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Sample records for extended multiplicative signal

  1. Extended use of incremental signal-to-noise ratio as reliability criterion for multiple-slope wide-dynamic-range image capture

    NASA Astrophysics Data System (ADS)

    Hertel, Dirk

    2010-01-01

    Mobile applications present new image quality challenges. Automotive vision requires reliable capture of scene detail. Photospace measurements have shown that the extremely wide intrascene dynamic range of traffic scenes necessitates wide-dynamic-range (WDR) technology. Multiple-slope complementary metal-oxide semiconductor (CMOS) technology adaptively extends dynamic range by partially resetting the pixel, resulting in a response curve with piecewise linear slopes of progressively increasing compression. As compression and thus dynamic range increase, a trade-off against detail loss is observed. Incremental signal-to-noise ratio (iSNR) has been proposed in ISO/TC42 standards for determining dynamic range, and this work describes how to adapt these to WDR. Measurements and computer simulations reveal that the observed trade-off between WDR extension and the loss of local detail can be explained by a drop in iSNR at each reset point. If a reset is not timed optimally, then iSNR may drop below the detection limit causing an iSNR hole to appear within the dynamic range. Thus iSNR has extended utility: it not only determines the dynamic range limits but also defines dynamic range as the luminance range where detail detection is reliable. It has become the critical criterion when maximizing dynamic range to maintain the minimum necessary level of detection reliability.

  2. Extended use of ISO 15739 incremental signal-to-noise ratio as reliability criterion for multiple-slope wide dynamic range image capture

    NASA Astrophysics Data System (ADS)

    Hertel, Dirk

    2009-01-01

    In the emerging field of automotive vision, video capture is the critical front-end of driver assistance and active safety systems. Previous photospace measurements have shown that light levels in natural traffic scenes may contain an extremely wide intra-scene intensity range. This requires the camera to have a wide dynamic range (WDR) for it to adapt quickly to changing lighting conditions and to reliably capture all scene detail. Multiple-slope CMOS technology offers a cost-effective way of adaptively extending dynamic range by partially resetting (recharging) the CMOS pixel once or more often within each frame time. This avoids saturation and leads to a response curve with piecewise linear slopes of progressively increasing compression. It was observed that the image quality from multiple-slope image capture is strongly dependent on the control (height and time) of each reset barrier. As compression and thus dynamic range increase there is a trade-off against contrast and detail loss. Incremental signal-to-noise ratio (iSNR) is proposed in ISO 15739 for determining dynamic range. Measurements and computer simulations revealed that the observed trade-off between WDR extension and the loss of local detail could be explained by a drop in iSNR at each reset point. If a reset barrier is not optimally placed then iSNR may drop below the detection limit so that an 'iSNR hole' appears in the dynamic range. Thus ISO 15739 iSNR has gained extended utility: it not only measures the dynamic range limits but also defines dynamic range as the intensity range where detail detection is reliable. It has become a critical criterion when designing adaptive barrier control algorithms that maximize dynamic range while maintaining the minimum necessary level of detection reliability.

  3. Chemical activation of a food deprivation signal extends lifespan.

    PubMed

    Lucanic, Mark; Garrett, Theo; Yu, Ivan; Calahorro, Fernando; Asadi Shahmirzadi, Azar; Miller, Aaron; Gill, Matthew S; Hughes, Robert E; Holden-Dye, Lindy; Lithgow, Gordon J

    2016-10-01

    Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology. PMID:27220516

  4. An extended car-following model at signalized intersections

    NASA Astrophysics Data System (ADS)

    Yu, Shaowei; Shi, Zhongke

    2014-08-01

    To simulate car-following behaviors better when the traffic light is red, three successive car-following data at a signalized intersection of Jinan in China were collected by using a new proposed data acquisition method and then analyzed to select input variables of the extended car-following model. An extended car-following model considering two leading cars' accelerations was proposed, calibrated and verified with field data obtained on the basis of the full velocity difference model and then a comparative model used for comparative research was also proposed and calibrated in the light of the GM model. The results indicate that the extended car-following model could fit measured data well, and that the fitting precision of the extended model is prior to the comparative model, whose mean absolute error is reduced by 22.83%. Finally a theoretical car-following model considering multiple leading cars' accelerations was put forward which has potential applicable to vehicle automation system and vehicle safety early warning system, and then the linear stability analysis and numerical simulations were conducted to analyze some observed physical features existing in the realistic traffic.

