations and operational amplifier feedback resistance and input resistance values determine pathway gain and rate constants. The understanding provided by pathway modeling and simulation is strategically important in order to establish experimental controls for assay protocol structure, time frames specified between assays, and assay concentration variation limits; to ensure accuracy and reproducibility of results.

  11. A Perspective on Studying G-Protein-Coupled Receptor Signaling with Resonance Energy Transfer Biosensors in Living Organisms.

    PubMed

    van Unen, Jakobus; Woolard, Jeanette; Rinken, Ago; Hoffmann, Carsten; Hill, Stephen J; Goedhart, Joachim; Bruchas, Michael R; Bouvier, Michel; Adjobo-Hermans, Merel J W

    2015-09-01

    The last frontier for a complete understanding of G-protein-coupled receptor (GPCR) biology is to be able to assess GPCR activity, interactions, and signaling in vivo, in real time within biologically intact systems. This includes the ability to detect GPCR activity, trafficking, dimerization, protein-protein interactions, second messenger production, and downstream signaling events with high spatial resolution and fast kinetic readouts. Resonance energy transfer (RET)-based biosensors allow for all of these possibilities in vitro and in cell-based assays, but moving RET into intact animals has proven difficult. Here, we provide perspectives on the optimization of biosensor design, of signal detection in living organisms, and the multidisciplinary development of in vitro and cell-based assays that more appropriately reflect the physiologic situation. In short, further development of RET-based probes, optical microscopy techniques, and mouse genome editing hold great potential over the next decade to bring real-time in vivo GPCR imaging to the forefront of pharmacology.

  12. A mechanism regulating G protein-coupled receptor signaling that requires cycles of protein palmitoylation and depalmitoylation.

    PubMed

    Jia, Lixia; Chisari, Mariangela; Maktabi, Mohammad H; Sobieski, Courtney; Zhou, Hao; Konopko, Aaron M; Martin, Brent R; Mennerick, Steven J; Blumer, Kendall J

    2014-02-28

    Reversible attachment and removal of palmitate or other long-chain fatty acids on proteins has been hypothesized, like phosphorylation, to control diverse biological processes. Indeed, palmitate turnover regulates Ras trafficking and signaling. Beyond this example, however, the functions of palmitate turnover on specific proteins remain poorly understood. Here, we show that a mechanism regulating G protein-coupled receptor signaling in neuronal cells requires palmitate turnover. We used hexadecyl fluorophosphonate or palmostatin B to inhibit enzymes in the serine hydrolase family that depalmitoylate proteins, and we studied R7 regulator of G protein signaling (RGS)-binding protein (R7BP), a palmitoylated allosteric modulator of R7 RGS proteins that accelerate deactivation of Gi/o class G proteins. Depalmitoylation inhibition caused R7BP to redistribute from the plasma membrane to endomembrane compartments, dissociated R7BP-bound R7 RGS complexes from Gi/o-gated G protein-regulated inwardly rectifying K(+) (GIRK) channels and delayed GIRK channel closure. In contrast, targeting R7BP to the plasma membrane with a polybasic domain and an irreversibly attached lipid instead of palmitate rendered GIRK channel closure insensitive to depalmitoylation inhibitors. Palmitate turnover therefore is required for localizing R7BP to the plasma membrane and facilitating Gi/o deactivation by R7 RGS proteins on GIRK channels. Our findings broaden the scope of biological processes regulated by palmitate turnover on specific target proteins. Inhibiting R7BP depalmitoylation may provide a means of enhancing GIRK activity in neurological disorders.

  13. Different types of signal coupling in the visual cortex related to neural mechanisms of associative processing and perception.

    PubMed

    Eckhorn, Reinhard; Gail, Alexander M; Bruns, Andreas; Gabriel, Andreas; Al-Shaikhli, Basim; Saam, Mirko

    2004-09-01

    The hypothesis of object representation by synchronization in the visual cortex has been supported by our recent experiments in monkeys. They demonstrated local synchrony among gamma activities (30-90 Hz) and their perceptual modulation, according to the rules of figure-ground segregation. However, gamma-synchrony in primary visual cortex is restricted to few mm, challenging the synchronization hypothesis for larger cortical object representations. The restriction is due to randomly changing phase relations among locally synchronized patches which, however, form continuous waves of gamma-activity, traveling across object representations. The phase continuity of these waves may support coding of object continuity. Interactions across still larger distances, measured among cortical areas in human data, involve amplitude envelopes of gamma signals. Based on models with spiking neurons we discuss potentially underlying mechanisms. Most important for gamma synchronization are local facilitatory connections with distance-dependent delays. They also explain the occurrence of gamma waves and the restriction of gamma-synchrony. Fast local feedback inhibition generates gamma oscillations and supports local synchrony, while slow shunting inhibitory feedback supports figure-ground segregation. Finally, dispersion in inter-areal far projections destroys coherence of gamma signals, but preserves their amplitude modulations. In conclusion, we propose that the hypothesis of associative processing by gamma synchronization be extended to more general forms of signal coupling.

  14. Diagnostic study of coupled solar wind-magnetosphere-ionosphere dynamics in D-region ionosphere via VLF signal propagation characteristic

    NASA Astrophysics Data System (ADS)

    Nwankwo, Victor U. J.; Chakrabarti, Sandip Kumar

    2016-07-01

    Geomagnetic disturbances and storms are known to produce significant global disturbances in the ionosphere, including the middle atmosphere and troposphere. There is little understanding about the mechanism and dynamics that drive these processes in lower ionosphere. The ionosphere is also thought to be sensitive to seismic events, and it is believed that it exhibits precursory characteristics as reported in studies via characteristic anomalies in VLF signal. However, distinguishing or separating seismically induced ionospheric fluctuations from those of other origins (e.g., Solar activity, planetary and tidal waves, stratospheric warming etc.) remain vital to robust conclusion, and challenging too. The unique propagation characteristic of VLF radio signal makes it an ideal tool for the study and diagnosis of variability of D-region ionosphere. In this work, we present the analysis of solar wind-magnetosphere-ionosphere coupling dynamics in D-region ionosphere using VLF signal characteristics, and performed an investigation of previously reported 'ionospheric precursors' to understand the true origins of measured anomalies.

  15. Evaluation of Phase-Amplitude Coupling in Resting State Magnetoencephalographic Signals: Effect of Surrogates and Evaluation Approach

    PubMed Central

    Gohel, Bakul; Lim, Sanghyun; Kim, Min-Young; An, Kyung-min; Kim, Ji-Eun; Kwon, Hyukchan; Kim, Kiwoong

    2016-01-01

    Phase-amplitude coupling (PAC) plays an important role in neural communication and computation. Interestingly, recent studies have indicated the presence of ubiquitous PAC phenomenon even during the resting state. Despite the importance of PAC phenomenon, estimation of significant physiological PAC is challenging because of the lack of appropriate surrogate measures to control false positives caused by non-physiological PAC. Therefore, in the present study, we evaluated PAC phenomenon during resting-state magnetoencephalography (MEG) signal and considered various surrogate measures and computational approaches widely used in the literature in addition to proposing new ones. We evaluated PAC phenomenon over the entire length of the MEG signal and for multiple shorter time segments. The results indicate that the extent of PAC phenomenon mainly depends on the surrogate measures and PAC computational methods used, as well as the evaluation approach. After a careful and critical evaluation, we found that resting-state MEG signals failed to exhibit ubiquitous PAC phenomenon, contrary to what has been suggested previously. PMID:27932971

  16. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2.

    PubMed

    Whalen, Erin J; Foster, Matthew W; Matsumoto, Akio; Ozawa, Kentaro; Violin, Jonathan D; Que, Loretta G; Nelson, Chris D; Benhar, Moran; Keys, Janelle R; Rockman, Howard A; Koch, Walter J; Daaka, Yehia; Lefkowitz, Robert J; Stamler, Jonathan S

    2007-05-04

    beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signaling and target receptors for internalization. Nitric oxide (NO) and/or S-nitrosothiols (SNOs) can prevent the loss of beta-AR signaling in vivo, but the molecular details are unknown. Here we show in mice that SNOs increase beta-AR expression and prevent agonist-stimulated receptor downregulation; and in cells, SNOs decrease GRK2-mediated beta-AR phosphorylation and subsequent recruitment of beta-arrestin to the receptor, resulting in the attenuation of receptor desensitization and internalization. In both cells and tissues, GRK2 is S-nitrosylated by SNOs as well as by NO synthases, and GRK2 S-nitrosylation increases following stimulation of multiple GPCRs with agonists. Cys340 of GRK2 is identified as a principal locus of inhibition by S-nitrosylation. Our studies thus reveal a central molecular mechanism through which GPCR signaling is regulated.

  17. Lipid signalling couples translational surveillance to systemic detoxification in Caenorhabditis elegans

    PubMed Central

    Govindan, J. Amaranath; Jayamani, Elamparithi; Zhang, Xinrui; Breen, Peter; Larkins-Ford, Jonah; Mylonakis, Eleftherios

    2015-01-01

    Translation in eukaryotes is surveilled to detect toxins and virulence factors and coupled to the induction of defense pathways. C. elegans germline-specific mutations in translation components are detected by this system to induce detoxification and immune responses in distinct somatic cells. An RNAi screen revealed gene inactivations that act at multiple steps in lipid biosynthetic and kinase pathways that act upstream of MAP kinase to mediate the systemic communication of translation-defects to induce detoxification genes. Mammalian bile acids can rescue the defect in detoxification gene induction caused by C. elegans lipid biosynthetic gene inactivations. Extracts prepared from C. elegans with translation deficits but not from wild type can also rescue detoxification gene induction in lipid biosynthetic defective strains. These eukaryotic antibacterial countermeasures are not ignored by bacteria: particular bacterial species suppress normal C. elegans detoxification responses to mutations in translation factors. PMID:26322678

  18. Diverse feather shape evolution enabled by coupling anisotropic signalling modules with self-organizing branching programme

    PubMed Central

    Li, Ang; Figueroa, Seth; Jiang, Ting-Xin; Wu, Ping; Widelitz, Randall; Nie, Qing; Chuong, Cheng-Ming

    2017-01-01

    Adaptation of feathered dinosaurs and Mesozoic birds to new ecological niches was potentiated by rapid diversification of feather vane shapes. The molecular mechanism driving this spectacular process remains unclear. Here, through morphology analysis, transcriptome profiling, functional perturbations and mathematical simulations, we find that mesenchyme-derived GDF10 and GREM1 are major controllers for the topologies of rachidial and barb generative zones (setting vane boundaries), respectively, by tuning the periodic-branching programme of epithelial progenitors. Their interactions with the anterior–posterior WNT gradient establish the bilateral-symmetric vane configuration. Additionally, combinatory effects of CYP26B1, CRABP1 and RALDH3 establish dynamic retinoic acid (RA) landscapes in feather mesenchyme, which modulate GREM1 expression and epithelial cell shapes. Incremental changes of RA gradient slopes establish a continuum of asymmetric flight feathers along the wing, while switch-like modulation of RA signalling confers distinct vane shapes between feather tracts. Therefore, the co-option of anisotropic signalling modules introduced new dimensions of feather shape diversification. PMID:28106042

  19. Pulse-coupled neural nets: translation, rotation, scale, distortion, and intensity signal invariance for images.

    PubMed

    Johnson, J L

    1994-09-10

    The linking-field neural network model of Eckhorn et al. [Neural Comput. 2, 293-307 (1990)] was introduced to explain the experimentally observed synchronous activity among neural assemblies in the cat cortex induced by feature-dependent visual activity. The model produces synchronous bursts of pulses from neurons with similar activity, effectively grouping them by phase and pulse frequency. It gives a basic new function: grouping by similarity. The synchronous bursts are obtained in the limit of strong linking strengths. The linking-field model in the limit of moderate-to-weak linking characterized by few if any multiple bursts is investigated. In this limit dynamic, locally periodic traveling waves exist whose time signal encodes the geometrical structure of a two-dimensional input image. The signal can be made insensitive to translation, scale, rotation, distortion, and intensity. The waves transmit information beyond the physical interconnect distance. The model is implemented in an optical hybrid demonstration system. Results of the simulations and the optical system are presented.

  20. Single cell kinase signaling assay using pinched flow coupled droplet microfluidics.

    PubMed

    Ramji, Ramesh; Wang, Ming; Bhagat, Ali Asgar S; Tan Shao Weng, Daniel; Thakor, Nitish V; Teck Lim, Chwee; Chen, Chia-Hung

    2014-05-01

    Droplet-based microfluidics has shown potential in high throughput single cell assays by encapsulating individual cells in water-in-oil emulsions. Ordering cells in a micro-channel is necessary to encapsulate individual cells into droplets further enhancing the assay efficiency. This is typically limited due to the difficulty of preparing high-density cell solutions and maintaining them without cell aggregation in long channels (>5 cm). In this study, we developed a short pinched flow channel (5 mm) to separate cell aggregates and to form a uniform cell distribution in a droplet-generating platform that encapsulated single cells with >55% encapsulation efficiency beating Poisson encapsulation statistics. Using this platform and commercially available Sox substrates (8-hydroxy-5-(N,N-dimethylsulfonamido)-2-methylquinoline), we have demonstrated a high throughput dynamic single cell signaling assay to measure the activity of receptor tyrosine kinases (RTKs) in lung cancer cells triggered by cell surface ligand binding. The phosphorylation of the substrates resulted in fluorescent emission, showing a sigmoidal increase over a 12 h period. The result exhibited a heterogeneous signaling rate in individual cells and showed various levels of drug resistance when treated with the tyrosine kinase inhibitor, gefitinib.

  1. Acoustic-Seismic Coupling of Broadband Signals - Analysis of Potential Disturbances during CTBT On-Site Inspection Measurements

    NASA Astrophysics Data System (ADS)

    Liebsch, Mattes; Altmann, Jürgen

    2015-04-01

    For the verification of the Comprehensive Nuclear Test Ban Treaty (CTBT) the precise localisation of possible underground nuclear explosion sites is important. During an on-site inspection (OSI) sensitive seismic measurements of aftershocks can be performed, which, however, can be disturbed by other signals. To improve the quality and effectiveness of these measurements it is essential to understand those disturbances so that they can be reduced or prevented. In our work we focus on disturbing signals caused by airborne sources: When the sound of aircraft (as often used by the inspectors themselves) hits the ground, it propagates through pores in the soil. Its energy is transferred to the ground and soil vibrations are created which can mask weak aftershock signals. The understanding of the coupling of acoustic waves to the ground is still incomplete. However, it is necessary to improve the performance of an OSI, e.g. to address potential consequences for the sensor placement, the helicopter trajectories etc. We present our recent advances in this field. We performed several measurements to record sound pressure and soil velocity produced by various sources, e.g. broadband excitation by jet aircraft passing overhead and signals artificially produced by a speaker. For our experimental set-up microphones were placed close to the ground and geophones were buried in different depths in the soil. Several sensors were shielded from the directly incident acoustic signals by a box coated with acoustic damping material. While sound pressure under the box was strongly reduced, the soil velocity measured under the box was just slightly smaller than outside of it. Thus these soil vibrations were mostly created outside the box and travelled through the soil to the sensors. This information is used to estimate characteristic propagation lengths of the acoustically induced signals in the soil. In the seismic data we observed interference patterns which are likely caused by the

  2. Monodisperse Magnetite Nanoparticles Coupled with Nuclear Localization Signal Peptide for Cell-Nucleus Targeting

    PubMed Central

    Xu, Chenjie; Xie, Jin; Kohler, Nathan; Walsh, Edward G.; Chin, Y. Eugene; Sun, Shouheng

    2009-01-01

    Functionalization of monodisperse superparamagnetic magnetite (Fe3O4) nanoparticles for cell specific targeting is crucial for cancer diagnostics and therapeutics. Targeted magnetic nanoparticles can be used to enhance the tissue contrast in magnetic resonance imaging (MRI), to improve the efficiency in anticancer drug delivery, and to eliminate tumor cells by magnetic fluid hyperthermia. Herein we report the nucleus-targeting Fe3O4 nanoparticles functionalized with protein and nuclear localization signal (NLS) peptide. These NLS-coated nanoparticles were introduced into the HeLa cell cytoplasm and nucleus, where the particles were monodispersed and non-aggregated. The success of labeling was examined and identified by fluorescence microscopy and MRI. The work demonstrates that monodisperse magnetic nanoparticles can be readily functionalized and stabilized for potential diagnostic and therapeutic applications. PMID:18080259

  3. Hydrolysis of phosphatidylcholine couples Ras to activation of Raf protein kinase during mitogenic signal transduction.

    PubMed Central

    Cai, H; Erhardt, P; Troppmair, J; Diaz-Meco, M T; Sithanandam, G; Rapp, U R; Moscat, J; Cooper, G M

    1993-01-01

    We have investigated the relationship between hydrolysis of phosphatidylcholine (PC) and activation of the Raf-1 protein kinase in Ras-mediated transduction of mitogenic signals. As previously reported, cotransfection of a PC-specific phospholipase C (PC-PLC) expression plasmid bypassed the block to cell proliferation resulting from expression of the dominant inhibitory mutant Ras N-17. In contrast, PC-PLC failed to bypass the inhibitory effect of dominant negative Raf mutants, suggesting that PC-PLC functions downstream of Ras but upstream of Raf. Consistent with this hypothesis, treatment of quiescent cells with exogenous PC-PLC induced Raf activation, even when normal Ras function was blocked by Ras N-17 expression. Further, activation of Raf in response to mitogenic growth factors was blocked by inhibition of endogenous PC-PLC. Taken together, these results indicate that hydrolysis of PC mediates Raf activation in response to mitogenic growth factors. Images PMID:8246981

  4. Peptide modifications differentially alter G protein-coupled receptor internalization and signaling bias.

    PubMed

    Mäde, Veronika; Babilon, Stefanie; Jolly, Navjeet; Wanka, Lizzy; Bellmann-Sickert, Kathrin; Diaz Gimenez, Luis E; Mörl, Karin; Cox, Helen M; Gurevich, Vsevolod V; Beck-Sickinger, Annette G

    2014-09-15

    Although G protein-coupled receptors (GPCRs) are targeted by more clinically used drugs than any other type of protein, their ligand development is particularly challenging. Humans have four neuropeptide Y receptors: hY1R and hY5R are orexigenic, while hY2R and hY4R are anorexigenic, and represent important anti-obesity drug targets. We show for the first time that PEGylation and lipidation, chemical modifications that prolong the plasma half-lives of peptides, confer additional benefits. Both modifications enhance pancreatic polypeptide preference for hY2R/hY4R over hY1R/hY5R. Lipidation biases the ligand towards arrestin recruitment and internalization, whereas PEGylation confers the opposite bias. These effects were independent of the cell system and modified residue. We thus provide novel insights into the mode of action of peptide modifications and open innovative venues for generating peptide agonists with extended therapeutic potential.

  5. Peptide Modifications Differentially Alter G Protein-Coupled Receptor Internalization and Signaling Bias**

    PubMed Central

    Mäde, Veronika; Babilon, Stefanie; Jolly, Navjeet; Wanka, Lizzy; Bellmann-Sickert, Kathrin; Diaz Gimenez, Luis E.; Mörl, Karin; Cox, Helen M.; Gurevich, Vsevolod V.; Beck-Sickinger, Annette G.

    2016-01-01

    Although G protein-coupled receptors (GPCRs) are targeted by more clinically used drugs than any other type of protein, their ligand development is particularly challenging. Humans have four neuropeptide Y receptors: hY1R and hY5R are orexigenic, while hY2R and hY4R are anorexigenic, and represent important anti-obesity drug targets. We show for the first time that PEGylation and lipidation, chemical modifications that prolong the plasma half-lives of peptides, confer additional benefits. Both modifications enhance pancreatic polypeptide preference for hY2R/hY4R over hY1R/hY5R. Lipidation biases the ligand towards arrestin recruitment and internalization, whereas PEGylation confers the opposite bias. These effects were independent of the cell system and modified residue. We thus provide novel insights into the mode of action of peptide modifications and open innovative venues for generating peptide agonists with extended therapeutic potential. PMID:25065900

  6. Imaging G Protein-coupled Receptor-mediated Chemotaxis and its Signaling Events in Neutrophil-like HL60 Cells

    PubMed Central

    Wen, Xi; Jin, Tian; Xu, Xuehua

    2016-01-01

    Eukaryotic cells sense and move towards a chemoattractant gradient, a cellular process referred as chemotaxis. Chemotaxis plays critical roles in many physiological processes, such as embryogenesis, neuron patterning, metastasis of cancer cells, recruitment of neutrophils to sites of inflammation, and the development of the model organism Dictyostelium discoideum. Eukaryotic cells sense chemo-attractants using G protein-coupled receptors. Visual chemotaxis assays are essential for a better understanding of how eukaryotic cells control chemoattractant-mediated directional cell migration. Here, we describe detailed methods for: 1) real-time, high-resolution monitoring of multiple chemotaxis assays, and 2) simultaneously visualizing the chemoattractant gradient and the spatiotemporal dynamics of signaling events in neutrophil-like HL60 cells. PMID:27684322

  7. Estradiol rapidly attenuates ORL-1 receptor-mediated inhibition of proopiomelanocortin neurons via Gq-coupled, membrane-initiated signaling

    PubMed Central

    Conde, Kristie; Meza, Cecilia; Kelly, Martin J.; Sinchak, Kevin; Wagner, Edward J.

    2016-01-01

    Estradiol rapidly regulates the activity of arcuate nucleus (ARH) proopiomelanocortin (POMC) neurons that project to the medial preoptic nucleus (MPN) to regulate lordosis. Orphanin FQ/nociceptin (OFQ/N) acts via opioid receptor-like (ORL)-1 receptors to inhibit these POMC neurons. Therefore, we tested the hypothesis that estradiol excites POMC neurons by rapidly attenuating inhibitory ORL-1 signaling in these cells. Hypothalamic slices through the ARH were prepared from ovariectomized rats injected with Fluorogold into the MPN. Electrophysiologic recordings were generated in ARH neurons held at or near −60 mV, and neuronal phenotype was determined posthoc by immunohistofluorescence. OFQ/N application induced robust outward currents and hyperpolarizations via GIRK channels that were attenuated by pretreatment with either 17-β estradiol (E2) or E2 conjugated to bovine serum albumin. This was blocked by the estrogen receptor (ER) antagonist ICI 182,780, and mimicked by the Gq-coupled, membrane ER (Gq-mER) ligand STX and the ERα agonist PPT. Inhibiting phosphatidylinositol-3-kinase (PI3K) blocked the estrogenic attenuation of ORL-1/GIRK currents. Antagonizing either phospholipase C (PLC), protein kinase C (PKC), protein kinase A (PKA) or neuronal nitric oxide synthase (nNOS) also abrogated E2 inhibition of ORL-1/GIRK currents, whereas activation of PKC, PKA, protein kinase B (Akt) and nNOS substrate L-arginine all attenuated the OFQ/N response. This was observed in 92 MPN-projecting, POMC-positive ARH neurons. Thus, ORL-1 receptor-mediated inhibition of POMC neurons is rapidly and negatively modulated by E2, an effect which is stereoselective and membrane initiated via Gq-coupled mER and ERα activation that signals through PLC, PKC, PKA, PI3K and nNOS. PMID:26765570

  8. A functional coupling between CRMP1 and Nav1.7 for retrograde propagation of Semaphorin3A signaling.

    PubMed

    Yamane, Masayuki; Yamashita, Naoya; Hida, Tomonobu; Kamiya, Yoshinori; Nakamura, Fumio; Kolattukudy, Pappachan; Goshima, Yoshio

    2017-03-02

    Semaphorin3A (Sema3A) is a secreted type of axon guidance molecules that regulates axon wiring through neuropilin-1 (NRP1) and PlexinAs (PlexAs) receptor complex. Sema3A regulates the dendritic branching through a tetrodotoxin (TTX)-sensitive retrograde axonal transport of PlexAs and Tropomyosin-related kinase A (TrkA) complex. We here demonstrate that Nav1.7, a TTX-sensitive Na(+) channel, by coupling with collapsin response mediator protein 1 (CRMP1), mediates the Sema3A-induced retrograde transport. In mouse dorsal root ganglion (DRG) neurons, Sema3A increased co-localization of PlexA4 and TrkA in the growth cones and axons. TTX treatment and RNAi knockdown of Nav1.7, sustained Sema3A-induced co-localized signals of PlexA4 and TrkA in growth cones, and suppressed the subsequent localization of PlexA4 and TrkA in distal axons. A similar localization phenotype was observed in crmp1(-/-) DRG neurons. Sema3A induced co-localization of CRMP1 and Nav1.7 in the growth cones. The half maximal voltage was increased in crmp1(-/-) neurons when compared to wild-type. In HEK293 cells, introduction of CRMP1 lowered the threshold of the coexpressed Nav1.7. These results suggest that Nav1.7 mediates through coupling with CRMP1 the axonal retrograde signaling of Sema3A.

  9. Tobacco LSU-like protein couples sulphur-deficiency response with ethylene signalling pathway

    PubMed Central

    Sirko, Agnieszka

    2013-01-01

    Most genes from the plant-specific family encoding Response to Low Sulphur (LSU)-like proteins are strongly induced in sulphur (S)-deficient conditions. The exact role of these proteins remains unclear; however, some data suggest their importance for plants’ adjustment to nutrient deficiency and other environmental stresses. This work established that the regulation of ethylene signalling is a part of plants’ response to S deficiency and showed the interaction between UP9C, a tobacco LSU family member, and one of the tobacco isoforms of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO2A). Increase in ethylene level induced by S deficiency does not take place in tobacco plants with UP9C expressed in an antisense orientation. Based on transcriptomics data, this work also demonstrated that the majority of tobacco’s response to S deficiency is misregulated in plants expressing UP9C-antisense. A link between response to S deficiency, ethylene sensing, and LSU-like proteins was emphasized by changes in expression of the genes encoding ethylene receptors and F-box proteins specific for the ethylene pathway. PMID:24085579

  10. Tobacco LSU-like protein couples sulphur-deficiency response with ethylene signalling pathway.

    PubMed

    Moniuszko, Grzegorz; Skoneczny, Marek; Zientara-Rytter, Katarzyna; Wawrzyńska, Anna; Głów, Dawid; Cristescu, Simona M; Harren, Frans J M; Sirko, Agnieszka

    2013-11-01

    Most genes from the plant-specific family encoding Response to Low Sulphur (LSU)-like proteins are strongly induced in sulphur (S)-deficient conditions. The exact role of these proteins remains unclear; however, some data suggest their importance for plants' adjustment to nutrient deficiency and other environmental stresses. This work established that the regulation of ethylene signalling is a part of plants' response to S deficiency and showed the interaction between UP9C, a tobacco LSU family member, and one of the tobacco isoforms of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO2A). Increase in ethylene level induced by S deficiency does not take place in tobacco plants with UP9C expressed in an antisense orientation. Based on transcriptomics data, this work also demonstrated that the majority of tobacco's response to S deficiency is misregulated in plants expressing UP9C-antisense. A link between response to S deficiency, ethylene sensing, and LSU-like proteins was emphasized by changes in expression of the genes encoding ethylene receptors and F-box proteins specific for the ethylene pathway.

  11. Carbon Ion-Irradiated Hepatoma Cells Exhibit Coupling Interplay between Apoptotic Signaling and Morphological and Mechanical Remodeling

    PubMed Central

    Zhang, Baoping; Li, Long; Li, Zhiqiang; Liu, Yang; Zhang, Hong; Wang, Jizeng

    2016-01-01

    A apoptotic model was established based on the results of five hepatocellular carcinoma cell (HCC) lines irradiated with carbon ions to investigate the coupling interplay between apoptotic signaling and morphological and mechanical cellular remodeling. The expression levels of key apoptotic proteins and the changes in morphological characteristics and mechanical properties were systematically examined in the irradiated HCC lines. We observed that caspase-3 was activated and that the Bax/Bcl-2 ratio was significantly increased over time. Cellular morphology and mechanics analyses indicated monotonic decreases in spatial sizes, an increase in surface roughness, a considerable reduction in stiffness, and disassembly of the cytoskeletal architecture. A theoretical model of apoptosis revealed that mechanical changes in cells induce the characteristic cellular budding of apoptotic bodies. Statistical analysis indicated that the projected area, stiffness, and cytoskeletal density of the irradiated cells were positively correlated, whereas stiffness and caspase-3 expression were negatively correlated, suggesting a tight coupling interplay between the cellular structures, mechanical properties, and apoptotic protein levels. These results help to clarify a novel arbitration mechanism of cellular demise induced by carbon ions. This biomechanics strategy for evaluating apoptosis contributes to our understanding of cancer-killing mechanisms in the context of carbon ion radiotherapy. PMID:27731354

  12. Balancing Vibrations at Harmonic Frequencies by Injecting Harmonic Balancing Signals into the Armature of a Linear Motor/Alternator Coupled to a Stirling Machine

    NASA Technical Reports Server (NTRS)

    Holliday, Ezekiel S. (Inventor)

    2014-01-01

    Vibrations at harmonic frequencies are reduced by injecting harmonic balancing signals into the armature of a linear motor/alternator coupled to a Stirling machine. The vibrations are sensed to provide a signal representing the mechanical vibrations. A harmonic balancing signal is generated for selected harmonics of the operating frequency by processing the sensed vibration signal with adaptive filter algorithms of adaptive filters for each harmonic. Reference inputs for each harmonic are applied to the adaptive filter algorithms at the frequency of the selected harmonic. The harmonic balancing signals for all of the harmonics are summed with a principal control signal. The harmonic balancing signals modify the principal electrical drive voltage and drive the motor/alternator with a drive voltage component in opposition to the vibration at each harmonic.

  13. Expression Pattern of the Alpha-Kafirin Promoter Coupled with a Signal Peptide from Sorghum bicolor L. Moench

    PubMed Central

    Ahmad, Norazlina; Sant, Rajnesh; Bokan, Milovan; Steadman, Kathryn J.; Godwin, Ian D.

    2012-01-01

    Regulatory sequences with endosperm specificity are essential for foreign gene expression in the desired tissue for both grain quality improvement and molecular pharming. In this study, promoters of seed storage α-kafirin genes coupled with signal sequence (ss) were isolated from Sorghum bicolor L. Moench genomic DNA by PCR. The α-kafirin promoter (α-kaf) contains endosperm specificity-determining motifs, prolamin-box, the O2-box 1, CATC, and TATA boxes required for α-kafirin gene expression in sorghum seeds. The constructs pMB-Ubi-gfp and pMB-kaf-gfp were microprojectile bombarded into various sorghum and sweet corn explants. GFP expression was detected on all explants using the Ubi promoter but only in seeds for the α-kaf promoter. This shows that the α-kaf promoter isolated was functional and demonstrated seed-specific GFP expression. The constructs pMB-Ubi-ss-gfp and pMB-kaf-ss-gfp were also bombarded into the same explants. Detection of GFP expression showed that the signal peptide (SP)::GFP fusion can assemble and fold properly, preserving the fluorescent properties of GFP. PMID:22315514

  14. PI3K/AKT signaling mediated by G protein‑coupled receptors is involved in neurodegenerative Parkinson's disease (Review).

    PubMed

    Nakano, Noriko; Matsuda, Satoru; Ichimura, Mayuko; Minami, Akari; Ogino, Mako; Murai, Toshiyuki; Kitagishi, Yasuko

    2017-02-01

    Parkinson's disease (PD) is a common progressive and multifactorial neurodegenerative disease, characterized by the loss of midbrain dopaminergic neurons. Numerous pathological processes including, inflammation, oxidative stress, mitochondrial dysfunction, neurotransmitter imbalance, and apoptosis as well as genetic factors may lead to neuronal degeneration. Motor deficits in PD are due mostly to the progressive loss of nigrostriatal dopaminergic neurons. Neuroprotection of functional neurons is of significance in the treatment of PD. G protein‑coupled receptors (GPCRs) have been implicated in the neuroprotection against PD through the survival of dopaminergic neurons. In addition, phosphatidyl‑inositol‑3‑kinase (PI3K)/AKT signaling has also been demonstrated to be neuroprotective. Knowledge of the mechanisms involved in this cellular protection could be critical for developing treatments to prevent this neurodegenerative disorder. In this review, we highlight the protective roles of the PI3K/AKT signaling pathway in the function of representative serotonin GPCRs. Particular attention is given to the molecular mechanisms of this pathway proposed to explain the favorable effects of food ingredients against neurodegenerative disease.

  15. Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling.

    PubMed

    Endo, Yoko; Suzuki, Masashi; Yamada, Hideomi; Horita, Shoko; Kunimi, Motoei; Yamazaki, Osamu; Shirai, Ayumi; Nakamura, Motonobu; Iso-O, Naoyuki; Li, Yuehong; Hara, Masumi; Tsukamoto, Kazuhisa; Moriyama, Nobuo; Kudo, Akihiko; Kawakami, Hayato; Yamauchi, Toshimasa; Kubota, Naoto; Kadowaki, Takashi; Kume, Haruki; Enomoto, Yutaka; Homma, Yukio; Seki, George; Fujita, Toshiro

    2011-05-04

    Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPARγ-Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPARγ-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARγ, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARγ and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARγ-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion.

  16. Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway

    PubMed Central

    2011-01-01

    Background The Fat mass and obesity gene (FTO) has been identified through genome wide association studies as an important genetic factor contributing to a higher body mass index (BMI). However, the molecular context in which this effect is mediated has yet to be determined. We investigated the potential molecular network for FTO by analyzing co-expression and protein-protein interaction databases, Coxpresdb and IntAct, as well as the functional coupling predicting multi-source database, FunCoup. Hypothalamic expression of FTO-linked genes defined with this bioinformatics approach was subsequently studied using quantitative real time-PCR in mouse feeding models known to affect FTO expression. Results We identified several candidate genes for functional coupling to FTO through database studies and selected nine for further study in animal models. We observed hypothalamic expression of Profilin 2 (Pfn2), cAMP-dependent protein kinase catalytic subunit beta (Prkacb), Brain derived neurotrophic factor (Bdnf), neurotrophic tyrosine kinase, receptor, type 2 (Ntrk2), Signal transducer and activator of transcription 3 (Stat3), and Btbd12 to be co-regulated in concert with Fto. Pfn2 and Prkacb have previously not been linked to feeding regulation. Conclusions Gene expression studies validate several candidates generated through database studies of possible FTO-interactors. We speculate about a wider functional role for FTO in the context of current and recent findings, such as in extracellular ligand-induced neuronal plasticity via NTRK2/BDNF, possibly via interaction with the transcription factor CCAAT/enhancer binding protein β (C/EBPβ). PMID:22087873

  17. G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling

    PubMed Central

    Nilsson, Bengt-Olof; Olde, Björn; Leeb-Lundberg, LM Fredrik

    2011-01-01

    Oestrogens are important sex hormones central to health and disease in both genders that have protective effects on the cardiovascular and metabolic systems. These hormones act in complex ways via both genomic and non-genomic mechanisms. The genomic mechanisms are relatively well characterized, whereas the non-genomic ones are only beginning to be explored. Two oestrogen receptors (ER), ERα and ERβ, have been described that act as nuclear transcription factors but can also associate with the plasma membrane and influence cytosolic signalling. ERα has been shown to mediate both anti-atherogenic effects and pro-survival effects in pancreatic β-cells. In recent years, a third membrane-bound ER has emerged, G protein-coupled receptor 30 or G protein-coupled oestrogen receptor 1 (GPER1), which mediates oestrogenic responses in cardiovascular and metabolic regulation. Both GPER1 knock-out models and pharmacological agents are now available to study GPER1 function. These tools have revealed that GPER1 activation may have several beneficial effects in the cardiovascular system including vasorelaxation, inhibition of smooth muscle cell proliferation, and protection of the myocardium against ischaemia/reperfusion injury, and in the metabolic system including stimulation of insulin release and protection against pancreatic β-cell apoptosis. Thus, GPER1 is emerging as a candidate therapeutic target in both cardiovascular and metabolic disease. LINKED ARTICLES This article is one of a set of reviews submitted to BJP in connection with talks given at the September 2010 meeting of the International Society of Hypertension in Vancouver, Canada. To view the other articles in this collection visit http://dx.doi.org/10.1111/j.1476-5381.2010.01167.x, http://dx.doi.org/10.1111/j.1476-5381.2011.01260.x and http://dx.doi.org/10.1111/j.1476-5381.2011.01366.x PMID:21250980

  18. Estradiol Rapidly Attenuates ORL-1 Receptor-Mediated Inhibition of Proopiomelanocortin Neurons via Gq-Coupled, Membrane-Initiated Signaling.

    PubMed

    Conde, Kristie; Meza, Cecilia; Kelly, Martin J; Sinchak, Kevin; Wagner, Edward J

    2016-01-01

    Estradiol rapidly regulates the activity of arcuate nucleus (ARH) proopiomelanocortin (POMC) neurons that project to the medial preoptic nucleus (MPN) to regulate lordosis. Orphanin FQ/nociceptin (OFQ/N) acts via opioid receptor-like (ORL)-1 receptors to inhibit these POMC neurons. Therefore, we tested the hypothesis that estradiol excites POMC neurons by rapidly attenuating inhibitory ORL-1 signaling in these cells. Hypothalamic slices through the ARH were prepared from ovariectomized rats injected with Fluorogold into the MPN. Electrophysiological recordings were generated in ARH neurons held at or near -60 mV, and neuronal phenotype was determined post hoc by immunohistofluorescence. OFQ/N application induced robust outward currents and hyperpolarizations via G protein-gated, inwardly rectifying K+ (GIRK) channels that were attenuated by pretreatment with either 17-β estradiol (E2) or E2 conjugated to bovine serum albumin. This was blocked by the estrogen receptor (ER) antagonist ICI 182,780 and mimicked by the Gq-coupled membrane ER (Gq-mER) ligand STX and the ERα agonist PPT. Inhibiting phosphatidylinositol-3-kinase (PI3K) blocked the estrogenic attenuation of ORL-1/GIRK currents. Antagonizing either phospholipase C (PLC), protein kinase C (PKC), protein kinase A (PKA) or neuronal nitric oxide synthase (nNOS) also abrogated E2 inhibition of ORL-1/GIRK currents, whereas activation of PKC, PKA, protein kinase B (Akt) and nNOS substrate L-arginine all attenuated the OFQ/N response. This was observed in 92 MPN-projecting, POMC-positive ARH neurons. Thus, ORL-1 receptor-mediated inhibition of POMC neurons is rapidly and negatively modulated by E2, an effect which is stereoselective and membrane initiated via Gq-mER and ERα activation that signals through PLC, PKC, PKA, PI3K and nNOS.

  19. Signal and noise transfer properties of CMOS based active pixel flat panel imager coupled to structured CsI:Tl.

    PubMed

    Arvanitis, C D; Bohndiek, S E; Blakesley, J; Olivo, A; Speller, R D

    2009-01-01

    Complementary metal-oxide-semiconductors (CMOS) active pixel sensors can be optically coupled to CsI:Tl phosphors forming a indirect active pixel flat panel imager (APFPI) for high performance medical imaging. The aim of this work is to determine the x-ray imaging capabilities of CMOS-based APFPI and study the signal and noise transfer properties of CsI:Tl phosphors. Three different CsI:Tl phosphors from two different vendors have been used to produce three system configurations. The performance of each system configuration has been studied in terms of the modulation transfer function (MTF), noise power spectra, and detective quantum efficiency (DQE) in the mammographic energy range. A simple method to determine quantum limited systems in this energy range is also presented. In addition, with aid of monochromatic synchrotron radiation, the effect of iodine characteristic x-rays of the CsI:Tl on the MTF has been determined. A Monte Carlo simulation of the signal transfer properties of the imager is also presented in order to study the stages that degrade the spatial resolution of our current system. The effect of using substrate patterning during the growth of CsI:Tl columnar structure was also studied, along with the effect of CsI:Tl fixed pattern noise due to local variations in the scintillation light. CsI:Tl fixed pattern noise appears to limit the performance of our current system configurations. All the system configurations are quantum limited at 0.23 microC/kg with two of them having DQE (0) equal to 0.57. Active pixel flat panel imagers are shown to be digital x-ray imagers with almost constant DQE throughout a significant part of their dynamic range and in particular at very low exposures.

  20. Imaging G-protein coupled receptor (GPCR)-mediated signaling events that control chemotaxis of Dictyostelium discoideum.

    PubMed

    Xu, Xuehua; Jin, Tian

    2011-09-20

    Many eukaryotic cells can detect gradients of chemical signals in their environments and migrate accordingly (1). This guided cell migration is referred as chemotaxis, which is essential for various cells to carry out their functions such as trafficking of immune cells and patterning of neuronal cells (2, 3). A large family of G-protein coupled receptors (GPCRs) detects variable small peptides, known as chemokines, to direct cell migration in vivo (4). The final goal of chemotaxis research is to understand how a GPCR machinery senses chemokine gradients and controls signaling events leading to chemotaxis. To this end, we use imaging techniques to monitor, in real time, spatiotemporal concentrations of chemoattractants, cell movement in a gradient of chemoattractant, GPCR mediated activation of heterotrimeric G-protein, and intracellular signaling events involved in chemotaxis of eukaryotic cells (5-8). The simple eukaryotic organism, Dictyostelium discoideum, displays chemotaxic behaviors that are similar to those of leukocytes, and D. discoideum is a key model system for studying eukaryotic chemotaxis. As free-living amoebae, D. discoideum cells divide in rich medium. Upon starvation, cells enter a developmental program in which they aggregate through cAMP-mediated chemotaxis to form multicullular structures. Many components involved in chemotaxis to cAMP have been identified in D. discoideum. The binding of cAMP to a GPCR (cAR1) induces dissociation of heterotrimeric G-proteins into Gγ and Gβγ subunits (7, 9, 10). Gβγ subunits activate Ras, which in turn activates PI3K, converting PIP(2;) into PIP(3;) on the cell membrane (11-13). PIP(3;) serve as binding sites for proteins with pleckstrin Homology (PH) domains, thus recruiting these proteins to the membrane (14, 15). Activation of cAR1 receptors also controls the membrane associations of PTEN, which dephosphorylates PIP(3;) to PIP(2;)(16, 17). The molecular mechanisms are evolutionarily conserved in

  1. Oxytocin receptors expressed and coupled to Ca2+ signalling in a human vascular smooth muscle cell line.

    PubMed

    Yazawa, H; Hirasawa, A; Horie, K; Saita, Y; Iida, E; Honda, K; Tsujimoto, G

    1996-03-01

    1. In a human vascular smooth muscle cell line (HVSMC), binding experiments with [3H]-arginine8-vasopressin (AVP) have shown the existence of a homogeneous population of binding sites with affinity (Kd value) of 0.65 nM and a maximum number of binding sites (Bmax) of 122 fmol mg-1 protein. 2. Nonlabelled compounds compete for [3H]-AVP binding in the HVSMC membrane with an order of potency of oxytocin > lyspressin > or = AVP > Thr4, Gly7-oxytocin > (beta-mercapto-beta-beta-cyclopentamethylenepropionyl-O-Me Tyr2, Arg8) vasopressin > desmopressin > OPC21268 > OPC31260. This order was markedly different from that observed in rat vascular smooth muscle cells (A10), a well-established V1A receptor system. 3. In HVSMC both oxytocin and AVP increased inositol 1,4,5-trisphosphate (IP3) production and [Ca2+]i response, but the efficacy of the responses was greater for oxytocin than AVP. 4. Reverse transcription-polymerase chain reaction (RT-PCR) assay detected only oxytocin receptor but not V1A or V2 receptors in HVSMC, whereas only V1A receptors were found in A10 cells. 5. In conclusion, in HVSMC only oxytocin receptors are expressed among the vasopressin receptor family, and they coupled to phosphatidyl inositol (PI) turnover/Ca2+ signalling. This unexpected observation should provide new insight into the functional role of the oxytocin receptor in a human vascular smooth muscle cell line.

  2. Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors.

    PubMed Central

    Hermans, E; Challiss, R A

    2001-01-01

    In 1991 a new type of G-protein-coupled receptor (GPCR) was cloned, the type 1a metabotropic glutamate (mGlu) receptor, which, despite possessing the defining seven-transmembrane topology of the GPCR superfamily, bore little resemblance to the growing number of other cloned GPCRs. Subsequent studies have shown that there are eight mammalian mGlu receptors that, together with the calcium-sensing receptor, the GABA(B) receptor (where GABA is gamma-aminobutyric acid) and a subset of pheromone, olfactory and taste receptors, make up GPCR family C. Currently available data suggest that family C GPCRs share a number of structural, biochemical and regulatory characteristics, which differ markedly from those of the other GPCR families, most notably the rhodopsin/family A GPCRs that have been most widely studied to date. This review will focus on the group I mGlu receptors (mGlu1 and mGlu5). This subgroup of receptors is widely and differentially expressed in neuronal and glial cells within the brain, and receptor activation has been implicated in the control of an array of key signalling events, including roles in the adaptative changes needed for long-term depression or potentiation of neuronal synaptic connectivity. In addition to playing critical physiological roles within the brain, the mGlu receptors are also currently the focus of considerable attention because of their potential as drug targets for the treatment of a variety of neurological and psychiatric disorders. PMID:11672421

  3. L1CAM Binds ErbB Receptors through Ig-Like Domains Coupling Cell Adhesion and Neuregulin Signalling

    PubMed Central

    Grijota-Martinez, Carmen; Lakomá, Jarmila; Baars, Sigrid; Garcia-Alonso, Luis; Cabedo, Hugo

    2012-01-01

    During nervous system development different cell-to-cell communication mechanisms operate in parallel guiding migrating neurons and growing axons to generate complex arrays of neural circuits. How such a system works in coordination is not well understood. Cross-regulatory interactions between different signalling pathways and redundancy between them can increase precision and fidelity of guidance systems. Immunoglobulin superfamily proteins of the NCAM and L1 families couple specific substrate recognition and cell adhesion with the activation of receptor tyrosine kinases. Thus it has been shown that L1CAM-mediated cell adhesion promotes the activation of the EGFR (erbB1) from Drosophila to humans. Here we explore the specificity of the molecular interaction between L1CAM and the erbB receptor family. We show that L1CAM binds physically erbB receptors in both heterologous systems and the mammalian developing brain. Different Ig-like domains located in the extracellular part of L1CAM can support this interaction. Interestingly, binding of L1CAM to erbB enhances its response to neuregulins. During development this may synergize with the activation of erbB receptors through L1CAM homophilic interactions, conferring diffusible neuregulins specificity for cells or axons that interact with the substrate through L1CAM. PMID:22815787

  4. Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91).

    PubMed Central

    Greenlund, A C; Farrar, M A; Viviano, B L; Schreiber, R D

    1994-01-01

    Herein we report that interferon-gamma (IFN gamma) induces the rapid and reversible tyrosine phosphorylation of the IFN gamma receptor. Using a panel of receptor intracellular domain mutants, we show that a membrane-proximal LPKS sequence (residues 266-269) is required for ligand-induced tyrosine kinase activation and/or kinase-receptor association and biological responsiveness, and a functionally critical membrane-distal tyrosine residue (Y440) is a target of the activated enzyme. The biological significance of Y440 phosphorylation was demonstrated by showing that a receptor-derived nonapeptide corresponding to receptor residues 436-444 and containing phosphorylated Y440 bound specifically to p91, blocked p91 phosphorylation and inhibited the generation of an active p91-containing transcription factor complex. In contrast, nonphosphorylated wild-type, phosphorylated mutant, or phosphorylated irrelevant peptides did not. Moreover, the phosphorylated Y440-containing peptide did not interact with a related but distinct latent transcription factor (p113) which is activatible by IFN alpha but not IFN gamma. These results thus document the specific and inducible association of p91 with the phosphorylated IFN gamma receptor and thereby elucidate the mechanism by which ligand couples the IFN gamma receptor to its signal transduction system. Images PMID:8156998

  5. Magnetically coupled signal isolator

    NASA Technical Reports Server (NTRS)

    Black, Jr., William C. (Inventor); Hermann, Theodore M. (Inventor)

    2001-01-01

    A current determiner having an output at which representations of input currents are provided having an input conductor for the input current and a current sensor supported on a substrate electrically isolated from one another but with the sensor positioned in the magnetic fields arising about the input conductor due to any input currents. The sensor extends along the substrate in a direction primarily perpendicular to the extent of the input conductor and is formed of at least a pair of thin-film ferromagnetic layers separated by a non-magnetic conductive layer. The sensor can be electrically connected to electronic circuitry formed in the substrate including a nonlinearity adaptation circuit to provide representations of the input currents of increased accuracy despite nonlinearities in the current sensor, and can include further current sensors in bridge circuits.

  6. Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling.