  5. Time-Extended Multiple Group Counseling.

    ERIC Educational Resources Information Center

    Ficek, Daniel E.

    Time-extended groups provide the following: (1) they ease the need to get things started immediately, (2) they provide the opportunity for interaction to be carried to its natural end-point, (3) they allow a greater range of techniques to be experienced by members, (4) they increase the chances for therapeutic contact, (5) they allow participants…

  6. Multiple source navigation signal generator

    NASA Astrophysics Data System (ADS)

    Bojda, Petr

    2010-09-01

    The paper presents a FPGA based digital VOR/LOC signal generator. It provides the composite signal, which consists of the particular signals of several predefined navigation sources - VOR beacons. Design of the generator is implemented into the two different FPGA DSP platforms.

  7. Affinity Propagation Clustering of Measurements for Multiple Extended Target Tracking.

    PubMed

    Zhang, Tao; Wu, Renbiao

    2015-01-01

    More measurements are generated by the target per observation interval, when the target is detected by a high resolution sensor, or there are more measurement sources on the target surface. Such a target is referred to as an extended target. The probability hypothesis density filter is considered an efficient method for tracking multiple extended targets. However, the crucial problem of how to accurately and effectively partition the measurements of multiple extended targets remains unsolved. In this paper, affinity propagation clustering is introduced into measurement partitioning for extended target tracking, and the elliptical gating technique is used to remove the clutter measurements, which makes the affinity propagation clustering capable of partitioning the measurement in a densely cluttered environment with high accuracy. The Gaussian mixture probability hypothesis density filter is implemented for multiple extended target tracking. Numerical results are presented to demonstrate the performance of the proposed algorithm, which provides improved performance, while obviously reducing the computational complexity. PMID:26370998

  8. Affinity Propagation Clustering of Measurements for Multiple Extended Target Tracking

    PubMed Central

    Zhang, Tao; Wu, Renbiao

    2015-01-01

    More measurements are generated by the target per observation interval, when the target is detected by a high resolution sensor, or there are more measurement sources on the target surface. Such a target is referred to as an extended target. The probability hypothesis density filter is considered an efficient method for tracking multiple extended targets. However, the crucial problem of how to accurately and effectively partition the measurements of multiple extended targets remains unsolved. In this paper, affinity propagation clustering is introduced into measurement partitioning for extended target tracking, and the elliptical gating technique is used to remove the clutter measurements, which makes the affinity propagation clustering capable of partitioning the measurement in a densely cluttered environment with high accuracy. The Gaussian mixture probability hypothesis density filter is implemented for multiple extended target tracking. Numerical results are presented to demonstrate the performance of the proposed algorithm, which provides improved performance, while obviously reducing the computational complexity. PMID:26370998

  9. Imaging the coordination of multiple signaling activities in living cells

    PubMed Central

    Welch, Christopher M.; Elliott, Hunter; Danuser, Gaudenz; Hahn, Klaus M.

    2013-01-01

    Preface Cellular signal transduction occurs in complex and redundant interaction networks that are best examined at the level of single cells by simultaneously monitoring the activation dynamics of multiple components. Recent advances in biosensor technology have made it possible to visualize and quantify the activation of multiple network nodes in the same living cell. The precision and scope of this approach has been greatly extended by novel computational approaches to determine the relationships between different networks, studied in separate cells. PMID:22016058

  10. Learning with Multiple Representations: Extending Multimedia Learning beyond the Lab

    ERIC Educational Resources Information Center

    Eilam, Billie; Poyas, Yael

    2008-01-01

    The present study extended multimedia learning principles beyond the lab to an ecologically valid setting (homework). Eighteen information cards were used to perform three homework tasks. The control group students learned from single representation (SR) cards that presented all information as printed text. The multiple representation (MR) group…