    PubMed

    Alvarez-Curto, Elisa; Inoue, Asuka; Jenkins, Laura; Raihan, Sheikh Zahir; Prihandoko, Rudi; Tobin, Andrew B; Milligan, Graeme

    2016-12-30

    G protein-coupled receptors (GPCRs) can initiate intracellular signaling cascades by coupling to an array of heterotrimeric G proteins and arrestin adaptor proteins. Understanding the contribution of each of these coupling options to GPCR signaling has been hampered by a paucity of tools to selectively perturb receptor function. Here we employ CRISPR/Cas9 genome editing to eliminate selected G proteins (Gαq and Gα11) or arrestin2 and arrestin3 from HEK293 cells together with the elimination of receptor phosphorylation sites to define the relative contribution of G proteins, arrestins, and receptor phosphorylation to the signaling outcomes of the free fatty acid receptor 4 (FFA4). A lack of FFA4-mediated elevation of intracellular Ca(2+) in Gαq/Gα11-null cells and agonist-mediated receptor internalization in arrestin2/3-null cells confirmed previously reported canonical signaling features of this receptor, thereby validating the genome-edited HEK293 cells. FFA4-mediated ERK1/2 activation was totally dependent on Gq/11 but intriguingly was substantially enhanced for FFA4 receptors lacking sites of regulated phosphorylation. This was not due to a simple lack of desensitization of Gq/11 signaling because the Gq/11-dependent calcium response was desensitized by both receptor phosphorylation and arrestin-dependent mechanisms, whereas a substantially enhanced ERK1/2 response was only observed for receptors lacking phosphorylation sites and not in arrestin2/3-null cells. In conclusion, we validate CRISPR/Cas9 engineered HEK293 cells lacking Gq/11 or arrestin2/3 as systems for GPCR signaling research and employ these cells to reveal a previously unappreciated interplay of signaling pathways where receptor phosphorylation can impact on ERK1/2 signaling through a mechanism that is likely independent of arrestins.

  7. Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling*

    PubMed Central

    Alvarez-Curto, Elisa; Inoue, Asuka; Jenkins, Laura; Raihan, Sheikh Zahir; Prihandoko, Rudi; Tobin, Andrew B.

    2016-01-01

    G protein-coupled receptors (GPCRs) can initiate intracellular signaling cascades by coupling to an array of heterotrimeric G proteins and arrestin adaptor proteins. Understanding the contribution of each of these coupling options to GPCR signaling has been hampered by a paucity of tools to selectively perturb receptor function. Here we employ CRISPR/Cas9 genome editing to eliminate selected G proteins (Gαq and Gα11) or arrestin2 and arrestin3 from HEK293 cells together with the elimination of receptor phosphorylation sites to define the relative contribution of G proteins, arrestins, and receptor phosphorylation to the signaling outcomes of the free fatty acid receptor 4 (FFA4). A lack of FFA4-mediated elevation of intracellular Ca2+ in Gαq/Gα11-null cells and agonist-mediated receptor internalization in arrestin2/3-null cells confirmed previously reported canonical signaling features of this receptor, thereby validating the genome-edited HEK293 cells. FFA4-mediated ERK1/2 activation was totally dependent on Gq/11 but intriguingly was substantially enhanced for FFA4 receptors lacking sites of regulated phosphorylation. This was not due to a simple lack of desensitization of Gq/11 signaling because the Gq/11-dependent calcium response was desensitized by both receptor phosphorylation and arrestin-dependent mechanisms, whereas a substantially enhanced ERK1/2 response was only observed for receptors lacking phosphorylation sites and not in arrestin2/3-null cells. In conclusion, we validate CRISPR/Cas9 engineered HEK293 cells lacking Gq/11 or arrestin2/3 as systems for GPCR signaling research and employ these cells to reveal a previously unappreciated interplay of signaling pathways where receptor phosphorylation can impact on ERK1/2 signaling through a mechanism that is likely independent of arrestins. PMID:27852822

  8. Endothelial Cell-Surface Gp60 Activates Vesicle Formation and Trafficking via Gi-Coupled Src Kinase Signaling Pathway

    PubMed Central

    Minshall, Richard D.; Tiruppathi, Chinnaswamy; Vogel, Stephen M.; Niles, Walter D.; Gilchrist, Annette; Hamm, Heidi E.; Malik, Asrar B.

    2000-01-01

    with caveolin-1, followed by the activation of the downstream Gi-coupled Src kinase signaling pathway. PMID:10973995

  9. Revisiting an old concept: the coupled oscillator model for VCD. Part 1: the generalised coupled oscillator mechanism and its intrinsic connection to the strength of VCD signals.

    PubMed

    Nicu, Valentin Paul

    2016-08-03

    Motivated by the renewed interest in the coupled oscillator (CO) model for VCD, in this work a generalised coupled oscillator (GCO) expression is derived by introducing the concept of a coupled oscillator origin. Unlike the standard CO expression, the GCO expression is exact within the harmonic approximation. Using two illustrative example molecules, the theoretical concepts introduced here are demonstrated by performing a GCO decomposition of the rotational strengths computed using DFT. This analysis shows that: (1) the contributions to the rotational strengths that are normally neglected in the standard CO model can be comparable to or larger than the CO contribution, and (2) the GCO mechanism introduced here can affect the VCD intensities of all types of modes in symmetric and asymmetric molecules.

  10. Galphas-coupled receptor signaling actively down-regulates α4β1-integrin affinity: A possible mechanism for cell de-adhesion

    PubMed Central

    Chigaev, Alexandre; Waller, Anna; Amit, Or; Sklar, Larry A

    2008-01-01

    Background Activation of integrins in response to inside-out signaling serves as a basis for leukocyte arrest on endothelium, and migration of immune cells. Integrin-dependent adhesion is controlled by the conformational state of the molecule (i.e. change in the affinity for the ligand and molecular unbending (extension)), which is regulated by seven-transmembrane Guanine nucleotide binding Protein-Coupled Receptors (GPCRs). α4β1-integrin (CD49d/CD29, Very Late Antigen-4, VLA-4) is expressed on leukocytes, hematopoietic stem cells, hematopoietic cancer cells, and others. Affinity and extension of VLA-4 are both rapidly up-regulated by inside-out signaling through several Gαi-coupled GPCRs. The goal of the current report was to study the effect of Gαs-coupled GPCRs upon integrin activation. Results Using real-time fluorescent ligand binding to assess affinity and a FRET based assay to probe α4β1-integrin unbending, we show that two Gαs-coupled GPCRs (H2-histamine receptor and β2-adrenergic receptor) as well as several cAMP agonists can rapidly down modulate the affinity of VLA-4 activated through two Gαi-coupled receptors (CXCR4 and FPR) in U937 cells and primary human peripheral blood monocytes. This down-modulation can be blocked by receptor-specific antagonists. The Gαs-induced responses were not associated with changes in the expression level of the Gαi-coupled receptors. In contrast, the molecular unbending of VLA-4 was not significantly affected by Gαs-coupled GPCR signaling. In a VLA-4/VCAM-1-specific myeloid cell adhesion system, inhibition of the VLA-4 affinity change by Gαs-coupled GPCR had a statistically significant effect upon cell aggregation. Conclusion We conclude that Gαs-coupled GPCRs can rapidly down modulate the affinity state of VLA-4 binding pocket through a cAMP dependent pathway. This plays an essential role in the regulation of cell adhesion. We discuss several possible implications of this described phenomenon. PMID:18534032

  11. A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing mitogenic signals initiated by G protein-coupled receptors.

    PubMed

    Vaqué, Jose P; Dorsam, Robert T; Feng, Xiaodong; Iglesias-Bartolome, Ramiro; Forsthoefel, David J; Chen, Qianming; Debant, Anne; Seeger, Mark A; Ksander, Bruce R; Teramoto, Hidemi; Gutkind, J Silvio

    2013-01-10

    Activating mutations in GNAQ and GNA11, encoding members of the Gα(q) family of G protein α subunits, are the driver oncogenes in uveal melanoma, and mutations in Gq-linked G protein-coupled receptors have been identified recently in numerous human malignancies. How Gα(q) and its coupled receptors transduce mitogenic signals is still unclear because of the complexity of signaling events perturbed upon Gq activation. Using a synthetic-biology approach and a genome-wide RNAi screen, we found that a highly conserved guanine nucleotide exchange factor, Trio, is essential for activating Rho- and Rac-regulated signaling pathways acting on JNK and p38, and thereby transducing proliferative signals from Gα(q) to the nucleus independently of phospholipase C-β. Indeed, whereas many biological responses elicited by Gq depend on the transient activation of second-messenger systems, Gq utilizes a hard-wired protein-protein-interaction-based signaling circuitry to achieve the sustained stimulation of proliferative pathways, thereby controlling normal and aberrant cell growth.

  12. Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons

    PubMed Central

    Nair, Anu G.; Eriksson, Olivia; Vincent, Pierre

    2015-01-01

    Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via Golf- and Gi/o-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an ACh dip is required to gate a subset of D1R/Golf-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2+ MSNs is under basal inhibition via D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting A2aR/Golf, but D2+ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by Gi/o and the importance of interactions between Gi/o and Golf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation. SIGNIFICANCE STATEMENT Dopamine transients are considered to carry reward-related signal in reinforcement learning. An increase in dopamine concentration is associated with an unexpected reward or salient stimuli, whereas a decrease is produced by omission of an expected reward. Often dopamine transients are accompanied by other neuromodulatory signals, such as acetylcholine and adenosine. We highlight the

  13. Differential pathway coupling efficiency of the activated insulin receptor drives signaling selectivity by xmeta, an allosteric partial agonist antibody

    Technology Transfer Automated Retrieval System (TEKTRAN)

    XMetA, an anti-insulin receptor (IR) monoclonal antibody, is an allosteric partial agonist of the IR. We have previously reported that XMetA activates the “metabolic-biased” Akt kinase signaling pathway while having little or no effect on the “mitogenic” MAPK signaling pathwayof ERK 1/2. To inves...

  14. βArrestins in cardiac G protein-coupled receptor signaling and function: partners in crime or "good cop, bad cop"?

    PubMed

    Lymperopoulos, Anastasios; Negussie, Shmuel

    2013-12-18

    βArrestin (βarr)-1 and -2 (βarrs) (or Arrestin-2 and -3, respectively) are universal G protein-coupled receptor (GPCR) adapter proteins expressed abundantly in extra-retinal tissues, including the myocardium. Both were discovered in the lab of the 2012 Nobel Prize in Chemistry co-laureate Robert Lefkowitz, initially as terminators of signaling from the β-adrenergic receptor (βAR), a process known as functional desensitization. They are now known to switch GPCR signaling from G protein-dependent to G protein-independent, which, in the case of βARs and angiotensin II type 1 receptor (AT1R), might be beneficial, e.g., anti-apoptotic, for the heart. However, the specific role(s) of each βarr isoform in cardiac GPCR signaling and function (or dysfunction in disease), remain unknown. The current consensus is that, whereas both βarr isoforms can desensitize and internalize cardiac GPCRs, they play quite different (even opposing in certain instances) roles in the G protein-independent signaling pathways they initiate in the cardiovascular system, including in the myocardium. The present review will discuss the current knowledge in the field of βarrs and their roles in GPCR signaling and function in the heart, focusing on the three most important, for cardiac physiology, GPCR types (β1AR, β2AR & AT1R), and will also highlight important questions that currently remain unanswered.

  15. Different cAMP sources are critically involved in G protein–coupled receptor CRHR1 signaling

    PubMed Central

    dos Santos Claro, Paula A.; Senin, Sergio A.; Maccarrone, Giuseppina; Turck, Christoph W.

    2016-01-01

    Corticotropin-releasing hormone receptor 1 (CRHR1) activates G protein–dependent and internalization-dependent signaling mechanisms. Here, we report that the cyclic AMP (cAMP) response of CRHR1 in physiologically relevant scenarios engages separate cAMP sources, involving the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). cAMP produced by tmACs and sAC is required for the acute phase of extracellular signal regulated kinase 1/2 activation triggered by CRH-stimulated CRHR1, but only sAC activity is essential for the sustained internalization-dependent phase. Thus, different cAMP sources are involved in different signaling mechanisms. Examination of the cAMP response revealed that CRH-activated CRHR1 generates cAMP after endocytosis. Characterizing CRHR1 signaling uncovered a specific link between CRH-activated CRHR1, sAC, and endosome-based signaling. We provide evidence of sAC being involved in an endocytosis-dependent cAMP response, strengthening the emerging model of GPCR signaling in which the cAMP response does not occur exclusively at the plasma membrane and introducing the notion of sAC as an alternative source of cAMP. PMID:27402953

  16. Different cAMP sources are critically involved in G protein-coupled receptor CRHR1 signaling.

    PubMed

    Inda, Carolina; Dos Santos Claro, Paula A; Bonfiglio, Juan J; Senin, Sergio A; Maccarrone, Giuseppina; Turck, Christoph W; Silberstein, Susana

    2016-07-18

    Corticotropin-releasing hormone receptor 1 (CRHR1) activates G protein-dependent and internalization-dependent signaling mechanisms. Here, we report that the cyclic AMP (cAMP) response of CRHR1 in physiologically relevant scenarios engages separate cAMP sources, involving the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). cAMP produced by tmACs and sAC is required for the acute phase of extracellular signal regulated kinase 1/2 activation triggered by CRH-stimulated CRHR1, but only sAC activity is essential for the sustained internalization-dependent phase. Thus, different cAMP sources are involved in different signaling mechanisms. Examination of the cAMP response revealed that CRH-activated CRHR1 generates cAMP after endocytosis. Characterizing CRHR1 signaling uncovered a specific link between CRH-activated CRHR1, sAC, and endosome-based signaling. We provide evidence of sAC being involved in an endocytosis-dependent cAMP response, strengthening the emerging model of GPCR signaling in which the cAMP response does not occur exclusively at the plasma membrane and introducing the notion of sAC as an alternative source of cAMP.

  17. Activation of the Cl− Channel ANO1 by Localized Calcium Signals in Nociceptive Sensory Neurons Requires Coupling with the IP3 Receptor*

    PubMed Central

    Jin, Xin; Shah, Shihab; Liu, Yani; Zhang, Huiran; Lees, Meredith; Fu, Zhaojun; Lippiat, Jonathan D.; Beech, David J.; Sivaprasadarao, Asipu; Baldwin, Stephen A.; Zhang, Hailin; Gamper, Nikita

    2014-01-01

    We report that ANO1 (also known as TMEM16A) Ca2+-activated Cl− channels in small neurons from dorsal root ganglia are preferentially activated by particular pools of intracellular Ca2+. These ANO1 channels can be selectively activated by the G protein-coupled receptor (GPCR)-induced release of Ca2+ from intracellular stores, but not by Ca2+ influx through voltage-gated Ca2+ channels. This ability to discriminate between Ca2+ pools was achieved by the tethering of ANO1-containing plasma membrane domains, which also contained GPCRs such as bradykinin receptor-2 and protease-activated receptor-2, to juxtamembrane regions of the endoplasmic reticulum. Interaction of the C-terminus and the first intracellular loop of ANO1 with IP3R1 (inositol 1,4,5-trisphosphate receptor 1) contributed to the tethering. Disruption of membrane microdomains blocked the ANO1 and IP3R1 interaction and resulted in the loss of coupling between GPCR signaling and ANO1. The junctional signaling complex enabled ANO1-mediated excitation in response to specific Ca2+ signals rather than to global changes in intracellular Ca2+. PMID:23982204

  18. The role(s) of astrocytes and astrocyte activity in neurometabolism, neurovascular coupling, and the production of functional neuroimaging signals.

    PubMed

    Figley, Chase R; Stroman, Patrick W

    2011-02-01

    Data acquired with functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) are often interpreted in terms of the underlying neuronal activity, despite mounting evidence that these signals do not always correlate with electrophysiological recordings. Therefore, considering the increasing popularity of functional neuroimaging, it is clear that a more comprehensive theory is needed to reconcile these apparent disparities and more accurately explain the mechanisms through which various PET and fMRI signals arise. In the present article, we have turned our attention to astrocytes, which vastly outnumber neurons and are known to serve a number of functions throughout the central nervous system (CNS). For example, astrocytes are known to be critically involved in neurotransmitter uptake and recycling, and empirical data suggests that brain activation increases both oxidative and glycolytic astrocyte metabolism. Furthermore, a number of recent studies imply that astrocytes are likely to play a key role in regulating cerebral blood delivery. Therefore, we propose that, by mediating neurometabolic and neurovascular processes throughout the CNS, astrocytes could provide a common physiological basis for fMRI and PET signals. Such a theory has significant implications for the interpretation of functional neuroimaging signals, because astrocytic changes reflect subthreshold neuronal activity, simultaneous excitatory/inhibitory synaptic inputs, and other transient metabolic demands that may not elicit electrophysiological changes. It also suggests that fMRI and PET signals may have inherently less sensitivity to decreases in synaptic input (i.e. 'negative activity') and/or inhibitory (GABAergic) neurotransmission.

  19. Submicroscopic calcium signals as fundamental events of excitation--contraction coupling in guinea-pig cardiac myocytes.

    PubMed Central

    Lipp, P; Niggli, E

    1996-01-01

    1. Subcellularly localized Ca2+ signals have been proposed to represent elementary events of cardiac Ca2+ signalling (Ca2+ sparks), whereby an individual sarcolemmal L-type Ca2+ channel locally controls opening of a single (or a few) Ca2+ release channels in the sarcoplasmic reticulum (SR). 2. To investigate directly the elementary nature of this Ca(2+)-induced Ca2+ release mechanism we used flash photolysis of caged Ca2+ while simultaneously measuring the intracellular Ca2+ concentration ([Ca2+]i) with a laser-scanning confocal microscope. 3. Power spectral analysis of the confocal images performed in the spatial domain revealed that only Ca2+ signalling events involving the L-type Ca2+ channel pathway gave rise to Ca2+ sparks. In contrast, SR Ca2+ release triggered by photolytic [Ca2+]i jumps resulted in Ca2+ transients that were always spatially homogeneous. 4. From these findings we conclude that the fundamental event of Ca2+ signalling in cardiac muscle may be smaller in size or amplitude than a Ca2+ spark. 5. We term this event a 'Ca2+ quark' possibly resulting from gating of a single SR Ca2+ release channel. It is proposed that concerted activation of several 'Ca2+ quarks' may be required for a Ca2+ spark. The 'Ca2+ quark' could also be the fundamental event in other cell types implementing a hierarchical Ca2+ signalling concept. Images Fig. 1 Figure 2 (cont.) Figure 2 Figure 3 PMID:8730580

  20. Signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum by biocomputation.

    PubMed

    Wang, Lin; Huang, Juxiang; Jiang, Minghu; Lin, Hong

    2012-07-01

    We constructed the high-expression signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum compared with low-expression (fold change ≥2) chimpanzee left cerebrum in GEO data set by using integration of gene regulatory network inference method with gene ontology (GO) analysis of STAT2-activated up- and downstream network. Our result showed that upstream RECQL, PDIA2, ENOSF1, THBS4, RASGRP1, PER2, PDE8A, ORC2L, DCI, OGG1_2, SMA4, GPD1, etc. activated STAT2, and downstream STAT2-activated GSTM3_1, GOSR1, SH3BGR, OSBPL8, PHYH, SAPS2, C21orf33, PDIA2, TRAPPC6A, ENOSF1, CAMTA1, GTF2I_2, etc. in human left cerebrum. STAT2-activated network enhanced regulation of small GTPase-mediated signal transduction, regulation of transcription, regulation of mitosis, regulation of cell growth, positive regulation of phosphoinositide 3-kinase cascade, positive regulation of fat cell differentiation, negative regulation of DNA replication, negative regulation of progression through cell cycle, cyclic nucleotide metabolism, lipid metabolism, carbohydrate metabolism, vitamin A metabolism, N-acetylglucosamine metabolism, UDP-N-acetylgalactosamine metabolism, fatty acid transport, intracellular protein transport, vesicle-mediated transport, lipid transport, retrograde transport, Ras protein signal transduction, Wnt receptor signaling pathway, nervous system development, cell extension, cell adhesion, cell differentiation, circadian rhythm, generation of precursor metabolites and energy, establishment of blood-nerve barrier, visual perception, sensory perception of sound, and poly-N-acetyllactosamine biosynthesis, as a result of inducing metabolism coupling postmitotic outgrowth to visual and sound perception in human left cerebrum.

  1. A signal-off sandwich photoelectrochemical immunosensor using TiO2 coupled with CdS as the photoactive matrix and copper (II) ion as inhibitor.

    PubMed

    Liu, Yixin; Li, Rongxia; Gao, Picheng; Zhang, Yong; Ma, Hongmin; Yang, Jiaojiao; Du, Bin; Wei, Qin

    2015-03-15

    In this work, a novel sandwich photoelectrochemical (PEC) biosensor was developed based on a signal-off strategy using TiO2 coupled with CdS quantum dots (QDs) as the photoactive matrix and copper (II) ion (Cu(2+)) as inhibitor. TiO2/CdS modified indium tin oxide (ITO) electrode was employed for primary antibody (Ab1) immobilization and the subsequent sandwich-type antibody-antigen (Ab-Ag) affinity interactions. Flower-like copper oxide (CuO) was used as labels of secondary antibody (Ab2) and immobilized on the modified electrode via specific affinity interactions between Ab2 and Ag. Cu(2+) was released by dissolving CuO with HCl, and then reacted with CdS to form CuxS (x=1, 2), which would create new energy levels for electron-hole recombination and resulted in a decrease of the photocurrent. CuO, as the labels of Ab2, was first applied in PEC biosensor based on the signal-off strategy of the Cu(2+) for CdS. Greatly enhanced sensitivity was achieved through the coupling of CdS QDs with TiO2. Besides, the introduction of polythiophene (PT-Cl) on the surface of TiO2 made the PEC signal more stable. Under 405nm irradiation at 0.1V, the PEC biosensor for H-IgG determination exhibited a linear range from 0.1pgmL(-1) to 100ngmL(-1) with a low detection limit of 0.03pgmL(-1). The proposed biosensor showed high sensitivity, stability and selectivity, which opens up a new promising signal-off PEC platform for future bioassay.

  2. Recent advances in drug action and therapeutics: Relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology

    PubMed Central

    Brink, C B; Harvey, B H; Bodenstein, J; Venter, D P; Oliver, D W

    2004-01-01

    Problem statement During especially the past two decades many discoveries in biological sciences, and in particular at the molecular and genetic level, have greatly impacted on our knowledge and understanding of drug action and have helped to develop new drugs and therapeutic strategies. Furthermore, many exciting new drugs acting via novel pharmacological mechanisms are expected to be in clinical use in the not too distant future. Scope and contents of review In this educational review, these concepts are explained and their relevance illustrated by examples of drugs used commonly in the clinical setting, with special reference to the pharmacology of G-protein-coupled receptors. The review also addresses the basic theoretical concepts of full and partial agonism, neutral antagonism, inverse agonism and protean and ligand-selective agonism, and the relevance of these concepts in current rational drug therapy. Moreover, the mechanisms whereby receptor signalling (and eventually response to drugs) is fine-tuned, such as receptor promiscuity, agonist-directed trafficking of receptor signalling, receptor trafficking, receptor ‘cross-talk’ and regulators of G-protein signalling (RGSs) are discussed, from theory to proposed therapeutic implications. Conclusions It is concluded that the understanding of molecular receptor and signal transduction pharmacology enables clinicians to improve their effective implementation of current and future pharmacotherapy, ultimately enhancing the quality of life of their patients. PMID:15025734

  3. Negative control of keratinocyte differentiation by Rho/CRIK signaling coupled with up-regulation of KyoT1/2 (FHL1) expression

    PubMed Central

    Grossi, Maddalena; Hiou-Feige, Agnès; Di Vignano, Alice Tommasi; Calautti, Enzo; Ostano, Paola; Lee, Sam; Chiorino, Giovanna; Dotto, G. Paolo

    2005-01-01

    Rho GTPases integrate control of cell structure and adhesion with downstream signaling events. In keratinocytes, RhoA is activated at early times of differentiation and plays an essential function in establishment of cell–cell adhesion. We report here that, surprisingly, Rho signaling suppresses downstream gene expression events associated with differentiation. Similar inhibitory effects are exerted by a specific Rho effector, CRIK (Citron kinase), which is selectively down-modulated with differentiation, thereby allowing the normal process to occur. The suppressing function of Rho/CRIK on differentiation is associated with induction of KyoT1/2, a LIM domain protein gene implicated in integrin-mediated processes and/or Notch signaling. Like activated Rho and CRIK, elevated KyoT1/2 expression suppresses differentiation. Thus, Rho signaling exerts an unexpectedly complex role in keratinocyte differentiation, which is coupled with induction of KyoT1/2, a LIM domain protein gene with a potentially important role in control of cell self renewal. PMID:16061799

  4. Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas

    PubMed Central

    Bognar, M K; Vincendeau, M; Erdmann, T; Seeholzer, T; Grau, M; Linnemann, J R; Ruland, J; Scheel, C H; Lenz, P; Ott, G; Lenz, G; Hauck, S M; Krappmann, D

    2016-01-01

    Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. PMID:26776161

  5. Specific Activation of the G Protein-coupled Receptor BNGR-A21 by the Neuropeptide Corazonin from the Silkworm, Bombyx mori, Dually Couples to the Gq and Gs Signaling Cascades*

    PubMed Central

    Yang, Jingwen; Huang, Haishan; Yang, Huipeng; He, Xiaobai; Jiang, Xue; Shi, Ying; Alatangaole, Damirin; Shi, Liangen; Zhou, Naiming

    2013-01-01

    Corazonin, an undecapeptide neurohormone sharing a highly conserved amino acid sequence across Insecta, plays different physiological roles in the regulation of heart contraction rates, silk spinning rates, the induction of dark color and morphometric phase changes, and ecdysis. Corazonin receptors have been identified in Drosophila melanogaster, Manduca sexta, and Musca domestica. However, detailed information on the signaling and major physiological functions of corazonin and its receptor is largely unknown. In the current study, using both the mammalian cell line HEK293 and insect cell lines BmN and Sf21, we paired the Bombyx corazonin neuropeptide as a specific endogenous ligand for the Bombyx neuropeptide G protein-coupled receptor A21 (BNGR-A21), and we therefore designated this receptor as BmCrzR. Further characterization indicated that synthetic BmCrz demonstrated a high affinity for and activated BmCrzR, resulting in intracellular cAMP accumulation, Ca2+ mobilization, and ERK1/2 phosphorylation via the Gq- and Gs-coupled signaling pathways. The direct interaction of BmCrzR with BmCrz was confirmed by a rhodamine-labeled BmCrz peptide. Moreover, experiments with double-stranded RNA and synthetic peptide injection suggested a possible role of BmCrz/BmCrzR in the regulation of larval growth and spinning rate. Our present results provide the first in-depth information on BmCrzR-mediated signaling for further elucidation of the BmCrz/BmCrzR system in the regulation of fundamental physiological processes. PMID:23457297

  6. Searches for the FCNC couplings from top-Higgs associated production signal with h → γγ at the LHC

    NASA Astrophysics Data System (ADS)

    Liu, Yao-Bei; Xiao, Zhen-Jun

    2016-12-01

    In this paper, we study the observability of the top-Higgs flavor changing neutral current (FCNC) tqh coupling through the process pp → qg → t (→ℓ+ bν) h (→ γγ) at the Large Hadron Collider (LHC), where ℓ = e , μ. Our numerical results show that, in some parameter regions, the LHC may observe the above signals at the 5σ level. Otherwise, the branching ratios Br (t → uh) and Br (t → ch) can be respectively probed to 0.036% and 0.13% at 3σ level at 14 TeV LHC with the high integrated luminosity of 3000 fb-1. On the other hand, studying the charge ratio for the lepton in top quark decay can be not only used to discriminate between signal and backgrounds, but also used to discriminate between tuh and tch couplings, for which anomalous single top production comes from the up initiated channel and charm initiated channel.

  7. Coupling of growth to nutritional status: The role of novel periphery-to-brain signaling by the CCHa2 peptide in Drosophila melanogaster

    PubMed Central

    Sano, Hiroko

    2015-01-01

    ABSTRACT The coupling of growth to nutritional status is an important adaptive response of living organisms to their environment. For this ability, animals have evolved various strategies, including endocrine systems that respond to changing nutritional conditions. In animals, nutritional information is mostly perceived by peripheral organs, such as the digestive tract and adipose tissues, and is subsequently transmitted to other peripheral organs or the brain, which integrates the incoming signals and orchestrates physiological and behavioral responses. In Drosophila melanogaster, adipose tissue, known as the fat body, functions as an endocrine organ that communicates with the brain. This fat body-brain axis coordinates growth with nutritional status by regulating the secretion of Drosophila insulin-like peptides (Dilps) from the brain. However, the molecular nature of the fat body-brain axis remains to be elucidated. We recently demonstrated that a small peptide, CCHamide-2 (CCHa2), expressed in the fat body and gut, directly stimulates its receptor (CCHa2-R) in the brain, leading to Dilp production. Notably, the expression of CCHa2 is sensitive to the presence of nutrients, particularly sugars. Our results, together with the results of previous studies, show that signaling between peripheral organs and the brain is a conserved strategy that couples nutritional availability to organismal physiology. PMID:26980588

  8. RDGBα, a PtdIns-PtdOH transfer protein, regulates G-protein-coupled PtdIns(4,5)P2 signalling during Drosophila phototransduction

    PubMed Central

    Yadav, Shweta; Garner, Kathryn; Georgiev, Plamen; Li, Michelle; Gomez-Espinosa, Evelyn; Panda, Aniruddha; Mathre, Swarna; Okkenhaug, Hanneke; Cockcroft, Shamshad; Raghu, Padinjat

    2015-01-01

    ABSTRACT Many membrane receptors activate phospholipase C (PLC) during signalling, triggering changes in the levels of several plasma membrane lipids including phosphatidylinositol (PtdIns), phosphatidic acid (PtdOH) and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2]. It is widely believed that exchange of lipids between the plasma membrane and endoplasmic reticulum (ER) is required to restore lipid homeostasis during PLC signalling, yet the mechanism remains unresolved. RDGBα (hereafter RDGB) is a multi-domain protein with a PtdIns transfer protein (PITP) domain (RDGB-PITPd). We find that, in vitro, the RDGB-PITPd binds and transfers both PtdOH and PtdIns. In Drosophila photoreceptors, which experience high rates of PLC activity, RDGB function is essential for phototransduction. We show that binding of PtdIns to RDGB-PITPd is essential for normal phototransduction; however, this property is insufficient to explain the in vivo function because another Drosophila PITP (encoded by vib) that also binds PtdIns cannot rescue the phenotypes of RDGB deletion. In RDGB mutants, PtdIns(4,5)P2 resynthesis at the plasma membrane following PLC activation is delayed and PtdOH levels elevate. Thus RDGB couples the turnover of both PtdIns and PtdOH, key lipid intermediates during G-protein-coupled PtdIns(4,5)P2 turnover. PMID:26203165

  9. Tumor necrosis factor receptor superfamily costimulation couples T cell receptor signal strength to thymic regulatory T cell differentiation

    PubMed Central

    Mahmud, Shawn A.; Manlove, Luke S.; Schmitz, Heather M.; Xing, Yan; Wang, Yanyan; Owen, David L.; Schenkel, Jason M.; Boomer, Jonathan S.; Green, Jonathan M.; Yagita, Hideo; Chi, Hongbo; Hogquist, Kristin A.; Farrar, Michael A.

    2014-01-01

    Regulatory T (Treg) cells express tumor necrosis factor receptor superfamily (TNFRSF) members, but their role in thymic Treg development is undefined. We demonstrate that Treg progenitors highly express the TNFRSF members GITR, OX40, and TNFR2. Expression of these receptors correlates directly with T cell receptor (TCR) signal strength, and requires CD28 and the kinase TAK1. Neutralizing TNFSF ligands markedly reduced Treg development. Conversely, TNFRSF agonists enhanced Treg differentiation by augmenting IL-2R/STAT5 responsiveness. GITR-ligand costimulation elicited a dose-dependent enrichment of lower-affinity cells within the Treg repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated Treg development. Thus TNFRSF expression on Treg progenitors translates strong TCR signals into molecular parameters that specifically promote Treg differentiation and shape the Treg repertoire. PMID:24633226

  10. Coupled Research in Ocean Acoustics and Signal Processing for the Next Generation of Underwater Acoustic Communication Systems

    DTIC Science & Technology

    2016-08-05

    order of millimeters in the tank with wind speeds up to 16 meters per second. The data from the experiment was all quality checked and found to be of...mechanism which remains stable (i.e., no vibration) at the wind speeds used in the experiment. The second purpose was to conduct the tests up to higher wind ...speeds to determine of the apparent plateauing of some quantitative signal characteristics with increasing wind speed at the upper limit of the usable

  11. An Adaptive Low-Cost GNSS/MEMS-IMU Tightly-Coupled Integration System with Aiding Measurement in a GNSS Signal-Challenged Environment

    PubMed Central

    Zhou, Qifan; Zhang, Hai; Li, You; Li, Zheng

    2015-01-01

    The main aim of this paper is to develop a low-cost GNSS/MEMS-IMU tightly-coupled integration system with aiding information that can provide reliable position solutions when the GNSS signal is challenged such that less than four satellites are visible in a harsh environment. To achieve this goal, we introduce an adaptive tightly-coupled integration system with height and heading aiding (ATCA). This approach adopts a novel redundant measurement noise estimation method for an adaptive Kalman filter application and also augments external measurements in the filter to aid the position solutions, as well as uses different filters to deal with various situations. On the one hand, the adaptive Kalman filter makes use of the redundant measurement system’s difference sequence to estimate and tune noise variance instead of employing a traditional innovation sequence to avoid coupling with the state vector error. On the other hand, this method uses the external height and heading angle as auxiliary references and establishes a model for the measurement equation in the filter. In the meantime, it also changes the effective filter online based on the number of tracked satellites. These measures have increasingly enhanced the position constraints and the system observability, improved the computational efficiency and have led to a good result. Both simulated and practical experiments have been carried out, and the results demonstrate that the proposed method is effective at limiting the system errors when there are less than four visible satellites, providing a satisfactory navigation solution. PMID:26393605

  12. The role of G protein coupled receptor-mediated signaling in the biological properties of Acanthamoeba castellanii of the T4 genotype.

    PubMed

    Aqeel, Yousuf; Siddiqui, Ruqaiyyah; Manan, Zainab; Khan, Naveed Ahmed

    2015-04-01

    Despite advances in antimicrobial chemotherapy and supportive care, the prognosis of Acanthamoeba infections remains poor, suggesting that new targets are needed that can affect parasite survival and host-pathogen interactions. G proteins and their coupled receptors are well known regulators of a variety of cellular functions. The overall aim of the present study was to study the role of G-protein coupled receptor, β adrenergic receptor on the biology and pathogenesis of keratitis isolate of Acanthamoeba castellanii of the T4 genotype. Inhibition of β adrenergic receptor using antagonist, propranolol had detrimental effects on the extracellular proteolytic activities A. castellanii as determined using zymographic assays. Conversely, β adrenergic receptor agonist, isoprenaline showed increased proteases. Interestingly, β adrenergic receptor inhibition affected A. castellanii growth (using amoebistatic assays), viability (using amoebicidal assays by measuring uptake of Trypan blue) and encystation as determined by trophozoite transformation into the cyst form. Pre-treatment of parasites with propranolol hampered A. castellanii-mediated human brain microvascular endothelial cell cytotoxicity, as measured by the lacatate dehydrogenase release. The aforementioned findings suggest that G-protein coupled receptor, β adrenergic receptor-mediated signaling in A. castellanii biology and pathogenesis may offer new pharmacological targets.

  13. An Adaptive Low-Cost GNSS/MEMS-IMU Tightly-Coupled Integration System with Aiding Measurement in a GNSS Signal-Challenged Environment.

    PubMed

    Zhou, Qifan; Zhang, Hai; Li, You; Li, Zheng

    2015-09-18

    The main aim of this paper is to develop a low-cost GNSS/MEMS-IMU tightly-coupled integration system with aiding information that can provide reliable position solutions when the GNSS signal is challenged such that less than four satellites are visible in a harsh environment. To achieve this goal, we introduce an adaptive tightly-coupled integration system with height and heading aiding (ATCA). This approach adopts a novel redundant measurement noise estimation method for an adaptive Kalman filter application and also augments external measurements in the filter to aid the position solutions, as well as uses different filters to deal with various situations. On the one hand, the adaptive Kalman filter makes use of the redundant measurement system's difference sequence to estimate and tune noise variance instead of employing a traditional innovation sequence to avoid coupling with the state vector error. On the other hand, this method uses the external height and heading angle as auxiliary references and establishes a model for the measurement equation in the filter. In the meantime, it also changes the effective filter online based on the number of tracked satellites. These measures have increasingly enhanced the position constraints and the system observability, improved the computational efficiency and have led to a good result. Both simulated and practical experiments have been carried out, and the results demonstrate that the proposed method is effective at limiting the system errors when there are less than four visible satellites, providing a satisfactory navigation solution.

  14. Non-Sinusoidal Activity Can Produce Cross-Frequency Coupling in Cortical Signals in the Absence of Functional Interaction between Neural Sources

    PubMed Central

    Ward, Andrew; Knight, Robert T.; Deouell, Leon Y.

    2016-01-01

    The analysis of cross-frequency coupling (CFC) has become popular in studies involving intracranial and scalp EEG recordings in humans. It has been argued that some cases where CFC is mathematically present may not reflect an interaction of two distinct yet functionally coupled neural sources with different frequencies. Here we provide two empirical examples from intracranial recordings where CFC can be shown to be driven by the shape of a periodic waveform rather than by a functional interaction between distinct sources. Using simulations, we also present a generalized and realistic scenario where such coupling may arise. This scenario, which we term waveform-dependent CFC, arises when sharp waveforms (e.g., cortical potentials) occur throughout parts of the data, in particular if they occur rhythmically. Since the waveforms contain both low- and high-frequency components, these components can be inherently phase-aligned as long as the waveforms are spaced with appropriate intervals. We submit that such behavior of the data, which seems to be present in various cortical signals, cannot be interpreted as reflecting functional modulation between distinct neural sources without additional evidence. In addition, we show that even low amplitude periodic potentials that cannot be readily observed or controlled for, are sufficient for significant CFC to occur. PMID:27941990

  15. A Fluorescent Live Imaging Screening Assay Based on Translocation Criteria Identifies Novel Cytoplasmic Proteins Implicated in G Protein-coupled Receptor Signaling Pathways.

    PubMed

    Lecat, Sandra; Matthes, Hans W D; Pepperkok, Rainer; Simpson, Jeremy C; Galzi, Jean-Luc

    2015-05-01

    Several cytoplasmic proteins that are involved in G protein-coupled receptor signaling cascades are known to translocate to the plasma membrane upon receptor activation, such as beta-arrestin2. Based on this example and in order to identify new cytoplasmic proteins implicated in the ON-and-OFF cycle of G protein-coupled receptor, a live-imaging screen of fluorescently labeled cytoplasmic proteins was performed using translocation criteria. The screening of 193 fluorescently tagged human proteins identified eight proteins that responded to activation of the tachykinin NK2 receptor by a change in their intracellular localization. Previously we have presented the functional characterization of one of these proteins, REDD1, that translocates to the plasma membrane. Here we report the results of the entire screening. The process of cell activation was recorded on videos at different time points and all the videos can be visualized on a dedicated website. The proteins BAIAP3 and BIN1, partially translocated to the plasma membrane upon activation of NK2 receptors. Proteins ARHGAP12 and PKM2 translocated toward membrane blebs. Three proteins that associate with the cytoskeleton were of particular interest : PLEKHH2 rearranged from individual dots located near the cell-substrate adhesion surface into lines of dots. The speriolin-like protein, SPATC1L, redistributed to cell-cell junctions. The Chloride intracellular Channel protein, CLIC2, translocated from actin-enriched plasma membrane bundles to cell-cell junctions upon activation of NK2 receptors. CLIC2, and one of its close paralogs, CLIC4, were further shown to respond with the same translocation pattern to muscarinic M3 and lysophosphatidic LPA receptors. This screen allowed us to identify potential actors in signaling pathways downstream of G protein-coupled receptors and could be scaled-up for high-content screening.

  16. Angiotensin II receptor subtypes are coupled with distinct signal-transduction mechanisms in neurons and astrocytes from rat brain

    SciTech Connect

    Sumners, C.; Wei Tang; Zelezna, B.; Raizada, M.K. )

    1991-09-01

    Both neurons and astrocytes contain specific receptors for angiotensin II (AII). The authors used selective ligands for the AT{sub 1} and AT{sub 2} types of AII receptors to investigate the expression of functional receptor subtypes in astrocyte cultures and neuron cultures from 1-day-old (neonatal) rat brain. In astrocyte cultures, competition of {sup 125}I-labeled AII ({sup 125}I-AII) specific binding with AT{sub 1} (DuP753) or AT{sub 2} {l brace}PD123177, CGP42112A, (Phe(p-NH{sub 2}){sup 6})AII{r brace} selective receptor ligands revealed a potency series of AII > DuP753 > > > CGP42112A > (Phe(p-NH{sub 2}){sup 6})AII > PD123177. These results suggest a predominance of the AT{sub 1} receptor subtype in neonatal astrocytes. {sup 125}I-AII specific binding to neonate neuronal cultures was reduced 73-84% by 1 {mu} MPD123177, and the residual {sup 125}I-AII specific binding was eliminated by DuP753. The results suggest that astrocyte cultures from neonatal rat brains contain predominantly AT{sub 1} receptors that are coupled to a stimulation of inositophospholipid hydrolysis. In contrast, neuron cultures from neonatal rat brain contain mostly AT{sub 2} receptors that are coupled to a reduction in basal cGMP levels, but a smaller population of AT{sub 1} receptors is also present in these neurons.

  17. The chemical biology of the persulfide (RSSH)/perthiyl (RSS·) redox couple and possible role in biological redox signaling.

    PubMed

    Bianco, Christopher L; Chavez, Tyler A; Sosa, Victor; Saund, Simran S; Nguyen, Q Nhu N; Tantillo, Dean J; Ichimura, Andrew S; Toscano, John P; Fukuto, Jon M

    2016-12-01

    The recent finding that hydropersulfides (RSSH) are biologically prevalent in mammalian systems has prompted further investigation of their chemical properties in order to provide a basis for understanding their potential functions, if any. Hydropersulfides have been touted as hyper-reactive thiol-like species that possess increased nucleophilicity and reducing capabilities compared to their thiol counterparts. Herein, using persulfide generating model systems, the ability of RSSH species to act as one-electron reductants has been examined. Not unexpectedly, RSSH is relatively easily oxidized, compared to thiols, by weak oxidants to generate the perthiyl radical (RSS·). Somewhat surprisingly, however, RSS· was found to be stable in the presence of both O2 and NO and only appears to dimerize. Thus, the RSSH/RSS· redox couple is readily accessible under biological conditions and since dimerization of RSS· may be a rare event due to low concentrations and/or sequestration within a protein, it is speculated that the general lack of reactivity of individual RSS· species may allow this couple to be utilized as a redox component in biological systems.

  18. Analysis and Quantification of Coupling Mechanisms of External Signal Perturbations on Silicon Detectors for Particle Physics Experiments

    NASA Astrophysics Data System (ADS)

    Arteche, F.; Rivetta, C.; Iglesias, M.; Echeverria, I.

    2016-05-01

    Silicon detectors have been used in astrophysics satellites and particle detectors for high energy physics (HEP) experiments. For HEP applications, EMC studies have been conducted in silicon detectors to characterize the impact of external noise on the system. They have shown that problems associated with the new generation of silicon detectors are related with interferences generated by the power supplies and auxiliary equipment connected to the device. Characterization of these interferences along with the coupling and their propagation into the susceptible front-end circuits is required for a successful integration of these systems. This paper presents the analysis of the sensitivity curves and coupling mechanisms between the noise and the front-end electronics that have been observed during the characterization of two silicon detector prototypes: the CMS-Silicon tracker detector (CMS-ST) and Silicon Vertex Detector (Belle II-SVD). As a result of these studies, it is possible to identify critical elements in prototypes to take corrective actions in the design and improve the front-end electronics performance.

  19. Evidence of the receptor-mediated influence of melatonin on pancreatic glucagon secretion via the Gαq protein-coupled and PI3K signaling pathways.

    PubMed

    Bähr, Ina; Mühlbauer, Eckhard; Albrecht, Elke; Peschke, Elmar

    2012-11-01

    Melatonin has been shown to modulate glucose metabolism by influencing insulin secretion. Recent investigations have also indicated a regulatory function of melatonin on the pancreatic α-cells. The present in vitro and in vivo studies evaluated whether melatonin mediates its effects via melatonin receptors and which signaling cascade is involved. Incubation experiments using the glucagon-producing mouse pancreatic α-cell line αTC1 clone 9 (αTC1.9) as well as isolated pancreatic islets of rats and mice revealed that melatonin increases glucagon secretion. Preincubation of αTC1.9 cells with the melatonin receptor antagonists luzindole and 4P-PDOT abolished the glucagon-stimulatory effect of melatonin. In addition, glucagon secretion was lower in the pancreatic islets of melatonin receptor knockout mice than in the islets of the wild-type (WT) control animals. Investigations of melatonin receptor knockout mice revealed decreased plasma glucagon concentrations and elevated mRNA expression levels of the hepatic glucagon receptor when compared to WT mice. Furthermore, studies using pertussis toxin, as well as measurements of cAMP concentrations, ruled out the involvement of Gαi- and Gαs-coupled signaling cascades in mediating the glucagon increase induced by melatonin. In contrast, inhibition of phospholipase C in αTC1.9 cells prevented the melatonin-induced effect, indicating the physiological relevance of the Gαq-coupled pathway. Our data point to the involvement of the phosphatidylinositol 3-kinase signaling cascade in mediating melatonin effects in pancreatic α-cells. In conclusion, these findings provide evidence that the glucagon-stimulatory effect of melatonin in pancreatic α-cells is melatonin receptor mediated, thus supporting the concept of melatonin-modulated and diurnal glucagon release.

  20. Regulation of FcϵRI Signaling in Mast Cells by G Protein-coupled Receptor Kinase 2 and Its RH Domain*

    PubMed Central

    Subramanian, Hariharan; Gupta, Kshitij; Parameswaran, Narayanan; Ali, Hydar

    2014-01-01

    Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) promotes their desensitization and internalization. Here, we sought to determine the role of GRK2 on FcϵRI signaling and mediator release in mast cells. The strategies utilized included lentiviral shRNA-mediated GRK2 knockdown, GRK2 gene deletion (GRK2flox/flox/cre recombinase) and overexpression of GRK2 and its regulator of G protein signaling homology (RH) domain (GRK2-RH). We found that silencing GRK2 expression caused ∼50% decrease in antigen-induced Ca2+ mobilization and degranulation but resulted in ablation of cytokine (IL-6 and IL-13) generation. The effect of GRK2 on cytokine generation does not require its catalytic activity but is mediated via the phosphorylation of p38 and Akt. Overexpression of GRK2 or its RH domain (GRK2-RH) enhanced antigen-induced mast cell degranulation and cytokine generation without affecting the expression levels of any of the FcϵRI subunits (α, β, and γ). GRK2 or GRK2-RH had no effect on antigen-induced phosphorylation of FcϵRIγ or Src but enhanced tyrosine phosphorylation of Syk. These data demonstrate that GRK2 modulates FcϵRI signaling in mast cells via at least two mechanisms. One involves GRK2-RH and modulates tyrosine phosphorylation of Syk, and the other is mediated via the phosphorylation of p38 and Akt. PMID:24904059

  1. Bright fluorescence monitoring system utilizing Zoanthus sp. green fluorescent protein (ZsGreen) for human G-protein-coupled receptor signaling in microbial yeast cells.

    PubMed

    Nakamura, Yasuyuki; Ishii, Jun; Kondo, Akihiko

    2013-01-01

    G-protein-coupled receptors (GPCRs) are currently the most important pharmaceutical targets for drug discovery because they regulate a wide variety of physiological processes. Consequently, simple and convenient detection systems for ligands that regulate the function of GPCR have attracted attention as powerful tools for new drug development. We previously developed a yeast-based fluorescence reporter ligand detection system using flow cytometry. However, using this conventional detection system, fluorescence from a cell expressing GFP and responding to a ligand is weak, making detection of these cells by fluorescence microscopy difficult. We here report improvements to the conventional yeast fluorescence reporter assay system resulting in the development of a new highly-sensitive fluorescence reporter assay system with extremely bright fluorescence and high signal-to-noise (S/N) ratio. This new system allowed the easy detection of GPCR signaling in yeast using fluorescence microscopy. Somatostatin receptor and neurotensin receptor (implicated in Alzheimer's disease and Parkinson's disease, respectively) were chosen as human GPCR(s). The facile detection of binding to these receptors by cognate peptide ligands was demonstrated. In addition, we established a highly sensitive ligand detection system using yeast cell surface display technology that is applicable to peptide screening, and demonstrate that the display of various peptide analogs of neurotensin can activate signaling through the neurotensin receptor in yeast cells. Our system could be useful for identifying lead peptides with agonistic activity towards targeted human GPCR(s).