  11. Signal simulation and signal processing for multiple reference optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Neuhaus, Kai; Subhash, Hrebesh; Dsouza, Roshan; Hogan, Josh; Wilson, Carol; Leahy, Martin

    2015-03-01

    The generation of a synthetic MR-OCT signal is presented and compared to a real acquired signal. Multiple reference optical coherence tomography (MR-OCT) is a novel time-domain interferometric system. The MR-OCT principle is adding a partial mirror to extend the axial scan range, which effectively extends the scan depth for imaging. The actuation of the scan mirror required for time-domain OCT, was demonstrated to operate with a low cost miniature voice coil, such as a speaker extracted from a smartphone or CD/DVD pick-up system. Building a compact and cost-effective optical imaging system will enable affordable medical diagnosis at low-resource setting applications. The partial mirror recirculates multiple reflections (orders) into the interferometric system and the increase of optical path delay does increase the beat frequency of the interference signal. The synthesis of such an interference signal using a numerical method is described in this manuscript.

  12. Efficient sliding spotlight SAR raw signal simulation of extended scenes

    NASA Astrophysics Data System (ADS)

    Xu, Wei; Huang, Pingping; Deng, Yunkai

    2011-12-01

    Sliding spotlight mode is a novel synthetic aperture radar (SAR) imaging scheme with an achieved azimuth resolution better than stripmap mode and ground coverage larger than spotlight configuration. However, its raw signal simulation of extended scenes may not be efficiently implemented in the two-dimensional (2D) Fourier transformed domain. This article presents a novel sliding spotlight raw signal simulation approach from the wide-beam SAR imaging modes. This approach can generate sliding spotlight raw signal not only from raw data evaluated by the simulators, but also from real data in the stripmap/spotlight mode. In order to obtain the desired raw data from conventional stripmap/spotlight mode, the azimuth time-varying filtering, which is implemented by de-rotation and low-pass filtering, is adopted. As raw signal of extended scenes in the stripmap/spotlight mode can efficiently be evaluated in the 2D Fourier domain, the proposed approach provides an efficient sliding spotlight SAR simulator of extended scenes. Simulation results validate this efficient simulator.

  13. Multiple Extended Target Tracking With Labeled Random Finite Sets

    NASA Astrophysics Data System (ADS)

    Beard, Michael; Reuter, Stephan; Granstrom, Karl; Vo, Ba-Tuong; Vo, Ba-Ngu; Scheel, Alexander

    2016-04-01

    Targets that generate multiple measurements at a given instant in time are commonly known as extended targets. These present a challenge for many tracking algorithms, as they violate one of the key assumptions of the standard measurement model. In this paper, a new algorithm is proposed for tracking multiple extended targets in clutter, that is capable of estimating the number of targets, as well the trajectories of their states, comprising the kinematics, measurement rates and extents. The proposed technique is based on modelling the multi-target state as a generalised labelled multi-Bernoulli (GLMB) random finite set (RFS), within which the extended targets are modelled using gamma Gaussian inverse Wishart (GGIW) distributions. A cheaper variant of the algorithm is also proposed, based on the labelled multi-Bernoulli (LMB) filter. The proposed GLMB/LMB-based algorithms are compared with an extended target version of the cardinalised probability hypothesis density (CPHD) filter, and simulation results show that the (G)LMB has improved estimation and tracking performance.

  14. Gibberellin Signaling in Plants – The Extended Version

    PubMed Central

    Schwechheimer, Claus

    2011-01-01

    The plant hormone gibberellin (GA) controls major aspects of plant growth such as germination, elongation growth, flower development, and flowering time. In recent years, a number of studies have revealed less apparent roles for GA in a surprisingly broad set of developmental as well as cell biological processes. The identification of GA receptor proteins on the one end of the signaling cascade, DELLA proteins as central repressors of the pathway and transcription regulators such as the phytochrome interacting factors and the GATA-type transcription factors GNC and CGA1/GNL on the current other end of the signaling cascade have extended our knowledge about how GA and DELLAs regulate a diverse set of plant responses. PMID:22645560