  2. Ccr4-Not Regulates RNA Polymerase I Transcription and Couples Nutrient Signaling to the Control of Ribosomal RNA Biogenesis

    PubMed Central

    Laribee, R. Nicholas; Hosni-Ahmed, Amira; Workman, Jason J.; Chen, Hongfeng

    2015-01-01

    Ribosomal RNA synthesis is controlled by nutrient signaling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. mTORC1 regulates ribosomal RNA expression by affecting RNA Polymerase I (Pol I)-dependent transcription of the ribosomal DNA (rDNA) but the mechanisms involved remain obscure. This study provides evidence that the Ccr4-Not complex, which regulates RNA Polymerase II (Pol II) transcription, also functions downstream of mTORC1 to control Pol I activity. Ccr4-Not localizes to the rDNA and physically associates with the Pol I holoenzyme while Ccr4-Not disruption perturbs rDNA binding of multiple Pol I transcriptional regulators including core factor, the high mobility group protein Hmo1, and the SSU processome. Under nutrient rich conditions, Ccr4-Not suppresses Pol I initiation by regulating interactions with the essential transcription factor Rrn3. Additionally, Ccr4-Not disruption prevents reduced Pol I transcription when mTORC1 is inhibited suggesting Ccr4-Not bridges mTORC1 signaling with Pol I regulation. Analysis of the non-essential Pol I subunits demonstrated that the A34.5 subunit promotes, while the A12.2 and A14 subunits repress, Ccr4-Not interactions with Pol I. Furthermore, ccr4Δ is synthetically sick when paired with rpa12Δ and the double mutant has enhanced sensitivity to transcription elongation inhibition suggesting that Ccr4-Not functions to promote Pol I elongation. Intriguingly, while low concentrations of mTORC1 inhibitors completely inhibit growth of ccr4Δ, a ccr4Δ rpa12Δ rescues this growth defect suggesting that the sensitivity of Ccr4-Not mutants to mTORC1 inhibition is at least partially due to Pol I deregulation. Collectively, these data demonstrate a novel role for Ccr4-Not in Pol I transcriptional regulation that is required for bridging mTORC1 signaling to ribosomal RNA synthesis. PMID:25815716

  3. Nicotine, alcohol and cocaine coupling to reward processes via endogenous morphine signaling: the dopamine-morphine hypothesis.

    PubMed

    Stefano, George B; Bianchi, Enrica; Guarna, Massimo; Fricchione, Gregory L; Zhu, Wei; Cadet, Patrick; Mantione, Kirk J; Casares, Federico M; Kream, Richard M; Esch, Tobias

    2007-06-01

    Pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, nicotine, cocaine and alcohol appear to exert their pleasure providing action via endogenous morphinergic mechanisms. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways, now, in part, via endogenous morphine processes.

  4. Activator-inhibitor coupling between Rho signaling and actin assembly make the cell cortex an excitable medium

    PubMed Central

    Bement, William M.; Leda, Marcin; Moe, Alison M.; Kita, Angela M.; Larson, Matthew E.; Golding, Adriana E.; Pfeuti, Courtney; Su, Kuan-Chung; Miller, Ann L.; Goryachev, Andrew B.; von Dassow, George

    2016-01-01

    Animal cell cytokinesis results from patterned activation of the small GTPase Rho, which directs assembly of actomyosin in the equatorial cortex. Cytokinesis is restricted to a portion of the cell cycle following anaphase onset in which the cortex is responsive to signals from the spindle. We show that shortly after anaphase onset oocytes and embryonic cells of frogs and echinoderms exhibit cortical waves of Rho activity and F-actin polymerization. The waves are modulated by cyclin-dependent kinase 1 (Cdk1) activity and require the Rho GEF (guanine nucleotide exchange factor), Ect2. Surprisingly, during wave propagation, while Rho activity elicits F-actin assembly, F-actin subsequently inactivates Rho. Experimental and modeling results show that waves represent excitable dynamics of a reaction diffusion system with Rho as the activator and F-actin the inhibitor. We propose that cortical excitability explains fundamental features of cytokinesis including its cell cycle regulation. PMID:26479320

  5. A new optical method coupling light polarization and Vis-NIR spectroscopy to improve the measured absorbance signal's quality of soil samples.

    NASA Astrophysics Data System (ADS)

    Gobrecht, Alexia; Bendoula, Ryad; Roger, Jean-Michel; Bellon-Maurel, Véronique

    2014-05-01

    Visible - Near-infrared spectroscopy (Vis-NIRS) is now commonly used to measure different physical and chemical parameters of soils, including carbon content. However, prediction model accuracy is insufficient for Vis-NIRS to replace routine laboratory analysis. One of the biggest issues this technique is facing up to is light scattering due to soil particles. It causes departure in the assumed linear relationship between the Absorbance spectrum and the concentration of the chemicals of interest as stated by Beer-Lambert's Law, which underpins the calibration models. Therefore it becomes essential to improve the metrological quality of the measured signal in order to optimize calibration as light/matter interactions are at the basis of the resulting linear modeling. Optics can help to mitigate scattering effect on the signal. We put forward a new optical setup coupling linearly polarized light with a Vis-NIR spectrometer to free the measured spectra from multi-scattering effect. The corrected measured spectrum was then used to compute an Absorbance spectrum of the sample, using Dahm's Equation in the frame of the Representative Layer Theory. This method has been previously tested and validated on liquid (milk+ dye) and powdered (sand + dye) samples showing scattering (and absorbing) properties. The obtained Absorbance was a very good approximation of the Beer-Lambert's law absorbance. Here, we tested the method on a set of 54 soil samples to predict Soil Organic Carbon content. In order to assess the signal quality improvement by this method, we built and compared calibration models using Partial Least Square (PLS) algorithm. The prediction model built from new Absorbance spectrum outperformed the model built with the classical Absorbance traditionally obtained with Vis-NIR diffuse reflectance. This study is a good illustration of the high influence of signal quality on prediction model's performances.

  6. OPTICAL RECORDING AND COMMUNICATION: Mismatch of the pump parameters of coupled chaotic lasers and the signal recovery errors in the data transmission scheme based on these lasers

    NASA Astrophysics Data System (ADS)

    Ledenev, V. I.

    2004-08-01

    The pulse characteristics of a periodically pumped chaotic CO2 laser are calculated numerically. The errors of the encoding-function recovery in the data transmission link based on two optically coupled chaotic CO2 lasers are studied depending on the amplitude mismatch and pump modulation frequencies. It is shown that the recovery error is minimal when the pump parameters of a transmitter and a receiver are identical. It is also shown that the mismatch of the pump amplitudes of the receiver and transmitter affects the recovery error much weaker than the mismatch of their periods. The dependences of the recovery error on the signal modulation degree are found. It is found that the shape of the recovered encoding function is determined by the type of a deviated parameter.

  7. Endogenous regulators of G protein signaling differentially modulate full and partial mu-opioid agonists at adenylyl cyclase as predicted by a collision coupling model.

    PubMed

    Clark, M J; Linderman, J J; Traynor, J R

    2008-05-01

    Regulator of G protein signaling (RGS) proteins accelerate the endogenous GTPase activity of Galpha(i/o) proteins to increase the rate of deactivation of active Galpha-GTP and Gbetagamma signaling molecules. Previous studies have suggested that RGS proteins are more effective on less efficiently coupled systems such as with partial agonist responses. To determine the role of endogenous RGS proteins in functional responses to mu-opioid agonists of different intrinsic efficacy, Galpha(i/o) subunits with a mutation at the pertussis toxin (PTX)-sensitive cysteine (C351I) and with or without a mutation at the RGS binding site (G184S) were stably expressed in C6 glioma cells expressing a mu-opioid receptor. Cells were treated overnight with PTX to inactivate endogenous G proteins. Maximal inhibition of forskolin-stimulated adenylyl cyclase by the low-efficacy partial agonists buprenorphine and nalbuphine was increased in cells expressing RGS-insensitive Galpha(o)(CIGS), Galpha(i2)(CIGS), or Galpha(i3)(CIGS) compared with their Galpha(CI) counterparts, but the RGS-insensitive mutation had little or no effect on the maximal inhibition by the higher efficacy agonists DAMGO and morphine. The potency of all the agonists to inhibit forskolin-stimulated adenylyl cyclase was increased in cells expressing RGS-insensitive Galpha(o)(CIGS), Galpha(i2)(CIGS), or Galpha(i3)(CIGS), regardless of efficacy. These data are comparable with predictions based on a collision coupling model. In this model, the rate of G protein inactivation, which is modulated by RGS proteins, and the rate of G protein activation, which is affected by agonist intrinsic efficacy, determine the maximal agonist response and potency at adenylyl cyclase under steady state conditions.

  8. Rapid and sensitive detection of Escherichia coli O157:H7 in milk and ground beef using magnetic bead-based immunoassay coupled with tyramide signal amplification.

    PubMed

    Aydin, Muhsin; Herzig, Gene P D; Jeong, Kwang Cheol; Dunigan, Samantha; Shah, Parth; Ahn, Soohyoun

    2014-01-01

    Escherichia coli O157:H7 is a major foodborne pathogen that has posed serious problems for food safety and public health. Recent outbreaks and recalls associated with various foods contaminated by E. coli O157:H7 clearly indicate its deleterious effect on food safety. A rapid and sensitive detection assay is needed for this harmful organism to prevent foodborne illnesses and control outbreaks in a timely manner. We developed a magnetic bead-based immunoassay for detection of E. coli O157:H7 (the most well-known Shiga toxigenic E. coli strain) with a 96-well microplate as an assay platform. Immunomagnetic separation (IMS) and tyramide signal amplification were coupled to the assay to increase its sensitivity and specificity. This immunoassay was able to detect E. coli O157:H7 in pure culture with a detection limit of 50 CFU/ml in less than 3 h without an enrichment step. The detection limit was decreased 10-fold to 5 CFU/ml with addition of a 3-h enrichment step. When this assay was tested with other nontarget foodborne pathogens and common enteric bacteria, no cross-reactivity was found. When tested with artificially contaminated ground beef and milk samples, the assay sensitivity decreased two- to fivefold, with detection limits of 250 and 100 CFU/ml, respectively, probably because of the food matrix effect. The assay results also were compared with those of a sandwich-type enzyme-linked immunosorbent assay (ELISA) and an ELISA coupled with IMS; the developed assay was 25 times and 4 times more sensitive than the standard ELISA and the IMS-ELISA, respectively. Tyramide signal amplification combined with IMS can improve sensitivity and specificity for detection of E. coli O157:H7. The developed assay could be easily adapted for other foodborne pathogens and will contribute to improved food safety and public health.

  9. Ultrasensitive electrochemical sensing platform for microRNA based on tungsten oxide-graphene composites coupling with catalyzed hairpin assembly target recycling and enzyme signal amplification.

    PubMed

    Shuai, Hong-Lei; Huang, Ke-Jing; Xing, Ling-Li; Chen, Ying-Xu

    2016-12-15

    An ultrasensitive electrochemical biosensor for microRNA (miRNA) is developed based on tungsten oxide-graphene composites coupling with catalyzed hairpin assembly target recycling and enzyme signal amplification. WO3-Gr is prepared by a simple hydrothermal method and then coupled with gold nanoparticles to act as a sensing platform. The thiol-terminated capture probe H1 is immobilized on electrode through Au-S interaction. In the presence of target miRNA, H1 opens its hairpin structure by hybridization with target miRNA. This hybridization can be displaced from the structure by another stable biotinylated hairpin DNA (H2), and target miRNA is released back to the sample solution for next cycle. Thus, a large amount of H1-H2 duplex is produced after the cyclic process. At this point, a lot of signal indicators streptavidin-conjugated alkaline phosphatase (SA-ALP) are immobilized on the electrode by the specific binding of avidin-biotin. Then, thousands of ascorbic acid, which is the enzymatic product of ALP, induces the electrochemical-chemical-chemical redox cycling to produce a strongly electrochemical response in the presence of ferrocene methanol and tris (2-carboxyethyl) phosphine. Under the optimal experimental conditions, the established biosensor can detect target miRNA down to 0.05fM (S/N=3) with a linear range from 0.1fM to 100pM, and discriminate target miRNA from mismatched miRNA with a high selectivity.

  10. SH3P7 is a cytoskeleton adapter protein and is coupled to signal transduction from lymphocyte antigen receptors.

    PubMed

    Larbolette, O; Wollscheid, B; Schweikert, J; Nielsen, P J; Wienands, J

    1999-02-01

    Lymphocytes respond to antigen receptor engagement with tyrosine phosphorylation of many cellular proteins, some of which have been identified and functionally characterized. Here we describe SH3P7, a novel substrate protein for Src and Syk family kinases. SH3P7 migrates in sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a 55-kDa protein that is preferentially expressed in brain, thymus, and spleen. It contains multiple amino acid sequence motifs, including two consensus tyrosine phosphorylation sites of the YXXP type and one SH3 domain. A region of sequence similarity, which we named SCAD, was found in SH3P7 and three actin-binding proteins. The SCAD region may represent a new type of protein-protein interaction domain that mediates binding to actin. Consistent with this possibility, SH3P7 colocalizes with actin filaments of the cytoskeleton. Altogether, our data implicate SH3P7 as an adapter protein which links antigen receptor signaling to components of the cytoskeleton.

  11. Enzyme-free and isothermal detection of microRNA based on click-chemical ligation-assisted hybridization coupled with hybridization chain reaction signal amplification.

    PubMed

    Oishi, Motoi

    2015-05-01

    An enzyme-free and isothermal microRNA (miRNA) detection method has been developed based on click-chemical ligation-assisted hybridization coupled with hybridization chain reaction (HCR) on magnetic beads (MBs). The click-chemical ligation between an azide-modified probe DNA and a dibenzocyclooctyne-modified probe DNA occurred through the hybridization of target miRNA (miR-141). HCR on MBs was performed by the addition of DNA hairpin monomers (H1 and H2). After magnetic separation and denaturation/rehybridization of HCR products ([H1/H2] n ), the resulting HCR products were analyzed by the fluorescence emitted from an intercalative dye, allowing amplification of the fluorescent signal. The proposed assay had a limit of detection of 0.55 fmol, which was 230-fold more sensitive than that of the HCR on the MBs coupled with a conventional sandwich hybridization assay (without click-chemical ligation) (limit of detection 127 fmol). Additionally, the proposed assay could discriminate between miR-141 and other miR-200 family members. In contrast to quantitative reverse transcription polymerase chain reaction techniques using enzymes and thermal cycling, this is an enzyme-free assay that can be conducted under isothermal conditions and can specifically detect miR-141 in fetal bovine serum.

  12. Wnt/β-catenin coupled with HIF-1α/VEGF signaling pathways involved in galangin neurovascular unit protection from focal cerebral ischemia.

    PubMed

    Wu, Chuanhong; Chen, Jianxin; Chen, Chang; Wang, Wei; Wen, Limei; Gao, Kuo; Chen, Xiuping; Xiong, Sihuai; Zhao, Huihui; Li, Shaojing

    2015-11-05

    Microenvironmental regulation has become a promising strategy for complex disease treatment. The neurovascular unit (NVU), as the key structural basis to maintain an optimal brain microenvironment, has emerged as a new paradigm to understand the pathology of stroke. In this study, we investigated the effects of galangin, a natural flavonoid isolated from the rhizome of Alpina officinarum Hance, on NVU microenvironment improvement and associated signal pathways in rats impaired by middle cerebral artery occlusion (MCAO). Galangin ameliorated neurological scores, cerebral infarct volume and cerebral edema and reduced the concentration of Evans blue (EB) in brain tissue. NVU ultrastructural changes were also improved by galangin. RT-PCR and western blot revealed that galangin protected NVUs through the Wnt/β-catenin pathway coupled with HIF-1α and vascular endothelial growth factor (VEGF). VEGF and β-catenin could be the key nodes of these two coupled pathways. In conclusion, Galangin might function as an anti-ischemic stroke drug by improving the microenvironment of NVUs.

  13. γ-Aminobutyric Acid B Receptor Mediated Inhibition of Gonadotropin-Releasing Hormone Neurons Is Suppressed by Kisspeptin-G Protein-Coupled Receptor 54 Signaling

    PubMed Central

    Zhang, Chunguang; Bosch, Martha A.; Rønnekleiv, Oline K.; Kelly, Martin J.

    2009-01-01

    γ-Aminobutyric acid (GABA) is one of the most important neurotransmitters that regulate the excitability of GnRH neurons. Numerous studies have shown that GABA activates Cl− currents in GnRH neurons, and these effects are antagonized by GABAA receptor antagonists. The GABAB receptor is a heterodimer composed of GABAB R1 and R2, and although both subunits have been localized in GnRH neurons, nothing is known about the cellular signaling of this Gαi,o-coupled receptor in GnRH neurons. Using whole-cell recordings from mouse enhanced green fluorescent protein-GnRH neurons, we found that the GABAB receptor agonist baclofen hyperpolarized GnRH neurons through activation of an inwardly rectifying K+ current in a concentration-dependent manner. The effects of baclofen were antagonized by the selective GABAB receptor antagonist CGP 52432 with a Ki (inhibitory constant) of 85 nm. Furthermore, in the presence of the GABAA receptor antagonist picrotoxin, GABA hyperpolarized GnRH neurons in a similar manner. Treatment with 17β-estradiol as compared with oil vehicle did not significantly alter either the EC50 for the baclofen-induced response (0.8 ± 0.1 vs. 1.0 ± 0.1 μm, respectively) or the maximal outward current (10.8 ± 1.7 pA vs. 11.4 ± 0.6 pA, respectively) in GnRH neurons. However, the outward current (and membrane hyperpolarization) was abrogated by submaximal concentrations of the G protein-coupled receptor 54 (GPR54) agonist kisspeptin-10 in both groups, indicating that Gαq-coupled (GPR54) can desensitize the GABAB receptor-mediated response. Therefore, the activation of GABAB receptors in GnRH neurons may provide increased inhibitory tone during estrogen-negative feedback states that is attenuated by kisspeptin during positive feedback. PMID:19164470

  14. Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy.

    PubMed

    Obre, Emilie; Rossignol, Rodrigue

    2015-02-01

    The field of energy metabolism dramatically progressed in the last decade, owing to a large number of cancer studies, as well as fundamental investigations on related transcriptional networks and cellular interactions with the microenvironment. The concept of metabolic flexibility was clarified in studies showing the ability of cancer cells to remodel the biochemical pathways of energy transduction and linked anabolism in response to glucose, glutamine or oxygen deprivation. A clearer understanding of the large-scale bioenergetic impact of C-MYC, MYCN, KRAS and P53 was obtained, along with its modification during the course of tumor development. The metabolic dialog between different types of cancer cells, but also with the stroma, also complexified the understanding of bioenergetics and raised the concepts of metabolic symbiosis and reverse Warburg effect. Signaling studies revealed the role of respiratory chain-derived reactive oxygen species for metabolic remodeling and metastasis development. The discovery of oxidative tumors in human and mice models related to chemoresistance also changed the prevalent view of dysfunctional mitochondria in cancer cells. Likewise, the influence of energy metabolism-derived oncometabolites emerged as a new means of tumor genetic regulation. The knowledge obtained on the multi-site regulation of energy metabolism in tumors was translated to cancer preclinical studies, supported by genetic proof of concept studies targeting LDHA, HK2, PGAM1, or ACLY. Here, we review those different facets of metabolic remodeling in cancer, from its diversity in physiology and pathology, to the search of the genetic determinants, the microenvironmental regulators and pharmacological modulators.

  15. Butyl benzyl phthalate blocks Ca{sup 2+} signaling coupled with purinoceptor in rat PC12 cells

    SciTech Connect

    Liu, P.-S. . E-mail: psliu@mail.scu.edu.tw; Chen, Y.-Y.

    2006-01-15

    Butyl benzyl phthalate (BBP) is a plasticizer and causes public concern because of its genomic estrogenic effects via estrogen receptors. We previously found that BBP has non-genomic effects, exerting inhibitory effects on the functional activities of nicotinic acetylcholine receptors (nAChR) in bovine adrenal chromaffin cells. nAChR belongs to the superfamily of neurotransmitter-gated channels, so does P2X purinoceptor that is widely distributed in the nervous system and play a role in pain reactions. In this study, we investigated the effects of BBP on the change of [Ca{sup 2+}]{sub c} (cytosolic calcium ion concentration) under the stimulation of purinoceptors in PC12 cells and found that BBP inhibited ATP-induced [Ca{sup 2+}]{sub c} rise (IC{sub 5} = 8.3 {mu}M). The inhibitory rate of BBP remained under the increase of ATP concentration; therefore, the possibility of competitive inhibition was excluded. The inhibition of BBP on P2Y was excluded because its inhibition on ATP-induced [Ca{sup 2+}]{sub c} rise was not found in the absence of extracellular Ca{sup 2+}. BBP might have some actions on voltage-operated Ca{sup 2+} channels (VOCCs) since BBP inhibited the Ca{sup 2+} signaling responding to high K{sup +} stimulation (IC{sub 5} = 1.2 {mu}M). We suggest that BBP inhibits the ATP-induced [Ca{sup 2+}]{sub c} rise via its non-competitive inhibition on P2X purinoceptors and VOCCs in the plasma membrane.

  16. Cilostazol Modulates Autophagic Degradation of β-Amyloid Peptide via SIRT1-Coupled LKB1/AMPKα Signaling in Neuronal Cells

    PubMed Central

    Lee, Won Suk; Shin, Hwa Kyoung; Kim, Hye Young; Hong, Ki Whan; Kim, Chi Dae

    2016-01-01

    A neuroprotective role of autophagy mediates the degradation of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). The previous study showed cilostazol modulates autophagy by increasing beclin1, Atg5 and LC3-II expressions, and depletes intracellular Aβ accumulation. This study elucidated the mechanisms through which cilostazol modulates the autophagic degradation of Aβ in neurons. In N2a cells, cilostazol (10–30 μM), significantly increased the expression of P-AMPKα (Thr 172) and downstream P-ACC (acetyl-CoA carboxylase) (Ser 79) as did resveratrol (SIRT1 activator), or AICAR (AMPK activator), which were blocked by KT5720, compound C (AMPK inhibitor), or sirtinol. Furthermore, phosphorylated-mTOR (Ser 2448) and phosphorylated-P70S6K (Thr 389) expressions were suppressed, and LC3-II levels were elevated in association with decreased P62/Sqstm1 by cilostazol. Cilostazol increased cathepsin B activity and decreased p62/SQSTM 1, consequently decreased accumulation of Aβ1–42 in the activated N2aSwe cells, and these results were blocked by sirtinol, compound C and bafilomycin A1 (autophagosome blocker), suggesting enhanced autophagosome formation by cilostazol. In SIRT1 gene-silenced N2a cells, cilostazol failed to increase the expressions of P-LKB1 (Ser 428) and P-AMPKα, which contrasted with its effect in negative control cells transfected with scrambled siRNA duplex. Further, N2a cells transfected with expression vectors encoding pcDNA SIRT1 showed increased P-AMPKα expression, which mimicked the effect of cilostazol in N2a cells; suggesting cilostazol-stimulated expressions of P-LKB1 and P-AMPKα were SIRT1-dependent. Unlike their effects in N2a cells, in HeLa cells, which lack LKB1, cilostazol and resveratrol did not elevate SIRT1 or P-AMPKα expression, indicating cilostazol and resveratrol-stimulated expressions of SIRT1 and P-AMPKα are LKB1-dependent. In conclusion, cilostazol upregulates autophagy by activating SIRT1-coupled P-LKB1/P-AMPKα and

  17. Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis.

    PubMed

    Lee, Jayhun; Kang, Sangjo; Lilja, Karin C; Colletier, Keegan J; Scheitz, Cornelia Johanna Franziska; Zhang, Ying V; Tumbar, Tudorita

    2016-04-15

    Mechanisms of plasticity to acquire different cell fates are critical for adult stem cell (SC) potential, yet are poorly understood. Reduced global histone methylation is an epigenetic state known to mediate plasticity in cultured embryonic SCs and T-cell progenitors. Here we find histone H3 K4/K9/K27me3 levels actively reduced in adult mouse skin and hair follicle stem cells (HFSCs) during G0 quiescence. The level of marks over specific gene promoters did not correlate to mRNA level changes in quiescent HFSCs. Skin hypomethylation during quiescence was necessary for subsequent progression of hair homeostasis (cycle). Inhibiting BMP signal, a known HFSC anti-proliferative factor, elevated HFSC methylation in vivo during quiescence prior to proliferation onset. Furthermore, removal of proliferation factors and addition of BMP4 reduced histone methylases and increased demethylases mRNAs in cultured skin epithelial cells. We conclude that signalling couples hair follicle stem cell quiescence with reduced H3 K4/K9/K27me3 levels for proper tissue homeostasis.

  18. Signalling couples hair follicle stem cell quiescence with reduced histone H3 K4/K9/K27me3 for proper tissue homeostasis

    PubMed Central

    Lee, Jayhun; Kang, Sangjo; Lilja, Karin C.; Colletier, Keegan J.; Scheitz, Cornelia Johanna Franziska; Zhang, Ying V.; Tumbar, Tudorita

    2016-01-01

    Mechanisms of plasticity to acquire different cell fates are critical for adult stem cell (SC) potential, yet are poorly understood. Reduced global histone methylation is an epigenetic state known to mediate plasticity in cultured embryonic SCs and T-cell progenitors. Here we find histone H3 K4/K9/K27me3 levels actively reduced in adult mouse skin and hair follicle stem cells (HFSCs) during G0 quiescence. The level of marks over specific gene promoters did not correlate to mRNA level changes in quiescent HFSCs. Skin hypomethylation during quiescence was necessary for subsequent progression of hair homeostasis (cycle). Inhibiting BMP signal, a known HFSC anti-proliferative factor, elevated HFSC methylation in vivo during quiescence prior to proliferation onset. Furthermore, removal of proliferation factors and addition of BMP4 reduced histone methylases and increased demethylases mRNAs in cultured skin epithelial cells. We conclude that signalling couples hair follicle stem cell quiescence with reduced H3 K4/K9/K27me3 levels for proper tissue homeostasis. PMID:27080563

  19. Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice.

    PubMed

    Bourque, Mélanie; Morissette, Marc; Di Paolo, Thérèse

    2014-10-01

    Raloxifene, used in the clinic, is reported to protect brain dopaminergic neurons in mice. Raloxifene was shown to mediate an effect through the G protein-coupled estrogen receptor 1 (GPER1). We investigated if raloxifene neuroprotective effect in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice is mediated through GPER1 by using its antagonist G15. Striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid to dopamine ratio as well as dopamine transporter and vesicular monoamine transporter 2 showed that raloxifene neuroprotection of dopaminergic neurons was blocked by G15. Protection by raloxifene was accompanied by activation of striatal Akt signaling (but not ERK1/2 signaling) and increased Bcl-2 and brain-derived neurotrophic factor levels; these effects were abolished by coadministration with G15. The effect of raloxifene was not mediated through increased levels of 17β-estradiol. MPTP mice had decreased plasma testosterone, dihydrotestosterone, and 3β-diol levels; this was prevented in raloxifene-treated MPTP mice. Our results suggest that raloxifene acted through GPER1 to mediate Akt activation, increase Bcl-2 and brain-derived neurotrophic factor levels, and protection of dopaminergic neurons and plasma androgens.

  20. Acoustic-seismic coupling for a wide range of angles of incidence and frequencies using signals of jet-aircraft overflights

    NASA Astrophysics Data System (ADS)

    Liebsch, Mattes; Altmann, Jürgen

    2016-12-01

    We present the excitation of soil vibration at the surface and at depths to 0.6 m caused by the sound of jet-aircraft overflights. By evaluating a multitude of overflight events we show that the coupling coefficient between soil velocity and sound pressure is only dependent on the angle of incidence of the acoustic wave and the frequency and thus can be averaged over the events. While previous publications presented only pointwise measurements we present signals for a wide range of angles of incidence and frequencies. In the seismic signal we found frequency bands of increased and decreased soil velocity caused by interference of the directly excited seismic wave with waves propagating in the ground and reflected at an underground boundary and at the surface. We use this seismic response to the broadband acoustic excitation to estimate soil characteristics e.g. P-wave velocity and depth of the boundary. The behaviour at depths > 0 m can be explained by an additional reflection at the surface. Here the reflection coefficient from theory was used successfully. The reflection coefficient of the P wave at that boundary - where insufficient information is available for its derivation from theory - was estimated from amplitude ratios at the surface.

  1. The ETS domain transcriptional repressor Anterior open inhibits MAP kinase and Wingless signaling to couple tracheal cell fate with branch identity.

    PubMed

    Caviglia, Sara; Luschnig, Stefan

    2013-03-01

    Cells at the tips of budding branches in the Drosophila tracheal system generate two morphologically different types of seamless tubes. Terminal cells (TCs) form branched lumenized extensions that mediate gas exchange at target tissues, whereas fusion cells (FCs) form ring-like connections between adjacent tracheal metameres. Each tracheal branch contains a specific set of TCs, FCs, or both, but the mechanisms that select between the two tip cell types in a branch-specific fashion are not clear. Here, we show that the ETS domain transcriptional repressor anterior open (aop) is dispensable for directed tracheal cell migration, but plays a key role in tracheal tip cell fate specification. Whereas aop globally inhibits TC and FC specification, MAPK signaling overcomes this inhibition by triggering degradation of Aop in tip cells. Loss of aop function causes excessive FC and TC specification, indicating that without Aop-mediated inhibition, all tracheal cells are competent to adopt a specialized fate. We demonstrate that Aop plays a dual role by inhibiting both MAPK and Wingless signaling, which induce TC and FC fate, respectively. In addition, the branch-specific choice between the two seamless tube types depends on the tracheal branch identity gene spalt major, which is sufficient to inhibit TC specification. Thus, a single repressor, Aop, integrates two different signals to couple tip cell fate selection with branch identity. The switch from a branching towards an anastomosing tip cell type may have evolved with the acquisition of a main tube that connects separate tracheal primordia to generate a tubular network.

  2. Coupling of D2R Short but not D2R Long receptor isoform to the Rho/ROCK signaling pathway renders striatal neurons vulnerable to mutant huntingtin.

    PubMed

    Galan-Rodriguez, Beatriz; Martin, Elodie; Brouillet, Emmanuel; Déglon, Nicole; Betuing, Sandrine; Caboche, Jocelyne

    2017-01-01

    Huntington's disease, an inherited neurodegenerative disorder, results from abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted in synergy with expanded huntingtin to increase aggregates formation and striatal death through activation of the Rho/ROCK signaling pathway. In vivo, in a lentiviral-mediated model of expanded huntingtin expression in the rat striatum, we found that the D2 antagonist haloperidol protects striatal neurons against expanded huntingtin-mediated toxicity. Two variant transcripts are generated by alternative splicing of the of D2 receptor gene, the D2R-Long and the D2R-Short, which are thought to play different functional roles. We show herein that overexpression of D2R-Short, but not D2R-Long in cell lines is associated with activation of the RhoA/ROCK signaling pathway. In striatal neurons in culture, the selective D2 agonist Quinpirole triggers phosphorylation of cofilin, a downstream effector of ROCK, which is abrogated by siRNAs that knockdown both D2R-Long and D2R-Short, but not by siRNAs targeting D2R-Long alone. Aggregate formation and neuronal death induced by expanded huntingtin, were potentiated by Quinpirole. This D2 agonist-mediated effect was selectively inhibited by the siRNA targeting both D2R-Long and D2R-Short but not D2R-Long alone. Our data provide evidence for a specific coupling of D2R-Short to the RhoA/ROCK/cofilin pathway, and its involvement in striatal vulnerability to expanded huntingtin. A new route for targeting Rho-ROCK signaling in Huntington's disease is unraveled with our findings.

  3. The Effect of Gap Junctional Coupling on the Spatiotemporal Patterns of Ca2+ Signals and the Harmonization of Ca2+-Related Cellular Responses

    PubMed Central

    Dougoud, Michaël; Mazza, Christian; Schwaller, Beat; Pecze, László

    2016-01-01

    Calcium ions (Ca2+) are important mediators of a great variety of cellular activities e.g. in response to an agonist activation of a receptor. The magnitude of a cellular response is often encoded by frequency modulation of Ca2+ oscillations and correlated with the stimulation intensity. The stimulation intensity highly depends on the sensitivity of a cell to a certain agonist. In some cases, it is essential that neighboring cells produce a similar and synchronized response to an agonist despite their different sensitivity. In order to decipher the presumed function of Ca2+ waves spreading among connecting cells, a mathematical model was developed. This model allows to numerically modifying the connectivity probability between neighboring cells, the permeability of gap junctions and the individual sensitivity of cells to an agonist. Here, we show numerically that strong gap junctional coupling between neighbors ensures an equilibrated response to agonist stimulation via formation of Ca2+ phase waves, i.e. a less sensitive neighbor will produce the same or similar Ca2+ signal as its highly sensitive neighbor. The most sensitive cells within an ensemble are the wave initiator cells. The Ca2+ wave in the cytoplasm is driven by a sensitization wave front in the endoplasmic reticulum. The wave velocity is proportional to the cellular sensitivity and to the strength of the coupling. The waves can form different patterns including circular rings and spirals. The observed pattern depends on the strength of noise, gap junctional permeability and the connectivity probability between neighboring cells. Our simulations reveal that one highly sensitive region gradually takes the lead within the entire noisy system by generating directed circular phase waves originating from this region. PMID:28027293

  4. Causal Therapy of Breast Cancer Irrelevant of Age, Tumor Stage and 
ER-Status: Stimulation of Estrogen Signaling Coupled With Breast 
Conserving Surgery

    PubMed Central

    Suba, Zsuzsanna

    2016-01-01

    Abstract: Background Results of long-term studies justify that the rate of breast cancer recurrence and tumor-related mortality remains quite unpredictable, regardless of the use of any current therapeutic measures. Objective Since the application of standard therapies, such as surgery, radiation, chemotherapy and antiestrogen administration does not work as might be expected; our therapeutic practice requires thorough rethinking. Method Published long-term therapeutic results on breast cancer cases were analyzed in correlation with stage at diagnosis, ER-status of tumors and patients’ age. The effectiveness of current therapeutic measures was also compared by estimating the rate of tumor-free survival, breast cancer recurrence and breast cancer-specific mortality. Results Diagnosis and treatment of breast cancer at an early stage cannot improve the rate of tumor-free survival. Poor differentiation of tumors, ER-negativity in particular, defines poor prognosis even after applying aggressive therapies. In patients treated with in situ breast cancer, the recurrence-rate of invasive tumor increased directly with ageing irrespective of tumor size or ER-status at diagnosis. Women who underwent lumpectomy without adjuvant radiation or chemotherapy exhibited significantly better overall and breast cancer specific survival rates than those receiving mastectomy, regardless of stage and ER-status of tumors. Antiestrogen treatment exhibited unforeseeable effectiveness even on targeted ER-positive tumors. Recent patents propose the detection of ESR1-gene amplification or restoration of ER-alpha expression for prediction of effective antiestrogen treatment, suggesting a crucial inhibitory role of estrogen-signaling against tumor-growth. Conclusion Estradiol-induced upregulation of estrogen signaling coupled with sparing of the estrogen-rich mammary fatpad are the most effective strategies against breast cancer. PMID:27087654

  5. Activation of G-Protein-Coupled Estrogen Receptor Inhibits the Migration of Human Nonsmall Cell Lung Cancer Cells via IKK-β/NF-κB Signals.

    PubMed

    Zhu, Guangfa; Huang, Yan; Wu, Chunting; Wei, Dong; Shi, Yingxin

    2016-08-01

    Estrogen signals have been suggested to modulate the progression and metastasis of nonsmall cell lung cancer (NSCLC), which is one of the leading causes of cancer deaths worldwide. While there are limited data concerning the roles and effects of G-protein-coupled estrogen receptor (GPER) on the progression of NSCLC, our present study reveals that the expression of GPER in NSCLC cells is obviously greater than that in lung fibroblast cell line MRC-5. Activation of GPER via its specific agonist G-1 decreases the in vitro motility of A549 and H358 cells and the expression of matrix metalloproteinase 2 (MMP-2) and MMP-9. Further, G-1 treatment can rapidly decrease the phosphorylation, nuclear translocation, and promoter activities of NF-κB in NSCLC cells. BAY 11-7082, the inhibitor of NF-κB, also inhibits the expression of MMP-2/9, while overexpression of p65 significantly attenuates G-1-induced downregulation of MMP-2/9. It suggests that inhibition of NF-κB mediates G-1-induced MMP-2/9 downregulation. G-1 treatment significantly down regulates the phosphorylation of IκB kinase β (IKK-β) and IκBα, while not IKK-α, in both 549 and H358 cells. ACHP, the specific inhibitor of IKK-β, can reinforce G-1-induced MMP-2/9 downregulation and invasion suppression of A549 cells. Collectively, our results suggest that activation of GPER can inhibit the migration of human NSCLC cells via suppression of IKK-β/NF-κB signals. These findings will help to better understand the roles and mechanisms of GPER as a potential therapy target for NSCLC patients.

  6. Prunetin signals via G-protein-coupled receptor, GPR30(GPER1): Stimulation of adenylyl cyclase and cAMP-mediated activation of MAPK signaling induces Runx2 expression in osteoblasts to promote bone regeneration.

    PubMed

    Khan, Kainat; Pal, Subhashis; Yadav, Manisha; Maurya, Rakesh; Trivedi, Arun Kumar; Sanyal, Sabyasachi; Chattopadhyay, Naibedya

    2015-12-01

    Prunetin is found in red clover and fruit of Prunus avium (red cherry). The effect of prunetin on osteoblast function, its mode of action and bone regeneration in vivo were investigated. Cultures of primary osteoblasts, osteoblastic cell line and HEK293T cells were used for various in vitro studies. Adult female rats received drill-hole injury at the femur diaphysis to assess the bone regenerative effect of prunetin. Prunetin at 10nM significantly (a) increased proliferation and differentiation of primary cultures of osteoblasts harvested from rats and (b) promoted formation of mineralized nodules by bone marrow stromal/osteoprogenitor cells. At this concentration, prunetin did not activate any of the two nuclear estrogen receptors (α and β). However, prunetin triggered signaling via a G-protein-coupled receptor, GPR30/GPER1, and enhanced cAMP levels in osteoblasts. G15, a selective GPR30 antagonist, abolished prunetin-induced increases in osteoblast proliferation, differentiation and intracellular cAMP. In osteoblasts, prunetin up-regulated runt-related transcription factor 2 (Runx2) protein through cAMP-dependent Erk/MAP kinase activation that ultimately resulted in the up-regulation of GPR30. Administration of prunetin at 0.25mg/kg given to rats stimulated bone regeneration at the site of drill hole and up-regulated Runx2 expression in the fractured callus and the effect was comparable to human parathyroid hormone, the only clinically used osteogenic therapy. We conclude that prunetin promotes osteoinduction in vivo and the mechanism is defined by signaling through GPR30 resulting in the up-regulation of the key osteogenic gene Runx2 that in turn up-regulates GPR30.

  7. Measuring carbon and oxygen isotope signals of photosynthesis and respiration: first field results from a chamber system coupled to tunable diode laser spectrometers

    NASA Astrophysics Data System (ADS)

    Wingate, L.; Burlett, R.; Bosc, A.; Cross, A.; Devaux, M.; Grace, J.; Loustau, D.; Seibt, U.; Ogée, J.

    2007-12-01

    Studying the carbon and oxygen stable isotope signals from plants and soils can help us gain insight to mechanistic processes responsible for the net exchange of CO2 and water cycled between terrestrial ecosystems and the atmosphere. Chamber field measurements of component fluxes and their isotopic composition have been reported for a few ecosystems. These observations have revealed that isotopic signals for carbon and oxygen are dynamic over relatively short time scales (hrs and days) for both branches and soils (Seibt et al., 2006a; 2006b; Wingate et al., 2007), and not fully explained by currently available models (Seibt et al., 2006b; Wingate et al., 2007). Ecosystem isotope studies have been limited by flask sampling requirements in the past. To evaluate and refine our models of isotopic fractionation by plants and soil, we need high resolution continuous isotopic measurements over the growing season for different ecosystems. In this study, we coupled chambers with tunable diode laser spectroscopy techniques in the field to continuously capture the isotopic signals from the most important component fluxes contributing to the net ecosystem exchange of CO2 in a Pinus pinaster forest in south-west France. We obtained profiles of the carbon and oxygen isotope content of CO2 within and above the forest canopy. In addition, we measured branch photosynthetic 13C and 18O discrimination alongside the 13C and 18O isotopic composition of the branch, stem and soil respiration during a 6-month period in 2007. In this talk, we will present the first results from this field campaign. References Seibt, U., Wingate, L., Berry, J.A. and Lloyd, J. (2006a) Non steady state effects in diurnal 18O discrimination by Picea sitchensis branches in the field. Plant, Cell and Environment Vol 29, 928-939. Seibt, U., Wingate, L., Lloyd, J. and Berry, J.A. (2006b) Diurnally variable δ18O signatures of soil CO2 fluxes indicate carbonic anhydrase activity in a forest soil. JGR

  8. G protein-coupled receptor 30 ligand G-1 increases aryl hydrocarbon receptor signalling by inhibition of tubulin assembly and cell cycle arrest in human MCF-7 cells.

    PubMed

    Tarnow, Patrick; Tralau, Tewes; Luch, Andreas

    2016-08-01

    Regulatory crosstalk between the aryl hydrocarbon receptor (AHR) and oestrogen receptor α (ERα) is well established. Apart from the nuclear receptors ERα and ERβ, oestrogen signalling further involves an unrelated G protein-coupled receptor termed GPR30. In order to investigate potential regulatory crosstalk, this study investigated the influence of G-1 as one of the few GPR30-specific ligands on the AHR regulon in MCF-7 cells. As a well-characterised model system, these human mammary carcinoma cells co-express all three receptors (AHR, ERα and GPR30) and are thus ideally suited to study corresponding regulatory pathway interactions on transcript level. Indeed, treatment with micromolar concentrations of the GPR30-specific agonist G-1 resulted in up-regulation of AHR as well as the transcripts for cytochromes P450 1A1 and 1B1, two well-known targets of the AHR regulon. While this was partly attributable to G-1-mediated inhibition of tubulin assembly and subsequent cell cycle arrest in the G2/M phase, the effects nevertheless required functional AHR. However, G-1-induced up-regulation of CYP 1A1 was not mediated by GPR30, as G15 antagonist treatment as well as a knockdown of GPR30 and AHR failed to inhibit this effect.

  9. Signaling through the G-protein-coupled receptor Rickets is important for polarity, detachment, and migration of the border cells in Drosophila.

    PubMed

    Anllo, Lauren; Schüpbach, Trudi

    2016-06-15

    Cell migration plays crucial roles during development. An excellent model to study coordinated cell movements is provided by the migration of border cell clusters within a developing Drosophila egg chamber. In a mutagenesis screen, we isolated two alleles of the gene rickets (rk) encoding a G-protein-coupled receptor. The rk alleles result in border cell migration defects in a significant fraction of egg chambers. In rk mutants, border cells are properly specified and express the marker Slbo. Yet, analysis of both fixed as well as live samples revealed that some single border cells lag behind the main border cell cluster during migration, or, in other cases, the entire border cell cluster can remain tethered to the anterior epithelium as it migrates. These defects are observed significantly more often in mosaic border cell clusters, than in full mutant clusters. Reduction of the Rk ligand, Bursicon, in the border cell cluster also resulted in migration defects, strongly suggesting that Rk signaling is utilized for communication within the border cell cluster itself. The mutant border cell clusters show defects in localization of the adhesion protein E-cadherin, and apical polarity proteins during migration. E-cadherin mislocalization occurs in mosaic clusters, but not in full mutant clusters, correlating well with the rk border cell migration phenotype. Our work has identified a receptor with a previously unknown role in border cell migration that appears to regulate detachment and polarity of the border cell cluster coordinating processes within the cells of the cluster themselves.

  10. The regulator of G protein signaling (RGS) domain of G protein–coupled receptor kinase 5 (GRK5) regulates plasma membrane localization and function

    PubMed Central

    Xu, Hua; Jiang, Xiaoshan; Shen, Ke; Fischer, Christopher C.; Wedegaertner, Philip B.

    2014-01-01

    The G protein–coupled receptor (GPCR) kinases (GRKs) phosphorylate activated GPCRs at the plasma membrane (PM). Here GRK5/GRK4 chimeras and point mutations in GRK5 identify a short sequence within the regulator of G protein signaling (RGS) domain in GRK5 that is critical for GRK5 PM localization. This region of the RGS domain of GRK5 coincides with a region of GRK6 and GRK1 shown to form a hydrophobic dimeric interface (HDI) in crystal structures. Coimmunoprecipitation (coIP) and acceptor photobleaching fluorescence resonance energy transfer assays show that expressed GRK5 self-associates in cells, whereas GRK5-M165E/F166E (GRK5-EE), containing hydrophilic mutations in the HDI region of the RGS domain, displays greatly decreased coIP interactions. Both forcing dimerization of GRK5-EE, via fusion to leucine zipper motifs, and appending an extra C-terminal membrane-binding region to GRK5-EE (GRK5-EE-CT) recover PM localization. In addition, GRK5-EE displays a decreased ability to inhibit PAR1-induced calcium release compared with GRK5 wild type (wt). In contrast, PM-localized GRK5-EE-CaaX (appending a C-terminal prenylation and polybasic motif from K-ras) or GRK5-EE-CT shows comparable ability to GRK5 wt to inhibit PAR1-induced calcium release. The results suggest a novel model in which GRK5 dimerization is important for its plasma membrane localization and function. PMID:24807909

  11. The regulator of G protein signaling (RGS) domain of G protein-coupled receptor kinase 5 (GRK5) regulates plasma membrane localization and function.

    PubMed

    Xu, Hua; Jiang, Xiaoshan; Shen, Ke; Fischer, Christopher C; Wedegaertner, Philip B

    2014-07-01

    The G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate activated GPCRs at the plasma membrane (PM). Here GRK5/GRK4 chimeras and point mutations in GRK5 identify a short sequence within the regulator of G protein signaling (RGS) domain in GRK5 that is critical for GRK5 PM localization. This region of the RGS domain of GRK5 coincides with a region of GRK6 and GRK1 shown to form a hydrophobic dimeric interface (HDI) in crystal structures. Coimmunoprecipitation (coIP) and acceptor photobleaching fluorescence resonance energy transfer assays show that expressed GRK5 self-associates in cells, whereas GRK5-M165E/F166E (GRK5-EE), containing hydrophilic mutations in the HDI region of the RGS domain, displays greatly decreased coIP interactions. Both forcing dimerization of GRK5-EE, via fusion to leucine zipper motifs, and appending an extra C-terminal membrane-binding region to GRK5-EE (GRK5-EE-CT) recover PM localization. In addition, GRK5-EE displays a decreased ability to inhibit PAR1-induced calcium release compared with GRK5 wild type (wt). In contrast, PM-localized GRK5-EE-CaaX (appending a C-terminal prenylation and polybasic motif from K-ras) or GRK5-EE-CT shows comparable ability to GRK5 wt to inhibit PAR1-induced calcium release. The results suggest a novel model in which GRK5 dimerization is important for its plasma membrane localization and function.

  12. Involvement of a putative intercellular signal-recognizing G protein-coupled receptor in the engulfment of Salmonella by the protozoan Tetrahymena.

    PubMed

    Agbedanu, P N; Brewer, M T; Day, T A; Kimber, M J; Anderson, K L; Rasmussen, S K; Rasmussen, M A; Carlson, S A

    2013-01-01

    In an effort to investigate the molecular basis of protozoa engulfment-mediated hypervirulence of Salmonella in cattle, we evaluated protozoan G protein-coupled receptors (GPCRs) as transducers of Salmonella engulfment by the model protozoan Tetrahymena. Our laboratory previously demonstrated that non-pathogenic protozoa (including Tetrahymena) engulf Salmonella and then exacerbate its virulence in cattle, but the mechanistic details of the phenomenon are not fully understood. GPCRs were investigated since these receptors facilitate phagocytosis of particulates by Tetrahymena, and a GPCR apparently modulates bacterial engulfment for the pathogenic protozoan Entamoeba histolytica. A database search identified three putative Tetrahymena GPCRs, based on sequence homologies and predicted transmembrane domains, that were the focus of this study. Salmonella engulfment by Tetrahymena was assessed in the presence of suramin, a non-specific GPCR inhibitor. Salmonella engulfment was also assessed in Tetrahymena in which expression of putative GPCRs was knocked-down using RNAi. A candidate GPCR was then expressed in a heterologous yeast expression system for further characterization. Our results revealed that Tetrahymena were less efficient at engulfing Salmonella in the presence of suramin. Engulfment was reduced concordantly with a reduction in the density of protozoa. RNAi-based studies revealed that knock-down of one the Tetrahymena GPCRs caused diminished engulfment of Salmonella. Tetrahymena lysates activated this receptor in the heterologous expression system. These data demonstrate that the Tetrahymena receptor is a putative GPCR that facilitates bacterial engulfment by Tetrahymena. Activation of the putative GPCR seemed to be related to protozoan cell density, suggesting that its cognate ligand is an intercellular signaling molecule.