  15. Multiple signals in anterior cingulate cortex

    PubMed Central

    Kolling, N; Behrens, TEJ; Wittmann, MK; Rushworth, MFS

    2016-01-01

    Activity in anterior cingulate cortex (ACC) has been linked both to commitment to a course of action, even when it is associated with costs, and to exploring or searching for alternative courses of action. Here we review evidence that this is due to the presence of multiple signals in ACC reflecting the updating of beliefs and internal models of the environment and encoding aspects of choice value, including the average value of choices afforded by the environment (‘search value’). We contrast this evidence with the influential view that ACC activity is better described as reflecting task difficulty. A consideration of cortical neural network properties explains why ACC may carry such signals and also exhibit sensitivity to task difficulty. PMID:26774693

  16. Extended flowering intervals of bamboos evolved by discrete multiplication.

    PubMed

    Veller, Carl; Nowak, Martin A; Davis, Charles C

    2015-07-01

    Numerous bamboo species collectively flower and seed at dramatically extended, regular intervals - some as long as 120 years. These collective seed releases, termed 'masts', are thought to be a strategy to overwhelm seed predators or to maximise pollination rates. But why are the intervals so long, and how did they evolve? We propose a simple mathematical model that supports their evolution as a two-step process: First, an initial phase in which a mostly annually flowering population synchronises onto a small multi-year interval. Second, a phase of successive small multiplications of the initial synchronisation interval, resulting in the extraordinary intervals seen today. A prediction of the hypothesis is that mast intervals observed today should factorise into small prime numbers. Using a historical data set of bamboo flowering observations, we find strong evidence in favour of this prediction. Our hypothesis provides the first theoretical explanation for the mechanism underlying this remarkable phenomenon. PMID:25963600

  17. Neutrino signal from extended Galactic sources in IceCube

    NASA Astrophysics Data System (ADS)

    Tchernin, C.; Aguilar, J. A.; Neronov, A.; Montaruli, T.

    2013-12-01

    Context. The Galactic plane is the brightest source of γ rays in the sky. It should also be one of the brightest very-high-energy neutrino sources, if a neutrino flux comparable to the γ-ray flux is produced by the cosmic ray interactions in the interstellar medium. Aims: We explore the detectability of the neutrino flux from the entire Galactic plane or from a part of it with the IceCube neutrino detector. Methods: We calculated the normalization and the spectral index of the neutrino power-law spectrum from different regions of the Galactic plane, based on the observed spectral characteristics of the pion decay γ-ray diffuse emission observed by the Fermi/LAT telescope in the energy band above 100 GeV. We compared the neutrino flux calculated in this way with the sensitivity of IceCube for the detection of extended sources. Results: Assuming a binned extended source analysis method, we find that the only possible evidence of neutrino emission for sources located in the northern hemisphere after 20 years of exposure is from the Cygnus region. For other parts of the Galactic plane even a 20 year exposure with IceCube is not sufficient for the detection. Taking into account marginal significance of the detectable source in the Cygnus region, we find a precise position and size of the source region that optimizes the signal-to-noise ratio for neutrinos. We also calculated the low-energy threshold above which the neutrino signal can be detected with the highest signal-to-noise ratio. This calculation of precise source position, size, and energy range, based on the γ-ray data, can be used to remove the so-called trial factor in the analysis of the real neutrino data of IceCube. We notice that the diffuse neutrino emission from the inner Galactic plane in the southern hemisphere is much brighter. A neutrino detector with characteristics equivalent to IceCube, but placed at the northern hemisphere (such as KM3NeT), would detect several isolated neutrino sources in

  18. Technique for extending the range of a signal measuring circuit

    DOEpatents

    Chaprnka, Anthony G.; Sun, Shan C.; Vercellotti, Leonard C.

    1978-01-01

    An input signal supplied to a signal measuring circuit is either amplified or attenuated as necessary to establish the magnitude of the input signal within the defined dynamic range of the measuring circuit and the output signal developed by the measuring circuit is subsequently readjusted through amplification or attenuation to develop an output signal which corresponds to the magnitude of the initial input signal.