  13. From land use to land cover: Restoring the afforestation signal in a coupled integrated assessment - earth system model and the implications for CMIP5 RCP simulations

    SciTech Connect

    Di Vittorio, Alan V.; Chini, Louise M.; Bond-Lamberty, Benjamin; Mao, Jiafu; Shi, Xiaoying; Truesdale, John E.; Craig, Anthony P.; Calvin, Katherine V.; Jones, Andrew D.; Collins, William D.; Edmonds, James A.; Hurtt, George; Thornton, Peter E.; Thomson, Allison M.

    2014-11-27

    Climate projections depend on scenarios of fossil fuel emissions and land use change, and the IPCC AR5 parallel process assumes consistent climate scenarios across Integrated Assessment and Earth System Models (IAMs and ESMs). To facilitate consistency, CMIP5 used a novel land use harmonization to provide ESMs with seamless, 1500-2100 land use trajectories generated by historical data and four IAMs. However, we have identified and partially addressed a major gap in the CMIP5 land coupling design. The CMIP5 Community ESM (CESM) global afforestation is only 22% of RCP4.5 afforestation from 2005 to 2100. Likewise, only 17% of the Global Change Assessment Model’s (GCAM’s) 2040 RCP4.5 afforestation signal, and none of the pasture loss, were transmitted to CESM within a newly integrated model. This is a critical problem because afforestation is necessary for achieving the RCP4.5 climate stabilization. We attempted to rectify this problem by modifying only the ESM component of the integrated model, enabling CESM to simulate 66% of GCAM’s afforestation in 2040, and 94% of GCAM’s pasture loss as grassland and shrubland losses. This additional afforestation increases vegetation carbon gain by 19 PgC and decreases atmospheric CO2 gain by 8 ppmv from 2005 to 2040, implying different climate scenarios between CMIP5 GCAM and CESM. Similar inconsistencies likely exist in other CMIP5 model results, primarily because land cover information is not shared between models, with possible contributions from afforestation exceeding model-specific, potentially viable forest area. Further work to harmonize land cover among models will be required to adequately rectify this problem.

  14. Quantitative analysis of trace elements in environmental powders with laser ablation inductively coupled mass spectrometry using non-sample-corresponding reference materials for signal evaluation

    NASA Astrophysics Data System (ADS)

    Bauer, Gerald; Limbeck, Andreas

    2015-11-01

    Laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) is an attractive alternative to traditional procedures for the analysis of environmental samples (i.e., conventional liquid measurement after sample digestion). However, for accurate quantification, certified reference materials (CRM) are necessary which match the composition of the sample and include all elements of interest at the required concentration levels. The limited availability of appropriate CRMs hampers therefore substantial application. In this work, an LA-ICP-MS procedure allowing for accurate determination of trace element contents in powdered environmental samples is presented. For LA-ICP-MS analysis, the samples are mixed with an internal standard (silver oxide) and a binder (sodium tetra borate) and subsequently pressed to pellets. Quantification is accomplished using a calibration function determined using CRMs with varying matrix composition and analyte content, pre-treated and measured in the same way as the samples. With this approach, matrix-induced ablation differences resulting from varying physical/chemical properties of the individual CRMs could be compensated. Furthermore, ICP-related matrix-effects could be minimized using collision/reaction cell technology. Applicability of the procedure has been demonstrated by assessment of Cd, Cu, Ni, and Zn in four different environmental CRMs (NIST SRM1648a (urban particulate matter), NIST SRM2709 (San Joaquin Soil), BCR144 (sewage sludge), and BCR723 (road dust)). Signal evaluation was performed by alternative use of three CRMs for calculation of the calibration function whereas the remaining fourth CRM acted as unknown sample, resulting in a good agreement between measured and certified values for all elements and reference materials.

  15. Magnetoelectric coupling study in multiferroic Pb(Fe{sub 0.5}Nb{sub 0.5})O{sub 3} ceramics through small and large electric signal standard measurements

    SciTech Connect

    Raymond, Oscar; Siqueiros, Jesus M.; Font, Reynaldo; Portelles, Jorge

    2011-05-01

    Multifunctional multiferroic materials such as the single phase compound Pb(Fe{sub 0.5}Nb{sub 0.5})O{sub 3} (PFN), where ferroelectric and antiferromagnetic order coexist, are very promising and have great interest from the academic and technological points of view. In this work, coupling of the ferroelectric and magnetic moments is reported. For this study, a combination of the small signal response using the impedance spectroscopy technique and the electromechanical resonance method with the large signal response through standard ferroelectric hysteresis measurement, has been used with and without an applied magnetic field. The measurements to determine the electrical properties of the ceramic were performed as functions of the bias and poling electric fields. A simultaneous analysis of the complex dielectric constant {epsilon}-tilde, impedance Z-tilde, electric modulus M-tilde, admittance Y-tilde, and the electromechanical parameters and coupling factors is presented. The results are correlated with a previous study of structural, morphological, small signal dielectric frequency-temperature response, and the ferroelectric hysteretic, magnetic and magnetodielectric behaviors. The observed shifts of the resonance and antiresonance frequency values can be associated with change of the ferroelectric domain size favored by the readjustment of the oxygen octahedron when the magnetic field is applied. From P-E hysteresis loops obtained without and with an external applied magnetic field, a dc magnetoelectric coupling effect with maximum value of 4 kV/cm T (400 mV/cm Oe) was obtained.

  16. Coupling strength versus coupling impact in nonidentical bidirectionally coupled dynamics

    NASA Astrophysics Data System (ADS)

    Laiou, Petroula; Andrzejak, Ralph G.

    2017-01-01

    The understanding of interacting dynamics is important for the characterization of real-world networks. In general, real-world networks are heterogeneous in the sense that each node of the network is a dynamics with different properties. For coupled nonidentical dynamics symmetric interactions are not straightforwardly defined from the coupling strength values. Thus, a challenging issue is whether we can define a symmetric interaction in this asymmetric setting. To address this problem we introduce the notion of the coupling impact. The coupling impact considers not only the coupling strength but also the energy of the individual dynamics, which is conveyed via the coupling. To illustrate this concept, we follow a data-driven approach by analyzing signals from pairs of coupled model dynamics using two different connectivity measures. We find that the coupling impact, but not the coupling strength, correctly detects a symmetric interaction between pairs of coupled dynamics regardless of their degree of asymmetry. Therefore, this approach allows us to reveal the real impact that one dynamics has on the other and hence to define symmetric interactions in pairs of nonidentical dynamics.

  17. Differential pathway coupling efficiency of the activated insulin receptor drives signaling selectivity by XMetA, an allosteric partial agonist antibody

    Technology Transfer Automated Retrieval System (TEKTRAN)

    XMetA, an anti-insulin receptor (IR) monoclonal antibody, is an allosteric partial agonist of the IR. We have previously reported that XMetA activates the “metabolic-biased” Akt kinase signaling pathway while having little or no effect on the “mitogenic” MAPK signaling pathwayof ERK 1/2. To inves...

  18. Searches for top-Higgs FCNC couplings via the W h j signal with h →γ γ at the LHC

    NASA Astrophysics Data System (ADS)

    Liu, Yao-Bei; Xiao, Zhen-Jun

    2016-09-01

    In this paper, we investigated the process p p →W-h j induced by the top-Higgs flavor-changing neutral current couplings at the LHC. We found that the cross section of p p →W-h j mainly comes from the resonant process p p →W-t →W-h q due to the anomalous t q H couplings (where q denotes up and charm quarks). We further studied the observability of the top-Higgs flavor-changing neutral current couplings through the process p p →W-(→ℓ-ν¯ ℓ)h (→γ γ )j and found that the branching ratios Br (t →q h ) can be probed to 0.16% at 3 σ level at 14 TeV LHC with an integrated luminosity of 3000 fb-1 .

  19. Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation

    PubMed Central

    Lee, Jandee; Lee, Woo Kyung; Seol, Mi-Youn; Lee, Seul Gi; Kim, Daham; Kim, Hyunji; Park, Jongsun; Jung, Sang Geun; Chung, Woong Youn; Lee, Eun Jig; Jo, Young Suk

    2016-01-01

    Persistent cellular proliferation and metabolic reprogramming are essential processes in carcinogenesis. Here, we performed Gene Set Enrichment Analysis (GSEA) and found that that LETM1, a mitochondrial calcium transporter, is associated with cellular growth signals such as platelet-derived growth factor (PDGF) receptor signaling and insulin signaling pathways. These results were then verified by qRT-PCR and immnunoblotting. Mechanistically, up-regulation of LETM1 induced YAP1 nuclear accumulation, increasing the expression of PDGFB, PDGFRB and THBS4. Consistent with this, LETM1 silencing caused loss of YAP1 nuclear signal, decreasing the expression of PDGFB, PDGFRB and THBS4. Immunohistochemical staining consistently indicated a positive association between LETM1 up-regulation, YAP1 nuclear localization and high PDGFB expression. In clinical data analysis, LETM1 up-regulation in thyroid cancer was found to be related to aggressive tumor features such as lymphovascular invasion (LVI, P < 0.001) and lymph node metastasis (LNM, P = 0.011). Multivariate analysis demonstrated that LETM1 up-regulation increases the risk of LVI and LNM (OR = 3.455, 95% CI = 1.537–7.766 and OR = 3.043, 95% CI = 1.282–7.225, respectively). Collectively, these data suggest that up-regulation of LETM1 induces sustained activation of proliferative signaling pathways, such as PDGF signal pathway by AKT induced YAP1 transactivation, resulting in aggressive thyroid cancer phenotypes. PMID:27556512

  20. From land use to land cover: restoring the afforestation signal in a coupled integrated assessment-earth system model and the implications for CMIP5 RCP simulations

    NASA Astrophysics Data System (ADS)

    Di Vittorio, A. V.; Chini, L. P.; Bond-Lamberty, B.; Mao, J.; Shi, X.; Truesdale, J.; Craig, A.; Calvin, K.; Jones, A.; Collins, W. D.; Edmonds, J.; Hurtt, G. C.; Thornton, P.; Thomson, A.

    2014-11-01

    Climate projections depend on scenarios of fossil fuel emissions and land use change, and the Intergovernmental Panel on Climate Change (IPCC) AR5 parallel process assumes consistent climate scenarios across integrated assessment and earth system models (IAMs and ESMs). The CMIP5 (Coupled Model Intercomparison Project Phase 5) project used a novel "land use harmonization" based on the Global Land use Model (GLM) to provide ESMs with consistent 1500-2100 land use trajectories generated by historical data and four IAMs. A direct coupling of the Global Change Assessment Model (GCAM), GLM, and the Community ESM (CESM) has allowed us to characterize and partially address a major gap in the CMIP5 land coupling design: the lack of a corresponding land cover harmonization. For RCP4.5, CESM global afforestation is only 22% of GCAM's 2005 to 2100 afforestation. Likewise, only 17% of GCAM's 2040 afforestation, and zero pasture loss, were transmitted to CESM within the directly coupled model. This is a problem because GCAM relied on afforestation to achieve RCP4.5 climate stabilization. GLM modifications and sharing forest area between GCAM and GLM within the directly coupled model did not increase CESM afforestation. Modifying the land use translator in addition to GLM, however, enabled CESM to include 66% of GCAM's afforestation in 2040, and 94% of GCAM's pasture loss as grassland and shrubland losses. This additional afforestation increases CESM vegetation carbon gain by 19 PgC and decreases atmospheric CO2 gain by 8 ppmv from 2005 to 2040, which demonstrates that CESM without additional afforestation simulates a different RCP4.5 scenario than prescribed by GCAM. Similar land cover inconsistencies exist in other CMIP5 model results, primarily because land cover information is not shared between models. Further work to harmonize land cover among models will be required to increase fidelity between IAM scenarios and ESM simulations and realize the full potential of scenario

  1. Isomer-nonspecific action of dichlorodiphenyltrichloroethane on aryl hydrocarbon receptor and G-protein-coupled receptor 30 intracellular signaling in apoptotic neuronal cells.

    PubMed

    Kajta, M; Litwa, E; Rzemieniec, J; Wnuk, A; Lason, W; Zelek-Molik, A; Nalepa, I; Grzegorzewska-Hiczwa, M; Tokarski, K; Golas, A; Guzik, E; Grochowalski, A; Szychowski, K A; Wojtowicz, A K

    2014-07-05

    Extended residual persistence of the pesticide dichlorodiphenyltrichloroethane (DDT) raises concerns about its long-term neurotoxic effects. Little is known, however, about DDT toxicity during the early stages of neural development. This study demonstrated that DDT-induced apoptosis of mouse embryonic neuronal cells is a caspase-9-, caspase-3-, and GSK-3β-dependent process, which involves p,p'-DDT-specific impairment of classical ERs. It also provided evidence for DDT-isomer-nonspecific alterations of AhR- and GPR30-mediated intracellular signaling, including changes in the levels of the receptor and receptor-regulated mRNAs, and also changes in the protein levels of the receptors. DDT-induced stimulation of AhR-signaling and reduction of GPR30-signaling were verified using selective ligands and specific siRNAs. Co-localization of the receptors was demonstrated with confocal microscopy, and the presence of functional GPR30 was detected by electrophysiology. This study demonstrates that stimulation of AhR-signaling and impairment of GPR30-signaling play important roles in the propagation of DDT-induced apoptosis during the early stages of neural development.

  2. Involvement of Saccharomyces cerevisiae Avo3p/Tsc11p in maintaining TOR complex 2 integrity and coupling to downstream signaling.

    PubMed

    Ho, Hsiang-Ling; Lee, Hsin-Yi; Liao, Hsien-Ching; Chen, Mei-Yu

    2008-08-01

    Target-of-rapamycin proteins (TORs) are Ser/Thr kinases serving a central role in cell growth control. TORs function in two conserved multiprotein complexes, TOR complex 1 (TORC1) and TORC2; the mechanisms underlying their actions and regulation are not fully elucidated. Saccharomyces TORC2, containing Tor2p, Avo1p, Avo2p, Avo3p/Tsc11p, Bit61p, and Lst8p, regulates cell integrity and actin organization. Two classes of avo3 temperature-sensitive (avo3(ts)) mutants that we previously identified display cell integrity and actin defects, yet one is suppressed by AVO1 while the other is suppressed by AVO2 or SLM1, defining two TORC2 downstream signaling mechanisms, one mediated by Avo1p and the other by Avo2p/Slm1p. Employing these mutants, we explored Avo3p functions in TORC2 structure and signaling. By observing binary protein interactions using coimmunoprecipitation, we discovered that the composition of TORC2 and its recruitment of the downstream effectors Slm1p and Slm2p were differentially affected in different avo3(ts) mutants. These molecular defects can be corrected only by expressing AVO3, not by expressing suppressors, highlighting the role of Avo3p as a structural and signaling scaffold for TORC2. Phenotypic modifications of avo3(ts) mutants by deletion of individual Rho1p-GTPase-activating proteins indicate that two TORC2 downstream signaling branches converge on Rho1p activation. Our results also suggest that Avo2p/Slm1p-mediated signaling, but not Avo1p-mediated signaling, links to Rho1p activation specifically through the Rho1p-guanine nucleotide exchange factor Tus1p.

  3. Functional Analysis of Arabidopsis Mutants Points to Novel Roles for Glutathione in Coupling H2O2 to Activation of Salicylic Acid Accumulation and Signaling

    PubMed Central

    Han, Yi; Chaouch, Sejir; Mhamdi, Amna; Queval, Guillaume; Zechmann, Bernd

    2013-01-01

    Abstract Aims: Through its interaction with H2O2, glutathione is a candidate for transmission of signals in plant responses to pathogens, but identification of signaling roles is complicated by its antioxidant function. Using a genetic approach based on a conditional catalase-deficient Arabidopsis mutant, cat2, this study aimed at establishing whether GSH plays an important functional role in the transmission of signals downstream of H2O2. Results: Introducing the cad2 or allelic mutations in the glutathione synthesis pathway into cat2 blocked H2O2-triggered GSH oxidation and accumulation. While no effects on NADP(H) or ascorbate were observed, and H2O2-induced decreases in growth were maintained, blocking GSH modulation antagonized salicylic acid (SA) accumulation and SA-dependent responses. Other novel double and triple mutants were produced and compared with cat2 cad2 at the levels of phenotype, expression of marker genes, nontargeted metabolite profiling, accumulation of SA, and bacterial resistance. Most of the effects of the cad2 mutation on H2O2-triggered responses were distinct from those produced by mutations for GLUTATHIONE REDUCTASE1 (GR1) or NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1), and were linked to compromised induction of ISOCHORISMATE SYNTHASE1 (ICS1) and ICS1-dependent SA accumulation. Innovation: A novel genetic approach was used in which GSH content or antioxidative capacity was independently modified in an H2O2 signaling background. Analysis of new double and triple mutants allowed us to infer previously undescribed regulatory roles for GSH. Conclusion: In parallel to its antioxidant role, GSH acts independently of NPR1 to allow increased intracellular H2O2 to activate SA signaling, a key defense response in plants. Antioxid. Redox Signal. 18, 2106–2121. PMID:23148658

  4. Information-theoretic secure key distribution based on common random-signal induced synchronization in unidirectionally-coupled cascades of semiconductor lasers.

    PubMed

    Koizumi, Hayato; Morikatsu, Shinichiro; Aida, Hiroki; Nozawa, Takahiro; Kakesu, Izumi; Uchida, Atsushi; Yoshimura, Kazuyuki; Muramatsu, Jun; Davis, Peter

    2013-07-29

    It has been proposed that a secure key distribution scheme using correlated random bit sequences can be implemented using common random-signal induced synchronization of semiconductor laser systems. In this scheme it is necessary to use laser systems consisting of multiple cascaded lasers to be secure against a powerful eavesdropper. In this paper, we report the results of an experimental study that demonstrate that the common random-signal induced synchronization is possible in cascaded semiconductor laser systems. We also show that the correlated random bit sequences generated in the synchronized cascaded laser systems can be used to create an information-theoretically secure key between two legitimate users.

  5. From land use to land cover: Restoring the afforestation signal in a coupled integrated assessment - earth system model and the implications for CMIP5 RCP simulations

    NASA Astrophysics Data System (ADS)

    Di Vittorio, Alan; Chini, Louise; Bond-Lamberty, Ben; Mao, Jiafu; Shi, Xiaoying; Truesdale, John; Craig, Anthony; Calvin, Kate; Jones, Andrew; Collins, William; Edmonds, Jae; Hurtt, George; Thornton, Peter; Thomson, Allison

    2015-04-01

    Climate projections depend on scenarios of fossil fuel emissions and land use change, and the IPCC AR5 parallel process assumes consistent climate scenarios across Integrated Assessment and Earth System Models (IAMs and ESMs). The CMIP5 project used a novel "land use harmonization" based on the Global Land use Model (GLM) to provide ESMs with consistent 1500-2100 land use trajectories generated by historical data and four IAMs. A direct coupling of the Global Change Assessment Model (GCAM), GLM, and the Community ESM (CESM) has allowed us to characterize and partially address a major gap in the CMIP5 land coupling design: the lack of a corresponding land cover harmonization. For RCP4.5, CESM global afforestation is only 22% of GCAM's 2005 to 2100 afforestation. Likewise, only 17% of GCAM's 2040 afforestation, and zero pasture loss, were transmitted to CESM within the directly coupled model. This is a problem because GCAM relied on afforestation to achieve RCP4.5 climate stabilization. GLM modifications and sharing forest area between GCAM and GLM within the directly coupled model did not increase CESM afforestation. Modifying the land use translator in addition to GLM, however, enabled CESM to include 66% of GCAM's afforestation in 2040, and 94% of GCAM's pasture loss as grassland and shrubland losses. This additional afforestation increases CESM vegetation carbon gain by 19 PgC and decreases atmospheric CO2 gain by 8 ppmv from 2005 to 2040, which demonstrates that CESM without additional afforestation simulates a different RCP4.5 scenario than prescribed by GCAM. Similar land cover inconsistencies exist in other CMIP5 model results, primarily because land cover information is not shared between models. Further work to harmonize land cover among models will be required to increase fidelity between IAM scenarios and ESM simulations and realize the full potential of scenario-based earth system simulations.

  6. Coupling calcium/calmodulin-mediated signaling and herbivore-induced plant response calmodulin-binding transcription factor AtSR1/CAMTA3

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Calcium/calmodulin (Ca2+/CaM) has long been considered a crucial component in wound signaling pathway. However, no functional significance of Ca2+/CaM-binding proteins has been identified in plant responses to herbivore attack/wounding stress. We have reported earlier that a family of Ca2+/CaM-bindi...

  7. Microgravity and Signaling Molecules in Rat Osteoblasts: Downstream of Receptor Tyrosine Kinase, G-Protein-Coupled Receptor, and Small GTP-Binding Proteins

    NASA Technical Reports Server (NTRS)

    Kumel, Yasuhiro; Shimokawa, Hitoyata; Morita, Sadao; Katano, Hisako; Akiyama, Hideo; Hirano, Masahiko; Ohya, Keiichi; Sams, Clarence F.; Whitson, Peggy A.

    2005-01-01

    Rat osteoblasts were cultured for 4 and 5 days aboard Space Shuttle and solubilized on board. The mRNA levels of the post-receptor signaling molecules were analyzed by quantitative RT-PCR. The G-protein alpha subunit G(alpha)q mRNA levels were elevated 3-fold by microgravity. G(alpha)q stimulates PLC(beta), and then PKC. PKC(delta) and PKC(theta) mRNA levels were increased 2- to 5-fold by microgravity The mRNA levels of SOS and Ras GRF were increased 4 to 5-fold by microgravity, while Ras GAP was not altered. Spaceflight-induced bone loss might be attributed to microgravity modulation of the signaling pathway in osteoblasts.

  8. H⁺-activated Na⁺ influx in the ventricular myocyte couples Ca²⁺-signalling to intracellular pH.

    PubMed

    Garciarena, Carolina D; Youm, Jae Boum; Swietach, Pawel; Vaughan-Jones, Richard D

    2013-08-01

    Acid extrusion on Na(+)-coupled pH-regulatory proteins (pH-transporters), Na(+)/H(+) exchange (NHE1) and Na(+)-HCO3(-) co-transport (NBC), drives Na(+) influx into the ventricular myocyte. This H(+)-activated Na(+)-influx is acutely up-regulated at pHi<7.2, greatly exceeding Na(+)-efflux on the Na(+)/K(+) ATPase. It is spatially heterogeneous, due to the co-localisation of NHE1 protein (the dominant pH-transporter) with gap-junctions at intercalated discs. Overall Na(+)-influx via NBC is considerably lower, but much is co-localised with L-type Ca(2+)-channels in transverse-tubules. Through a functional coupling with Na(+)/Ca(2+) exchange (NCX), H(+)-activated Na(+)-influx increases sarcoplasmic-reticular Ca(2+)-loading and release during intracellular acidosis. This raises Ca(2+)-transient amplitude, rescuing it from direct H(+)-inhibition. Functional coupling is biochemically regulated and linked to membrane receptors, through effects on NHE1 and NBC. It requires adequate cytoplasmic Na(+)-mobility, as NHE1 and NCX are spatially separated (up to 60μm). The relevant functional NCX activity must be close to dyads, as it exerts no effect on bulk diastolic Ca(2+). H(+)-activated Na(+)-influx is up-regulated during ischaemia-reperfusion and some forms of maladaptive hypertrophy and heart failure. It is thus an attractive system for therapeutic manipulation. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".

  9. Fusarium oxysporum f.sp. ciceri Race 1 Induced Redox State Alterations Are Coupled to Downstream Defense Signaling in Root Tissues of Chickpea (Cicer arietinum L.)

    PubMed Central

    Chatterjee, Moniya; Das, Sampa

    2013-01-01

    Reactive oxygen species are known to play pivotal roles in pathogen perception, recognition and downstream defense signaling. But, how these redox alarms coordinate in planta into a defensive network is still intangible. Present study illustrates the role of Fusarium oxysporum f.sp ciceri Race1 (Foc1) induced redox responsive transcripts in regulating downstream defense signaling in chickpea. Confocal microscopic studies highlighted pathogen invasion and colonization accompanied by tissue damage and deposition of callose degraded products at the xylem vessels of infected roots of chickpea plants. Such depositions led to the clogging of xylem vessels in compatible hosts while the resistant plants were devoid of such obstructions. Lipid peroxidation assays also indicated fungal induced membrane injury. Cell shrinkage and gradual nuclear adpression appeared as interesting features marking fungal ingress. Quantitative real time polymerase chain reaction exhibited differential expression patterns of redox regulators, cellular transporters and transcription factors during Foc1 progression. Network analysis showed redox regulators, cellular transporters and transcription factors to coordinate into a well orchestrated defensive network with sugars acting as internal signal modulators. Respiratory burst oxidase homologue, cationic peroxidase, vacuolar sorting receptor, polyol transporter, sucrose synthase, and zinc finger domain containing transcription factor appeared as key molecular candidates controlling important hubs of the defense network. Functional characterization of these hub controllers may prove to be promising in understanding chickpea–Foc1 interaction and developing the case study as a model for looking into the complexities of wilt diseases of other important crop legumes. PMID:24058463

  10. Fusarium oxysporum f.sp. ciceri race 1 induced redox state alterations are coupled to downstream defense signaling in root tissues of chickpea (Cicer arietinum L.).

    PubMed

    Gupta, Sumanti; Bhar, Anirban; Chatterjee, Moniya; Das, Sampa

    2013-01-01

    Reactive oxygen species are known to play pivotal roles in pathogen perception, recognition and downstream defense signaling. But, how these redox alarms coordinate in planta into a defensive network is still intangible. Present study illustrates the role of Fusarium oxysporum f.sp ciceri Race1 (Foc1) induced redox responsive transcripts in regulating downstream defense signaling in chickpea. Confocal microscopic studies highlighted pathogen invasion and colonization accompanied by tissue damage and deposition of callose degraded products at the xylem vessels of infected roots of chickpea plants. Such depositions led to the clogging of xylem vessels in compatible hosts while the resistant plants were devoid of such obstructions. Lipid peroxidation assays also indicated fungal induced membrane injury. Cell shrinkage and gradual nuclear adpression appeared as interesting features marking fungal ingress. Quantitative real time polymerase chain reaction exhibited differential expression patterns of redox regulators, cellular transporters and transcription factors during Foc1 progression. Network analysis showed redox regulators, cellular transporters and transcription factors to coordinate into a well orchestrated defensive network with sugars acting as internal signal modulators. Respiratory burst oxidase homologue, cationic peroxidase, vacuolar sorting receptor, polyol transporter, sucrose synthase, and zinc finger domain containing transcription factor appeared as key molecular candidates controlling important hubs of the defense network. Functional characterization of these hub controllers may prove to be promising in understanding chickpea-Foc1 interaction and developing the case study as a model for looking into the complexities of wilt diseases of other important crop legumes.

  11. In vivo absolute quantification for mouse muscle metabolites using an inductively coupled synthetic signal injection method and newly developed 1H/31P dual tuned probe

    PubMed Central

    Lee, Donghoon; Marro, Kenneth; Mathis, Mark; Shankland, Eric; Hayes, Cecil

    2013-01-01

    Purpose To obtain robust estimates of 31P metabolite content in mouse skeletal muscles using our recently developed MR absolute quantification method and a custom-built 1H/31P dual tuned radiofrequency (RF) coil optimized for mouse leg. Materials and Methods We designed and fabricated a probe consisting of two dual tuned 1H/31P solenoid coils: one leg was inserted to each solenoid. The mouse leg volume coil was incorporated with injector coils for MR absolute quantification. The absolute quantification method uses a synthetic reference signal injection approach and solves several challenges in MR absolute quantification including changes of coil loading and receiver gains. Results The 1H/31P dual tuned probe was composed of two separate solenoid coils, one for each leg, to increase coil filling factors and signal-to-noise ratio. Each solenoid was equipped with a second coil to allow injection of reference signals. 31P metabolite concentrations determined for normal mice were well within the expected range reported in the literature. Conclusion We developed an RF probe and an absolute quantification approach adapted for mouse skeletal muscle. PMID:24464912

  12. A microRNA program in the C. elegans hypodermis couples to intestinal mTORC2/PQM-1 signaling to modulate fat transport

    PubMed Central

    Dowen, Robert H.; Breen, Peter C.; Tullius, Thomas; Conery, Annie L.; Ruvkun, Gary

    2016-01-01

    Animals integrate metabolic, developmental, and environmental information before committing key resources to reproduction. In Caenorhabditis elegans, adult animals transport fat from intestinal cells to the germline to promote reproduction. We identified a microRNA (miRNA)-regulated developmental timing pathway that functions in the hypodermis to nonautonomously coordinate the mobilization of intestinal fat stores to the germline upon initiation of adulthood. This developmental timing pathway, which is controlled by the lin-4 and let-7 miRNAs, engages mTOR signaling in the intestine. The intestinal signaling component is specific to mTORC2 and functions in parallel to the insulin pathway to modulate the activity of the serum/glucocorticoid-regulated kinase (SGK-1). Surprisingly, SGK-1 functions independently of DAF-16/FoxO; instead, SGK-1 promotes the cytoplasmic localization of the PQM-1 transcription factor, which antagonizes intestinal fat mobilization at the transcriptional level when localized to the nucleus. These results revealed that a non-cell-autonomous developmental input regulates intestinal fat metabolism by engaging mTORC2 signaling to promote the intertissue transport of fat reserves from the soma to the germline. PMID:27401555

  13. Functional nanoscale coupling of Lyn kinase with IgE-FcεRI is restricted by the actin cytoskeleton in early antigen-stimulated signaling

    PubMed Central

    Shelby, Sarah A.; Veatch, Sarah L.; Holowka, David A.; Baird, Barbara A.

    2016-01-01

    The allergic response is initiated on the plasma membrane of mast cells by phosphorylation of the receptor for immunoglobulin E (IgE), FcεRI, by Lyn kinase after IgE-FcεRI complexes are cross-linked by multivalent antigen. Signal transduction requires reorganization of receptors and membrane signaling proteins, but this spatial regulation is not well defined. We used fluorescence localization microscopy (FLM) and pair-correlation analysis to measure the codistribution of IgE-FcεRI and Lyn on the plasma membrane of fixed cells with 20- to 25-nm resolution. We directly visualized Lyn recruitment to IgE-FcεRI within 1 min of antigen stimulation. Parallel FLM experiments captured stimulation-induced FcεRI phosphorylation and colocalization of a saturated lipid-anchor probe derived from Lyn’s membrane anchorage. We used cytochalasin and latrunculin to investigate participation of the actin cytoskeleton in regulating functional interactions of FcεRI. Inhibition of actin polymerization by these agents enhanced colocalization of IgE-FcεRI with Lyn and its saturated lipid anchor at early stimulation times, accompanied by augmented phosphorylation within FcεRI clusters. Ising model simulations provide a simplified model consistent with our results. These findings extend previous evidence that IgE-FcεRI signaling is initiated by colocalization with Lyn in ordered lipid regions and that the actin cytoskeleton regulates this functional interaction by influencing the organization of membrane lipids. PMID:27682583

  14. From land use to land cover: restoring the afforestation signal in a coupled integrated assessment - earth system model and the implications for CMIP5 RCP simulations

    NASA Astrophysics Data System (ADS)

    Di Vittorio, A. V.; Chini, L. P.; Bond-Lamberty, B.; Mao, J.; Shi, X.; Truesdale, J.; Craig, A.; Calvin, K.; Jones, A.; Collins, W. D.; Edmonds, J.; Hurtt, G. C.; Thornton, P.; Thomson, A.

    2014-05-01

    Climate projections depend on scenarios of fossil fuel emissions and land use change, and the IPCC AR5 parallel process assumes consistent climate scenarios across Integrated Assessment and Earth System Models (IAMs and ESMs). The CMIP5 project used a novel "land use harmonization" based on the Global Land use Model (GLM) to provide ESMs with consistent 1500-2100 land use trajectories generated by historical data and four IAM projections. A direct coupling of the Global Change Assessment Model (GCAM), GLM, and the Community ESM (CESM) has allowed us to characterize and partially address a major gap in the CMIP5 land coupling design: the lack of a corresponding land cover harmonization. The CMIP5 CESM global afforestation is only 22% of GCAM's 2005 to 2100 RCP4.5 afforestation. Likewise, only 17% of GCAM's 2040 RCP4.5 afforestation, and zero pasture loss, were transmitted to CESM within the directly coupled model. This is a problem because afforestation was relied upon to achieve RCP4.5 climate stabilization. GLM modifications within the directly coupled model did not increase CESM afforestation. Modifying the land use translator in addition to GLM, however, enabled CESM to simulate 66% of GCAM's afforestation in 2040, and 94% of GCAM's pasture loss as grassland and shrubland losses. This additional afforestation increases vegetation carbon gain by 19 PgC and decreases atmospheric CO2 gain by 8 ppmv from 2005 to 2040, implying different RCP4.5 climate scenarios between CMIP5 GCAM and CESM. Although the IAMs and ESMs were not expected to have exactly the same climate forcing, due in part to different terrestrial carbon cycles and atmospheric radiation algorithms, the ESMs were expected to project climates representative of the RCP scenarios. Similar land cover inconsistencies exist in other CMIP5 model results, primarily because land cover information is not shared between models. High RCP4.5 afforestation might also contribute to inconsistencies as some ESMs might

  15. From Land Use to Land Cover: Restoring the Afforestation Signal in a Coupled Integrated Assessment - Earth System Model and the Implications for CMIP5 RCP Simulations

    NASA Astrophysics Data System (ADS)

    Di Vittorio, A. V.; Chini, L. P.; Bond-Lamberty, B. P.; Mao, J.; Shi, X.; Truesdale, J. E.; Craig, A.; Calvin, K. V.; Jones, A. D.; Collins, W.; Edmonds, J.; Hurtt, G. C.; Thornton, P. E.; Thomson, A. M.

    2014-12-01

    Climate projections depend on scenarios of fossil fuel emissions and land use change, and the IPCC AR5 parallel process assumes consistent climate scenarios across Integrated Assessment and Earth System Models (IAMs and ESMs). The CMIP5 project used a novel "land use harmonization" based on the Global Land use Model (GLM) to provide ESMs with consistent 1500-2100 land use trajectories generated by historical data and four IAM projections. A direct coupling of the Global Change Assessment Model (GCAM), GLM, and the Community ESM (CESM) has allowed us to characterize and partially address a major gap in the CMIP5 land coupling design: the lack of a corresponding land cover harmonization. The CMIP5 CESM global afforestation is only 22% of GCAM's 2005 to 2100 RCP4.5 afforestation. Likewise, only 17% of GCAM's 2040 RCP4.5 afforestation, and zero pasture loss, were transmitted to CESM within the directly coupled model. This is a problem because afforestation was relied upon to achieve RCP4.5 climate stabilization. GLM modifications within the directly coupled model did not increase CESM afforestation. Modifying the CESM land use translator in addition to GLM, however, enabled CESM to simulate 66% of GCAM's afforestation in 2040, and 94% of GCAM's pasture loss as grassland and shrubland losses. This additional afforestation increases vegetation carbon gain by 19 PgC and decreases atmospheric CO2 gain by 8 ppmv from 2005 to 2040, implying different RCP4.5 climate scenarios between CMIP5 GCAM and CESM. Although the IAMs and ESMs were not expected to have exactly the same climate forcing, due in part to different terrestrial carbon cycles and atmospheric radiation algorithms, the ESMs were expected to project climates representative of the RCP scenarios. Similar land cover inconsistencies exist in other CMIP5 model results, primarily because land cover information is not shared between IAM and ESM models. High RCP4.5 afforestation might also contribute to inconsistencies as

  16. Stimulation of α₁-adrenoceptor or angiotensin type 1 receptor enhances DNA synthesis in human-induced pluripotent stem cells via Gq-coupled receptor-dependent signaling pathways.

    PubMed

    Ishizuka, Toshiaki; Goshima, Hazuki; Ozawa, Ayako; Watanabe, Yasuhiro

    2013-08-15

    Stimulation of either α₁-adrenoceptor or angiotensin type 1 receptor (AT₁ receptor) induces proliferation of mouse induced pluripotent stem (iPS) cells. Both α₁-adrenoceptor and AT₁ receptor are guanine nucleotide-binding protein q polypeptide (Gq)-coupled receptors. However, it is not fully understood whether stimulation of these Gq-coupled receptors exert a similar effect in human iPS cells, i.e. proliferation of human iPS cells. In this study, we evaluated the involvement of α₁-adrenoceptor and AT₁ receptor in the DNA synthesis of human iPS cells. Treatment with either l-phenylephrine (a selective α₁-adrenoceptor agonist) or angiotensin II (Ang II) significantly increased DNA synthesis in human iPS cells. Enhanced DNA synthesis was significantly inhibited by pretreatment with protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) inhibitor, or phosphatidylinositol-3 phosphate kinase (PI3K) inhibitor. Treatment with either l-phenylephrine or Ang II significantly increased Akt and p44/42 MAPK phosphorylation. Short interfering RNA (siRNA) directed against Gq significantly inhibited DNA synthesis and phosphorylation of Akt and p44/42 MAPK enhanced by l-phenylephrine or Ang II. These results suggest that stimulation of α₁-adrenoceptor or AT₁ receptor may enhance DNA synthesis in human iPS cells via Gq-coupled receptor-dependent signaling pathways.

  17. Award 1 Title: Acoustic Communications 2011 Experiment: Deployment Support and Post Experiment Data Handling and Analysis. Award 2 Title: Exploiting Structured Dependencies in the Design of Adaptive Algorithms for Underwater Communication Award. 3 Title: Coupled Research in Ocean Acoustics and Signal Processing for the Next Generation of Underwater Acoustic Communication Systems

    DTIC Science & Technology

    2015-09-30

    Exploiting Structured Dependencies in the Design of Adaptive Algorithms for Underwater Communication Award #3 Title Coupled Research in Ocean Acoustics...depend on the physical oceanography and pushing the state of the art in our understanding of adaptive signal processing algorithms relevant to...deployable VHF acoustic data transmission and acquisition system. 3. Develop signal models and processing algorithms that reduce to the extent

  18. Icariin attenuates high glucose-induced type IV collagen and fibronectin accumulation in glomerular mesangial cells by inhibiting transforming growth factor-β production and signalling through G protein-coupled oestrogen receptor 1.

    PubMed

    Li, Yi-Chen; Ding, Xuan-Sheng; Li, Hui-Mei; Zhang, Cheng

    2013-09-01

    Icariin has been shown to attenuate diabetic nephropathy in rats by decreasing transforming growth factor-β (TGF-β) and type IV collagen expression, but its mode of action in glomerular mesangial cells is uncertain. The present study aimed to investigate the effect of icariin on excess mesangial type IV collagen and fibronectin accumulation induced by high glucose, and to determine the mechanism underlying its protective effects. Under high-glucose conditions, icariin diminished type IV collagen and fibronectin accumulation, as well as TGF-β production in human and rat mesangial cells. Mesangial cells treated with icariin after TGF-β1 exposure expressed less type IV collagen and fibronectin than those without icariin treatment, suggesting inhibition by icariin of TGF-β1 downstream pathways. On TGF-β1 stimulation, icariin inhibited TGF-β canonical Smad signalling and extracellular signal-regulated kinase (ERK)1/2 signalling by decreasing Smad2/3 and ERK1/2 phosphorylation in a dose-dependent manner. U0126, which blocked the ERK1/2 pathway, exerted an additive effect on the icariin suppression of type IV collagen and fibronectin expression, enhancing the beneficial effects of icariin. The G protein-coupled oestrogen receptor 1 (GPER) antagonist, G-15, abolished the icariin-induced inhibition of type IV collagen, and fibronectin overproduction and TGF-β signalling. Treatment of cells with fulvestrant, a downregulator of the oestrogen receptor, enhanced the action of icariin. In conclusion, icariin decreased type IV collagen and fibronectin accumulation induced by high glucose in mesangial cells by inhibiting TGF-β production, as well as Smad and ERK signalling in a GPER-dependent manner.

  19. Momordin Ic couples apoptosis with autophagy in human hepatoblastoma cancer cells by reactive oxygen species (ROS)-mediated PI3K/Akt and MAPK signaling pathways.

    PubMed

    Mi, Yashi; Xiao, Chunxia; Du, Qingwei; Wu, Wanqiang; Qi, Guoyuan; Liu, Xuebo

    2016-01-01

    Momordin Ic is a principal saponin constituent of Fructus Kochiae, which acts as an edible and pharmaceutical product more than 2000 years in China. Our previous research found momordin Ic induced apoptosis by PI3K/Akt and MAPK signaling pathways in HepG2 cells. While the role of autophagy in momordin Ic induced cell death has not been discussed, and the connection between the apoptosis and autophagy is not clear yet. In this work, we reported momordin Ic promoted the formation of autophagic vacuole and expression of Beclin 1 and LC-3 in a dose- and time-dependent manner. Compared with momordin Ic treatment alone, the autophagy inhibitor 3-methyladenine (3-MA) also can inhibit apoptosis, while autophagy activator rapamycin (RAP) has the opposite effect, and the apoptosis inhibitor ZVAD-fmk also inhibited autophagy induced by momordin Ic. Momordin Ic simultaneously induces autophagy and apoptosis by suppressing the ROS-mediated PI3K/Akt and activating the ROS-related JNK and P38 pathways. Additionally, momordin Ic induces apoptosis by suppressing PI3K/Akt-dependent NF-κB pathways and promotes autophagy by ROS-mediated Erk signaling pathway. Those results suggest that momordin Ic has great potential as a nutritional preventive strategy in cancer therapy.

  20. NOX3 NADPH Oxidase Couples Transient Receptor Potential Vanilloid 1 to Signal Transducer and Activator of Transcription 1-Mediated Inflammation and Hearing Loss

    PubMed Central

    Mukherjea, Debashree; Jajoo, Sarvesh; Sheehan, Kelly; Kaur, Tejbeer; Sheth, Sandeep; Bunch, Jennifer; Perro, Christopher; Rybak, Leonard P.

    2011-01-01

    Abstract Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24 h, which recovered by 72 h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss. Antioxid. Redox Signal. 14, 999–1010. PMID:20712533

  1. Nrf2-Mediated HO-1 Induction Coupled with the ERK Signaling Pathway Contributes to Indirect Antioxidant Capacity of Caffeic Acid Phenethyl Ester in HepG2 Cells

    PubMed Central

    Kim, Jin-Kyoung; Jang, Hae-Dong

    2014-01-01

    The objective of this study is to investigate the contributing effect of the nuclear transcription factor-erythroid 2-related factor 2 (Nrf2)-mediated signaling pathway on the indirect antioxidant capacity of caffeic acid phenethyl ester (CAPE) against oxidative stress in HepG2 cells. The result of an antioxidant response element (ARE)-luciferase assay showed that CAPE stimulated ARE promoter activity resulting in increased transcriptional and translational activities of heme oxygenase-1 (HO-1). In addition, CAPE treatment enhanced Nrf2 accumulation in the nucleus and the post-translational phosphorylation level of extracellular signal-regulated kinase (ERK) among several protein kinases tested. Treatment with ERK inhibitor U126 completely suppressed CAPE-induced ERK phosphorylation and HO-1 expression, but it only partly inhibited CAPE-induced Nrf2 accumulation and ARE promoter. Using the 2',7'-dichlorofluorescein-diacetate (DCFH-DA) method, the cellular antioxidant capacity of CAPE against 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH)- or H2O2-induced oxidative stress also was shown to be partially suppressed by the ERK inhibitor. From the overall results it is proposed that the indirect antioxidant activity of CAPE against oxidative stress in HepG2 cells is partially attributed to induction of HO-1, which is regulated by Kelch-like erythroid-cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1)-independent Nrf2 activation relying on post-translational phosphorylation of ERK. PMID:25007817

  2. Different signaling pathway between sphingosine-1-phosphate and lysophosphatidic acid in Xenopus oocytes: functional coupling of the sphingosine-1-phosphate receptor to PLC-xbeta in Xenopus oocytes.

    PubMed

    Noh, S J; Kim, M J; Shim, S; Han, J K

    1998-08-01

    In Xenopus oocytes, both sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) activate Ca2+-dependent oscillatory Cl- currents by acting through membrane-bound receptors. External application of 50 microM S1P elicited a long-lasting oscillatory current that continued over 30 min from the beginning of oscillation, with 300 nA (n = 11) as a usual maximum peak of current, whereas 1-microM LPA treatment showed only transiently oscillating but more vigorous current responses, with 2,800 nA (n = 18) as a maximum peak amplitude. Both phospholipid-induced Ca2+-dependent Cl- currents were observed in the absence of extracellular Ca2+, were blocked by intracellular injection of the Ca2+ chelator, EGTA, and could not be elicited by treatment with thapsigargin, an inhibitor of endoplasmic reticulum (ER) Ca2+ ATPase. Intracellular Ca2+ release appeared to be from inositol 1,4,5-trisphosphate (IP3)-sensitive Ca2+ store, because Cl- currents were blocked by heparin injection. Pretreatment with the aminosteroid, U-73122, an inhibitor of G protein-mediated phospholipase C (PLC) activation, to oocytes inhibited the current responses evoked both by S1P and LPA. However, when they were injected with 10 ng of antisense oligonucleotide (AS-ODN) against Xenopus phospholipase C (PLC-xbeta), oocytes could not respond to S1P application, whereas they responded normally to LPA, indicating that the S1P signaling pathway goes through PLC-xbeta, whereas LPA signaling goes through another unknown PLC. To determine the types of G proteins involved, we introduced AS-ODNs against four types of G-protein alpha subunits that were identified in Xenopus laevis; G(q)alpha, G11alpha, G0alpha, and G(i1)alpha. Among AS-ODNs against the G alphas tested, AS-G(q)alpha and AS-G(i1)alpha to S1P and AS-G(q)alpha and AS-G11alpha to LPA specifically reduced current responses, respectively, to about 20-30% of controls. These results demonstrate that LPA and S1P, although they have similar structural

  3. Independent expression of human. alpha. or. beta. platelet-derived growth factor receptor cDNAs in a naive hematopoietic cell leads to functional coupling with mitogenic and chemotactic signaling pathways

    SciTech Connect

    Matsui, T.; Pierce, J.H.; Fleming, T.P.; LaRochelle, W.J.; Ruggiero, M.; Aaronson, S.A. ); Greenberger, J.S. )

    1989-11-01

    Distinct genes encode {alpha} and {beta} platelet-derived growth factor (PDGF) receptors that differ in their abilities to be triggered by three dimeric forms of the PDGF molecule. The authors show that PDGF-receptor mitogenic function can be reconstituted in a naive hematopoietic cell line by introduction of expression vectors for either {alpha} or {beta} PDGF receptor cDNAs. Thus, each receptor is independently capable of coupling with mitogenic signal-transduction pathways inherently present in these cells. Activation of either receptor also resulted in chemotaxis, alterations in inositol lipid metabolism, and mobilization of intracellular Ca{sup 2+}. The magnitude of these functional responses correlated well with the binding properties of the different PDGF isoforms to each receptor. Thus, availability of specific PDGF isoforms and relative expression of each PDGF-receptor gene product are major determinants of the spectrum of known PDGF responses.

  4. Structural Elements in the Gαs and Gαq C Termini That Mediate Selective G Protein-coupled Receptor (GPCR) Signaling.

    PubMed

    Semack, Ansley; Sandhu, Manbir; Malik, Rabia U; Vaidehi, Nagarajan; Sivaramakrishnan, Sivaraj

    2016-08-19

    Although the importance of the C terminus of the α subunit of the heterotrimeric G protein in G protein-coupled receptor (GPCR)-G protein pairing is well established, the structural basis of selective interactions remains unknown. Here, we combine live cell FRET-based measurements and molecular dynamics simulations of the interaction between the GPCR and a peptide derived from the C terminus of the Gα subunit (Gα peptide) to dissect the molecular mechanisms of G protein selectivity. We observe a direct link between Gα peptide binding and stabilization of the GPCR conformational ensemble. We find that cognate and non-cognate Gα peptides show deep and shallow binding, respectively, and in distinct orientations within the GPCR. Binding of the cognate Gα peptide stabilizes the agonist-bound GPCR conformational ensemble resulting in favorable binding energy and lower flexibility of the agonist-GPCR pair. We identify three hot spot residues (Gαs/Gαq-Gln-384/Leu-349, Gln-390/Glu-355, and Glu-392/Asn-357) that contribute to selective interactions between the β2-adrenergic receptor (β2-AR)-Gαs and V1A receptor (V1AR)-Gαq The Gαs and Gαq peptides adopt different orientations in β2-AR and V1AR, respectively. The β2-AR/Gαs peptide interface is dominated by electrostatic interactions, whereas the V1AR/Gαq peptide interactions are predominantly hydrophobic. Interestingly, our study reveals a role for both favorable and unfavorable interactions in G protein selection. Residue Glu-355 in Gαq prevents this peptide from interacting strongly with β2-AR. Mutagenesis to the Gαs counterpart (E355Q) imparts a cognate-like interaction. Overall, our study highlights the synergy in molecular dynamics and FRET-based approaches to dissect the structural basis of selective G protein interactions.

  5. Au nanoparticles/hollow molybdenum disulfide microcubes based biosensor for microRNA-21 detection coupled with duplex-specific nuclease and enzyme signal amplification.

    PubMed

    Shuai, Hong-Lei; Huang, Ke-Jing; Chen, Ying-Xu; Fang, Lin-Xia; Jia, Meng-Pei

    2017-03-15

    An ultrasensitive electrochemical biosensor for detecting microRNAs is fabricated based on hollow molybdenum disulfide (MoS2) microcubes. Duplex-specific nuclease, enzyme and electrochemical-chemical-chemical redox cycling are used for signal amplification. Hollow MoS2 microcubes constructed by ultrathin nanosheets are synthesized by a facile template-assisted strategy and used as supporting substrate. For biosensor assembling, biotinylated ssDNA capture probes are first immobilized on Au nanoparticles (AuNPs)/MoS2 modified electrode in order to combine with streptavidin-conjugated alkaline phosphatase (SA-ALP). When capture probes hybridize with miRNAs, duplex-specific nuclease cleaves the formative duplexes. At the moment, the biotin group strips from the electrode surface and SA-ALP is incapacitated to attach onto electrode. Then, ascorbic acids induce the electrochemical-chemical-chemical redox cycling to produce electrochemical response in the presence of ferrocene methanol and tris (2-carboxyethyl) phosphine. Under optimum conditions, the proposed biosensor shows a good linear relationship between the current variation and logarithm of the microRNAs concentration ranging from 0.1fM to 0.1pM with a detection limit of 0.086fM (S/N=3). Furthermore, the biosensor is successfully applied to detect target miRNA-21 in human serum samples.

  6. NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss.

    PubMed

    Mukherjea, Debashree; Jajoo, Sarvesh; Sheehan, Kelly; Kaur, Tejbeer; Sheth, Sandeep; Bunch, Jennifer; Perro, Christopher; Rybak, Leonard P; Ramkumar, Vickram

    2011-03-15

    Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24 h, which recovered by 72 h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss.

  7. Toll-Like Receptor 3 Signalling Up-Regulates Expression of the HIV Co-Receptor G-Protein Coupled Receptor 15 on Human CD4+ T Cells

    PubMed Central

    Kiene, Miriam; Rethi, Bence; Jansson, Marianne; Dillon, Stephanie; Lee, Eric; Lantto, Rebecka; Wilson, Cara; Pöhlmann, Stefan; Chiodi, Francesca

    2014-01-01

    Background Many HIV-2 and SIV isolates, as well as some HIV-1 strains, can use the orphan 7-transmembrane receptor GPR15 as co-receptor for efficient entry into host cells. GPR15 is expressed on central memory and effector memory CD4+ T cells in healthy individuals and a subset of these cells is susceptible to HIV-1 and SIV infection. However, it has not been determined whether GPR15 expression is altered in the context of HIV-1 infection. Results Here, we show that GPR15 expression in CD4+ T cells is markedly up-regulated in some HIV-1 infected individuals compared to the rest of the infected patients and to healthy controls. Infection of the PM1 T cell line with primary HIV-1 isolates was found to up-regulate GPR15 expression on the infected cells, indicating that viral components can induce GPR15 expression. Up-regulation of GPR15 expression on CD4+ T cells was induced by activation of Toll-like receptor 3 signalling via TIR-domain-containing adapter-inducing interferon-β (TRIF) and was more prominent on gut-homing compared to lymph node-homing CD4+ T cells. Conclusion These results suggest that infection-induced up-regulation of GPR15 expression could increase susceptibility of CD4+ T cells to HIV infection and target cell availability in the gut in some infected individuals. PMID:24558379

  8. The MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells

    PubMed Central

    Li, Xiaomu; Cheng, Kenneth K. Y.; Liu, Zhuohao; Yang, Jin-Kui; Wang, Baile; Jiang, Xue; Zhou, Yawen; Hallenborg, Philip; Hoo, Ruby L. C.; Lam, Karen S. L.; Ikeda, Yasuhiro; Gao, Xin; Xu, Aimin

    2016-01-01

    Mitochondrial metabolism is pivotal for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. However, little is known about the molecular machinery that controls the homeostasis of intermediary metabolites in mitochondria. Here we show that the activation of p53 in β-cells, by genetic deletion or pharmacological inhibition of its negative regulator MDM2, impairs GSIS, leading to glucose intolerance in mice. Mechanistically, p53 activation represses the expression of the mitochondrial enzyme pyruvate carboxylase (PC), resulting in diminished production of the TCA cycle intermediates oxaloacetate and NADPH, and impaired oxygen consumption. The defective GSIS and mitochondrial metabolism in MDM2-null islets can be rescued by restoring PC expression. Under diabetogenic conditions, MDM2 and p53 are upregulated, whereas PC is reduced in mouse β-cells. Pharmacological inhibition of p53 alleviates defective GSIS in diabetic islets by restoring PC expression. Thus, the MDM2–p53–PC signalling axis links mitochondrial metabolism to insulin secretion and glucose homeostasis, and could represent a therapeutic target in diabetes. PMID:27265727

  9. Melatonin Suppresses Toll Like Receptor 4-Dependent Caspase-3 Signaling Activation Coupled with Reduced Production of Proinflammatory Mediators in Hypoxic Microglia

    PubMed Central

    Yao, Linli; Lu, Pengfei; Ling, Eng-Ang

    2016-01-01

    Microglia activation and associated inflammatory response play pivotal roles in the pathogenesis of different neurodegenerative diseases including neonatal hypoxic brain injury. Here we show that caspase3 expression was upregulated in activated microglia after hypoxic exposure, and remarkably, the cell viability remained unaffected alluding to the possibility of a non-apoptotic role of caspase3 in activated microglia. Chemical inhibition of caspase3 suppressed microglia activation as evident by an obvious reduction in expression of proinflammatory mediators and NF-κB signaling activation. Hypoxia induced caspase3 activation was TLR4 dependent as supported by the fact that caspase3 activation was hindered in cells with TLR4 knockdown. Interestingly, melatonin treatment significantly suppressed caspase3 activation. More importantly, melatonin also inhibited the increase in TLR4 protein and mRNA expression in hypoxic microglia. Inhibition of TLR4 expression by melatonin was also found in microglia of postnatal rats subjected to hypoxic exposure. Taken together, it is concluded that melatonin could inhibit TLR4 expression in hypoxic microglia followed by suppression of caspase3 activation leading to decrease in production of proinflammatory mediators. PMID:27812200

  10. Clustered, Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-coupled Affinity Purification/Mass Spectrometry Analysis Revealed a Novel Role of Neurofibromin in mTOR Signaling.

    PubMed

    Li, Xu; Gao, Min; Choi, Jong Min; Kim, Beom-Jun; Zhou, Mao-Tian; Chen, Zhen; Jain, Antrix N; Jung, Sung Yun; Yuan, Jingsong; Wang, Wenqi; Wang, Yi; Chen, Junjie

    2017-04-01

    Neurofibromin (NF1) is a well known tumor suppressor that is commonly mutated in cancer patients. It physically interacts with RAS and negatively regulates RAS GTPase activity. Despite the importance of NF1 in cancer, a high quality endogenous NF1 interactome has yet to be established. In this study, we combined clustered, regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated gene knock-out technology with affinity purification using antibodies against endogenous proteins, followed by mass spectrometry analysis, to sensitively and accurately detect NF1 protein-protein interactions in unaltered in vivo settings. Using this system, we analyzed endogenous NF1-associated protein complexes and identified 49 high-confidence candidate interaction proteins, including RAS and other functionally relevant proteins. Through functional validation, we found that NF1 negatively regulates mechanistic target of rapamycin signaling (mTOR) in a LAMTOR1-dependent manner. In addition, the cell growth and survival of NF1-deficient cells have become dependent on hyperactivation of the mTOR pathway, and the tumorigenic properties of these cells have become dependent on LAMTOR1. Taken together, our findings may provide novel insights into therapeutic approaches targeting NF1-deficient tumors.

  11. Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/μR-coupled TLR4 signalling

    PubMed Central

    Honda, Shin-ichiro; Sato, Kazuki; Totsuka, Naoya; Fujiyama, Satoshi; Fujimoto, Manabu; Miyake, Kensuke; Nakahashi-Oda, Chigusa; Tahara-Hanaoka, Satoko; Shibuya, Kazuko; Shibuya, Akira

    2016-01-01

    Marginal zone (MZ) B cells produce a first wave of antibodies for protection from blood-borne pathogens. However, the role of MZ B cells in inflammatory responses has not been elucidated. Here we show that MZ B cells produce pro-inflammatory cytokines, such as interleukin-6 (IL-6), and exacerbate systemic inflammatory responses to lipopolysaccharide (LPS). After intravenous injection of LPS or E. coli, mice deficient in MZ B cells or IL-6 only in MZ B cells have attenuated systemic inflammatory responses and prolonged survival compared with wild-type mice. LPS directly stimulates MZ B cells via Toll-like receptor 4 (TLR4) and MyD88 pathways for IL-6 production. Furthermore, TLR4 requires physical and functional association with Fcα/μR (CD351) for its oligomer formation, NF-κB signalling and IL-6 production from MZ B cells; this association is responsible for systemic inflammatory responses and endotoxic shock. These results reveal a pro-inflammatory role of MZ B cells in endotoxic shock. PMID:27146354

  12. Pasteurella multocida toxin activates the inositol triphosphate signaling pathway in Xenopus oocytes via G(q)alpha-coupled phospholipase C-beta1.

    PubMed

    Wilson, B A; Zhu, X; Ho, M; Lu, L

    1997-01-10

    Pasteurella multocida toxin (PMT) has been hypothesized to cause activation of a GTP-binding protein (G-protein)-coupled phosphatidylinositol-specific phospholipase C (PLC) in intact cells. We used voltage-clamped Xenopus oocytes to test for direct PMT-mediated stimulation of PLC by monitoring the endogenous Ca2+-dependent C1- current. Injection of PMT induced an inward, two-component Cl- current, similar to that evoked by injection of IP3 through intracellular Ca2+ mobilization and Ca2+ influx through voltage-gated Ca2+ channels. These PMT-induced currents were blocked by specific inhibitors of Ca2+ and Cl- channels, removal of extracellular Ca2+, or chelation of intracellular Ca2+. Specific antibodies directed against an N-terminal, but not a C-terminal, peptide of PMT inhibited the toxin-induced currents, implicating that the N terminus of PMT is important for toxin activity. Injection with specific antibodies against PLCbeta1, PLCbeta2, PLCbeta3, or PLCgamma1 identified PLCbeta1 as the primary mediator of the PMT-induced Cl- currents. Injection with guanosine 5'-O-(2-(thio)diphosphate), antibodies to the common GTP-binding region of G-protein alpha subunits, or antibodies to different regions of G-protein beta subunits established the involvement of a G-protein alpha subunit in PMT-activation of PLCbeta1. Injection with specific antibodies against the alpha-subunits of G(q/11), G(s/olf), G(i/o/t/z), or G(i-1/i-2/i-3) isoforms confirmed the involvement of Gq/11alpha. Preinjection of oocytes with pertussis toxin enhanced the PMT response. Overexpression of G(q)alpha in oocytes could enhance the PMT response by 30-fold to more than 300-fold, whereas introduction of antisense G(q)alpha cRNA reduced the response by 7-fold. The effects of various specific antibodies on the PMT response were reproduced in oocytes overexpressing G(q)alpha.

  13. The Selective Estrogen Receptor Modulator Raloxifene Regulates Arginine-Vasopressin Gene Expression in Human Female Neuroblastoma Cells Through G Protein-Coupled Estrogen Receptor and ERK Signaling.

    PubMed

    Grassi, Daniela; Ghorbanpoor, Samar; Acaz-Fonseca, Estefania; Ruiz-Palmero, Isabel; Garcia-Segura, Luis M

    2015-10-01

    The selective estrogen receptor modulator raloxifene reduces blood pressure in hypertensive postmenopausal women. In the present study we have explored whether raloxifene regulates gene expression of arginine vasopressin (AVP), which is involved in the pathogenesis of hypertension. The effect of raloxifene was assessed in human female SH-SY5Y neuroblastoma cells, which have been recently identified as a suitable cellular model to study the estrogenic regulation of AVP. Raloxifene, within a concentration ranging from 10(-10) M to 10(-6) M, decreased the mRNA levels of AVP in SH-SY5Y cells with maximal effect at 10(-7) M. This effect of raloxifene was imitated by an agonist (±)-1-[(3aR*,4S*,9bS*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone of G protein-coupled estrogen receptor-1 (GPER) and blocked by an antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline of GPER and by GPER silencing. Raloxifene induced a time-dependent increase in the level of phosphorylated ERK1 and ERK2, by a mechanism blocked by the GPER antagonist. The treatment of SH-SY5Y cells with either a MAPK/ERK kinase 1/2-specific inhibitor (1,4-diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadine) or a protein kinase C inhibitor (sotrastaurin) blocked the effects of raloxifene on the phosphorylation of ERK1/2 and the regulation of AVP mRNA levels. These results reveal a mechanism mediating the regulation of AVP expression by raloxifene, involving the activation of GPER, which in turn activates protein kinase C, MAPK/ERK kinase, and ERK. The regulation of AVP by raloxifene and GPER may have implications for the treatment of blood hypertension(.).

  14. G-protein coupled receptor 56 promotes myoblast fusion through serum response factor- and nuclear factor of activated T-cell-mediated signalling but is not essential for muscle development in vivo.

    PubMed

    Wu, Melissa P; Doyle, Jamie R; Barry, Brenda; Beauvais, Ariane; Rozkalne, Anete; Piao, Xianhua; Lawlor, Michael W; Kopin, Alan S; Walsh, Christopher A; Gussoni, Emanuela

    2013-12-01

    Mammalian muscle cell differentiation is a complex process of multiple steps for which many of the factors involved have not yet been defined. In a screen to identify the regulators of myogenic cell fusion, we found that the gene for G-protein coupled receptor 56 (GPR56) was transiently up-regulated during the early fusion of human myoblasts. Human mutations in the gene for GPR56 cause the disease bilateral frontoparietal polymicrogyria; however, the consequences of receptor dysfunction on muscle development have not been explored. Using knockout mice, we defined the role of GPR56 in skeletal muscle. GPR56(-/-) myoblasts have decreased fusion and smaller myotube sizes in culture. In addition, a loss of GPR56 expression in muscle cells results in decreases or delays in the expression of myogenic differentiation 1, myogenin and nuclear factor of activated T-cell (NFAT)c2. Our data suggest that these abnormalities result from decreased GPR56-mediated serum response element and NFAT signalling. Despite these changes, no overt differences in phenotype were identified in the muscle of GPR56 knockout mice, which presented only a mild but statistically significant elevation of serum creatine kinase compared to wild-type. In agreement with these findings, clinical data from 13 bilateral frontoparietal polymicrogyria patients revealed mild serum creatine kinase increase in only two patients. In summary, targeted disruption of GPR56 in mice results in myoblast abnormalities. The absence of a severe muscle phenotype in GPR56 knockout mice and human patients suggests that other factors may compensate for the lack of this G-protein coupled receptor during muscle development and that the motor delay observed in these patients is likely not a result of primary muscle abnormalities.

  15. DC coupled Doppler radar physiological monitor.

    PubMed

    Zhao, Xi; Song, Chenyan; Lubecke, Victor; Boric-Lubecke, Olga

    2011-01-01

    One of the challenges in Doppler radar systems for physiological monitoring is a large DC offset in baseband outputs. Typically, AC coupling is used to eliminate this DC offset. Since the physiological signals of interest include frequency content near DC, it is not desirable to simply use AC coupling on the radar outputs. While AC coupling effectively removes DC offset, it also introduces a large time delay and distortion. This paper presents the first DC coupled IQ demodulator printed circuit board (PCB) design and measurements. The DC coupling is achieved by using a mixer with high LO to RF port isolation, resulting in a very low radar DC offset on the order of mV. The DC coupled signals from the PCB radar system were successfully detected with significant LNA gain without saturation. Compared to the AC coupled results, the DC coupled results show great advantages of less signal distortion and more accurate rate estimation.

  16. Helix coupling

    DOEpatents

    Ginell, William S.

    1989-04-25

    A coupling for connecting helix members in series, which consists of a pair of U-shaped elements, one of which is attached to each helix end with the "U" sections of the elements interlocked. The coupling is particularly beneficial for interconnecting helical Nitinol elements utilized in thermal actuators or engines. Each coupling half is attached to the associated helix at two points, thereby providing axial load while being easily removed from the helix, and reusable.

  17. Helix coupling

    DOEpatents

    Ginell, W.S.

    1982-03-17

    A coupling for connecting helix members in series, which consists of a pair of U-shaped elements, one of which is attached to each helix end with the U sections of the elements interlocked. The coupling is particularly beneficial for interconnecting helical Nitinol elements utilized in thermal actuators or engines. Each coupling half is attached to the associated helix at two points, thereby providing axial load while being easily removed from the helix, and reusable.

  18. G protein-coupled receptors (GPCRs) That Signal via Protein Kinase A (PKA) Cross-talk at Insulin Receptor Substrate 1 (IRS1) to Activate the phosphatidylinositol 3-kinase (PI3K)/AKT Pathway.

    PubMed

    Law, Nathan C; White, Morris F; Hunzicker-Dunn, Mary E

    2016-12-30

    G protein-coupled receptors (GPCRs) activate PI3K/v-AKT thymoma viral oncoprotein (AKT) to regulate many cellular functions that promote cell survival, proliferation, and growth. However, the mechanism by which GPCRs activate PI3K/AKT remains poorly understood. We used ovarian preantral granulosa cells (GCs) to elucidate the mechanism by which the GPCR agonist FSH via PKA activates the PI3K/AKT cascade. Insulin-like growth factor 1 (IGF1) is secreted in an autocrine/paracrine manner by GCs and activates the IGF1 receptor (IGF1R) but, in the absence of FSH, fails to stimulate YXXM phosphorylation of IRS1 (insulin receptor substrate 1) required for PI3K/AKT activation. We show that PKA directly phosphorylates the protein phosphatase 1 (PP1) regulatory subunit myosin phosphatase targeting subunit 1 (MYPT1) to activate PP1 associated with the IGF1R-IRS1 complex. Activated PP1 is sufficient to dephosphorylate at least four IRS1 Ser residues, Ser(318), Ser(346), Ser(612), and Ser(789), and promotes IRS1 YXXM phosphorylation by the IGF1R to activate the PI3K/AKT cascade. Additional experiments indicate that this mechanism also occurs in breast cancer, thyroid, and preovulatory granulosa cells, suggesting that the PKA-dependent dephosphorylation of IRS1 Ser/Thr residues is a conserved mechanism by which GPCRs signal to activate the PI3K/AKT pathway downstream of the IGF1R.

  19. Planar slot coupled microwave hybrid

    DOEpatents

    Petter, Jeffrey K.

    1991-01-01

    A symmetrical 180.degree. microwave hybrid is constructed by opening a slot line in a ground plane below a conducting strip disposed on a dielectric substrate, creating a slot coupled conductor. Difference signals propagating on the slot coupled conductor are isolated on the slot line leaving sum signals to propagate on the microstrip. The difference signal is coupled from the slot line onto a second microstrip line for transmission to a desired location. The microstrip branches in a symmetrical fashion to provide the input/output ports of the 180.degree. hybrid. The symmetry of the device provides for balance and isolation between sum and difference signals, and provides an advantageous balance between the power handling capabilities and the bandwidth of the device.

  20. Signal voter

    DOEpatents

    Goodwin, Roy L.

    1981-01-01

    A voter for providing a single accurate output signal that is derived from the closest two signal levels of three input signals, each of which signals represents a measurement of the same phenomena. By means of the voting circuit, the signals are first sorted by level of amplitude and then ranked as highest, middle or lowest. The highest or lowest signal that is furthest from the middle signal is rejected, while the other highest or lowest signal is selected for processing. The selected high or low signal is then averaged with the middle signal to provide the output signal.

  1. Signal voter

    SciTech Connect

    Goodwin, R.L.

    1981-04-28

    A voter for providing a single accurate output signal that is derived from the closest two signal levels of three input signals , each of which signals represents a measurement of the same phenomena. By means of the voting circuit, the signals are first sorted by level of amplitude and then ranked as highest, middle or lowest. The highest or lowest signal that is furthest from the middle signal is rejected, while the other highest or lowest signal is selected for processing. The selected high or low signal is then averaged with the middle signal to provide the output signal.

  2. Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell–matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis

    SciTech Connect

    Chen, Yan; Li, Zheng; He, Yan; Shang, Dandan; Pan, Jigang; Wang, Hongmei; Chen, Huamei; Zhu, Zhuxia; Wang, Xudong

    2014-03-01

    Fulvestrant (ICI 182 780, ICI) has been used in treating patients with hormone-sensitive breast cancer, yet initial or acquired resistance to endocrine therapies frequently arises and, in particular, cancer recurs as metastasis. We demonstrate here that both 17-beta-estradiol (E2) and ICI enhance cell adhesion to matrigel in MCF-7 breast cancer cells, with increased autolysis of calpain 1 (large subunit) and proteolysis of focal adhesion kinase (FAK), indicating calpain activation. Additionally, either E2 or ICI induced down-regulation of estrogen receptor α without affecting G protein coupled estrogen receptor 30 (GPR30) expression. Interestingly, GPR30 agonist G1 triggered calpain 1 autolysis but not calpain 2, whereas ER agonist diethylstilbestrol caused no apparent calpain autolysis. Furthermore, the actions of E2 and ICI on calpain and cell adhesion were tremendously suppressed by G15, or knockdown of GPR30. E2 and ICI also induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 phosphorylation by U0126 profoundly impeded calpain activation triggered by estrogenic and antiestrogenic stimulations indicating implication of ERK1/2 in the GPR30-mediated action. Lastly, the E2- or ICI-induced cell adhesion was dramatically impaired by calpain-specific inhibitors, ALLN or calpeptin, suggesting requirement of calpain in the GPR30-associated action. These data show that enhanced cell adhesion by E2 and ICI occurs via a novel GPR30-ERK1/2-calpain pathway. Our results indicate that targeting the GPR30 signaling may be a potential strategy to reduce metastasis and improve the efficacy of antiestrogens in treatment of advanced breast cancer. - Highlights: • Estrogen and ICI augment adhesion to matrigel with calpain activation in MCF-7 cells. • GPR30 mediates cell–matrigel adhesion and calpain activation via ERK1/2. • Calpain is required in the cell–matrigel adhesion induced by E2 and ICI.

  3. Inhibitory effects of omega-3 fatty acids on early brain injury after subarachnoid hemorrhage in rats: Possible involvement of G protein-coupled receptor 120/β-arrestin2/TGF-β activated kinase-1 binding protein-1 signaling pathway.

    PubMed

    Yin, Jia; Li, Haiying; Meng, Chengjie; Chen, Dongdong; Chen, Zhouqing; Wang, Yibin; Wang, Zhong; Chen, Gang

    2016-06-01

    Omega-3 fatty acids have been reported to improve neuron functions during aging and in patients affected by mild cognitive impairment, and mediate potent anti-inflammatory via G protein-coupled receptor 120 (GPR120) signal pathway. Neuron dysfunction and inflammatory response also contributed to the progression of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). This study was to examine the effects of omega-3 fatty acids on SAH-induced EBI. Two weeks before SAH, 30% Omega-3 fatty acids was administered by oral gavage at 1g/kg body weight once every 24h. Specific siRNA for GPR120 was exploited. Terminal deoxynucleotidyl transferase dUTP nick end labeling, fluoro-Jade B staining, and neurobehavioral scores and brain water content test showed that omega-3 fatty acids effectively suppressed SAH-induced brain cell apoptosis and neuronal degradation, behavioral impairment, and brain edema. Western blot, immunoprecipitation, and electrophoretic mobility shift assays results showed that omega-3 fatty acids effectively suppressed SAH-induced elevation of inflammatory factors, including cyclooxygenase-2, monocyte chemoattractant protein-1, and inducible nitric oxide synthase. In addition, omega-3 fatty acids could inhibit phosphorylation of transforming growth factor β activated kinase-1 (TAK1), MEK4, c-Jun N-terminal kinase, and IkappaB kinase as well as activation of nuclear factor kappa B through regulating GPR120/β-arrestin2/TAK1 binding protein-1 pathway. Furthermore, siRNA-induced GPR120 silencing blocked the protective effects of omega-3 fatty acids. Here, we show that stimulation of GPR120 with omega-3 fatty acids pretreatment causes anti-apoptosis and anti-inflammatory effects via β-arrestin2/TAK1 binding protein-1/TAK1 pathway in the brains of SAH rats. Fish omega-3 fatty acids as part of a daily diet may reduce EBI in an experimental rat model of SAH.

  4. Nonadiabatic Coupling

    NASA Astrophysics Data System (ADS)

    Kryachko, Eugene S.

    The general features of the nonadiabatic coupling and its relation to molecular properties are surveyed. Some consequences of the [`]equation of motion', formally expressing a [`]smoothness' of a given molecular property within the diabatic basis, are demonstrated. A particular emphasis is made on the relation between a [`]smoothness' of the electronic dipole moment and the generalized Mulliken-Hush formula for the diabatic electronic coupling.

  5. FLEXIBLE COUPLING

    DOEpatents

    Babelay, E.F.

    1962-02-13

    A flexible shaft coupling for operation at speeds in excess of 14,000 rpm is designed which requires no lubrication. A driving sleeve member and a driven sleeve member are placed in concentric spaced relationship. A torque force is transmitted to the driven member from the driving member through a plurality of nylon balls symmetrically disposed between the spaced sleeves. The balls extend into races and recesses within the respective sleeve members. The sleeve members have a suitable clearance therebetween and the balls have a suitable radial clearance during operation of the coupling to provide a relatively loose coupling. These clearances accommodate for both parallel and/or angular misalignments and avoid metal-tometal contact between the sleeve members during operation. Thus, no lubrication is needed, and a minimum of vibrations is transmitted between the sleeve members. (AEC)

  6. Prosthesis coupling

    NASA Technical Reports Server (NTRS)

    Reswick, J. B.; Mooney, V.; Bright, C. W.; Owens, L. J. (Inventor)

    1979-01-01

    A coupling for use in an apparatus for connecting a prosthesis to the bone of a stump of an amputated limb is described which permits a bio-compatible carbon sleeve forming a part of the prosthesis connector to float so as to prevent disturbing the skin seal around the carbon sleeve. The coupling includes a flexible member interposed between a socket that is inserted within an intermedullary cavity of the bone and the sleeve. A lock pin is carried by the prosthesis and has a stem portion which is adapted to be coaxially disposed and slideably within the tubular female socket for securing the prosthesis to the stump. The skin around the percutaneous carbon sleeve is able to move as a result of the flexing coupling so as to reduce stresses caused by changes in the stump shape and/or movement between the bone and the flesh portion of the stump.

  7. Signal conditioning system

    NASA Technical Reports Server (NTRS)

    Zahzah, Mohamad (Inventor); Korkosz, Gregory J. (Inventor); Bohr, Gerald (Inventor)

    2000-01-01

    A current-driven signal conditioning system comprising a first terminal, a second terminal, a strain gauge, and an instrumentation amplifier is disclosed. The strain gauge is adapted to measure a deformation of a structure and to generate a resistance which corresponds to the measured deformation. The instrumentation amplifier is adapted to be connected between the first terminal and the second terminal. The instrumentation amplifier is further adapted to be connected to the strain gauge and to place an output current on the second terminal. The output current is proportional to the resistance generated by the strain gauge. An output resister is coupled between the strain gauge and the second terminal, and a capacitor is coupled between the resister and the first terminal. A zenor diode is coupled between the first terminal and the strain gauge, and a diode is also coupled between the first terminal and the strain gauge.

  8. Nonlinear interaction of meta-atoms through optical coupling

    SciTech Connect

    Slobozhanyuk, A. P.; Kapitanova, P. V.; Filonov, D. S.; Belov, P. A.; Powell, D. A.; Shadrivov, I. V.; Kivshar, Yu. S.; Lapine, M.; McPhedran, R. C.

    2014-01-06

    We propose and experimentally demonstrate a multi-frequency nonlinear coupling mechanism between split-ring resonators. We engineer the coupling between two microwave resonators through optical interaction, whilst suppressing the direct electromagnetic coupling. This allows for a power-dependent interaction between the otherwise independent resonators, opening interesting opportunities to address applications in signal processing, filtering, directional coupling, and electromagnetic compatibility.

  9. Nucleotide signalling during inflammation

    PubMed Central

    Idzko, Marco; Ferrari, Davide; Eltzschig, Holger K.

    2014-01-01

    Inflammatory conditions are associated with the extracellular release of nucleotides, particularly ATP. In the extracellular compartment, ATP predominantly functions as a signalling molecule through the activation of purinergic P2 receptors. Metabotropic P2Y receptors are G-protein-coupled, whereas ionotropic P2X receptors are ATP-gated ion channels. Here we discuss how signalling events through P2 receptors alter the outcomes of inflammatory or infectious diseases. Recent studies implicate a role for P2X/P2Ysignalling in mounting appropriate inflammatory responses critical for host defence against invading pathogens or tumours. Conversely, P2X/P2Y signalling can promote chronic inflammation during ischaemia and reperfusion injury, inflammatory bowel disease or acute and chronic diseases of the lungs. Although nucleotide signalling has been used clinically in patients before, research indicates an expanding field of opportunities for specifically targeting individual P2 receptors for the treatment of inflammatory or infectious diseases. PMID:24828189

  10. Magic-T-Coupled Magnetrons

    NASA Technical Reports Server (NTRS)

    Dickinson, R. M.

    1985-01-01

    Outputs of two magnetrons added coherently in scheme based on resonant waveguide coupling and injection phase locking. In addition, filaments are turned off after starting. Overall effect is relatively-inexpensive, lowpower, noisy magnetrons generate clean carrier signals of higher power that ordinarily require more expensive klystrons.

  11. Tubular Coupling

    NASA Technical Reports Server (NTRS)

    Rosenbaum, Bernard J. (Inventor)

    2000-01-01

    A system for coupling a vascular overflow graft or cannula to a heart pump. A pump pipe outlet is provided with an external tapered surface which receives the end of a compressible connula. An annular compression ring with a tapered internal bore surface is arranged about the cannula with the tapered internal surface in a facing relationship to the external tapered surface. The angle of inclination of the tapered surfaces is converging such that the spacing between the tapered surfaces decreases from one end of the external tapered surface to the other end thereby providing a clamping action of the tapered surface on a cannula which increases as a function of the length of cannula segment between the tapered surfaces. The annular compression ring is disposed within a tubular locking nut which threadedly couples to the pump and provides a compression force for urging the annular ring onto the cannula between the tapered surfaces. The nut has a threaded connection to the pump body. The threaded coupling to the pump body provides a compression force for the annular ring. The annular ring has an annular enclosure space in which excess cannula material from the compression between the tapered surfaces to "bunch up" in the space and serve as an enlarged annular ring segment to assist holding the cannula in place. The clamped cannula provides a seamless joint connection to the pump pipe outlet where the clamping force is uniformly applied to the cannula because of self alignment of the tapered surfaces. The nut can be easily disconnected to replace the pump if necessary.

  12. Signaling on the endocytic pathway.

    PubMed

    McPherson, P S; Kay, B K; Hussain, N K

    2001-06-01

    Ligand binding to receptor tyrosine kinases and G-protein-coupled receptors initiates signal transduction events and induces receptor endocytosis via clathrin-coated pits and vesicles. While receptor-mediated endocytosis has been traditionally considered an effective mechanism to attenuate ligand-activated responses, more recent studies demonstrate that signaling continues on the endocytic pathway. In fact, certain signaling events, such as the activation of the extracellular signal-regulated kinases, appear to require endocytosis. Protein components of signal transduction cascades can assemble at clathrin coated pits and remain associated with endocytic vesicles following their dynamin-dependent release from the plasma membrane. Thus, endocytic vesicles can function as a signaling compartment distinct from the plasma membrane. These observations demonstrate that endocytosis plays an important role in the activation and propagation of signaling pathways.

  13. Biasing GPCR signaling from inside.

    PubMed

    Shukla, Arun K

    2014-01-28

    The discovery of "functional selectivity" or "biased signaling" through G protein-coupled receptors (GPCRs) has redefined the classical GPCR signaling paradigm. Moreover, the therapeutic potential of biased signaling by and biased ligands for GPCRs is changing the landscape of GPCR drug discovery. The concept of biased signaling has primarily been developed and discussed in the context of ligands that bind to the extracellular regions of GPCRs. However, two recent reports demonstrate that it is also possible to bias GPCR signaling from inside the cell by targeting intracellular regions of these receptors. These findings present a novel handle for delineating the functional outcomes of biased signaling by GPCRs. Moreover, these approaches also uncover a previously unexplored framework for biasing GPCR signaling for drug discovery.

  14. High temperature pressure coupled ultrasonic waveguide

    DOEpatents

    Caines, Michael J.

    1983-01-01

    A pressure coupled ultrasonic waveguide is provided to which one end may be attached a transducer and at the other end a high temperature material for continuous ultrasonic testing of the material. The ultrasonic signal is coupled from the waveguide into the material through a thin, dry copper foil.

  15. Thermoacoustic couple

    DOEpatents

    Wheatley, J.C.; Swift, G.W.; Migliori, A.

    1983-10-04

    An apparatus and method for determining acoustic power density level and its direction in a fluid using a single sensor are disclosed. The preferred embodiment of the apparatus, which is termed a thermoacoustic couple, consists of a stack of thin, spaced apart polymeric plates, selected ones of which include multiple bimetallic thermocouple junctions positioned along opposite end edges thereof. The thermocouple junctions are connected in series in the nature of a thermopile, and are arranged so as to be responsive to small temperature differences between the opposite edges of the plates. The magnitude of the temperature difference, as represented by the magnitude of the electrical potential difference generated by the thermopile, is found to be directly related to the level of acoustic power density in the gas.

  16. Dark coupling

    SciTech Connect

    Gavela, M.B.; Hernández, D.; Honorez, L. Lopez; Mena, O.; Rigolin, S. E-mail: d.hernandez@uam.es E-mail: omena@ific.uv.es

    2009-07-01

    The two dark sectors of the universe—dark matter and dark energy—may interact with each other. Background and linear density perturbation evolution equations are developed for a generic coupling. We then establish the general conditions necessary to obtain models free from non-adiabatic instabilities. As an application, we consider a viable universe in which the interaction strength is proportional to the dark energy density. The scenario does not exhibit ''phantom crossing'' and is free from instabilities, including early ones. A sizeable interaction strength is compatible with combined WMAP, HST, SN, LSS and H(z) data. Neutrino mass and/or cosmic curvature are allowed to be larger than in non-interacting models. Our analysis sheds light as well on unstable scenarios previously proposed.

  17. Signaling aggression.

    PubMed

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds.

  18. Digital Fluoroscopy with AN Optically Coupled Charge-Coupled Device

    NASA Astrophysics Data System (ADS)

    Liu, Hong

    1992-01-01

    This research was aimed at investigating the potential of developing an optically coupled charge-coupled device (CCD) imaging system for some digital fluoroscopic applications. The viability of this concept for fluoroscopic imaging was studied with respect to image intensifier-television (II -TV) techniques. The anticipated advantages of the optically coupled CCD, compared with II-TV, include higher contrast sensitivity, larger dynamic range, moderate spatial resolution and clinically acceptable dose. Following an investigation of some theoretical and practical issues concerning the optical coupling efficiency between the intensifying screen and the CCD imager, mathematical methods were developed to relate the signal, signal-to -noise ratio, and x-ray quantum efficiency of the optically coupled CCD imaging chain. The spatial resolution of the system was also analyzed. Using an ultra-sensitive CCD, as well as improved scintillating and optical coupling techniques, we built a laboratory system for experiments. We conducted measurements of the modulation transfer function (MTF), contrast sensitivity, contrast-detail detectability and detector contrast. The results suggest that the lesion detectability of our sub-optimal system was comparable to that of a screen-film technique under the same radiation dose, and was significantly better than II-TV fluoroscopy. Potential clinical applications of our system include mammography, pre-operational localization, pediatric chest radiography, and single tracer autoradiography. Images of selected phantoms, pathological specimens and small animals were acquired to demonstrate the radiologic quality attainable for such procedures. We conclude that developing an x-ray quantum limited, pseudo-real time, digital fluoroscopic imaging system (for some applications) without an II appears to be theoretically and technically feasible. The successful development of optically coupled CCD fluoroscopy has the potential for improving the

  19. Source location of the 19 February 2008 Oregon bolide using seismic networks and infrasound arrays

    NASA Astrophysics Data System (ADS)

    Walker, Kristoffer T.; Hedlin, Michael A. H.; de Groot-Hedlin, Catherine; Vergoz, Julien; Le Pichon, Alexis; Drob, Douglas P.

    2010-12-01

    On 19 February 2008 a bolide traveled across the sky along a southern trajectory ending in a terminal burst above Oregon. The event was well recorded by the USArray, other seismic networks, four infrasound arrays, and several video cameras. We compare the results of locating the burst using these different sensor networks. Specifically, we reverse time migrate acoustic-to-seismic coupled signals recorded by the USArray out to 800 km range to image the source in 2-D space and time. We also apply a grid search over source altitude and time, minimizing the misfit between observed and predicted arrival times using 3-D ray tracing with a high-resolution atmospheric velocity model. Our seismic and video results suggest a point source rather than a line source associated with a hypersonic trajectory. We compare the seismic source locations to those obtained by using different combinations of observed infrasound array signal back azimuths and arrival times. We find that all locations are consistent. However, the seismic location is more accurate than the infrasound locations due to the larger number of seismic sensors, a more favorable seismic source-receiver geometry, and shorter ranges to the seismometers. For the infrasound array locations, correcting for the wind improved the accuracy, but implementing arrival times while increasing the precision reduced the accuracy presumably due to limitations of the source location method and/or atmospheric velocity model. We show that despite known complexities associated with acoustic-to-seismic coupling, aboveground infrasound sources can be located with dense seismic networks with remarkably high accuracy and precision.

  20. Discrete signal transduction pathway utilization by a neuropeptide (PACAP) and a cytokine (TNF-alpha) first messenger in chromaffin cells, inferred from coupled transcriptome-promoter analysis of regulated gene cohorts.

    PubMed

    Samal, Babru; Ait-Ali, Djida; Bunn, Stephen; Mustafa, Tomris; Eiden, Lee E

    2013-07-01

    Cultured bovine adrenal chromaffin cells (BCCs) are employed to study first messenger-specific signaling by cytokines and neurotransmitters occurring in the adrenal medulla following immune-related stress responses. Here, we show that the cytokine TNF-alpha, and the neuropeptide transmitter PACAP, acting through the TNFR2 and PAC1 receptors, activate distinct signaling pathways, with correspondingly distinct transcriptomic signatures in chromaffin cells. We have carried out a comprehensive integrated transcriptome analysis of TNF-alpha and PACAP gene regulation in BCCs using two microarray platforms to maximize transcript identification. Microarray data were validated using qRT-PCR. More than 90% of the transcripts up-regulated either by TNF-alpha or PACAP were specific to a single first messenger. The final list of transcripts induced by each first messenger was subjected to multiple algorithms to identify promoter/enhancer response elements for trans-acting factors whose activation could account for gene expression by either TNF-alpha or PACAP. Distinct groups of transcription factors potentially controlling the expression of TNF-alpha or PACAP-responsive genes were found: most of the genes up-regulated by TNF-alpha contained transcription factor binding sites for members of the Rel transcription factor family, suggesting TNF-alpha-TNFR2 signaling occurs mainly through the NF-KB signaling pathway. Surprisingly, EGR1 was predicted to be the primary transcription factor controlling PACAP-modulated genes, suggesting PACAP signaling to the nucleus occurs predominantly through ERK, rather than CREB activation. Comparison of TNFR2-dependent versus TNFR1-dependent gene induction, and EGR1-mediated transcriptional activation, may provide a pharmacological avenue to the unique pathways activated by the first messengers TNF-alpha and PACAP in neuronal and endocrine cells.

  1. Signal Words

    MedlinePlus

    ... product. The signal word can be ei- ther: DANGER,WARNING or CAUTION. Products with the DANGER signal word are the most toxic. Products with ... causes moderate eye or skin irritation. 2,4 DANGER means that the pesticide product is highly toxic ...

  2. Comparison of an Analytical and Numerical Solution for the Landmine Detection Problem

    DTIC Science & Technology

    2008-10-01

    frequency and c is the sound speed in the medium. Morse and Ingard 3 argue that modifications are necessary for sound transmission in a porous...landmine detection using acoustic to seismic coupling, J. Acoust. Soc. Am., 115(5), 1993-2002 (2004) 3. P. Morse and K. Ingard , Theoretical

  3. Calcium in plant defence-signalling pathways.

    PubMed

    Lecourieux, David; Ranjeva, Raoul; Pugin, Alain

    2006-01-01

    In plant cells, the calcium ion is a ubiquitous intracellular second messenger involved in numerous signalling pathways. Variations in the cytosolic concentration of Ca2+ ([Ca2+]cyt) couple a large array of signals and responses. Here we concentrate on calcium signalling in plant defence responses, particularly on the generation of the calcium signal and downstream calcium-dependent events participating in the establishment of defence responses with special reference to calcium-binding proteins.

  4. Calcium signaling and cytotoxicity.

    PubMed Central

    Kass, G E; Orrenius, S

    1999-01-01

    The divalent calcium cation Ca(2+) is used as a major signaling molecule during cell signal transduction to regulate energy output, cellular metabolism, and phenotype. The basis to the signaling role of Ca(2+) is an intricate network of cellular channels and transporters that allow a low resting concentration of Ca(2+) in the cytosol of the cell ([Ca(2+)]i) but that are also coupled to major dynamic and rapidly exchanging stores. This enables extracellular signals from hormones and growth factors to be transduced as [Ca(2+)]i spikes that are amplitude and frequency encoded. There is considerable evidence that a number of toxic environmental chemicals target these Ca(2+) signaling processes, alter them, and induce cell death by apoptosis. Two major pathways for apoptosis will be considered. The first one involves Ca(2+)-mediated expression of ligands that bind to and activate death receptors such as CD95 (Fas, APO-1). In the second pathway, Ca(2+) has a direct toxic effect and its primary targets include the mitochondria and the endoplasmic reticulum (ER). Mitochondria may respond to an apoptotic Ca(2+) signal by the selective release of cytochrome c or through enhanced production of reactive oxygen species and opening of an inner mitochondrial membrane pore. Toxic agents such as the environmental pollutant tributyltin or the natural plant product thapsigargin, which deplete the ER Ca(2+) stores, will induce as a direct result of this effect the opening of plasma membrane Ca(2+) channels and an ER stress response. In contrast, under some conditions, Ca(2+) signals may be cytoprotective and antagonize the apoptotic machinery. Images Figure 1 Figure 2 Figure 3 PMID:10229704

  5. Pituitary Somatostatin Receptor Signaling

    PubMed Central

    Ben-Shlomo, Anat; Melmed, Shlomo

    2010-01-01

    Somatostatin (SRIF) is a major regulator of pituitary function, mostly inhibiting hormone secretion and to a lesser extent pituitary cell growth. Five SRIF receptor subtypes (SSTR1–5) are ubiquitously expressed G-protein coupled receptors. In the pituitary, SSTR1, SSTR2, SSTR3 and SSTR5 are expressed, with SSTR2 and SSTR5 predominating. As new SRIF-analogs have recently been introduced for treatment of pituitary disease, we evaluate the current knowledge of cell-specific pituitary SRIF receptor signaling and highlight areas of future research for comprehensive understanding of these mechanisms. Elucidating pituitary SRIF receptor signaling enables understanding of pituitary hormone secretion and cell growth, and also points to future therapeutic development for pituitary disorders. PMID:20149677

  6. Contextual signaling in cancer.

    PubMed

    Smithson, Laura J; Anastasaki, Corina; Chen, Ran; Toonen, Joseph A; Williams, Sidney B; Gutmann, David H

    2016-10-01

    The formation and maintenance of an organism are highly dependent on the orderly control of cell growth, differentiation, death, and migration. These processes are tightly regulated by signaling cascades in which a limited number of molecules dictate these cellular events. While these signaling pathways are highly conserved across species and cell types, the functional outcomes that result from their engagement are specified by the context in which they are activated. Using the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome as an illustrative platform, we discuss how NF1/RAS signaling can create functional diversity at multiple levels (molecular, cellular, tissue, and genetic/genomic). As such, the ability of related molecules (e.g., K-RAS, H-RAS) to activate distinct effectors, as well as cell type- and tissue-specific differences in molecular composition and effector engagement, generate numerous unique functional effects. These variations, coupled with a multitude of extracellular cues and genomic/genetic changes that each modify the innate signaling properties of the cell, enable precise control of cellular physiology in both health and disease. Understanding these contextual influences is important when trying to dissect the underlying pathogenic mechanisms of cancer relevant to molecularly-targeted therapeutics.

  7. Signaling by Sensory Receptors

    PubMed Central

    Julius, David; Nathans, Jeremy

    2012-01-01

    Sensory systems detect small molecules, mechanical perturbations, or radiation via the activation of receptor proteins and downstream signaling cascades in specialized sensory cells. In vertebrates, the two principal categories of sensory receptors are ion channels, which mediate mechanosensation, thermosensation, and acid and salt taste; and G-protein-coupled receptors (GPCRs), which mediate vision, olfaction, and sweet, bitter, and umami tastes. GPCR-based signaling in rods and cones illustrates the fundamental principles of rapid activation and inactivation, signal amplification, and gain control. Channel-based sensory systems illustrate the integration of diverse modulatory signals at the receptor, as seen in the thermosensory/pain system, and the rapid response kinetics that are possible with direct mechanical gating of a channel. Comparisons of sensory receptor gene sequences reveal numerous examples in which gene duplication and sequence divergence have created novel sensory specificities. This is the evolutionary basis for the observed diversity in temperature- and ligand-dependent gating among thermosensory channels, spectral tuning among visual pigments, and odorant binding among olfactory receptors. The coding of complex external stimuli by a limited number of sensory receptor types has led to the evolution of modality-specific and species-specific patterns of retention or loss of sensory information, a filtering operation that selectively emphasizes features in the stimulus that enhance survival in a particular ecological niche. The many specialized anatomic structures, such as the eye and ear, that house primary sensory neurons further enhance the detection of relevant stimuli. PMID:22110046

  8. Coupled heterocellular arrays in the brain.

    PubMed

    Fróes, M M; Menezes, J R L

    2002-11-01

    Gap junctions are transcellular pathways that enable a dynamic metabolic coupling and a selective exchange of biological signaling mediators. Throughout the course of the brain development these intercellular channels are assembled into regionally and temporally defined patterns. The present review summarizes the possibilities of heterocellular gap junctional pairing in the brain parenchyma, involving glial cells, neurons and neural precursors as well as it highlights on the meaningfulness of these coupled arrays to the concept of brain functional compartments.

  9. Electrical coupling in multi-array charge coupled devices

    NASA Astrophysics Data System (ADS)

    Singh, Parul; Sakarvadiya, Vishal; Dubey, Neeraj; Kirkire, Shweta; Thapa, Nitesh; Banerjee, Arup

    2016-05-01

    Silicon based charge coupled device (CCD) performances have improved immensely over the years. Scientific community across the globe target challenging remote sensing applications with CCD as optical imaging detector. Over the years, both pixel count (from few hundreds to few tens of thousands) and line readout rate (from few kHz to few tens of kHz) have increased considerably. Pixels are readout using a large number of output ports driven up to few tens of MHz Moreover, for multi-spectral applications, same Si die contains multiple arrays sharing input stimuli. This is usually done to optimize package pin count. Si die as well as package level layout of clock and bias lines become critical for closely spaced multi-array devices. The inter-array separation may go down to few hundreds of microns when filter coating is laid on top of the die. Die level layout becomes quite critical for devices with such architecture. The inter-array (consecutive arrays) separation is optimized to reduce optical coupling / stray light in devices integrated multi-band strip filter. Layout constraints along with shared bias/clock lines are known to produce electrical cross-talk or coupling. Effect of this (within one array or between two arrays) cross-talk is more pronounced in systems having low noise floor. Video signal dependent coupling in a multi-port system becomes quite complex and leads to a relatively noisier system (post correction). The paper presents results of simulations and tests (pre and post correction) addressing this type of electrical coupling. The paper presents cause, impact and possible remedial measures to minimize such coupling in a multi-array, multi-port TDI CCD from 1.3% to below 0.06%.

  10. The ROS-mediated pathway coupled with the MAPK-p38 signalling pathway and antioxidant system plays roles in the responses of Mytilus edulis haemocytes induced by BDE-47.

    PubMed

    Jiang, Yongshun; Tang, Xuexi; Zhou, Bin; Sun, Tianli; Chen, Hongmei; Zhao, Xinyu; Wang, You

    2017-03-18

    Our previous study found that BDE-47 could change the immune function of haemocytes in Mytilus edulis, and reactive oxygen species (ROS) might be involved in the process of physiological alteration. Here, we aimed to better understand this relationship. To accomplish this, we analysed changes in different ROS as well as various antioxidant system components. Additionally, the expression of MAPK-p38, a signalling protein regulated by ROS that helps to regulate numerous cellular processes, was also analysed. BDE-47 was given at low, medium, and high amounts. The results showed that (1) BDE-47 significantly affected ROS component levels in haemocytes. O2(-) content was increased under all conditions. H2O2 content was also increased under all conditions, except in the middle concentration group. In contrast, OH content was increased in the low and middle concentration groups and decreased in the high concentration group. (2) Estimations of the antioxidant systems revealed concentration-dependent changes. Catalase activity was increased throughout the experiment, while superoxide dismutase (SOD) exhibited a decreasing trend in the tested groups with an increase of exposure time. On day 21, only the high concentration group showed a slight increase in SOD activity compared to the control. Furthermore, glutathione peroxidase and glutathione reductase activity increased in the low and middle concentration groups but decreased in the high concentration group. The GSH/GSSG ratio increased for all treatments over time, indicating that changes in redox status occurred. (3) MAPK-p38 was activated following BDE-47 exposure. Based on our previous study, we speculate that BDE-47 exposure induces ROS production and affects the ROS-mediated pathway, which may explain the resultant functional damage observed in haemocytes. Furthermore, BDE-47 also affected the antioxidant system and altered redox status, although these changes did not ameliorate the damage caused by ROS.

  11. Bradykinin-activated transmembrane signals are coupled via N/sub o/ or N/sub i/ to production of inositol 1,4,5-trisphosphate, a second messenger in NG108-15 neuroblastoma-glioma hybrid cells

    SciTech Connect

    Higashida, H.; Streaty, R.A.; Klee, W.; Nirenberg, M.

    1986-02-01

    The addition of bradykinin to NG108-15 cells results in a transient hyperpolarization followed by prolonged cell depolarization. Injection of inositol 1,4,5-trisphosphate or CaS into the cytoplasm of NG108-15 cells also elicits cell hyperpolarization followed by depolarization. Tetraethylammonium ions inhibit the hyperpolarizing response of cells to bradykinin or inositol 1,4,5-trisphosphate. Thus, the hyperpolarizing phase of the cell response may be due to inositol 1,4,5-trisphosphate-dependent release of stored UVCa-labelled CaS into the cytoplasm, which activates CaS -dependent K channels. The depolarizing phase of the cell response to bradykinin is due largely to inhibition of M channels, thereby decreasing the rate of K efflux from cells and, to a lesser extent, to activation of CaS -dependent ion channels and CaS channels. In contrast, injection of inositol 1,4,5-trisphosphate or CaS into the cytosol did not alter M channel activity. Incubation of NG108-15 cells with pertussis toxin inhibits bradykinin-dependent cell hyperpolarization and depolarization. Bradykinin stimulates low K/sub m/ GTPase activity and inhibits adenylate cyclase in NG108-15 membrane preparations but not in membranes prepared from cells treated with pertussis toxin. These results show that (bradykinin-receptor) complexes interact with N/sub o/ or N/sub i/ and suggest that N/sub o/ and/or N/sub i/ mediate the transduction of signals from bradykinin receptors to phospholipase C and adenylate cyclase.

  12. Neurovascular coupling: a parallel implementation

    PubMed Central

    Dormanns, Katharina; Brown, Richard G.; David, Tim

    2015-01-01

    A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K+ and the smooth muscle cell (SMC) Ca2+ pathway termed a neurovascular unit (NVU). Luminal agonists acting on P2Y receptors on the endothelial cell (EC) surface provide a flux of inositol trisphosphate (IP3) into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between EC and SMC providing a source of sarcoplasmic derived Ca2+ in the SMC. The model is able to relate a neuronal input signal to the corresponding vessel reaction (contraction or dilation). A tissue slice consisting of blocks, each of which contain an NVU is connected to a space filling H-tree, simulating a perfusing arterial tree (vasculature) The model couples the NVUs to the vascular tree via a stretch mediated Ca2+ channel on both the EC and SMC. The SMC is induced to oscillate by increasing an agonist flux in the EC and hence increased IP3 induced Ca2+ from the SMC stores with the resulting calcium-induced calcium release (CICR) oscillation inhibiting NVC thereby relating blood flow to vessel contraction and dilation following neuronal activation. The coupling between the vasculature and the set of NVUs is relatively weak for the case with agonist induced where only the Ca2+ in cells inside the activated area becomes oscillatory however, the radii of vessels both inside and outside the activated area oscillate (albeit small for those outside). In addition the oscillation profile differs between coupled and decoupled states with the time required to refill the cytosol with decreasing Ca2+ and increasing frequency with coupling. The solution algorithm is shown to have excellent weak and strong scaling. Results have been generated for tissue slices containing up to 4096 blocks. PMID:26441619

  13. Pharmacology of intracellular signalling pathways

    PubMed Central

    Nahorski, Stefan R

    2006-01-01

    This article provides a brief and somewhat personalized review of the dramatic developments that have occurred over the last 45 years in our understanding of intracellular signalling pathways associated with G-protein-coupled receptor activation. Signalling via cyclic AMP, the phosphoinositides and Ca2+ is emphasized and these systems have already been revealed as new pharmacological targets. The therapeutic benefits of most of such targets are, however, yet to be realized, but it is certain that the discipline of pharmacology needs to widen its boundaries to meet these challenges in the future. PMID:16402119

  14. Signal Processing

    DTIC Science & Technology

    1989-03-01

    ORGANIZATION Univ of Minnesota (f*fto U. S. Army Research Office 6c. ADDRESS (City, State, and ZIP Code) 7b. ADDRESS (Wiy Stat, and ZIP Code...Minneapolis, MN 55455 P. 0. Box 12211 Research Triangle Park, NC 27709-2211 Sa. NAME Of FUNDING ISPONSORING Sb. OFFICE SYMBOL 9. PROCUREMENT INSTRUMENT...PROJECT ITASK jWORK UNIT Research Triangle Park, NC 27709-2211 EMNTO.I NO NO CESOIO 11. TITLE (Incudt Security Classifiratio") Signal Processing of, he auth

  15. Signal processing

    NASA Astrophysics Data System (ADS)

    Norman, David M.

    The application of signal processing technology to conventional weapons systems can lower operator workloads and enhance kill probabilities, while automating wide-area surveillance, target search and classification, target tracking, and aimpoint selection. Immediate opportunities exist for automatic target cueing in underwater and over-the-horizon targeting, as well as for airborne multiple-target fire control. By embedding the transit/receive electronics into conformal aircraft sensor arrays, a 'smart' skin can be created. Electronically scanned phased arrays can be used to yield accurate azimuthal and elevation positions while nullifying EW threats. Attention is given to major development thrusts in algorithm design.

  16. Inductively coupled wireless RF coil arrays.

    PubMed

    Bulumulla, S B; Fiveland, E; Park, K J; Foo, T K; Hardy, C J

    2015-04-01

    As the number of coils increases in multi-channel MRI receiver-coil arrays, RF cables and connectors become increasingly bulky and heavy, degrading patient comfort and slowing workflow. Inductive coupling of signals provides an attractive "wireless" approach, with the potential to reduce coil weight and cost while simplifying patient setup. In this work, multi-channel inductively coupled anterior arrays were developed and characterized for 1.5T imaging. These comprised MR receiver coils inductively (or "wirelessly") linked to secondary or "sniffer" coils whose outputs were transmitted via preamps to the MR system cabinet. The induced currents in the imaging coils were blocked by passive diode circuits during RF transmit. The imaging arrays were totally passive, obviating the need to deliver power to the coils, and providing lightweight, untethered signal reception with easily positioned coils. Single-shot fast spin echo images were acquired from 5 volunteers using a 7-element inductively coupled coil array and a conventionally cabled 7-element coil array of identical geometry, with the inductively-coupled array showing a relative signal-to-noise ratio of 0.86 +/- 0.07. The concept was extended to a larger 9-element coil array to demonstrate the effect of coil element size on signal transfer and RF-transmit blocking.

  17. Signalling properties of lysophosphatidic acid.

    PubMed

    Durieux, M E; Lynch, K R

    1993-06-01

    Lysophosphatidic acid (LPA) is the simplest natural phospholipid, primarily known as a membrane component and metabolic intermediate. However, a remarkable variety of biological effects of this compound have come to light, seemingly pointing to an additional role for LPA as a signalling molecule. In this review, Marcel Durieux and Kevin Lynch integrate the recent information that indicates that LPA could be an intercellular messenger, possibly acting through a G protein-coupled receptor, and with a role in cell growth and motility.

  18. Couple communication in stepfamilies.

    PubMed

    Halford, Kim; Nicholson, Jan; Sanders, Matthew

    2007-12-01

    Effective communication is assumed to help sustain couple relationships and is a key focus of most relationship education programs. We assessed couple problem-solving communication in 65 stepfamily and 52 first-time-marrying couples, with each group stratified into high risk and low risk for relationship problems based on family-of-origin experiences. Relative to partners in first-time couples, partners in stepfamily couples were less positive, less negative, and more likely to withdraw from discussion. Risk was associated with communication in first-time but not stepfamily couples. Stepfamily couples do not exhibit the negative communication evident in high-risk first-time-marrying couples, and available relationship education programs that focus on reducing negative communication are unlikely to meet the needs of stepfamilies.

  19. Synchronization of coupled Boolean phase oscillators

    NASA Astrophysics Data System (ADS)

    Rosin, David P.; Rontani, Damien; Gauthier, Daniel J.

    2014-04-01

    We design, characterize, and couple Boolean phase oscillators that include state-dependent feedback delay. The state-dependent delay allows us to realize an adjustable coupling strength, even though only Boolean signals are exchanged. Specifically, increasing the coupling strength via the range of state-dependent delay leads to larger locking ranges in uni- and bidirectional coupling of oscillators in both experiment and numerical simulation with a piecewise switching model. In the unidirectional coupling scheme, we unveil asymmetric triangular-shaped locking regions (Arnold tongues) that appear at multiples of the natural frequency of the oscillators. This extends observations of a single locking region reported in previous studies. In the bidirectional coupling scheme, we map out a symmetric locking region in the parameter space of frequency detuning and coupling strength. Because of the large scalability of our setup, our observations constitute a first step towards realizing large-scale networks of coupled oscillators to address fundamental questions on the dynamical properties of networks in a new experimental setting.

  20. Collider Signal I :. Resonance

    NASA Astrophysics Data System (ADS)

    Tait, Tim M. P.

    2010-08-01

    These TASI lectures were part of the summer school in 2008 and cover the collider signal associated with resonances in models of physics beyond the Standard Model. I begin with a review of the Z boson, one of the best-studied resonances in particle physics, and review how the Breit-Wigner form of the propagator emerges in perturbation theory and discuss the narrow width approximation. I review how the LEP and SLAC experiments could use the kinematics of Z events to learn about fermion couplings to the Z. I then make a brief survey of models of physics beyond the Standard Model which predict resonances, and discuss some of the LHC observables which we can use to discover and identify the nature of the BSM physics. I finish up with a discussion of the linear moose that one can use for an effective theory description of a massive color octet vector particle.

  1. Mutual Coupling Compensation on Spectral-based DOA Algorithm

    NASA Astrophysics Data System (ADS)

    Sanudin, R.

    2016-11-01

    Direction of arrival (DOA) estimation using isotropic antenna arrays are commonly being implemented without considering the mutual coupling effect in between the array elements. This paper presents an analysis of DOA estimation with mutual coupling compensation using a linear antenna array. Mutual coupling effect is represented by mutual coupling coefficients and taken into account when calculating the array output. The mutual coupling compensation technique exploits a banded mutual coupling matrix to reduce the computational complexity. The banded matrix reflects the relationship between mutual coupling effect and the element spacing in an antenna array. The analysis is being carried out using the Capon algorithm, one of spectral-based DOA algorithms, for estimating the DOA of incoming signals. Computer simulations are performed to show the performance of the mutual coupling compensation technique on DOA estimation. Simulation results show that, in term of estimation resolution, the mutual coupling compensation technique manages to obtain a comparable results compared to the case without mutual coupling consideration. However, the mutual coupling compensation technique produces significant estimation error compared to the case without mutual coupling. The study concludes that the banded matrix of mutual coupling coefficients should be properly designed to improve the performance of mutual coupling compensation technique in DOA estimation.

  2. Simultaneous Continuous Wave Signals

    DTIC Science & Technology

    2015-09-30

    signals are transmitted from a source and incident signals are received at a receiver for processing . The processed signals provide...in Doppler resolution. This is because the narrowband signal can be filtered from the other signals and processed as if it was sent alone. [0011... signals are filtered to separate narrowband and broadband incident signals before processing each signal type. The incident signals may then be used

  3. Optical filter having coupled whispering-gallery-mode resonators

    NASA Technical Reports Server (NTRS)

    Savchenkov, Anatoliy (Inventor); Ilchenko, Vladimir (Inventor); Maleki, Lutfollah (Inventor); Handley, Timothy A. (Inventor)

    2006-01-01

    Optical filters having at least two coupled whispering-gallery-mode (WGM) optical resonators to produce a second order or higher order filter function with a desired spectral profile. At least one of the coupled WGM optical resonators may be tunable by a control signal to adjust the filtering function.

  4. Toroid Joining Gun For Fittings And Couplings

    NASA Technical Reports Server (NTRS)

    Fox, Robert L.; Swaim, Robert J.; Johnson, Samuel D.; Buckley, John D.; Copeland, Carl E.; Coultrip, Robert H.; Johnston, David F.; Phillips, William M.

    1992-01-01

    Hand-held gun used to join metal heat-to-shrink couplings. Uses magnetic induction (eddy currents) to produce heat in metal coupling, and thermocouple to measure temperature and signals end of process. Gun, called "toroid joining gun" concentrates high levels of heat in localized areas. Reconfigured for use on metal heat-to-shrink fitting and coupling applications. Provides rapid heating, operates on low power, lightweight and portable. Safe for use around aircraft fuel and has no detrimental effects on surrounding surfaces or objects. Reliable in any environment and under all weather conditions. Gun logical device for taking full advantage of capabilities of new metal heat-to-shrink couplings and fittings.

  5. Conduction-coupled Tesla transformer.

    PubMed

    Reed, J L

    2015-03-01

    A proof-of-principle Tesla transformer circuit is introduced. The new transformer exhibits the high voltage-high power output signal of shock-excited transformers. The circuit, with specification of proper circuit element values, is capable of obtaining extreme oscillatory voltages. The primary and secondary portions of the circuit communicate solely by conduction. The destructive arcing between the primary and secondary inductors in electromagnetically coupled transformers is ubiquitous. Flashover is eliminated in the new transformer as the high-voltage inductors do not interpenetrate and so do not possess an annular volume of electric field. The inductors are remote from one another. The high voltage secondary inductor is isolated in space, except for a base feed conductor, and obtains earth by its self-capacitance to the surroundings. Governing equations, for the ideal case of no damping, are developed from first principles. Experimental, theoretical, and circuit simulator data are presented for the new transformer. Commercial high-temperature superconductors are discussed as a means to eliminate the counter-intuitive damping due to small primary inductances in both the electromagnetic-coupled and new conduction-coupled transformers.

  6. Calcium signalling in diabetes.

    PubMed

    Guerrero-Hernandez, Agustin; Verkhratsky, Alexei

    2014-11-01

    Molecular cascades responsible for Ca(2+) homeostasis and Ca(2+) signalling could be assembled in highly plastic toolkits that define physiological adaptation of cells to the environment and which are intimately involved in all types of cellular pathology. Control over Ca(2+) concentration in different cellular compartments is intimately linked to cell metabolism, because (i) ATP production requires low Ca(2+), (ii) Ca(2+) homeostatic systems consume ATP and (iii) Ca(2+) signals in mitochondria stimulate ATP synthesis being an essential part of excitation-metabolic coupling. The communication between the ER and mitochondria plays an important role in this metabolic fine tuning. In the insulin resistance state and diabetes this communication has been impaired leading to different disorders, for instance, diminished insulin production by pancreatic β cells, reduced heart and skeletal muscle contractility, reduced NO production by endothelial cells, increased glucose production by liver, increased lipolysis by adipose cells, reduced immune responses, reduced cognitive functions, among others. All these processes eventually trigger degenerative events resulting in overt diabetes due to reduction of pancreatic β cell mass, and different complications of diabetes, such as retinopathy, nephropathy, neuropathy, and different cardiovascular diseases.

  7. Urothelial Signaling

    PubMed Central

    Andersson, Karl-Erik

    2013-01-01

    The urothelium, which lines the inner surface of the renal pelvis, the ureters, and the urinary bladder, not only forms a high-resistance barrier to ion, solute and water flux, and pathogens, but also functions as an integral part of a sensory web which receives, amplifies, and transmits information about its external milieu. Urothelial cells have the ability to sense changes in their extracellular environment, and respond to chemical, mechanical and thermal stimuli by releasing various factors such as ATP, nitric oxide, and acetylcholine. They express a variety of receptors and ion channels, including P2X3 purinergic receptors, nicotinic and muscarinic receptors, and TRP channels, which all have been implicated in urothelial-neuronal interactions, and involved in signals that via components in the underlying lamina propria, such as interstitial cells, can be amplified and conveyed to nerves, detrusor muscle cells, and ultimately the central nervous system. The specialized anatomy of the urothelium and underlying structures, and the possible communication mechanisms from urothelial cells to various cell types within the bladder wall are described. Changes in the urothelium/lamina propria (“mucosa”) produced by different bladder disorders are discussed, as well as the mucosa as a target for therapeutic interventions. PMID:23589830

  8. Radio frequency coupling apparatus and method for measuring minority carrier lifetimes in semiconductor materials

    DOEpatents

    Johnston, Steven W.; Ahrenkiel, Richard K.

    2002-01-01

    An apparatus for measuring the minority carrier lifetime of a semiconductor sample using radio-frequency coupling. The measuring apparatus includes an antenna that is positioned a coupling distance from a semiconductor sample which is exposed to light pulses from a laser during sampling operations. A signal generator is included to generate high frequency, such as 900 MHz or higher, sinusoidal waveform signals that are split into a reference signal and a sample signal. The sample signal is transmitted into a sample branch circuit where it passes through a tuning capacitor and a coaxial cable prior to reaching the antenna. The antenna is radio-frequency coupled with the adjacent sample and transmits the sample signal, or electromagnetic radiation corresponding to the sample signal, to the sample and receives reflected power or a sample-coupled-photoconductivity signal back. To lower impedance and speed system response, the impedance is controlled by limiting impedance in the coaxial cable and the antenna reactance. In one embodiment, the antenna is a waveguide/aperture hybrid antenna having a central transmission line and an adjacent ground flange. The sample-coupled-photoconductivity signal is then transmitted to a mixer which also receives the reference signal. To enhance the sensitivity of the measuring apparatus, the mixer is operated to phase match the reference signal and the sample-coupled-photoconductivity signal.

  9. Investigation of Charge Coupled Devices for Signal Processing.

    DTIC Science & Technology

    1980-12-01

    capacitor biased into inversion range but neglecting the interface edge effect to be illustrated in Fig.5.5. . 31 5.4 Lumped equivalent circuit model...Complete and simplifed equivalent circuit models for n-type MOS capacitor in inversion with interface edge effect . (a) Two-dimensional model. (b), (c...device is biased into inversion and the interface edge effect is neglected, the equivalent circuit of Figure 3.1 can be 29 OXIDE 1 BULK SEMICONDUCTOR

  10. Diffusible Driving and Coupling Signals of the Biological Clock

    DTIC Science & Technology

    1993-05-18

    349-374, Oxford University Press , New York. Majzoub, J.A., B.C. Robinson, and R.L. Emanuel (1991) Suprachiasmatic nuclear rhythms of vasopressin mRNA in...vivo. In: The Suprachiasmatic Nucleus: The Mind’s Clock. D.C. Klein, R.Y. Moore, S.M. Reppert, Eds. pp. 177-190, Oxford University Press , New York...control of circadian rhythms. In: The Suprachiasmatic Nucleus: The Mind’s Clock. D.C. Klein, R.Y. Moore, S.M. Reppert, Eds. pp. 77-106, Oxford University Press , New

  11. The LSR/2 Optically Coupled Signal Transmission Link.

    DTIC Science & Technology

    1979-12-01

    OPTICAL SCI DIV ATTN DYR, R&D DIV WASHINGTON, DC 20375 ATTN XO, DIR TEST ARNOLD AIR FORCE STATION, TN 37389 COMMANDER NAVAL SEA SYSTEMS COMMAND HQ DIRECTOR...AIRCRAFT COMPANY SCIENCE APPLICATIONS, INC. ATTN R. BLAIR ATTN P. MILLER MALIBU CANYON ROAD 1257 TASMAN DRIVE MALIBU, CA 90265 SUNNYVALE, CA 94086 24

  12. Coupling of Hyperband Signals with an Underground Cable

    NASA Astrophysics Data System (ADS)

    Sunitha, K.; Thomas, M. Joy; Giri, D. V.

    This is an adaptation of Interaction Notes 612. The Impulse Radiating Antennae (IRA) find immense applications in the military and civilian domains. These antennae are of reflector-type geometry. The interference caused on underground cables due to electromagnetic fields from IRA is an interesting subject of study. The determination of the induced current and voltage on a cable when it gets illuminated by an IRA will give the intensity of the interference. Prior to the computation of induced parameters, the radiated electromagnetic fields from an IRA are determined both in the near-field and in the far-field regions.

  13. Automatic Alignment Fiber Optic Coupling System for Optimal Signal Transmission

    DTIC Science & Technology

    2014-03-01

    Devices Packaging,” Proc. of the 2005 IEEE International Conference on Mechatronics , July 10-12, Taiwan, 2005. [3] C.L. Chang, C.Y. Tseng, and J.P...Conference on Mechatronics and Automation, June 25-28, China, 2006. 5f. WORK UNIT NUMBER REPORT DOCUMENTATION PAGE Form Approved OMB No. 0704-01-0188

  14. Device and method for redirecting electromagnetic signals

    DOEpatents

    Garcia, Ernest J.

    1999-01-01

    A device fabricated to redirect electromagnetic signals, the device including a primary driver adapted to provide a predetermined force, a linkage system coupled to the primary driver, a pusher rod rotationally coupled to the linkage system, a flexible rod element attached to the pusher rod and adapted to buckle upon the application of the predetermined force, and a mirror structure attached to the flexible rod element at one end and to the substrate at another end. When the predetermined force buckles the flexible rod element, the mirror structure and the flexible rod element both move to thereby allow a remotely-located electromagnetic signal directed towards the device to be redirected.

  15. Advanced Digital Signal Processing for Hybrid Lidar

    DTIC Science & Technology

    2014-10-30

    was moved in 10 cm increments from a range of 1.35 m to 3.05 m. The photomultiplier tube ( PMT ) collected light scattered from the submerged target...through the window. A bias-tee at the output of the PMT separated the DC and AC components of the photocurrent. The DC-coupled signal was monitored on a...multimeter to ensure that the PMT remained within its linear operating region. The AC-coupled signal was demodulated and digitized in the software

  16. Advanced Digital Signal Processing for Hybrid Lidar

    DTIC Science & Technology

    2014-09-30

    The target was moved in 10 cm increments from a range of 1.35 m to 3.05 m. The photomultiplier tube ( PMT ) collected light scattered from the...submerged target through the window. A bias-tee at the output of the PMT separated the DC and AC components of the photocurrent. The DC-coupled signal was...monitored on a multimeter to ensure that the PMT remained within its linear operating region. The AC-coupled signal was demodulated and digitized in

  17. Classical and quantum distinctions between weak and strong coupling

    NASA Astrophysics Data System (ADS)

    Rahimzadeh-Kalaleh Rodriguez, Said

    2016-03-01

    Coupled systems subject to dissipation exhibit two different regimes known as weak coupling and strong coupling. Two damped coupled harmonic oscillators (CHOs) constitute a model system where the key features of weak and strong coupling can be identified. Several of these features are common to classical and quantum systems, as a number of quantum-classical correspondences have shown. However, the condition defining the boundary between weak and strong coupling is distinct in classical and quantum formalisms. Here we describe the origin of two widely used definitions of strong coupling. Using a classical CHO model, we show that energy exchange cycles and avoided resonance crossings signal the onset of strong coupling according to one criterion. From the classical CHO model we derive a non-Hermitian Hamiltonian describing open quantum systems. Based on the analytic properties of the Hamiltonian, we identify the boundary between weak and strong coupling with a different feature: a non-Hermitian degeneracy known as the exceptional point. For certain parameter ranges the classical and quantum criterion for strong coupling coincide; for other ranges they do not. Examples of systems in strong coupling according to one or another criterion, but not both, are illustrated. The framework here presented is suitable for introducing graduate or advanced undegraduate students to the basic properties of strongly coupled systems, as well as to the similarities and subtle differences between classical and quantum descriptions of coupled dissipative systems.

  18. 49 CFR 236.509 - Two or more locomotives coupled.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RULES, STANDARDS, AND INSTRUCTIONS GOVERNING THE INSTALLATION... Train Stop, Train Control and Cab Signal Systems Standards § 236.509 Two or more locomotives coupled. The automatic train stop, train control or cab signal apparatus shall be arranged so that when two...

  19. 49 CFR 236.509 - Two or more locomotives coupled.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RULES, STANDARDS, AND INSTRUCTIONS GOVERNING THE INSTALLATION... Train Stop, Train Control and Cab Signal Systems Standards § 236.509 Two or more locomotives coupled. The automatic train stop, train control or cab signal apparatus shall be arranged so that when two...

  20. 49 CFR 236.509 - Two or more locomotives coupled.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RULES, STANDARDS, AND INSTRUCTIONS GOVERNING THE INSTALLATION... Train Stop, Train Control and Cab Signal Systems Standards § 236.509 Two or more locomotives coupled. The automatic train stop, train control or cab signal apparatus shall be arranged so that when two...

  1. 49 CFR 236.509 - Two or more locomotives coupled.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RULES, STANDARDS, AND INSTRUCTIONS GOVERNING THE INSTALLATION... Train Stop, Train Control and Cab Signal Systems Standards § 236.509 Two or more locomotives coupled. The automatic train stop, train control or cab signal apparatus shall be arranged so that when two...

  2. 49 CFR 236.509 - Two or more locomotives coupled.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RULES, STANDARDS, AND INSTRUCTIONS GOVERNING THE INSTALLATION... Train Stop, Train Control and Cab Signal Systems Standards § 236.509 Two or more locomotives coupled. The automatic train stop, train control or cab signal apparatus shall be arranged so that when two...

  3. Decoding Ca2+ signals in plants

    NASA Technical Reports Server (NTRS)

    Sathyanarayanan, P. V.; Poovaiah, B. W.

    2004-01-01

    Different input signals create their own characteristic Ca2+ fingerprints. These fingerprints are distinguished by frequency, amplitude, duration, and number of Ca2+ oscillations. Ca(2+)-binding proteins and protein kinases decode these complex Ca2+ fingerprints through conformational coupling and covalent modifications of proteins. This decoding of signals can lead to a physiological response with or without changes in gene expression. In plants, Ca(2+)-dependent protein kinases and Ca2+/calmodulin-dependent protein kinases are involved in decoding Ca2+ signals into phosphorylation signals. This review summarizes the elements of conformational coupling and molecular mechanisms of regulation of the two groups of protein kinases by Ca2+ and Ca2+/calmodulin in plants.

  4. Response reactions: equilibrium coupling.

    PubMed

    Hoffmann, Eufrozina A; Nagypal, Istvan

    2006-06-01

    It is pointed out and illustrated in the present paper that if a homogeneous multiple equilibrium system containing k components and q species is composed of the reactants actually taken and their reactions contain only k + 1 species, then we have a unique representation with (q - k) stoichiometrically independent reactions (SIRs). We define these as coupling reactions. All the other possible combinations with k + 1 species are the coupled reactions that are in equilibrium when the (q - k) SIRs are in equilibrium. The response of the equilibrium state for perturbation is determined by the coupling and coupled equilibria. Depending on the circumstances and the actual thermodynamic data, the effect of coupled equilibria may overtake the effect of the coupling ones, leading to phenomena that are in apparent contradiction with Le Chatelier's principle.

  5. Three tooth kinematic coupling

    DOEpatents

    Hale, Layton C.

    2000-01-01

    A three tooth kinematic coupling based on having three theoretical line contacts formed by mating teeth rather than six theoretical point contacts. The geometry requires one coupling half to have curved teeth and the other coupling half to have flat teeth. Each coupling half has a relieved center portion which does not effect the kinematics, but in the limit as the face width approaches zero, three line contacts become six point contacts. As a result of having line contact, a three tooth coupling has greater load capacity and stiffness. The kinematic coupling has application for use in precision fixturing for tools or workpieces, and as a registration device for a work or tool changer or for optics in various products.

  6. Novel mid-IR quantum cascade laser waveguide coupling techniques

    NASA Astrophysics Data System (ADS)

    Shyu, David; Choa, Fow-Sen; Chen, Xing; Trivedi, Sudhir

    2011-02-01

    Signal modulations and coherent signal detections are important for both communications and remote sensing applications. Photonic integration reduces size, weight, cost, and improves the performance of these systems as demonstrated by integrated DFB-laser modulators, receivers and transceivers at near-IR wavelength regions. However, due to the difficulties of waveguide coupling, photonic integration in the mid-IR wavelength range is under-developed. We developed a technique that can monitor mid-IR coupling based on the negative photoconductivity in quantum cascaded (QC) materials that can simplify and optimize laser waveguide coupling in the mid-IR wavelength range.

  7. A stable snow-atmosphere coupled mode

    NASA Astrophysics Data System (ADS)

    Zhao, Liang; Zhu, Yuxiang; Liu, Haiwen; Liu, Zhongfang; Liu, Yanju; Li, Xiuping; Chen, Zhou

    2016-10-01

    Snow is both an important lower boundary forcing of the atmosphere and a response to atmospheric forcing in the extratropics. It is still unclear whether a stable snow-atmosphere coupled mode exists in the extratropics, like the ENSO in the tropics. Using Sliding Correlation analysis over Any Window, the present study quantitatively evaluates the stability of coupling relationships between the major modes of winter snow over the Northern Hemisphere and the winter atmospheric Arctic Oscillation (AO), the Antarctic Oscillation (AAO) and the Siberian High over the period 1872-2010, and discusses their possible relationships for different seasons. Results show that the first mode of the winter snow cover fraction and the winter AO together constitute a stable snow-atmosphere coupled mode, the SNAO. The coupled mode is stronger during recent decades than before. The snow anomaly over Europe is one key factor of the SNAO mode due to the high stability there, and the polar vortex anomaly in the atmosphere is its other key factor. The continuity of signals in the SNAO between autumn and winter is weaker than that between winter and spring. The second winter snow mode is generally stably correlated with the winter AAO and was more stable before the 1970s. The AAO signal with boreal snow has a strong continuity in seasonal transition. Generally, through these coupled modes, snow and atmosphere can interact in the same season or between different seasons: autumn snow can influence the winter atmosphere; the winter atmosphere can influence spring snow.

  8. [Sexuality among infertile couples].

    PubMed

    Alvarez-Díaz, Jorge Alberto

    2007-01-01

    A monographic type, bibliographic and hemerographic study on the sexuality in couples with fertility problems is presented. The study is based on the Rubio Aurioles' model of human sexuality, and the four holones (reproductivity, eroticism, affective bonds, gender) in couples with fertility problems are described. A review of clinical studies on the prevailing sexuality in this kind of couples and some theoretical reflections are also presented.

  9. Automatic quadrature control and measuring system. [using optical coupling circuitry

    NASA Technical Reports Server (NTRS)

    Hamlet, J. F. (Inventor)

    1974-01-01

    A quadrature component cancellation and measuring system comprising a detection system for detecting the quadrature component from a primary signal, including reference circuitry to define the phase of the quadrature component for detection is described. A Raysistor optical coupling control device connects an output from the detection system to a circuit driven by a signal based upon the primary signal. Combining circuitry connects the primary signal and the circuit controlled by the Raysistor device to subtract quadrature components. A known current through the optically sensitive element produces a signal defining the magnitude of the quadrature component.

  10. DREADD: A Chemogenetic GPCR Signaling Platform

    PubMed Central

    Zhu, Hu

    2015-01-01

    Recently, we created a family of engineered G protein-coupled receptors (GPCRs) called DREADD (designer receptors exclusively activated by designer drugs) which can precisely control three major GPCR signaling pathways (Gq, Gi, and Gs). DREADD technology has been successfully applied in a variety of in vivo studies to control GPCR signaling, and here we describe recent advances of DREADD technology and discuss its potential application in drug discovery, gene therapy, and tissue engineering. PMID:25522378

  11. Scram signal generator

    DOEpatents

    Johanson, Edward W.; Simms, Richard

    1981-01-01

    A scram signal generating circuit for nuclear reactor installations monitors a flow signal representing the flow rate of the liquid sodium coolant which is circulated through the reactor, and initiates reactor shutdown for a rapid variation in the flow signal, indicative of fuel motion. The scram signal generating circuit includes a long-term drift compensation circuit which processes the flow signal and generates an output signal representing the flow rate of the coolant. The output signal remains substantially unchanged for small variations in the flow signal, attributable to long term drift in the flow rate, but a rapid change in the flow signal, indicative of a fast flow variation, causes a corresponding change in the output signal. A comparator circuit compares the output signal with a reference signal, representing a given percentage of the steady state flow rate of the coolant, and generates a scram signal to initiate reactor shutdown when the output signal equals the reference signal.

  12. Scram signal generator

    DOEpatents

    Johanson, E.W.; Simms, R.

    A scram signal generating circuit for nuclear reactor installations monitors a flow signal representing the flow rate of the liquid sodium coolant which is circulated through the reactor, and initiates reactor shutdown for a rapid variation in the flow signal, indicative of fuel motion. The scram signal generating circuit includes a long-term drift compensation circuit which processes the flow signal and generates an output signal representing the flow rate of the coolant. The output signal remains substantially unchanged for small variations in the flow signal, attributable to long term drift in the flow rate, but a rapid change in the flow signal, indicative of a fast flow variation, causes a corresponding change in the output signal. A comparator circuit compares the output signal with a reference signal, representing a given percentage of the steady state flow rate of the coolant, and generates a scram signal to initiate reactor shutdown when the output signal equals the reference signal.

  13. A study of coupling two thermoacoustic lasers

    NASA Astrophysics Data System (ADS)

    Surathu, Rohit

    Thermoacoustics is a field studying the effects of applying heat to particular resonator geometries, resulting in the oscillations of gas and thereby producing sound waves. This field is a rich blend of many other scientific fields: acoustics, thermodynamics, and fluid mechanics. Thermoacoustic engines work on a similar principle as traditional heat engines. The main difference between a traditional heat engine and a thermoacoustic engine is that an acoustic wave drives the thermodynamic process in the latter. These engines are easy to construct, and there are no moving parts, which reduces the mechanical wear and tear. In our case, we fabricated the simpler thermoacoustic lasers to conduct the analysis. In most previous work within this field, different designs were tested and studied for a single laser operation from which extensive experimental data sets were collected and analyzed. Design and operation of a thermoacoustic laser pair is more complicated. Even though there have been a few coupling studies, detailed information about the acoustic field of multiple thermoacoustic lasers is lacking. Hence, an effort was made to study the interaction between the sound waves by acoustically coupling two thermoacoustic lasers. The acoustic coupling was varied using 4 different configurations. First, the lasers were placed parallel to each other, with their open ends separated by a 1 m distance (0° crossing angle). Next, the sound waves of the two lasers were focused at a particular point, with their openings in proximity at a fixed crossing angle (30 or 90°). Finally, the spatial distance between the openings of the 30 and 90° crossing lasers was increased in their own respective angles. The signals were read using three different measuring devices: a sound pressure level meter, a unidirectional microphone or an omnidirectional miniature microphone. The signals read using both microphones were collected, measured, and analyzed. The results proved that coupling

  14. Evaluation of Air Coupled Ultrasound for Composite Aerospace Structure

    NASA Astrophysics Data System (ADS)

    Tat, H.; Georgeson, G.; Bossi, R.

    2009-03-01

    Non-contact air coupled ultrasound suffers from the high acoustic impedance mismatch characteristics of air to solid interfaces. Advances in transducer technology, particularly MEMS, have improved the acoustic impedance match at the transmission stage and the signal to noise at the reception stage. Comparisons of through transmission (TTU) scanning of laminate and honeycomb test samples using conventional piezoelectric air coupled transducers, new MEMS air coupled transducers, and standard water coupled inspections have been performed to assess the capability. An additional issue for air coupled UT inspection is the need for a lean implementation for both manufacturing and in-service operations. Concepts and applications utilizing magnetic coupling of transducers have been developed that allows air coupled inspection operations in compact low cost configurations.

  15. Discriminating Valid from Spurious Indices of Phase-Amplitude Coupling

    PubMed Central

    Spaak, Eelke

    2016-01-01

    Abstract Recently there has been a strong interest in cross-frequency coupling, the interaction between neuronal oscillations in different frequency bands. In particular, measures quantifying the coupling between the phase of slow oscillations and the amplitude of fast oscillations have been applied to a wide range of data recorded from animals and humans. Some of the measures applied to detect phase-amplitude coupling have been criticized for being sensitive to nonsinusoidal properties of the oscillations and thus spuriously indicate the presence of coupling. While such instances of spurious identification of coupling have been observed, in this commentary we give concrete examples illustrating cases when the identification of cross-frequency coupling can be trusted. These examples are based on control analyses and empirical observations rather than signal-processing tools. Finally, we provide concrete advice on how to determine when measures of phase-amplitude coupling can be considered trustworthy. PMID:28101528

  16. Adenylate Kinase and AMP Signaling Networks: Metabolic Monitoring, Signal Communication and Body Energy Sensing

    PubMed Central

    Dzeja, Petras; Terzic, Andre

    2009-01-01

    Adenylate kinase and downstream AMP signaling is an integrated metabolic monitoring system which reads the cellular energy state in order to tune and report signals to metabolic sensors. A network of adenylate kinase isoforms (AK1-AK7) are distributed throughout intracellular compartments, interstitial space and body fluids to regulate energetic and metabolic signaling circuits, securing efficient cell energy economy, signal communication and stress response. The dynamics of adenylate kinase-catalyzed phosphotransfer regulates multiple intracellular and extracellular energy-dependent and nucleotide signaling processes, including excitation-contraction coupling, hormone secretion, cell and ciliary motility, nuclear transport, energetics of cell cycle, DNA synthesis and repair, and developmental programming. Metabolomic analyses indicate that cellular, interstitial and blood AMP levels are potential metabolic signals associated with vital functions including body energy sensing, sleep, hibernation and food intake. Either low or excess AMP signaling has been linked to human disease such as diabetes, obesity and hypertrophic cardiomyopathy. Recent studies indicate that derangements in adenylate kinase-mediated energetic signaling due to mutations in AK1, AK2 or AK7 isoforms are associated with hemolytic anemia, reticular dysgenesis and ciliary dyskinesia. Moreover, hormonal, food and antidiabetic drug actions are frequently coupled to alterations of cellular AMP levels and associated signaling. Thus, by monitoring energy state and generating and distributing AMP metabolic signals adenylate kinase represents a unique hub within the cellular homeostatic network. PMID:19468337

  17. Bibliographic Coupling: A Review

    ERIC Educational Resources Information Center

    Weinberg, Bella Hass

    1974-01-01

    The theory and practical applications of bibliographic coupling are reviewed. The reviewer takes issue with the use of bibliographic coupling for information retrieval and automatic classification on logical grounds, and for reasons relating to uncontrolled citation practices. The usefulness of the procedure for the study of the science of science…

  18. Translation-coupling systems

    DOEpatents

    Pfleger, Brian; Mendez-Perez, Daniel

    2013-11-05

    Disclosed are systems and methods for coupling translation of a target gene to a detectable response gene. A version of the invention includes a translation-coupling cassette. The translation-coupling cassette includes a target gene, a response gene, a response-gene translation control element, and a secondary structure-forming sequence that reversibly forms a secondary structure masking the response-gene translation control element. Masking of the response-gene translation control element inhibits translation of the response gene. Full translation of the target gene results in unfolding of the secondary structure and consequent translation of the response gene. Translation of the target gene is determined by detecting presence of the response-gene protein product. The invention further includes RNA transcripts of the translation-coupling cassettes, vectors comprising the translation-coupling cassettes, hosts comprising the translation-coupling cassettes, methods of using the translation-coupling cassettes, and gene products produced with the translation-coupling cassettes.

  19. Translation-coupling systems

    DOEpatents

    Pfleger, Brian; Mendez-Perez, Daniel

    2015-05-19

    Disclosed are systems and methods for coupling translation of a target gene to a detectable response gene. A version of the invention includes a translation-coupling cassette. The translation-coupling cassette includes a target gene, a response gene, a response-gene translation control element, and a secondary structure-forming sequence that reversibly forms a secondary structure masking the response-gene translation control element. Masking of the response-gene translation control element inhibits translation of the response gene. Full translation of the target gene results in unfolding of the secondary structure and consequent translation of the response gene. Translation of the target gene is determined by detecting presence of the response-gene protein product. The invention further includes RNA transcripts of the translation-coupling cassettes, vectors comprising the translation-coupling cassettes, hosts comprising the translation-coupling cassettes, methods of using the translation-coupling cassettes, and gene products produced with the translation-coupling cassettes.

  20. Coupled trivial maps.

    PubMed

    Bunimovich, L. A.; Livi, R.; Martinez-Mekler, G.; Ruffo, S.

    1992-07-01

    The first nontrivial example of coupled map lattices that admits a rigorous analysis in the whole range of the strength of space interactions is considered. This class is generated by one-dimensional maps with a globally attracting superstable periodic trajectory that are coupled by a diffusive nearest-neighbor interaction.

  1. Gear Spline Coupling Program

    SciTech Connect

    Guo, Yi; Errichello, Robert

    2013-08-29

    An analytical model is developed to evaluate the design of a spline coupling. For a given torque and shaft misalignment, the model calculates the number of teeth in contact, tooth loads, stiffnesses, stresses, and safety factors. The analytic model provides essential spline coupling design and modeling information and could be easily integrated into gearbox design and simulation tools.

  2. Study of digital charge coupled devices

    NASA Technical Reports Server (NTRS)

    Wilson, D. D.; Young, V. F.

    1980-01-01

    Charge coupled devices represent unique usage of the metal oxide semiconductor concept. These devices can sample an AC signal at the input, transfer charge proportional to this signal through the CCD shift register and then provide an output of the same frequency and shape as the input. The delay time between input and output is controlled by the CCD operating frequency and the number of stages in the shift resistor. This work is a reliability evaluation of the buried channel and surface channel CCD technologies. The constructions are analyzed, failure modes are described, and test results are reported.

  3. G-protein-coupled receptors and cancer.

    PubMed

    Dorsam, Robert T; Gutkind, J Silvio

    2007-02-01

    G-protein-coupled receptors (GPCRs), the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis. Malignant cells often hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase their blood supply, invade their surrounding tissues and disseminate to other organs. This Review will address our current understanding of the many roles of GPCRs and their signalling circuitry in tumour progression and metastasis. We will also discuss how interfering with GPCRs might provide unique opportunities for cancer prevention and treatment.

  4. Depression: The Differing Narratives of Couples in Couple Therapy

    ERIC Educational Resources Information Center

    Rautiainen, Eija-Liisa; Aaltonen, Jukka

    2010-01-01

    How does the spouse of a person with depression take part in constructing narratives of depression in couple therapy? In this study we examined couples' ways of co-constructing narratives of depression in couple therapy. Three couple therapy processes were chosen for the study, one spouse in each couple having been referred to an outpatient clinic…

  5. Regulation of CXCR4 Signaling

    PubMed Central

    Busillo, John M.; Benovic, Jeffrey L.

    2007-01-01

    The chemokine receptor CXCR4 belongs to the large superfamily of G protein-coupled receptors, and is directly involved in a number of biological processes including organogenesis, hematopoeisis, and immune response. Recent evidence has highlighted the role of CXCR4 in a variety of diseases including HIV, cancer, and WHIM syndrome. Importantly, the involvement of CXCR4 in cancer metastasis and WHIM syndrome appears to be due to dysregulation of the receptor leading to enhanced signaling. Herein we review what is currently known regarding the regulation of CXCR4 and how dysregulation contributes to disease progression. PMID:17169327

  6. Contactless Rotary Electrical Couplings

    NASA Technical Reports Server (NTRS)

    Kumagai, Hiroyuki

    2003-01-01

    Rotary electrical couplings based on induction (transformer action) rather than conduction between rotating and stationary circuitry have been invented. These couplings provide an alternative to slip rings and contact brushes. Mechanical imperfections of slip-ring and brush contact surfaces and/or dust particles trapped between these surfaces tend to cause momentary interruptions in electrical contact and thereby give rise to electrical noise. This source of noise can be eliminated in the inductive rotary couplings because no direct contact is necessary for transformer action.

  7. A Simple Structure for Signal Amplification

    NASA Astrophysics Data System (ADS)

    Ding, Wan-Xiang; Gu, Chang-Gui; Liang, Xiao-Ming

    2016-02-01

    It has been found that a triple-node feed-forward motif has a function of signal amplification, where two input nodes receive the external weak signal and jointly modulate the response of the third output node [Liang et al., Phys. Rev. E 88 (2013) 012910]. We here show that the signal amplification can be further enhanced by adding a link between the two input nodes in the feed-forward motif. We further reveal that the coupling strength of the link regulates the enhancement of signal amplification in the modified feed-forward motif. We finally analyze the mechanism of signal amplification of such simple structure. Supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning under Grant No. QD2015016, the National Natural Science Foundation of China under Grant Nos. 11505114 and 11305078

  8. Transmembrane signaling proteoglycans.

    PubMed

    Couchman, John R

    2010-01-01

    Virtually all metazoan cells contain at least one and usually several types of transmembrane proteoglycans. These are varied in protein structure and type of polysaccharide, but the total number of vertebrate genes encoding transmembrane proteoglycan core proteins is less than 10. Some core proteins, including those of the syndecans, always possess covalently coupled glycosaminoglycans; others do not. Syndecan has a long evolutionary history, as it is present in invertebrates, but many other transmembrane proteoglycans are vertebrate inventions. The variety of proteins and their glycosaminoglycan chains is matched by diverse functions. However, all assume roles as coreceptors, often working alongside high-affinity growth factor receptors or adhesion receptors such as integrins. Other common themes are an ability to signal through their cytoplasmic domains, often to the actin cytoskeleton, and linkage to PDZ protein networks. Many transmembrane proteoglycans associate on the cell surface with metzincin proteases and can be shed by them. Work with model systems in vivo and in vitro reveals roles in growth, adhesion, migration, and metabolism. Furthermore, a wide range of phenotypes for the core proteins has been obtained in mouse knockout experiments. Here some of the latest developments in the field are examined in hopes of stimulating further interest in this fascinating group of molecules.

  9. The coupling of engines

    NASA Technical Reports Server (NTRS)

    Boccaccio, Paul

    1921-01-01

    This report examines the idea of coupling numerous engines together to turn a single propeller, which the author feels would free aircraft design from the problems of multi-engine and propeller design.

  10. Coupling in the Tevatron

    SciTech Connect

    Gelfand, N.M.

    1994-12-01

    The performance of the Fermilab Tevatron Collider at the commencement of run Ib was far below expectations. After a frustrating period of several months, a low-{beta} quad downstream of the interaction point at B0 was found to be rolled. This rolled quadrupole coupled the horizontal and vertical motion of the Tevatron beams. It also made matching the beam from the Main Ring to the Tevatron impossible, resulting in emittance blow up on injection. The net result of the roll was a significant reduction in the Tevatron luminosity. When the roll in the quadrupole was corrected the performance of the Tevatron improved dramatically. This note will discuss the experimental data indicating the presence of coupling and subsequent calculations which show how coupling an affect the luminosity. It is not intended to exhaust a discussion of coupling, which hopefully will be understood well enough to be discussed in a subsequent note.

  11. Disformally coupled inflation

    SciTech Connect

    De Bruck, Carsten van; Longden, Chris; Koivisto, Tomi E-mail: timoko@kth.se

    2016-03-01

    A disformal coupling between two scalar fields is considered in the context of cosmological inflation. The coupling introduces novel derivative interactions mixing the kinetic terms of the fields but without introducing superluminal or unstable propagation of the two scalar fluctuation modes. Though the typical effect of the disformal coupling is to inhibit one of the fields from inflating the universe, the energy density of the other field can drive viable near Sitter -inflation in the presence of nontrivial disformal dynamics, in particular when one assumes exponential instead of power-law form for the couplings. The linear perturbation equations are written for the two-field system, its canonical degrees of freedom are quantised, their spectra are derived and the inflationary predictions are reported for numerically solved exponential models. A generic prediction is low tensor-to-scalar ratio.

  12. Ascaroside signaling in C. elegans.

    PubMed

    Ludewig, Andreas H; Schroeder, Frank C

    2013-01-18

    Over the past 10 years, the relevance of small-molecule signaling for many aspects of C. elegans development and behavior has become apparent. One prominent group of small-molecule signals are the ascarosides, which control dauer entry and exit as well as a variety of sex-specific and social behaviors, including male attraction, hermaphrodite repulsion, olfactory plasticity, and aggregation. This wide range of biological functions is facilitated by a great diversity of ascaroside chemical structures. These are based on the sugar ascarylose, which is linked to fatty acid-like side chains of varying lengths and often decorated further with building blocks derived from amino acids, folate, and other primary metabolites. Different ascarosides or combinations of ascarosides mediate different phenotypes, and even small differences in chemical structures are often associated with strongly altered activity profiles. Additional complexity arises from concentration-dependent effects and synergism between different ascarosides. The ascarosides are sensed by several types of chemosensory head neurons, including the ASK, ASI, and ADL neurons as well as the male-specific CEM neurons. Ascaroside perception is mediated by diverse families of G-protein coupled membrane receptors that act upstream of conserved signal transduction pathways, including insulin/IGF-1 signaling and transforming growth factor beta (TGF-β) signaling. Biosynthesis of the ascarosides appears to integrate input from several primary metabolic pathways, including peroxisomal β-oxidation of long-chain fatty acids and amino acid catabolism. Life stage, sex, as well as food availability and other environmental factors affect ascaroside biosynthesis, suggesting that ascaroside signaling communicates detailed information about life history and metabolic state.

  13. Ascaroside signaling in C. elegans.

    PubMed Central

    Ludewig, Andreas H; Schroeder, Frank C

    2013-01-01

    Over the past 10 years, the relevance of small-molecule signaling for many aspects of C. elegans development and behavior has become apparent. One prominent group of small-molecule signals are the ascarosides, which control dauer entry and exit as well as a variety of sex-specific and social behaviors, including male attraction, hermaphrodite repulsion, olfactory plasticity, and aggregation. This wide range of biological functions is facilitated by a great diversity of ascaroside chemical structures. These are based on the sugar ascarylose, which is linked to fatty acid-like side chains of varying lengths and often decorated further with building blocks derived from amino acids, folate, and other primary metabolites. Different ascarosides or combinations of ascarosides mediate different phenotypes, and even small differences in chemical structures are often associated with strongly altered activity profiles. Additional complexity arises from concentration-dependent effects and synergism between different ascarosides. The ascarosides are sensed by several types of chemosensory head neurons, including the ASK, ASI, and ADL neurons as well as the male-specific CEM neurons. Ascaroside perception is mediated by diverse families of G-protein coupled membrane receptors that act upstream of conserved signal transduction pathways, including insulin/IGF-1 signaling and transforming growth factor beta (TGF-β) signaling. Biosynthesis of the ascarosides appears to integrate input from several primary metabolic pathways, including peroxisomal β-oxidation of long-chain fatty acids and amino acid catabolism. Life stage, sex, as well as food availability and other environmental factors affect ascaroside biosynthesis, suggesting that ascaroside signaling communicates detailed information about life history and metabolic state. PMID:23355522

  14. The spatiotemporal order of signaling events unveils the logic of development signaling

    PubMed Central

    Zhu, Hao; Owen, Markus R.; Mao, Yanlan

    2016-01-01

    Motivation: Animals from worms and insects to birds and mammals show distinct body plans; however, the embryonic development of diverse body plans with tissues and organs within is controlled by a surprisingly few signaling pathways. It is well recognized that combinatorial use of and dynamic interactions among signaling pathways follow specific logic to control complex and accurate developmental signaling and patterning, but it remains elusive what such logic is, or even, what it looks like. Results: We have developed a computational model for Drosophila eye development with innovated methods to reveal how interactions among multiple pathways control the dynamically generated hexagonal array of R8 cells. We obtained two novel findings. First, the coupling between the long-range inductive signals produced by the proneural Hh signaling and the short-range restrictive signals produced by the antineural Notch and EGFR signaling is essential for generating accurately spaced R8s. Second, the spatiotemporal orders of key signaling events reveal a robust pattern of lateral inhibition conducted by Ato-coordinated Notch and EGFR signaling to collectively determine R8 patterning. This pattern, stipulating the orders of signaling and comparable to the protocols of communication, may help decipher the well-appreciated but poorly defined logic of developmental signaling. Availability and implementation: The model is available upon request. Contact: hao.zhu@ymail.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153573

  15. Signal processor for processing ultrasonic receiver signals

    DOEpatents

    Fasching, George E.

    1980-01-01

    A signal processor is provided which uses an analog integrating circuit in conjunction with a set of digital counters controlled by a precision clock for sampling timing to provide an improved presentation of an ultrasonic transmitter/receiver signal. The signal is sampled relative to the transmitter trigger signal timing at precise times, the selected number of samples are integrated and the integrated samples are transferred and held for recording on a strip chart recorder or converted to digital form for storage. By integrating multiple samples taken at precisely the same time with respect to the trigger for the ultrasonic transmitter, random noise, which is contained in the ultrasonic receiver signal, is reduced relative to the desired useful signal.

  16. Developmental aspects of perception-action coupling in multi-limb coordination: rhythmic sensorimotor synchronization.

    PubMed

    Getchell, Nancy

    2007-01-01

    The current research examines the development of perception-action coupling through childhood, specifically coupling multi-limb actions to rhythmic, auditory signals. Sixty participants in five age groups (4, 6, 8, 10, and 24 years, with 12 per group) clapped while walking in four conditions: No coupling instructions, with instructions to couple clap to walk, and with instructions to couple clap and walk to the metronome in two different frequency conditions. Statistically significant developmental differences existed in frequency locking (matching limb frequency to metronome or other limb) and phase locking (stably coupling to one point in the cycle). The intent to couple proved to be as important in producing less variable coupling patterns than adding a metronome beat. In addition, children's groups differed in variability within metronome conditions; these may be due to the increasing challenge encountered in coupling at a higher frequency. These results were discussed developmentally, with implications for the perception-action coupling throughout childhood.

  17. Signal verification can promote reliable signalling

    PubMed Central

    Broom, Mark; Ruxton, Graeme D.; Schaefer, H. Martin

    2013-01-01

    The central question in communication theory is whether communication is reliable, and if so, which mechanisms select for reliability. The primary approach in the past has been to attribute reliability to strategic costs associated with signalling as predicted by the handicap principle. Yet, reliability can arise through other mechanisms, such as signal verification; but the theoretical understanding of such mechanisms has received relatively little attention. Here, we model whether verification can lead to reliability in repeated interactions that typically characterize mutualisms. Specifically, we model whether fruit consumers that discriminate among poor- and good-quality fruits within a population can select for reliable fruit signals. In our model, plants either signal or they do not; costs associated with signalling are fixed and independent of plant quality. We find parameter combinations where discriminating fruit consumers can select for signal reliability by abandoning unprofitable plants more quickly. This self-serving behaviour imposes costs upon plants as a by-product, rendering it unprofitable for unrewarding plants to signal. Thus, strategic costs to signalling are not a prerequisite for reliable communication. We expect verification to more generally explain signal reliability in repeated consumer–resource interactions that typify mutualisms but also in antagonistic interactions such as mimicry and aposematism. PMID:24068354

  18. Retroactive Signaling in Short Signaling Pathways

    PubMed Central

    Sepulchre, Jacques-Alexandre; Merajver, Sofía D.; Ventura, Alejandra C.

    2012-01-01

    In biochemical signaling pathways without explicit feedback connections, the core signal transduction is usually described as a one-way communication, going from upstream to downstream in a feedforward chain or network of covalent modification cycles. In this paper we explore the possibility of a new type of signaling called retroactive signaling, offered by the recently demonstrated property of retroactivity in signaling cascades. The possibility of retroactive signaling is analysed in the simplest case of the stationary states of a bicyclic cascade of signaling cycles. In this case, we work out the conditions for which variables of the upstream cycle are affected by a change of the total amount of protein in the downstream cycle, or by a variation of the phosphatase deactivating the same protein. Particularly, we predict the characteristic ranges of the downstream protein, or of the downstream phosphatase, for which a retroactive effect can be observed on the upstream cycle variables. Next, we extend the possibility of retroactive signaling in short but nonlinear signaling pathways involving a few covalent modification cycles. PMID:22848403

  19. Algorithm for astronomical, point source, signal to noise ratio calculations

    NASA Technical Reports Server (NTRS)

    Jayroe, R. R.; Schroeder, D. J.

    1984-01-01

    An algorithm was developed to simulate the expected signal to noise ratios as a function of observation time in the charge coupled device detector plane of an optical telescope located outside the Earth's atmosphere for a signal star, and an optional secondary star, embedded in a uniform cosmic background. By choosing the appropriate input values, the expected point source signal to noise ratio can be computed for the Hubble Space Telescope using the Wide Field/Planetary Camera science instrument.

  20. Current induced interlayer coupling

    NASA Astrophysics Data System (ADS)

    Levy, Peter M.; Heide, Carsten; Zhang, Shufeng; Fert, Albert

    2001-03-01

    It has recently been shown that a perpendicular current in a magnetically multilayered structures induces an unusual bilinear coupling between the magnetizations of the layers [1]. While this was demonstrated in the ballistic regime, transport is likely to be diffusive in the structures where this may be relevant to the role of currents in switching the magnetization of the layers. We have derived the current induced coupling by using the Boltzmann equation in terms of the parameters used to describe the giant magnetoresistance of magnetically layered structures, and thereby estimate the strength of this coupling. Work supported in part by DARPA and ONR. [1] C.Heide and R.J.Elliott, Europhys. Lett. 50, 271 (2000).

  1. Tube coupling device

    NASA Technical Reports Server (NTRS)

    Myers, William N. (Inventor); Hein, Leopold A. (Inventor)

    1987-01-01

    A first annular ring of a tube coupling device has a keyed opening sized to fit around the nut region of a male coupling, and a second annular ring has a keyed opening sized to fit around the nut of a female coupling. Each ring has mating ratchet teeth and these rings are biased together, thereby engaging these teeth and preventing rotation of these rings. This in turn prevents the rotation of the male nut region with respect to the female nut. For tube-to-bulkhead locking, one facet of one ring is notched, and a pin is pressed into an opening in the bulkhead. This pin is sized to fit within one of the notches in the ring, thereby preventing rotation of this ring with respect to the bulkhead.

  2. Coupled nonlinear dynamical systems

    NASA Astrophysics Data System (ADS)

    Sun, Hongyan

    In this dissertation, we study coupled nonlinear dynamical systems that exhibit new types of complex behavior. We numerically and analytically examine a variety of dynamical models, ranging from systems of ordinary differential equations (ODE) with novel elements of feedback to systems of partial differential equations (PDE) that model chemical pattern formation. Chaos, dynamical uncertainty, synchronization, and spatiotemporal pattern formation constitute the primary topics of the dissertation. Following the introduction in Chapter 1, we study chaos and dynamical uncertainty in Chapter 2 with coupled Lorenz systems and demonstrate the existence of extreme complexity in high-dimensional ODE systems. In Chapter 3, we demonstrate that chaos synchronization can be achieved by mutual and multiplicative coupling of dynamical systems. Chapter 4 and 5 focus on pattern formation in reaction-diffusion systems, and we investigate segregation and integration behavior of populations in competitive and cooperative environments, respectively.

  3. Saturation in coupled oscillators

    NASA Astrophysics Data System (ADS)

    Roman, Ahmed; Hanna, James

    2015-03-01

    We consider a weakly nonlinear system consisting of a resonantly forced oscillator coupled to an unforced oscillator. It has long been known that, for quadratic nonlinearities and a 2:1 resonance between the oscillators, a perturbative solution of the dynamics exhibits a phenomenon known as saturation. At low forcing, the forced oscillator responds, while the unforced oscillator is quiescent. Above a critical value of the forcing, the forced oscillator's steady-state amplitude reaches a plateau, while that of the unforced oscillator increases without bound. We show that, contrary to established folklore, saturation is not unique to quadratically nonlinear systems. We present conditions on the form of the nonlinear couplings and resonance that lead to saturation. Our results elucidate a mechanism for localization or diversion of energy in systems of coupled oscillators, and suggest new approaches for the control or suppression of vibrations in engineered systems.

  4. Status of Higgs couplings after run 1 of the LHC

    NASA Astrophysics Data System (ADS)

    Bernon, Jérémy; Dumont, Béranger; Kraml, Sabine

    2014-10-01

    We provide an update of the global fits of the couplings of the 125.5 GeV Higgs boson using all publicly available experimental results from run 1 of the LHC as per summer 2014. The fits are done by means of the new public code Lilith 1.0. We present a selection of results given in terms of signal strengths, reduced couplings, and for the two-Higgs-doublet models of type I and II.

  5. Actively coupled optical waveguides

    NASA Astrophysics Data System (ADS)

    Alexeeva, N. V.; Barashenkov, I. V.; Rayanov, K.; Flach, S.

    2014-01-01

    We consider light propagation through a pair of nonlinear optical waveguides with absorption, placed in a medium with power gain. The active medium boosts the in-phase component of the overlapping evanescent fields of the guides, while the nonlinearity of the guides couples it to the damped out-of-phase component creating a feedback loop. As a result, the structure exhibits stable stationary and oscillatory regimes in a wide range of gain-loss ratios. We show that the pair of actively coupled (AC) waveguides can act as a stationary or integrate-and-fire comparator sensitive to tiny differences in their input powers.

  6. Multidimensional signal processing for ultrasonic signal classification

    NASA Astrophysics Data System (ADS)

    Kim, J.; Ramuhalli, P.; Udpa, L.; Udpa, S.

    2001-04-01

    Neural network based signal classification systems are being used increasingly in the analysis of large volumes of data obtained in NDE applications. One example is in the interpretation on ultrasonic signals obtained from inspection of welds where signals can be due to porosity, slag, lack of fusion and cracks in the weld region. Standard techniques rely on differences in individual A-scans to classify the signals. This paper proposes an ultrasonic signal classification technique based on the information in a group of signals and examining the statistical characteristics of the signals. The method was 2-dimensional signal processing algorithms to analyze the information in B- and B'-scan images. In this paper, 2-dimensional transform based coefficients of the images are used as features and a multilayer perceptron is used to classify them. These results are then combined to get the final classification for the inspected region. Results of applying the technique to data obtained from the inspection of welds are presented.

  7. Air-coupled ultrasonic assessment of wood veneer.

    PubMed

    Blomme, Erik; Bulcaen, Dirk; Cool, Tijl; Declercq, Filip; Lust, Pieter

    2010-02-01

    Air-coupled ultrasound (ACU) provides a tool to evaluate wood samples of small or moderate thickness (<30 mm) thereby avoiding direct contact or liquid coupling. Results of through-transmission ACU measurements on wood veneer samples and related products are reported with respect to a wide variety of quality aspects. Fluctuations in the averaged received signal levels appear to be correlated to the presence of natural or machine-induced thickness and density variations, flaws and grain damage, errors produced by the manufacturing process, insufficient bonding on a substrate, etc. In addition it is seen that the variability of the signal levels enables to distinguish between quarter and crown areas.

  8. Subcellular optogenetics – controlling signaling and single-cell behavior

    PubMed Central

    Karunarathne, W. K. Ajith; O'Neill, Patrick R.; Gautam, Narasimhan

    2015-01-01

    ABSTRACT Variation in signaling activity across a cell plays a crucial role in processes such as cell migration. Signaling activity specific to organelles within a cell also likely plays a key role in regulating cellular functions. To understand how such spatially confined signaling within a cell regulates cell behavior, tools that exert experimental control over subcellular signaling activity are required. Here, we discuss the advantages of using optogenetic approaches to achieve this control. We focus on a set of optical triggers that allow subcellular control over signaling through the activation of G-protein-coupled receptors (GPCRs), receptor tyrosine kinases and downstream signaling proteins, as well as those that inhibit endogenous signaling proteins. We also discuss the specific insights with regard to signaling and cell behavior that these subcellular optogenetic approaches can provide. PMID:25433038

  9. ERK Signals: Scaffolding Scaffolds?

    PubMed Central

    Casar, Berta; Crespo, Piero

    2016-01-01

    ERK1/2 MAP Kinases become activated in response to multiple intra- and extra-cellular stimuli through a signaling module composed of sequential tiers of cytoplasmic kinases. Scaffold proteins regulate ERK signals by connecting the different components of the module into a multi-enzymatic complex by which signal amplitude and duration are fine-tuned, and also provide signal fidelity by isolating this complex from external interferences. In addition, scaffold proteins play a central role as spatial regulators of ERKs signals. In this respect, depending on the subcellular localization from which the activating signals emanate, defined scaffolds specify which substrates are amenable to be phosphorylated. Recent evidence has unveiled direct interactions among different scaffold protein species. These scaffold-scaffold macro-complexes could constitute an additional level of regulation for ERK signals and may serve as nodes for the integration of incoming signals and the subsequent diversification of the outgoing signals with respect to substrate engagement. PMID:27303664

  10. Sequential pattern formation governed by signaling gradients

    NASA Astrophysics Data System (ADS)

    Jörg, David J.; Oates, Andrew C.; Jülicher, Frank

    2016-10-01

    Rhythmic and sequential segmentation of the embryonic body plan is a vital developmental patterning process in all vertebrate species. However, a theoretical framework capturing the emergence of dynamic patterns of gene expression from the interplay of cell oscillations with tissue elongation and shortening and with signaling gradients, is still missing. Here we show that a set of coupled genetic oscillators in an elongating tissue that is regulated by diffusing and advected signaling molecules can account for segmentation as a self-organized patterning process. This system can form a finite number of segments and the dynamics of segmentation and the total number of segments formed depend strongly on kinetic parameters describing tissue elongation and signaling molecules. The model accounts for existing experimental perturbations to signaling gradients, and makes testable predictions about novel perturbations. The variety of different patterns formed in our model can account for the variability of segmentation between different animal species.

  11. GPCR signaling and cardiac function.

    PubMed

    Capote, Leany A; Mendez Perez, Roberto; Lymperopoulos, Anastasios

    2015-09-15

    G protein-coupled receptors (GPCRs), such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, i.e. myocytes, fibroblasts and endothelial cells, play crucial roles in regulating cardiac function and morphology. Their importance in cardiac physiology and disease is reflected by the fact that, collectively, they represent the direct targets of over a third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of their structure, function and the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart disease therapy. Here, we review these signaling modalities employed by GPCRs known to be expressed in the cardiac myocyte membranes and to directly modulate cardiac contractility. We also highlight drugs and drug classes that directly target these GPCRs to modulate cardiac function, as well as molecules involved in cardiac GPCR signaling that have the potential of becoming novel drug targets for modulation of cardiac function in the future.

  12. IBEX magnetic coupling experiments

    SciTech Connect

    Frost, C.A.; Kiekel, P.D.; Miller, R.B.; Ekdahl, C.A.; Wagner, J.; Ramirez, J.J.

    1985-01-01

    The magnetic coupling of one pulse to another is a key issue for some modes of high-current beam propagation. Experiments are in progress on Sandia's IBEX accelerator to address issues relevant to magnetic coupling. The IBEX experiments differ from previous experiments in that the B/sub theta/ field acting on the second pulse is the result of residual plasma current from the first pulse rather than current applied by an external means. This new feature makes the propagation sensitive to beam and plasma current profiles that are key to the physics of the magnetic coupling problem. These experiments do not attempt to study the air chemistry issues, as this would require much higher current densities than are available from IBEX. We are using the IBEX accelerator with a mismatched magnetized diode to produce two high-current pulses separated by approx.130 nsec. A pulse pair has been propagated over a 1.5-m path in low pressure air. Extraction of two pulses, each having different parameters, complicates the experiment but also provides new insight into the magnetic coupling proplem. 7 figs.

  13. Coupling Gammasphere and ORRUBA

    SciTech Connect

    Ratkiewicz, A.; Cizewski, J. A.; Manning, B.; Pain, S. D.; Bardayan, D. W.; Blackmon, J. C.; Matos, M.; Chipps, K. A.; Hardy, S.; Shand, C.; Jones, K. L.; Kozub, R. L.; Lister, C. J.; Peters, W. A.; Seweryniak, D.

    2013-04-19

    The coincident detection of particles and gamma rays allows the study of the structure of exotic nuclei via inverse kinematics reactions using radioactive ion beams and thick targets. We report on the status of the project to couple the highresolution charged-particle detector ORRUBA to Gammasphere, a high-efficiency, high-resolution gamma ray detector.

  14. Too Many Couples

    ERIC Educational Resources Information Center

    Kay, Joseph

    2007-01-01

    In this article, the author offers his ad hoc reflections on the question of just how many academic couples a department could comfortably accommodate from the point of view of good governance, in the hope of getting an honest dialogue started and seeing some reasonable guidelines eventually created by one organization or another as a result. He…

  15. Gravitationally coupled electroweak monopole

    NASA Astrophysics Data System (ADS)

    Cho, Y. M.; Kimm, Kyoungtae; Yoon, J. H.

    2016-10-01

    We present a family of gravitationally coupled electroweak monopole solutions in Einstein-Weinberg-Salam theory. Our result confirms the existence of globally regular gravitating electroweak monopole which changes to the magnetically charged black hole as the Higgs vacuum value approaches to the Planck scale. Moreover, our solutions could provide a more accurate description of the monopole stars and magnetically charged black holes.

  16. Harmonic coupling of steady-state visual evoked potentials.

    PubMed

    Krusienski, Dean J; Allison, Brendan Z

    2008-01-01

    Steady-state visual evoked potentials (SSVEPs) are oscillating components of the electroencephalogram (EEG) that are detected over the occipital areas, having frequencies corresponding to visual stimulus frequencies. SSVEPs have been demonstrated to be reliable control signals for operating a brain-computer interface (BCI). This study uses offline analyses to investigate the characteristics of SSVEP harmonic amplitude and phase coupling and the impact of using this information to construct a matched filter for continuously tracking the signal.

  17. A monoclonal antibody for G protein-coupled receptor crystallography.

    PubMed

    Day, Peter W; Rasmussen, Søren G F; Parnot, Charles; Fung, Juan José; Masood, Asna; Kobilka, Tong Sun; Yao, Xiao-Jie; Choi, Hee-Jung; Weis, William I; Rohrer, Daniel K; Kobilka, Brian K

    2007-11-01

    G protein-coupled receptors (GPCRs) constitute the largest family of signaling proteins in mammals, mediating responses to hormones, neurotransmitters, and senses of sight, smell and taste. Mechanistic insight into GPCR signal transduction is limited by a paucity of high-resolution structural information. We describe the generation of a monoclonal antibody that recognizes the third intracellular loop (IL3) of the native human beta(2) adrenergic (beta(2)AR) receptor; this antibody was critical for acquiring diffraction-quality crystals.

  18. High-frequency generation in two coupled semiconductor superlattices

    NASA Astrophysics Data System (ADS)

    Matharu, Satpal; Kusmartsev, Feodor V.; Balanov, Alexander G.

    2013-10-01

    We theoretically show that two semiconductor superlattices arranged on the same substrate and coupled with the same resistive load can be used for a generation of high-frequency periodic and quasiperiodic signals. Each superlattice involved is capable to generate current oscillations associated with drift of domains of high charge concentration. However, the coupling with the common load can eventually lead to synchronization of the current oscillations in the interacting superlattices. We reveal how synchronization depends on detuning between devices and the resistance of the common load, and discuss the effects of coupling and detuning on the high-frequency power output from the system.

  19. Coupled resonator vertical cavity laser

    SciTech Connect

    Choquette, K.D.; Chow, W.W.; Hou, H.Q.; Geib, K.M.; Hammons, B.E.

    1998-01-01

    The monolithic integration of coupled resonators within a vertical cavity laser opens up new possibilities due to the unique ability to tailor the interaction between the cavities. The authors report the first electrically injected coupled resonator vertical-cavity laser diode and demonstrate novel characteristics arising from the cavity coupling, including methods for external modulation of the laser. A coupled mode theory is used model the output modulation of the coupled resonator vertical cavity laser.

  20. Assessing transient cross-frequency coupling in EEG data.

    PubMed

    Cohen, Michael X

    2008-03-15

    Synchronization of oscillatory EEG signals across different frequency bands is receiving waxing interest in cognitive neuroscience and neurophysiology, and cross-frequency coupling is being increasingly linked to cognitive and perceptual processes. Several methods exist to examine cross-frequency coupling, although each has its limitations, typically by being flexible only over time or over frequency. Here, a method for assessing transient cross-frequency coupling is presented, which allows one to test for the presence of multiple, dynamic, and flexible cross-frequency coupling structure over both time and frequency. The method is applied to intracranial EEG data, and strong coupling between gamma ( approximately 40-80 Hz) and upper theta ( approximately 7-9 Hz) was observed. This method might have useful applications in uncovering the electrophysiological correlates of cognitive processes.

  1. A biomimetic coupled circuit based microphone array for sound source localization.

    PubMed

    Xu, Huping; Xu, Xiangyuan; Jia, Han; Guan, Luyang; Bao, Ming

    2015-09-01

    An equivalent analog circuit is designed to mimic the coupled ears of the fly Ormia ochracea for sound source localization. This coupled circuit receives two signals with tiny phase difference from a space closed two-microphone array, and produces two signals with obvious intensity difference. The response sensitivity can be adjusted through the coupled circuit parameters. The directional characteristics of the coupled circuit have been demonstrated in the experiment. The miniature microphone array can localize the sound source with low computational burden by using the intensity difference. This system has significant advantages in various applications where the array size is limited.

  2. Apparatus for millimeter-wave signal generation

    DOEpatents

    Vawter, G. Allen; Hietala, Vincent M.; Zolper, John C.; Mar, Alan; Hohimer, John P.

    1999-01-01

    An opto-electronic integrated circuit (OEIC) apparatus is disclosed for generating an electrical signal at a frequency .gtoreq.10 GHz. The apparatus, formed on a single substrate, includes a semiconductor ring laser for generating a continuous train of mode-locked lasing pulses and a high-speed photodetector for detecting the train of lasing pulses and generating the electrical signal therefrom. Embodiments of the invention are disclosed with an active waveguide amplifier coupling the semiconductor ring laser and the high-speed photodetector. The invention has applications for use in OEICs and millimeter-wave monolithic integrated circuits (MMICs).

  3. Signaling in myxobacteria.

    PubMed

    Kaiser, Dale

    2004-01-01

    Myxobacteria use soluble and cell-contact signals during their starvation-induced formation of fruiting bodies. These signals coordinate developmental gene expression with the cell movements that build fruiting bodies. Early in development, the quorum-sensing A-signal in Myxococcus xanthus helps to assess starvation and induce the first stage of aggregation. Later, the morphogenetic C-signal helps to pattern cell movement and shape the fruiting body. C-signal is a 17-kDa cell surface protein that signals by contact between the ends of two cells. The number of C-signal molecules per cell rises 100-fold from the beginning of fruiting body development to the end, when spores are formed. Traveling waves, streams, and sporulation have increasing thresholds for C-signal activity, and this progression ensures that spores form inside fruiting bodies.

  4. Signal sciences workshop proceedings

    SciTech Connect

    Candy, J.V.

    1997-05-01

    This meeting is aimed primarily at signal processing and controls. The technical program for the 1997 Workshop includes a variety of efforts in the Signal Sciences with applications in the Microtechnology Area a new program at LLNL and a future area of application for both Signal/Image Sciences. Special sessions organized by various individuals in Seismic and Optical Signal Processing as well as Micro-Impulse Radar Processing highlight the program, while the speakers at the Signal Processing Applications session discuss various applications of signal processing/control to real world problems. For the more theoretical, a session on Signal Processing Algorithms was organized as well as for the more pragmatic, featuring a session on Real-Time Signal Processing.

  5. Excitation-contraction coupling and mitochondrial energetics

    PubMed Central

    O’Rourke, Brian

    2009-01-01

    Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, Pi, and Ca2+. However, the kinetics of mitochondrial Ca2+-uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca2+ microdomain could explain seemingly controversial results on mitochondrial Ca2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca2+ uptake facilitated by microdomains may shape cytosolic Ca2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. PMID:17657400

  6. New signatures of flavor violating Higgs couplings

    NASA Astrophysics Data System (ADS)

    Buschmann, Malte; Kopp, Joachim; Liu, Jia; Wang, Xiao-Ping

    2016-06-01

    We explore several novel LHC signatures arising from quark or lepton flavor violating couplings in the Higgs sector, and we constrain such couplings using LHC data. Since the largest signals are possible in channels involving top quarks or tau leptons, we consider in particular the following flavor violating processes: (1) pp → thh (top plus di-Higgs final state) arising from a dimension six coupling of up-type quarks to three insertions of the Higgs field. We develop a search strategy for this final state and demonstrate that detection is possible at the high luminosity LHC if flavor violating top-up-Higgs couplings are not too far below the current limit. (2) pp → tH 0, where H 0 is the heavy neutral CP-even Higgs boson in a two Higgs doublet model (2HDM). We consider the decay channels H 0 → tu, WW, ZZ, hh and use existing LHC data to constrain the first three of them. For the fourth, we adapt our search for the thh final state, and we demonstrate that in large regions of the parameter space, it is superior to other searches, including searches for flavor violating top quark decays ( t → hq). (3) H 0 → τ μ, again in the context of a 2HDM. This channel is particularly well motivated by the recent CMS excess in h → τ μ, and we use the data from this search to constrain the properties of H 0.

  7. Optimizing plasmonic nanoantennas via coordinated multiple coupling

    PubMed Central

    Lin, Linhan; Zheng, Yuebing

    2015-01-01

    Plasmonic nanoantennas, which can efficiently convert light from free space into sub-wavelength scale with the local field enhancement, are fundamental building blocks for nanophotonic systems. Predominant design methods, which exploit a single type of near- or far-field coupling in pairs or arrays of plasmonic nanostructures, have limited the tunability of spectral response and the local field enhancement. To overcome this limit, we are developing a general strategy towards exploiting the coordinated effects of multiple coupling. Using Au bowtie nanoantenna arrays with metal-insulator-metal configuration as examples, we numerically demonstrate that coordinated design and implementation of various optical coupling effects leads to both the increased tunability in the spectral response and the significantly enhanced electromagnetic field. Furthermore, we design and analyze a refractive index sensor with an ultra-high figure-of-merit (254), a high signal-to-noise ratio and a wide working range of refractive indices, and a narrow-band near-infrared plasmonic absorber with 100% absorption efficiency, high quality factor of up to 114 and a wide range of tunable wavelength from 800 nm to 1,500 nm. The plasmonic nanoantennas that exploit coordinated multiple coupling will benefit a broad range of applications, including label-free bio-chemical detection, reflective filter, optical trapping, hot-electron generation, and heat-assisted magnetic recording. PMID:26423015

  8. Optimizing plasmonic nanoantennas via coordinated multiple coupling

    NASA Astrophysics Data System (ADS)

    Lin, Linhan; Zheng, Yuebing

    2015-10-01

    Plasmonic nanoantennas, which can efficiently convert light from free space into sub-wavelength scale with the local field enhancement, are fundamental building blocks for nanophotonic systems. Predominant design methods, which exploit a single type of near- or far-field coupling in pairs or arrays of plasmonic nanostructures, have limited the tunability of spectral response and the local field enhancement. To overcome this limit, we are developing a general strategy towards exploiting the coordinated effects of multiple coupling. Using Au bowtie nanoantenna arrays with metal-insulator-metal configuration as examples, we numerically demonstrate that coordinated design and implementation of various optical coupling effects leads to both the increased tunability in the spectral response and the significantly enhanced electromagnetic field. Furthermore, we design and analyze a refractive index sensor with an ultra-high figure-of-merit (254), a high signal-to-noise ratio and a wide working range of refractive indices, and a narrow-band near-infrared plasmonic absorber with 100% absorption efficiency, high quality factor of up to 114 and a wide range of tunable wavelength from 800 nm to 1,500 nm. The plasmonic nanoantennas that exploit coordinated multiple coupling will benefit a broad range of applications, including label-free bio-chemical detection, reflective filter, optical trapping, hot-electron generation, and heat-assisted magnetic recording.

  9. Danger signals in stroke.

    PubMed

    Gelderblom, Mathias; Sobey, Christopher G; Kleinschnitz, Christoph; Magnus, Tim

    2015-11-01

    Danger molecules are the first signals released from dying tissue after stroke. These danger signals bind to receptors on immune cells that will result in their activation and the release of inflammatory and neurotoxic mediators, resulting in amplification of the immune response and subsequent enlargement of the damaged brain volume. The release of danger signals is a central event that leads to a multitude of signals and cascades in the affected and neighbouring tissue, therefore providing a potential target for therapy.

  10. Staggered Costas signals

    NASA Astrophysics Data System (ADS)

    Freedman, Avraham; Levanon, Nadav

    1986-11-01

    A radar signal, based on coherent processing of a train of staggered Costas (1984) bursts is based on a minimum number of collocation of their individual ambiguity function sidelobe peaks. The resulting ambiguity function combines qualities of both 'thumbtack' and 'bed of nails' signals. Comparison with linear-FM, V-FM, and complementary phase coded signals is given, as well as comparison with hybrid signals consisting of both phase and frequency coding.

  11. Parametric amplification by coupled flux qubits

    SciTech Connect

    Rehák, M.; Neilinger, P.; Grajcar, M.; Oelsner, G.; Hübner, U.; Meyer, H.-G.; Il'ichev, E.

    2014-04-21

    We report parametric amplification of a microwave signal in a Kerr medium formed from superconducting qubits. Two mutually coupled flux qubits, embedded in the current antinode of a superconducting coplanar waveguide resonator, are used as a nonlinear element. Shared Josephson junctions provide the qubit-resonator coupling, resulting in a device with a tunable Kerr constant (up to 3 × 10{sup −3}) and a measured gain of about 20 dB. This arrangement represents a unit cell which can be straightforwardly extended to a quasi one-dimensional quantum metamaterial with large tunable Kerr nonlinearity, providing a basis for implementation of wide-band travelling wave parametric amplifiers.

  12. G Protein–Coupled Receptor Heteromers

    PubMed Central

    Gomes, Ivone; Ayoub, Mohammed Akli; Fujita, Wakako; Jaeger, Werner C.; Pfleger, Kevin D.G.; Devi, Lakshmi A.

    2016-01-01

    G protein–coupled receptors (GPCRs) compose one of the largest families of membrane proteins involved in intracellular signaling. They are involved in numerous physiological and pathological processes and are prime candidates for drug development. Over the past decade, an increasing number of studies have reported heteromerization between GPCRs. Many investigations in heterologous systems have provided important indications of potential novel pharmacology; however, the physiological relevance of these findings has yet to be established with endogenous receptors in native tissues. In this review, we focus on family A GPCRs and describe the techniques and criteria to assess their heteromerization. We conclude that advances in approaches to study receptor complex functionality in heterologous systems, coupled with techniques that enable specific examination of native receptor heteromers in vivo, are likely to establish GPCR heteromers as novel therapeutic targets. PMID:26514203

  13. Coupled External Cavity Photonic Crystal Enhanced Fluorescence

    PubMed Central

    Pokhriyal, Anusha; Lu, Meng; Ge, Chun; Cunningham, Brian T.

    2016-01-01

    We report a fundamentally new approach to enhance fluorescence in which surface adsorbed fluorophore-tagged biomolecules are excited on a photonic crystal surface that functions as a narrow bandwidth and tunable mirror of an external cavity laser. This scheme leads to ~10× increase in the electromagnetic enhancement factor compared to ordinary photonic crystal enhanced fluorescence. In our experiments, the cavity automatically tunes its lasing wavelength to the resonance wavelength of the photonic crystal, ensuring optimal on-resonance coupling even in the presence of variable device parameters and variations in the density of surface-adsorbed capture molecules. We achieve ~105× improvement in the limit of detection of a fluorophore-tagged protein compared to its detection on an unpatterned glass substrate. The enhanced fluorescence signal and easy optical alignment make cavity-coupled photonic crystals a viable approach for further reducing detection limits of optically-excited light emitters that are used in biological assays. PMID:23129575

  14. Coupled external cavity photonic crystal enhanced fluorescence.

    PubMed

    Pokhriyal, Anusha; Lu, Meng; Ge, Chun; Cunningham, Brian T

    2014-05-01

    We report a fundamentally new approach to enhance fluorescence in which surface adsorbed fluorophore-tagged biomolecules are excited on a photonic crystal surface that functions as a narrow bandwidth and tunable mirror of an external cavity laser. This scheme leads to ∼10× increase in the electromagnetic enhancement factor compared to ordinary photonic crystal enhanced fluorescence. In our experiments, the cavity automatically tunes its lasing wavelength to the resonance wavelength of the photonic crystal, ensuring optimal on-resonance coupling even in the presence of variable device parameters and variations in the density of surface-adsorbed capture molecules. We achieve ∼10(5) × improvement in the limit of detection of a fluorophore-tagged protein compared to its detection on an unpatterned glass substrate. The enhanced fluorescence signal and easy optical alignment make cavity-coupled photonic crystals a viable approach for further reducing detection limits of optically-excited light emitters that are used in biological assays.

  15. Synchronization in Networks of Coupled Chemical Oscillators

    NASA Astrophysics Data System (ADS)

    Showalter, Kenneth; Tinsley, Mark; Nkomo, Simbarashe; Ke, Hua

    2014-03-01

    We have studied networks of coupled photosensitive chemical oscillators. Experiments and simulations are carried out on networks with different topologies and modes of coupling. We describe experimental and modeling studies of chimera and phase-cluster states and their relation to other synchronization states. Networks of integrate-and-fire oscillators are also studied in which sustained coordinated activity is exhibited. Individual nodes display incoherent firing events; however, a dominant frequency within the collective signal is exhibited. The introduction of spike-timing-dependent plasticity allows the network to evolve and leads to a stable unimodal link-weight distribution. M. R. Tinsley et al., Nature Physics 8, 662 (2012); S. Nkomo et al., Phys. Rev. Lett. 110, 244102 (2013); H. Ke et al., in preparation.

  16. Excitation-Contraction Coupling Alterations in Myopathies

    PubMed Central

    Marty, Isabelle; Fauré, Julien

    2016-01-01

    During the complex series of events leading to muscle contraction, the initial electric signal coming from motor neurons is transformed into an increase in calcium concentration that triggers sliding of myofibrils. This process, referred to as excitation–contraction coupling, is reliant upon the calcium-release complex, which is restricted spatially to a sub-compartment of muscle cells (“the triad”) and regulated precisely. Any dysfunction in the calcium-release complex leads to muscle impairment and myopathy. Various causes can lead to alterations in excitation–contraction coupling and to muscle diseases. The latter are reviewed and classified into four categories: (i) mutation in a protein of the calcium-release complex; (ii) alteration in triad structure; (iii) modification of regulation of channels; (iv) modification in calcium stores within the muscle. Current knowledge of the pathophysiologic mechanisms in each category is described and discussed. PMID:27911331

  17. GPCR signalling to the translation machinery.

    PubMed

    Musnier, Astrid; Blanchot, Benoît; Reiter, Eric; Crépieux, Pascale

    2010-05-01

    G protein-coupled receptors (GPCRs) are involved in most physiological processes, many of them being engaged in fully differentiated cells. These receptors couple to transducers of their own, primarily G proteins and beta-arrestins, which launch intracellular signalling cascades. Some of these signalling events regulate the translational machinery to fine-tune general cell metabolism or to alter protein expression pattern. Though extensively documented for tyrosine kinase receptors, translational regulation by GPCRs is still poorly appreciated. The objective of this review paper is to address the following questions: i) is there a "GPCR signature" impacting on the translational machinery, and ultimately on the type of mRNA translated? ii) are the regulatory networks involved similar as those utilized by tyrosine kinase receptors? In particular, we will discuss the specific features of translational control mediated by GPCRs and highlight the intrinsic properties of GPCRs these mechanisms could rely on.

  18. Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

    PubMed Central

    Gerber, Kyle J.; Squires, Katherine E.

    2016-01-01

    The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Gα subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre- and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets. PMID:26655302

  19. Tetrapyrrole Signaling in Plants

    PubMed Central

    Larkin, Robert M.

    2016-01-01

    Tetrapyrroles make critical contributions to a number of important processes in diverse organisms. In plants, tetrapyrroles are essential for light signaling, the detoxification of reactive oxygen species, the assimilation of nitrate and sulfate, respiration, photosynthesis, and programed cell death. The misregulation of tetrapyrrole metabolism can produce toxic reactive oxygen species. Thus, it is not surprising that tetrapyrrole metabolism is strictly regulated and that tetrapyrrole metabolism affects signaling mechanisms that regulate gene expression. In plants and algae, tetrapyrroles are synthesized in plastids and were some of the first plastid signals demonstrated to regulate nuclear gene expression. In plants, the mechanism of tetrapyrrole-dependent plastid-to-nucleus signaling remains poorly understood. Additionally, some of experiments that tested ideas for possible signaling mechanisms appeared to produce conflicting data. In some instances, these conflicts are potentially explained by different experimental conditions. Although the biological function of tetrapyrrole signaling is poorly understood, there is compelling evidence that this signaling is significant. Specifically, this signaling appears to affect the accumulation of starch and may promote abiotic stress tolerance. Tetrapyrrole-dependent plastid-to-nucleus signaling interacts with a distinct plastid-to-nucleus signaling mechanism that depends on GENOMES UNCUOPLED1 (GUN1). GUN1 contributes to a variety of processes, such as chloroplast biogenesis, the circadian rhythm, abiotic stress tolerance, and development. Thus, the contribution of tetrapyrrole signaling to plant function is potentially broader than we currently appreciate. In this review, I discuss these aspects of tetrapyrrole signaling. PMID:27807442

  20. Signal Processing, Analysis, & Display

    SciTech Connect

    Lager, Darrell; Azevado, Stephen

    1986-06-01

    SIG is a general-purpose signal processing, analysis, and display program. Its main purpose is to perform manipulations on time- and frequency-domain signals. However, it has been designed to ultimately accommodate other representations for data such as multiplexed signals and complex matrices. Two user interfaces are provided in SIG - a menu mode for the unfamiliar user and a command mode for more experienced users. In both modes errors are detected as early as possible and are indicated by friendly, meaningful messages. An on-line HELP package is also included. A variety of operations can be performed on time- and frequency-domain signals including operations on the samples of a signal, operations on the entire signal, and operations on two or more signals. Signal processing operations that can be performed are digital filtering (median, Bessel, Butterworth, and Chebychev), ensemble average, resample, auto and cross spectral density, transfer function and impulse response, trend removal, convolution, Fourier transform and inverse window functions (Hamming, Kaiser-Bessel), simulation (ramp, sine, pulsetrain, random), and read/write signals. User definable signal processing algorithms are also featured. SIG has many options including multiple commands per line, command files with arguments,commenting lines, defining commands, and automatic execution for each item in a repeat sequence. Graphical operations on signals and spectra include: x-y plots of time signals; real, imaginary, magnitude, and phase plots of spectra; scaling of spectra for continuous or discrete domain; cursor zoom; families of curves; and multiple viewports.

  1. Magnetic coupling device

    DOEpatents

    Nance, Thomas A.

    2009-08-18

    A quick connect/disconnect coupling apparatus is provided in which a base member is engaged by a locking housing through a series of interengagement pins. The pins maintain the shaft in a locked position. Upon exposure to an appropriately positioned magnetic field, pins are removed a sufficient distance such that the shaft may be withdrawn from the locking housing. The ability to lock and unlock the connector assembly requires no additional tools or parts apart from a magnetic key.

  2. Thermal coupling measurement method

    NASA Technical Reports Server (NTRS)

    Rosenthal, L. A.; Menichelli, V. J.

    1974-01-01

    Heat flow from an embedded heated wire responds to a change in the ambient environment. The wire is part of a self-balancing bridge system, and heat flow is measured directly in watts. Steady-state and transient thermal coupling can be measured directly and is an indication of the thermal resistance and diffusivity for the system under study. The method is applied to an aerospace electroexplosive component.

  3. Quick connect coupling

    NASA Technical Reports Server (NTRS)

    Lomax, Curtis (Inventor); Webbon, Bruce (Inventor)

    1995-01-01

    A cooling apparatus includes a container filled with a quantity of coolant fluid initially cooled to a solid phase, a cooling loop disposed between a heat load and the container, a pump for circulating a quantity of the same type of coolant fluid in a liquid phase through the cooling loop, and a pair of couplings for communicating the liquid phase coolant fluid into the container in a direct interface with the solid phase coolant fluid.

  4. Gain Coupling VECSELs (POSTPRINT)

    DTIC Science & Technology

    2013-01-01

    NUMBER 2002 5e. TASK NUMBER IH 5f. WORK UNIT NUMBER Y053 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION ...platform in order to explore curious laser designs and systems as their high-power, high-brightness make them attractive for many applications , and their...Moreover, their high-brightness operation makes them attractive for many applications . In considering the methods of coupling VECSELs as well as their

  5. COAXIAL TUBE COUPLING

    DOEpatents

    Niemoth, H.R.

    1963-02-26

    BS>This patent shows a device for quickly coupling coaxial tubes in metal-to-metal fashion, so as to be suitable for use in a nuclear reactor. A threaded coliar urges a tapered metal extension on the outer coaxial tube into a tapered seat in the device and simultaneously exerts pressure through a coaxial helical spring so that a similar extension on the inner tube seats in a similar seat near the other end. (AEC)

  6. Low-voltage differentially-signaled modulators

    SciTech Connect

    Zortman, William A.; Lentine, Anthony L.; Hsia, Alexander H.; Watts, Michael R.

    2015-09-08

    Photonic modulators and methods of modulating an input optical signal are provided. A photonic modulator includes at least one modulator section and differential drive circuitry. The at least one modulator section includes a P-type layer and an N-type layer forming a PN junction in the modulator section. The differential drive circuitry is electrically coupled to the P-type layer and the N-type layer of the at least one modulator section.

  7. Electrotonic vascular signal conduction and nephron synchronization.

    PubMed

    Marsh, Donald J; Toma, Ildiko; Sosnovtseva, Olga V; Peti-Peterdi, Janos; Holstein-Rathlou, Niels-Henrik

    2009-04-01

    Tubuloglomerular feedback (TGF) and the myogenic mechanism control afferent arteriolar diameter in each nephron and regulate blood flow. Both mechanisms generate self-sustained oscillations, the oscillations interact, TGF modulates the frequency and amplitude of the myogenic oscillation, and the oscillations synchronize; a 5:1 frequency ratio is the most frequent. TGF oscillations synchronize in nephron pairs supplied from a common cortical radial artery, as do myogenic oscillations. We propose that electrotonic vascular signal propagation from one juxtaglomerular apparatus interacts with similar signals from other nephrons to produce synchronization. We tested this idea in tubular-vascular preparations from mice. Vascular smooth muscle cells were loaded with a fluorescent voltage-sensitive dye; fluorescence intensity was measured with confocal microscopy. Perfusion of the thick ascending limb activated TGF and depolarized afferent arteriolar smooth muscle cells. The depolarization spread to the cortical radial artery and other afferent arterioles and declined with distance from the perfused juxtaglomerular apparatus, consistent with electrotonic vascular signal propagation. With a mathematical model of two coupled nephrons, we estimated the conductance of nephron coupling by fitting simulated vessel diameters to experimental data. With this value, we simulated nephron pairs to test for synchronization. In single-nephron simulations, the frequency of the TGF oscillation varied with nephron length. Coupling nephrons of different lengths forced TGF frequencies of both pair members to converge to a common value. The myogenic oscillations also synchronized, and the synchronization between the TGF and the myogenic oscillations showed an increased stability against parameter perturbations. Electronic vascular signal propagation is a plausible mechanism for nephron synchronization. Coupling increased the stability of the various oscillations.

  8. Quick torque coupling

    DOEpatents

    Luft, Peter A.

    2009-05-12

    A coupling for mechanically connecting modular tubular struts of a positioning apparatus or space frame, comprising a pair of toothed rings (10, 12) attached to separate strut members (16), the teeth (18, 20) of the primary rings (10, 12) mechanically interlocking in both an axial and circumferential manner, and a third part comprising a sliding, toothed collar (14) the teeth (22) of which interlock the teeth (18, 20) of the primary rings (10, 12), preventing them from disengaging, and completely locking the assembly together. A secondary mechanism provides a nesting force for the collar, and/or retains it. The coupling is self-contained and requires no external tools for installation, and can be assembled with gloved hands in demanding environments. No gauging or measured torque is required for assembly. The assembly can easily be visually inspected to determine a "go" or "no-go" status. The coupling is compact and relatively light-weight. Because of it's triply interlocking teeth, the connection is rigid. The connection does not primarily rely on clamps, springs or friction based fasteners, and is therefore reliable in fail-safe applications.

  9. Dynamic coupling of plasmonic resonators

    PubMed Central

    Lee, Suyeon; Park, Q-Han

    2016-01-01

    We clarify the nature of dynamic coupling in plasmonic resonators and determine the dynamic coupling coefficient using a simple analytic model. We show that plasmonic resonators, such as subwavelength holes in a metal film which can be treated as bound charge oscillators, couple to each other through the retarded interaction of oscillating screened charges. Our dynamic coupling model offers, for the first time, a quantitative analytic description of the fundamental symmetric and anti-symmetric modes of coupled resonators which agrees with experimental results. Our model also reveals that plasmonic electromagnetically induced transparency arises in any coupled resonators of slightly unequal lengths, as confirmed by a rigorous numerical calculation and experiments. PMID:26911786

  10. Satellite signaling at synapses

    PubMed Central

    O'Connor-Giles, Kate M.; Ganetzky, Barry

    2013-01-01

    Neural function requires effective communication between neurons and their targets at synapses. Thus, proper formation, growth and plasticity of synapses are critical to behavior. A retrograde (muscle to neuron) BMP signal is required to promote synaptic growth, homeostasis and stability at Drosophila neuromuscular junctions (NMJs).1-4 We recently demonstrated that this signal constitutes an instructive signal that sculpts synaptic growth in a graded manner and uncovered a presynaptic endocytic mechanism that modulates BMP signaling levels. In the absence of this regulation, excessive BMP signaling results in overgrown NMJs with a proliferation of ectopic boutons.5 PMID:20798607

  11. Quadrupole sensitive pulse for signal filtering.

    PubMed

    Evgeny, Nimerovsky; Jerschow, Alexej

    2016-04-01

    A longstanding problem in quadrupolar NMR of semi-solids is the selection of signals originating from ordered nuclei, i.e. those that experience a non-vanishing quadrupolar coupling. Established techniques, such as for example multiple-quantum filters are not adequate in situations when the radio frequency power is on the order of the quadrupolar coupling or the quadrupolar relaxation rates, such as may be the case on an MRI scanner, or in ex situ applications. In this manuscript we show a new method for the selective excitation of ordered spin-3/2 nuclei, which produces the desired results when the radio frequency power is approximately equal or smaller than quadrupolar frequency. Using a combination of simulations and experiments with (23)Na in NaCl solution, Pf1-solutions, and bovine patellar cartilage samples we further show how the value of the quadrupolar frequency and global features of a quadrupolar coupling distribution can be extracted from these experiments.

  12. Quadrupole sensitive pulse for signal filtering

    NASA Astrophysics Data System (ADS)

    Evgeny, Nimerovsky; Jerschow, Alexej

    2016-04-01

    A longstanding problem in quadrupolar NMR of semi-solids is the selection of signals originating from ordered nuclei, i.e. those that experience a non-vanishing quadrupolar coupling. Established techniques, such as for example multiple-quantum filters are not adequate in situations when the radio frequency power is on the order of the quadrupolar coupling or the quadrupolar relaxation rates, such as may be the case on an MRI scanner, or in ex situ applications. In this manuscript we show a new method for the selective excitation of ordered spin-3/2 nuclei, which produces the desired results when the radio frequency power is approximately equal or smaller than quadrupolar frequency. Using a combination of simulations and experiments with 23Na in NaCl solution, Pf1-solutions, and bovine patellar cartilage samples we further show how the value of the quadrupolar frequency and global features of a quadrupolar coupling distribution can be extracted from these experiments.

  13. Calcium signaling as a mediator of cell energy demand and a trigger to cell death

    PubMed Central

    Bhosale, Gauri; Sharpe, Jenny A.; Sundier, Stephanie Y.

    2015-01-01

    Calcium signaling is pivotal to a host of physiological pathways. A rise in calcium concentration almost invariably signals an increased cellular energy demand. Consistent with this, calcium signals mediate a number of pathways that together serve to balance energy supply and demand. In pathological states, calcium signals can precipitate mitochondrial injury and cell death, especially when coupled to energy depletion and oxidative or nitrosative stress. This review explores the mechanisms that couple cell signaling pathways to metabolic regulation or to cell death. The significance of these pathways is exemplified by pathological case studies, such as those showing loss of mitochondrial calcium uptake 1 in patients and ischemia/reperfusion injury. PMID:26375864

  14. G Protein-Coupled Receptor Biased Agonism

    PubMed Central

    Hodavance, Sima Y.; Gareri, Clarice; Torok, Rachel D.; Rockman, Howard A.

    2016-01-01

    G protein-coupled receptors (GPCR) are the largest family of targets for current therapeutics. The classic model of their activation was binary, where agonist binding induced an active conformation and subsequent downstream signaling. Subsequently, the revised concept of biased agonism emerged, where different ligands at the same GPCR selectively activate one downstream pathway versus another. Advances in understanding the mechanism of biased agonism has led to the development of novel ligands, which have the potential for improved therapeutic and safety profiles. In this review, we summarize the theory and most recent breakthroughs in understanding biased signaling, examine recent laboratory investigations concerning biased ligands across different organ systems, and discuss the promising clinical applications of biased agonism. PMID:26751266

  15. The QCD running coupling

    NASA Astrophysics Data System (ADS)

    Deur, Alexandre; Brodsky, Stanley J.; de Téramond, Guy F.

    2016-09-01

    We review the present theoretical and empirical knowledge for αs, the fundamental coupling underlying the interactions of quarks and gluons in Quantum Chromodynamics (QCD). The dependence of αs(Q2) on momentum transfer Q encodes the underlying dynamics of hadron physics-from color confinement in the infrared domain to asymptotic freedom at short distances. We review constraints on αs(Q2) at high Q2, as predicted by perturbative QCD, and its analytic behavior at small Q2, based on models of nonperturbative dynamics. In the introductory part of this review, we explain the phenomenological meaning of the coupling, the reason for its running, and the challenges facing a complete understanding of its analytic behavior in the infrared domain. In the second, more technical, part of the review, we discuss the behavior of αs(Q2) in the high momentum transfer domain of QCD. We review how αs is defined, including its renormalization scheme dependence, the definition of its renormalization scale, the utility of effective charges, as well as "Commensurate Scale Relations" which connect the various definitions of the QCD coupling without renormalization-scale ambiguity. We also report recent significant measurements and advanced theoretical analyses which have led to precise QCD predictions at high energy. As an example of an important optimization procedure, we discuss the "Principle of Maximum Conformality", which enhances QCD's predictive power by removing the dependence of the predictions for physical observables on the choice of theoretical conventions such as the renormalization scheme. In the last part of the review, we discuss the challenge of understanding the analytic behavior αs(Q2) in the low momentum transfer domain. We survey various theoretical models for the nonperturbative strongly coupled regime, such as the light-front holographic approach to QCD. This new framework predicts the form of the quark-confinement potential underlying hadron spectroscopy and

  16. A system for tranmitting low frequency analog signals over ac power lines

    DOEpatents

    Baker, S.P.; Durall, R.L.; Haynes, H.D.

    1987-07-30

    A system for transmitting low frequency analog signals over ac power lines using FM modulation. A low frequency analog signal to be transmitted is first applied to a voltage-to-frequency converter where it is converted to a signal whose frequency varies in proportion to the analog signal amplitude. This signal is then used to modulate the carrier frequency of an FM transmitter coupled to an ac power line. The modulation signal frequency range is selected to be within the response band of the FM transmitter. The FM modulated carrier signal is received by an FM receiver coupled to the ac power line, demodulated and the demodulated signal frequency is converted by a frequency-to-voltage converter back to the form of the original low frequency analog input signal. 4 figs.

  17. System for transmitting low frequency analog signals over AC power lines

    DOEpatents

    Baker, Steven P.; Durall, Robert L.; Haynes, Howard D.

    1989-01-01

    A system for transmitting low frequency analog signals over AC power lines using FM modulation. A low frequency analog signal to be transmitted is first applied to a voltage-to-frequency converter where it is converted to a signal whose frequency varies in proportion to the analog signal amplitude. This signal is then used to modulate the carrier frequency of an FM transmitter coupled to an AC power line. The modulation signal frequency range in selected to be within the response band of the FM transmitter. The FM modulated carrier signal is received by an FM receiver coupled to the AC power line, demodulated and the demodulated signal frequency is converted by a frequency-to-voltage converter back to the form of the original low frequency analog input signal.

  18. System for transmitting low frequency analog signals over AC power lines

    DOEpatents

    Baker, Steven P.; Durall, Robert L.; Haynes, Howard D.

    1989-09-05

    A system for transmitting low frequency analog signals over AC power lines using FM modulation. A low frequency analog signal to be transmitted is first applied to a voltage-to-frequency converter where it is converted to a signal whose frequency varies in proportion to the analog signal amplitude. This signal is then used to modulate the carrier frequency of an FM transmitter coupled to an AC power line. The modulation signal frequency range in selected to be within the response band of the FM transmitter. The FM modulated carrier signal is received by an FM receiver coupled to the AC power line, demodulated and the demodulated signal frequency is converted by a frequency-to-voltage converter back to the form of the original low frequency analog input signal.

  19. Signal-sequence induced conformational changes in the signal recognition particle

    PubMed Central

    Hainzl, Tobias; Sauer-Eriksson, A. Elisabeth

    2015-01-01

    Co-translational protein targeting is an essential, evolutionarily conserved pathway for delivering nascent proteins to the proper cellular membrane. In this pathway, the signal recognition particle (SRP) first recognizes the N-terminal signal sequence of nascent proteins and subsequently interacts with the SRP receptor. For this, signal sequence binding in the SRP54 M domain must be effectively communicated to the SRP54 NG domain that interacts with the receptor. Here we present the 2.9 Å crystal structure of unbound- and signal sequence bound SRP forms, both present in the asymmetric unit. The structures provide evidence for a coupled binding and folding mechanism in which signal sequence binding induces the concerted folding of the GM linker helix, the finger loop, and the C-terminal alpha helix αM6. This mechanism allows for a high degree of structural adaptability of the binding site and suggests how signal sequence binding in the M domain is coupled to repositioning of the NG domain. PMID:26051119

  20. Acoustic Signal Processing

    NASA Astrophysics Data System (ADS)

    Hartmann, William M.; Candy, James V.

    Signal processing refers to the acquisition, storage, display, and generation of signals - also to the extraction of information from signals and the re-encoding of information. As such, signal processing in some form is an essential element in the practice of all aspects of acoustics. Signal processing algorithms enable acousticians to separate signals from noise, to perform automatic speech recognition, or to compress information for more efficient storage or transmission. Signal processing concepts are the building blocks used to construct models of speech and hearing. Now, in the 21st century, all signal processing is effectively digital signal processing. Widespread access to high-speed processing, massive memory, and inexpensive software make signal processing procedures of enormous sophistication and power available to anyone who wants to use them. Because advanced signal processing is now accessible to everybody, there is a need for primers that introduce basic mathematical concepts that underlie the digital algorithms. The present handbook chapter is intended to serve such a purpose.

  1. Signal velocity in oscillator arrays

    NASA Astrophysics Data System (ADS)

    Cantos, C. E.; Veerman, J. J. P.; Hammond, D. K.

    2016-09-01

    We investigate a system of coupled oscillators on the circle, which arises from a simple model for behavior of large numbers of autonomous vehicles where the acceleration of each vehicle depends on the relative positions and velocities between itself and a set of local neighbors. After describing necessary and sufficient conditions for asymptotic stability, we derive expressions for the phase velocity of propagation of disturbances in velocity through this system. We show that the high frequencies exhibit damping, which implies existence of well-defined signal velocitiesc+ > 0 and c- < 0 such that low frequency disturbances travel through the flock as f+(x - c+t) in the direction of increasing agent numbers and f-(x - c-t) in the other.

  2. Redox signaling in cardiac myocytes

    PubMed Central

    Santos, Celio X.C.; Anilkumar, Narayana; Zhang, Min; Brewer, Alison C.; Shah, Ajay M.

    2011-01-01

    The heart has complex mechanisms that facilitate the maintenance of an oxygen supply–demand balance necessary for its contractile function in response to physiological fluctuations in workload as well as in response to chronic stresses such as hypoxia, ischemia, and overload. Redox-sensitive signaling pathways are centrally involved in many of these homeostatic and stress-response mechanisms. Here, we review the main redox-regulated pathways that are involved in cardiac myocyte excitation–contraction coupling, differentiation, hypertrophy, and stress responses. We discuss specific sources of endogenously generated reactive oxygen species (e.g., mitochondria and NADPH oxidases of the Nox family), the particular pathways and processes that they affect, the role of modulators such as thioredoxin, and the specific molecular mechanisms that are involved—where this knowledge is available. A better understanding of this complex regulatory system may allow the development of more specific therapeutic strategies for heart diseases. PMID:21236334

  3. Neuronal signaling through endocytosis.

    PubMed

    Cosker, Katharina E; Segal, Rosalind A

    2014-02-01

    The distinctive morphology of neurons, with complex dendritic arbors and extensive axons, presents spatial challenges for intracellular signal transduction. The endosomal system provides mechanisms that enable signaling molecules initiated by extracellular cues to be trafficked throughout the expanse of the neuron, allowing intracellular signals to be sustained over long distances. Therefore endosomes are critical for many aspects of neuronal signaling that regulate cell survival, axonal growth and guidance, dendritic branching, and cell migration. An intriguing characteristic of neuronal signal transduction is that endosomal trafficking enables physiological responses that vary based on the subcellular location of signal initiation. In this review, we will discuss the specialized mechanisms and the functional significance of endosomal signaling in neurons, both during normal development and in disease.

  4. Neuronal Signaling through Endocytosis

    PubMed Central

    Cosker, Katharina E.; Segal, Rosalind A.

    2014-01-01

    The distinctive morphology of neurons, with complex dendritic arbors and extensive axons, presents spatial challenges for intracellular signal transduction. The endosomal system provides mechanisms that enable signaling molecules initiated by extracellular cues to be trafficked throughout the expanse of the neuron, allowing intracellular signals to be sustained over long distances. Therefore endosomes are critical for many aspects of neuronal signaling that regulate cell survival, axonal growth and guidance, dendritic branching, and cell migration. An intriguing characteristic of neuronal signal transduction is that endosomal trafficking enables physiological responses that vary based on the subcellular location of signal initiation. In this review, we will discuss the specialized mechanisms and the functional significance of endosomal signaling in neurons, both during normal development and in disease. PMID:24492712

  5. G-protein-coupled receptors: past, present and future

    PubMed Central

    Hill, Stephen J

    2006-01-01

    The G-protein-coupled receptor (GPCR) family represents the largest and most versatile group of cell surface receptors. Drugs active at these receptors have therapeutic actions across a wide range of human diseases ranging from allergic rhinitis to pain, hypertension and schizophrenia. This review provides a brief historical overview of the properties and signalling characteristics of this important family of receptors. PMID:16402114

  6. Conference on Charge-Coupled Device Technology and Applications

    NASA Technical Reports Server (NTRS)

    1976-01-01

    Papers were presented from the conference on charge coupled device technology and applications. The following topics were investigated: data processing; infrared; devices and testing; electron-in, x-ray, radiation; and applications. The emphasis was on the advances of mutual relevance and potential significance both to industry and NASA's current and future requirements in all fields of imaging, signal processing and memory.

  7. Chaotic Ising-like dynamics in traffic signals

    PubMed Central

    Suzuki, Hideyuki; Imura, Jun-ichi; Aihara, Kazuyuki

    2013-01-01

    The green and red lights of a traffic signal can be viewed as the up and down states of an Ising spin. Moreover, traffic signals in a city interact with each other, if they are controlled in a decentralised way. In this paper, a simple model of such interacting signals on a finite-size two-dimensional lattice is shown to have Ising-like dynamics that undergoes a ferromagnetic phase transition. Probabilistic behaviour of the model is realised by chaotic billiard dynamics that arises from coupled non-chaotic elements. This purely deterministic model is expected to serve as a starting point for considering statistical mechanics of traffic signals. PMID:23350034

  8. Sparse Bayesian Learning for DOA Estimation with Mutual Coupling

    PubMed Central

    Dai, Jisheng; Hu, Nan; Xu, Weichao; Chang, Chunqi

    2015-01-01

    Sparse Bayesian learning (SBL) has given renewed interest to the problem of direction-of-arrival (DOA) estimation. It is generally assumed that the measurement matrix in SBL is precisely known. Unfortunately, this assumption may be invalid in practice due to the imperfect manifold caused by unknown or misspecified mutual coupling. This paper describes a modified SBL method for joint estimation of DOAs and mutual coupling coefficients with uniform linear arrays (ULAs). Unlike the existing method that only uses stationary priors, our new approach utilizes a hierarchical form of the Student t prior to enforce the sparsity of the unknown signal more heavily. We also provide a distinct Bayesian inference for the expectation-maximization (EM) algorithm, which can update the mutual coupling coefficients more efficiently. Another difference is that our method uses an additional singular value decomposition (SVD) to reduce the computational complexity of the signal reconstruction process and the sensitivity to the measurement noise. PMID:26501284

  9. Optimizing information flow in small genetic networks. IV. Spatial coupling

    NASA Astrophysics Data System (ADS)

    Sokolowski, Thomas R.; Tkačik, Gašper

    2015-06-01

    We typically think of cells as responding to external signals independently by regulating their gene expression levels, yet they often locally exchange information and coordinate. Can such spatial coupling be of benefit for conveying signals subject to gene regulatory noise? Here we extend our information-theoretic framework for gene regulation to spatially extended systems. As an example, we consider a lattice of nuclei responding to a concentration field of a transcriptional regulator (the input) by expressing a single diffusible target gene. When input concentrations are low, diffusive coupling markedly improves information transmission; optimal gene activation functions also systematically change. A qualitatively different regulatory strategy emerges where individual cells respond to the input in a nearly steplike fashion that is subsequently averaged out by strong diffusion. While motivated by early patterning events in the Drosophila embryo, our framework is generically applicable to spatially coupled stochastic gene expression models.

  10. Optimizing information flow in small genetic networks. IV. Spatial coupling.

    PubMed

    Sokolowski, Thomas R; Tkačik, Gašper

    2015-06-01

    We typically think of cells as responding to external signals independently by regulating their gene expression levels, yet they often locally exchange information and coordinate. Can such spatial coupling be of benefit for conveying signals subject to gene regulatory noise? Here we extend our information-theoretic framework for gene regulation to spatially extended systems. As an example, we consider a lattice of nuclei responding to a concentration field of a transcriptional regulator (the input) by expressing a single diffusible target gene. When input concentrations are low, diffusive coupling markedly improves information transmission; optimal gene activation functions also systematically change. A qualitatively different regulatory strategy emerges where individual cells respond to the input in a nearly steplike fashion that is subsequently averaged out by strong diffusion. While motivated by early patterning events in the Drosophila embryo, our framework is generically applicable to spatially coupled stochastic gene expression models.

  11. Coupling light in photonic crystal waveguides: A review

    NASA Astrophysics Data System (ADS)

    Dutta, Hemant Sankar; Goyal, Amit Kumar; Srivastava, Varun; Pal, Suchandan

    2016-07-01

    Submicron scale structures with high index contrast are key to compact structures for realizing photonic integrated structures. Ultra-compact optical devices in silicon-on-insulator (SOI) substrates serve compatibility with semiconductor fabrication technology leading to reduction of cost and mass production. Photonic crystal structures possess immense potential for realizing various compact optical devices. However, coupling light to photonic crystal waveguide structures is crucial in order to achieve strong transmission and wider bandwidth of signal. Widening of bandwidth will increase potential for various applications and high transmission will make easy signal detection at the output. In this paper, the techniques reported so far for coupling light in photonic crystal waveguides have been reviewed and analyzed so that a comprehensive guide for an efficient coupling to photonic crystal waveguides can be made possible.

  12. ESPC Coupled Global Prediction System

    DTIC Science & Technology

    2014-09-30

    coupled air-sea momentum flux on the ocean circulation has been investigated in a series of near twin experiments, where aspects of the coupled wind stress...Award Number: N0001414WX20051 http://www.nrlmry.navy.mil LONG-TERM GOALS Develop and implement a fully coupled global atmosphere/wave/ ocean ...arise in the coupled system. Implement the tripolar grid for WaveWatch-III and wave forcing in the ocean . Incorporate time-dependent, radiatively

  13. Controllable optomechanical coupling in serially-coupled triple resonators

    SciTech Connect

    Huang, Chenguang Zhao, Yunsong; Fan, Jiahua; Zhu, Lin

    2014-12-15

    Radiation pressure can efficiently couple mechanical modes with optical modes in an optical cavity. The coupling efficiency is quite dependent on the interaction between the optical mode and mechanical mode. In this report, we investigate a serially-coupled triple resonator system, where a freestanding beam is placed in the vicinity of the middle resonator. In this coupled system, we demonstrate that the mechanical mode of the free-standing beam can be selectively coupled to different resonance supermodes through the near field interaction.

  14. Adaptive coupling and enhanced synchronization in coupled phase oscillators

    NASA Astrophysics Data System (ADS)

    Ren, Quansheng; Zhao, Jianye

    2007-07-01

    We study the dynamics of an adaptive coupled array of phase oscillators. The adaptive law is designed in such a way that the coupling grows stronger for the pairs which have larger phase incoherence. The proposed scheme enhances the synchronization and achieves a more reasonable coupling dynamics for the network of oscillators with different intrinsic frequencies. The synchronization speed and the steady-state phase difference can be adjusted by the parameters of the adaptive law. Besides global coupling, nearest-neighbor ring coupling is also considered to demonstrate the generality of the method.

  15. Characteristics of near-surface electrokinetic coupling

    NASA Astrophysics Data System (ADS)

    Beamish, David

    1999-04-01

    Naturally occurring electric potentials at the Earth's surface are traditionally studied using self-potential geophysics. Recent theoretical and experimental work has reinvestigated the manner in which the measurement can be made dynamically using a pressure source. The methodology, often referred to as seismoelectric, relies on electrokinetic coupling at interfaces in the streaming potential coefficient. The ultimate aim of the developing methodologies lies in the detection of zones of high fluid mobility (permeability) and fluid geochemical contrasts within the subsurface. As yet there are no standard methods of recording and interpretation: the technique remains experimental. Field measurements are made using a seismic source and by recording electric voltage across arrays of surface dipoles. This study presents observational characteristics of electrokinetic coupling based on experiments carried out in a wide range of environments. Theory concerning the coupled elastic and electromagnetic wave equations in a saturated porous medium is discussed. It is predicted that coupling will produce electromagnetic radiation patterns from vertical electric dipoles generated at interfaces. Surface- and body-wave coupling mechanisms should provide different time-distance patterns. Vertical electric dipole radiation sources are modelled and their spatial characteristics presented. A variety of experimental configurations have been used, and geometries that exploit phase asymmetry to enhance the separation of signal and noise are emphasized. The main experimental results presented are detailed observations in the immediate vicinity of the source. Simultaneous arrivals across arrays of surface dipoles are not common. The majority of such experiments have indicated that shot-symmetric voltages which display low-velocity moveout are the dominant received waveforms.

  16. Telephone multiline signaling using common signal pair

    NASA Technical Reports Server (NTRS)

    Goodloe, R. R.; Toole, P. C.; Belt, J. L.; Leininger, D. B. (Inventor)

    1979-01-01

    An operator can rapidly and automatically produce coded electrical signals by manipulating mechanical thumb wheel switches so as to instruct a service center to connect any number of telephone lines to the console thus enabling the operator to listen and/or talk over several lines simultaneously. The system includes an on-site console having several mechanically operated thumb wheel switches to which the desired lines to be connected can be dialed in. Electrical coded signals are fed to a number of banks of line AND gates representing units, tens and hundreds, a group of channel gates, and a command gate. These signals are gated out in a controlled manner to an encoder which generates tones that are transmitted over a single line to a communication service center.

  17. Quantitation of signal transduction.

    PubMed

    Krauss, S; Brand, M D

    2000-12-01

    Conventional qualitative approaches to signal transduction provide powerful ways to explore the architecture and function of signaling pathways. However, at the level of the complete system, they do not fully depict the interactions between signaling and metabolic pathways and fail to give a manageable overview of the complexity that is often a feature of cellular signal transduction. Here, we introduce a quantitative experimental approach to signal transduction that helps to overcome these difficulties. We present a quantitative analysis of signal transduction during early mitogen stimulation of lymphocytes, with steady-state respiration rate as a convenient marker of metabolic stimulation. First, by inhibiting various key signaling pathways, we measure their relative importance in regulating respiration. About 80% of the input signal is conveyed via identifiable routes: 50% through pathways sensitive to inhibitors of protein kinase C and MAP kinase and 30% through pathways sensitive to an inhibitor of calcineurin. Second, we quantify how each of these pathways differentially stimulates functional units of reactions that produce and consume a key intermediate in respiration: the mitochondrial membrane potential. Both the PKC and calcineurin routes stimulate consumption more strongly than production, whereas the unidentified signaling routes stimulate production more than consumption, leading to no change in membrane potential despite increased respiration rate. The approach allows a quantitative description of the relative importance of signal transduction pathways and the routes by which they activate a specific cellular process. It should be widely applicable.

  18. AC-coupled front-end for biopotential measurements.

    PubMed

    Spinelli, Enrique Mario; Pallàs-Areny, Ramon; Mayosky, Miguel Angel

    2003-03-01

    AC coupling is essential in biopotential measurements. Electrode offset potentials can be several orders of magnitude larger than the amplitudes of the biological signals of interest, thus limiting the admissible gain of a dc-coupled front end to prevent amplifier saturation. A high-gain input stage needs ac input coupling. This can be achieved by series capacitors, but in order to provide a bias path, grounded resistors are usually included, which degrade the common mode rejection ratio (CMRR). This paper proposes a novel balanced input ac-coupling network that provides a bias path without any connection to ground, thus resulting in a high CMRR. The circuit being passive, it does not limit the differential dc input voltage. Furthermore, differential signals are ac coupled, whereas common-mode voltages are dc coupled, thus allowing the closed-loop control of the dc common mode voltage by means of a driven-right-leg circuit. This makes the circuit compatible with common-mode dc shifting strategies intended for single-supply biopotential amplifiers. The proposed circuit allows the implementation of high-gain biopotential amplifiers with a reduced number of parts, thus resulting in low power consumption. An electrocardiogram amplifier built according to the proposed design achieves a CMRR of 123 dB at 50 Hz.

  19. Optical Fiber Delay Line Signal Processing.

    NASA Astrophysics Data System (ADS)

    Newton, Steven Arthur

    The delay line transversal filter is a basic component in analog signal processing systems. Unfortunately, conventional delay line devices, such as those that use surface acoustic waves, are largely limited to operation at frequencies of several hundred megahertz and below. In this work, single-mode optical fiber has been used as a delay medium to make transversal filters that extend this kind of signal processing to frequencies of one gigahertz and above. Single-mode optical fiber is an excellent delay medium because it exhibits extremely low loss and dispersion. By efficiently collecting, weighting, and combining signals extracted from a fiber delay line, single-mode fiber can be used, not only to transmit broadband signals, but to process them as well. The goals of the work have been to study efficient tapping mechanisms, and to construct fiber transversal filters capable of performing some basic signal processing functions. Several different tapped and recirculating delay line prototypes have been fabricated using a variety of tapping techniques, including macrobending and evanescent field coupling. These devices have been used to demonstrate basic signal processing functions, such as code generation, convolution, correlation, and frequency filtering, at frequencies that exceed those possible using conventional delay line technologies. Fiber recirculating delay line loops have also been demonstrated as transient memories for the temporary storage of signals and as a means of time division multiplexing via data rate transformation. These devices are the building blocks that are necessary to make systems capable of performing complex signal processing functions. With the recent development of high speed optical sources and detectors to interface with fiber systems of this kind, the real time processing of signals having bandwidths of tens of gigahertz is envisioned.

  20. Chaos synchronization by nonlinear coupling

    NASA Astrophysics Data System (ADS)

    Petereit, Johannes; Pikovsky, Arkady

    2017-03-01

    We study synchronization properties of three nonlinearly coupled chaotic maps. Coupling is introduced in such a way, that it cannot be reduced to pairwise terms, but includes combined action of all interacting units. For two models of nonlinear coupling we characterize the transition to complete synchrony, as well as partially synchronized states. Relation to hypernetworks of chaotic units is also discussed.

  1. Air-Coupled Vibrometry

    NASA Astrophysics Data System (ADS)

    Döring, D.; Solodov, I.; Busse, G.

    Sound and ultrasound in air are the products of a multitude of different processes and thus can be favorable or undesirable phenomena. Development of experimental tools for non-invasive measurements and imaging of airborne sound fields is of importance for linear and nonlinear nondestructive material testing as well as noise control in industrial or civil engineering applications. One possible solution is based on acousto-optic interaction, like light diffraction imaging. The diffraction approach usually requires a sophisticated setup with fine optical alignment barely applicable in industrial environment. This paper focuses on the application of the robust experimental tool of scanning laser vibrometry, which utilizes commercial off-the-shelf equipment. The imaging technique of air-coupled vibrometry (ACV) is based on the modulation of the optical path length by the acoustic pressure of the sound wave. The theoretical considerations focus on the analysis of acousto-optical phase modulation. The sensitivity of the ACV in detecting vibration velocity was estimated as ~1 mm/s. The ACV applications to imaging of linear airborne fields are demonstrated for leaky wave propagation and measurements of ultrasonic air-coupled transducers. For higher-intensity ultrasound, the classical nonlinear effect of the second harmonic generation was measured in air. Another nonlinear application includes a direct observation of the nonlinear air-coupled emission (NACE) from the damaged areas in solid materials. The source of the NACE is shown to be strongly localized around the damage and proposed as a nonlinear "tag" to discern and image the defects.

  2. Conformational biosensors reveal GPCR signalling from endosomes.

    PubMed

    Irannejad, Roshanak; Tomshine, Jin C; Tomshine, Jon R; Chevalier, Michael; Mahoney, Jacob P; Steyaert, Jan; Rasmussen, Søren G F; Sunahara, Roger K; El-Samad, Hana; Huang, Bo; von Zastrow, Mark

    2013-03-28

    A long-held tenet of molecular pharmacology is that canonical signal transduction mediated by G-protein-coupled receptor (GPCR) coupling to heterotrimeric G proteins is confined to the plasma membrane. Evidence supporting this traditional view is based on analytical methods that provide limited or no subcellular resolution. It has been subsequently proposed that signalling by internalized GPCRs is restricted to G-protein-independent mechanisms such as scaffolding by arrestins, or GPCR activation elicits a discrete form of persistent G protein signalling, or that internalized GPCRs can indeed contribute to the acute G-protein-mediated response. Evidence supporting these various latter hypotheses is indirect or subject to alternative interpretation, and it remains unknown if endosome-localized GPCRs are even present in an active form. Here we describe the application of conformation-specific single-domain antibodies (nanobodies) to directly probe activation of the β2-adrenoceptor, a prototypical GPCR, and its cognate G protein, Gs (ref. 12), in living mammalian cells. We show that the adrenergic agonist isoprenaline promotes receptor and G protein activation in the plasma membrane as expected, but also in the early endosome membrane, and that internalized receptors contribute to the overall cellular cyclic AMP response within several minutes after agonist application. These findings provide direct support for the hypothesis that canonical GPCR signalling occurs from endosomes as well as the plasma membrane, and suggest a versatile strategy for probing dynamic conformational change in vivo.

  3. The coupled atom transistor

    NASA Astrophysics Data System (ADS)

    Jehl, X.; Voisin, B.; Roche, B.; Dupont-Ferrier, E.; De Franceschi, S.; Sanquer, M.; Cobian, M.; Niquet, Y.-M.; Sklénard, B.; Cueto, O.; Wacquez, R.; Vinet, M.

    2015-04-01

    We describe the first implementation of a coupled atom transistor where two shallow donors (P or As) are implanted in a nanoscale silicon nanowire and their electronic levels are controlled with three gate voltages. Transport spectroscopy through these donors placed in series is performed both at zero and microwave frequencies. The coherence of the charge transfer between the two donors is probed by Landau-Zener-Stückelberg interferometry. Single-charge transfer at zero bias (electron pumping) has been performed and the crossover between the adiabatic and non-adiabatic regimes is studied.

  4. Sealing coupling. [LMFBR

    DOEpatents

    Pardini, J.A.; Brubaker, R.C.; Rusnak, J.J.

    1982-09-20

    Disclosed is a remotely operable releasable sealing coupling which provides fluid-tight joinder of upper and a lower conduit sections. Each conduit section has a concave conical sealing surface adjacent its end portion. A tubular sleeve having convex spherical ends is inserted between the conduit ends to form line contact with the concave conical end portions. An inwardly projecting lip located at one end of the sleeve cooperates with a retaining collar formed on the upper pipe end to provide swivel capture for the sleeve. The upper conduit section also includes a tapered lower end portion which engages the inside surface of the sleeve to limit misalignment of the connected conduit sections.

  5. Coupling stochastic PDEs

    NASA Astrophysics Data System (ADS)

    Hairer, Martin

    2006-03-01

    We consider a class of parabolic stochastic PDEs driven by white noise in time, and we are interested in showing ergodicity for some cases where the noise is degenerate, i.e., acts only on part of the equation. In some cases where the standard Strong Feller / Irreducibility argument fails, one can nevertheless implement a coupling construction that ensures uniqueness of the invariant measure. We focus on the example of the complex Ginzburg-Landau equation driven by real space-time white noise.

  6. Intrinsic Coupling Modes in Source-Reconstructed Electroencephalography

    PubMed Central

    Breakspear, Michael; Britz, Juliane; Boonstra, Tjeerd W.

    2014-01-01

    Abstract Intrinsic coupling of neuronal assemblies constitutes a key feature of ongoing brain activity, yielding the rich spatiotemporal patterns observed in neuroimaging data and putatively supporting cognitive processes. Intrinsic coupling has been investigated in electrophysiological recordings using two types of functional connectivity measures: amplitude and phase coupling. These two coupling modes differ in their likely causes and functions, and have been proposed to provide complementary insights into intrinsic neuronal interactions. Here, we investigate the relationship between amplitude and phase coupling in source-reconstructed electroencephalography (EEG). Volume conduction is a key obstacle for connectivity analysis in EEG—we therefore also test the envelope correlation of orthogonalized signals and the phase lag index. Functional connectivity between six seed source regions (bilateral visual, sensorimotor, and auditory cortices) and all other cortical voxels was computed. For all four measures, coupling between homologous sensory areas in both hemispheres was significantly higher than with other voxels at the same physical distance. The frequency of significant coupling differed between sensory areas: 10 Hz for visual, 30 Hz for auditory, and 40 Hz for sensorimotor cortices. By contrasting envelope correlations and phase locking values, we observed two distinct clusters of voxels showing a different relationship between amplitude and phase coupling. Large clusters contiguous to the seed regions showed an identity (1:1) relationship between amplitude and phase coupling, whereas a cluster located around the contralateral homologous regions showed higher phase than amplitude coupling. These results show a relationship between intrinsic coupling modes that is distinct from the effect of volume conduction. PMID:25230358

  7. Cytokine signalling in mammary gland development.

    PubMed

    Watson, Christine J; Oliver, Carrie H; Khaled, Walid T

    2011-03-01

    Mammary gland development occurs in three distinct stages during the lifetime of the female mammal: in embryonic, pubertal and reproductive life. At each of these developmental stages, different signalling molecules induce changes in both the epithelium and the surrounding stroma. However, it is during pregnancy that the most dramatic changes occur, resulting in a massive increase in the number of epithelial cells and in their function. Pregnancy initiates the development of a new epithelial lineage, the alveolar cells, which form the milk-producing lobuloalveolar structures. These cells become redundant at the end of lactation and are removed in an exquisitely controlled process of tissue remodelling coupled with extensive cell death. All of these events require not only steroid hormones but also sequential signalling by cytokines. A recent surprising discovery was that the signalling pathways and cytokines that regulate lineage determination in T helper cells are also involved in mammary gland development during pregnancy.

  8. The role of neuroimmune signaling in alcoholism.

    PubMed

    Crews, Fulton T; Lawrimore, Colleen J; Walter, T Jordan; Coleman, Leon G

    2017-02-01

    Alcohol consumption and stress increase brain levels of known innate immune signaling molecules. Microglia, the innate immune cells of the brain, and neurons respond to alcohol, signaling through Toll-like receptors (TLRs), high-mobility group box 1 (HMGB1), miRNAs, pro-inflammatory cytokines and their associated receptors involved in signaling between microglia, other glia and neurons. Repeated cycles of alcohol and stress cause a progressive, persistent induction of HMGB1, miRNA and TLR receptors in brain that appear to underlie the progressive and persistent loss of behavioral control, increased impulsivity and anxiety, as well as craving, coupled with increasing ventral striatal responses that promote reward seeking behavior and increase risk of developing alcohol use disorders. Studies employing anti-oxidant, anti-inflammatory, anti-depressant, and innate immune antagonists further link innate immune gene expression to addiction-like behaviors. Innate immune molecules are novel targets for addiction and affective disorders therapies.

  9. Signal transduction of stress via ceramide.

    PubMed Central

    Mathias, S; Peña, L A; Kolesnick, R N

    1998-01-01

    The sphingomyelin (SM) pathway is a ubiquitous, evolutionarily conserved signalling system analogous to conventional systems such as the cAMP and phosphoinositide pathways. Ceramide, which serves as second messenger in this pathway, is generated from SM by the action of a neutral or acidic SMase, or by de novo synthesis co-ordinated through the enzyme ceramide synthase. A number of direct targets for ceramide action have now been identified, including ceramide-activated protein kinase, ceramide-activated protein phosphatase and protein kinase Czeta, which couple the SM pathway to well defined intracellular signalling cascades. The SM pathway induces differentiation, proliferation or growth arrest, depending on the cell type. Very often, however, the outcome of signalling through this pathway is apoptosis. Mammalian systems respond to diverse stresses with ceramide generation, and recent studies show that yeast manifest a form of this response. Thus ceramide signalling is an older stress response system than the caspase/apoptotic death pathway, and hence these two pathways must have become linked later in evolution. Signalling of the stress response through ceramide appears to play a role in the development of human diseases, including ischaemia/reperfusion injury, insulin resistance and diabetes, atherogenesis, septic shock and ovarian failure. Further, ceramide signalling mediates the therapeutic effects of chemotherapy and radiation in some cells. An understanding of the mechanisms by which ceramide regulates physiological and pathological events in specific cells may provide new targets for pharmacological intervention. PMID:9794783

  10. Parallel-coupled dual racetrack silicon micro-resonators for quadrature amplitude modulation.

    PubMed

    Integlia, Ryan A; Yin, Lianghong; Ding, Duo; Pan, David Z; Gill, Douglas M; Jiang, Wei

    2011-08-01

    A parallel-coupled dual racetrack silicon micro-resonator structure is proposed and analyzed for M-ary quadrature amplitude modulation. The over-coupled, critically coupled, and under-coupled scenarios are systematically studied. Simulations indicate that only the over-coupled structures can generate arbitrary M-ary quadrature signals. Analytic study shows that the large dynamic range of amplitude and phase of a modulated over-coupled structure stems from the strong cross-coupling between two resonators, which can be understood through a delicate balance between the direct sum and the "interaction" terms. Potential asymmetries in the coupling constants and quality factors of the resonators are systematically studied. Compensations for these asymmetries by phase adjustment are shown feasible.

  11. Cytoskeleton in Mast Cell Signaling

    PubMed Central

    Dráber, Pavel; Sulimenko, Vadym; Dráberová, Eduarda

    2012-01-01

    Mast cell activation mediated by the high affinity receptor for IgE (FcεRI) is a key event in allergic response and inflammation. Other receptors on mast cells, as c-Kit for stem cell factor and G protein-coupled receptors (GPCRs) synergistically enhance the FcεRI-mediated release of inflammatory mediators. Activation of various signaling pathways in mast cells results in changes in cell morphology, adhesion to substrate, exocytosis, and migration. Reorganization of cytoskeleton is pivotal in all these processes. Cytoskeletal proteins also play an important role in initial stages of FcεRI and other surface receptors induced triggering. Highly dynamic microtubules formed by αβ-tubulin dimers as well as microfilaments build up from polymerized actin are affected in activated cells by kinases/phosphatases, Rho GTPases and changes in concentration of cytosolic Ca2+. Also important are nucleation proteins; the γ-tubulin complexes in case of microtubules or Arp 2/3 complex with its nucleation promoting factors and formins in case of microfilaments. The dynamic nature of microtubules and microfilaments in activated cells depends on many associated/regulatory proteins. Changes in rigidity of activated mast cells reflect changes in intermediate filaments build up from vimentin. This review offers a critical appraisal of current knowledge on the role of cytoskeleton in mast cells signaling. PMID:22654883

  12. Optical signal processing

    NASA Technical Reports Server (NTRS)

    Casasent, D.

    1978-01-01

    The article discusses several optical configurations used for signal processing. Electronic-to-optical transducers are outlined, noting fixed window transducers and moving window acousto-optic transducers. Folded spectrum techniques are considered, with reference to wideband RF signal analysis, fetal electroencephalogram analysis, engine vibration analysis, signal buried in noise, and spatial filtering. Various methods for radar signal processing are described, such as phased-array antennas, the optical processing of phased-array data, pulsed Doppler and FM radar systems, a multichannel one-dimensional optical correlator, correlations with long coded waveforms, and Doppler signal processing. Means for noncoherent optical signal processing are noted, including an optical correlator for speech recognition and a noncoherent optical correlator.

  13. [Growth hormone signaling pathways].

    PubMed

    Zych, Sławomir; Szatkowska, Iwona; Czerniawska-Piatkowska, Ewa

    2006-01-01

    The substantial improvement in the studies on a very complicated mechanism-- growth hormone signaling in a cell, has been noted in last decade. GH-induced signaling is characterized by activation of several pathways, including extracellular signal-regulated kinase (ERK), the signal transducer and activator of transcription and phosphatidylinositol-3 kinase (PI3) pathways. This review shows a current model of the growth hormone receptor dimerization, rotation of subunits and JAK2 kinase activation as the initial steps in the cascade of events. In the next stages of the signaling process, the GH-(GHR)2-(JAK2)2 complex may activate signaling molecules such as Stat, IRS-1 and IRS-2, and particularly all cascade proteins that activate MAP kinase. These pathways regulate basal cellular functions including target gene transcription, enzymatic activity and metabolite transport. Therefore growth hormone is considered as a major regulator of postnatal growth and metabolism, probably for mammary gland growth and development too.

  14. Wnt signaling in cancer

    PubMed Central

    Zhan, T; Rindtorff, N; Boutros, M

    2017-01-01

    Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches. PMID:27617575

  15. Signaling Mechanisms for Chemotaxis

    PubMed Central

    Wang, Yu; Chen, Chun-Lin; Iijima, Miho

    2011-01-01

    Cells recognize external chemical gradients and translate these environmental cues into amplified intracellular signaling that results in elongated cell shape, actin polymerization toward the leading edge, and movement along the gradient. Mechanisms underlying chemotaxis are conserved evolutionarily from Dictyostelium amoeba to mammalian neutrophils. Recent studies have uncovered several parallel intracellular signaling pathways that crosstalk in chemotaxing cells. Here, we review these signaling mechanisms in Dictyostelium discoideum. PMID:21585354

  16. Optical Signal Processing

    DTIC Science & Technology

    1990-02-28

    compatible with the laser cation in the on-line inspection of products such as source. Thus, if the laser wavelength is z850 nm, hypodermic needles ...content for cw signals, short pulse signals, and evolving pulse signals - - the most difficult ones to analyze. We performed an extensive analysis on a...agreer.nt with the theory , and support our claims concerning the high performance level of our acousto-optir. architecture. We recognized the opportunity to

  17. Civil Navigation Signal Status

    DTIC Science & Technology

    2015-04-29

    2015 04 29 _GPS Civil Navigation Signal Status UNCLASSIFIED/APPROVED FOR PUBLIC RELEASE UNCLASSIFIED/APPROVED FOR PUBLIC RELEASE Space and Missile...Systems Center Maj Michael Zollars 29 Apr 15 Civil Navigation Signal Status Report Documentation Page Form ApprovedOMB No. 0704-0188 Public...2015 4. TITLE AND SUBTITLE Civil Navigation Signal Status 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d

  18. Coupled biopolymer networks

    NASA Astrophysics Data System (ADS)

    Schwarz, J. M.; Zhang, Tao

    2015-03-01

    The actin cytoskeleton provides the cell with structural integrity and allows it to change shape to crawl along a surface, for example. The actin cytoskeleton can be modeled as a semiflexible biopolymer network that modifies its morphology in response to both external and internal stimuli. Just inside the inner nuclear membrane of a cell exists a network of filamentous lamin that presumably protects the heart of the cell nucleus--the DNA. Lamins are intermediate filaments that can also be modeled as semiflexible biopolymers. It turns out that the actin cytoskeletal biopolymer network and the lamin biopolymer network are coupled via a sequence of proteins that bridge the outer and inner nuclear membranes. We, therefore, probe the consequences of such a coupling via numerical simulations to understand the resulting deformations in the lamin network in response to perturbations in the cytoskeletal network. Such study could have implications for mechanical mechanisms of the regulation of transcription, since DNA--yet another semiflexible polymer--contains lamin-binding domains, and, thus, widen the field of epigenetics.

  19. Multiphysics Application Coupling Toolkit

    SciTech Connect

    Campbell, Michael T.

    2013-12-02

    This particular consortium implementation of the software integration infrastructure will, in large part, refactor portions of the Rocstar multiphysics infrastructure. Development of this infrastructure originated at the University of Illinois DOE ASCI Center for Simulation of Advanced Rockets (CSAR) to support the center's massively parallel multiphysics simulation application, Rocstar, and has continued at IllinoisRocstar, a small company formed near the end of the University-based program. IllinoisRocstar is now licensing these new developments as free, open source, in hopes to help improve their own and others' access to infrastructure which can be readily utilized in developing coupled or composite software systems; with particular attention to more rapid production and utilization of multiphysics applications in the HPC environment. There are two major pieces to the consortium implementation, the Application Component Toolkit (ACT), and the Multiphysics Application Coupling Toolkit (MPACT). The current development focus is the ACT, which is (will be) the substrate for MPACT. The ACT itself is built up from the components described in the technical approach. In particular, the ACT has the following major components: 1.The Component Object Manager (COM): The COM package provides encapsulation of user applications, and their data. COM also provides the inter-component function call mechanism. 2.The System Integration Manager (SIM): The SIM package provides constructs and mechanisms for orchestrating composite systems of multiply integrated pieces.

  20. Magnetically Coupled Calorimeters

    NASA Technical Reports Server (NTRS)

    Bandler, Simon

    2011-01-01

    Calorimeters that utilize the temperature sensitivity of magnetism have been under development for over 20 years. They have targeted a variety of different applications that require very high resolution spectroscopy. I will describe the properties of this sensor technology that distinguish it from other low temperature detectors and emphasize the types of application to which they appear best suited. I will review what has been learned so far about the best materials, geometries, and read-out amplifiers and our understanding of the measured performance and theoretical limits. I will introduce some of the applications where magnetic calorimeters are being used and also where they are in development for future experiments. So far, most magnetic calorimeter research has concentrated on the use of paramagnets to provide temperature sensitivity; recent studies have also focused on magnetically coupled calorimeters that utilize the diamagnetic response of superconductors. I will present some of the highlights of this research, and contrast the properties of the two magnetically coupled calorimeter types.