  19. Approach for LIDAR signals with multiple returns.

    PubMed

    Yin, Wenye; He, Weiji; Gu, Guohua; Chen, Qian

    2014-10-20

    Time-correlated single photon counting (TCSPC) and burst illumination laser (BIL) data can be used for depth reconstruction of a target surface; the problem is how to analyze the response for the reconstruction. We propose a fast-approach STMCMC (Simulated Tempering Markov Chain Monte Carlo) for LIDAR signals with multiple return, in order to obtain a complete characterization of a 3D surface by the laser range system. STMCMC is used to explore the spaces by the preset distributions instead of the prior distributions. Added active intervention tempering makes the Markov chain mix better through the temporary expansion of the solutions. The added step keeps the operation under control and yet retains the Markov characteristic of the operation. The theoretical analysis and the demonstrations on the practical data show flexible operation, and the parameters can be estimated to a high degree of accuracy. PMID:25402782

  20. Reconstructing spatially extended brain sources via enforcing multiple transform sparseness.

    PubMed

    Zhu, Min; Zhang, Wenbo; Dickens, Deanna L; Ding, Lei

    2014-02-01

    Accurate estimation of location and extent of neuronal sources from EEG/MEG remain challenging. In the present study, a new source imaging method, i.e. variation and wavelet based sparse source imaging (VW-SSI), is proposed to better estimate cortical source locations and extents. VW-SSI utilizes the L1-norm regularization method with the enforcement of transform sparseness in both variation and wavelet domains. The performance of the proposed method is assessed by both simulated and experimental MEG data, obtained from a language task and a motor task. Compared to L2-norm regularizations, VW-SSI demonstrates significantly improved capability in reconstructing multiple extended cortical sources with less spatial blurredness and less localization error. With the use of transform sparseness, VW-SSI overcomes the over-focused problem in classic SSI methods. With the use of two transformations, VW-SSI further indicates significantly better performance in estimating MEG source locations and extents than other SSI methods with single transformations. The present experimental results indicate that VW-SSI can successfully estimate neural sources (and their spatial coverage) located in close areas while responsible for different functions, i.e. temporal cortical sources for auditory and language processing, and sources on the pre-bank and post-bank of the central sulcus. Meantime, all other methods investigated in the present study fail to recover these phenomena. Precise estimation of cortical source locations and extents from EEG/MEG is of significance for applications in neuroscience and neurology. PMID:24103850

  1. Photonic generation and independent steering of multiple RF signals for software defined radars.

    PubMed

    Ghelfi, Paolo; Laghezza, Francesco; Scotti, Filippo; Serafino, Giovanni; Pinna, Sergio; Bogoni, Antonella

    2013-09-23

    As the improvement of radar systems claims for digital approaches, photonics is becoming a solution for software defined high frequency and high stability signal generation. We report on our recent activities on the photonic generation of flexible wideband RF signals, extending the proposed architecture to the independent optical beamforming of multiple signals. The scheme has been tested generating two wideband signals at 10 GHz and 40 GHz, and controlling their independent delays at two antenna elements. Thanks to the multiple functionalities, the proposed scheme allows to improve the effectiveness of the photonic approach, reducing its cost and allowing flexibility, extremely wide bandwidth, and high stability. PMID:24104176

  2. Performance of Multiple Pulse Multiple Delay Modulated UWB Signals in a Multiple Access Indoor Wireless Channel

    SciTech Connect

    Nekoogar, F

    2003-06-12

    In this paper, the performance of a two user UWB multiple access (UWB-MA) system based on multiple-pulse multiple-delay (MPMD) modulation scheme in an indoor wireless channel is evaluated by computer simulations. The indoor multipath propagation channel model used in this study is based on the modified statistical Saleh-Valenzuela model proposed by Foerester and Li from Intel. The simulation results indicate that the multipath performance of MPMD modulated signals in a multiple access system outperforms the nonmultipath case as the number of autocorrelation function (ACF) sampling points increases for each user. This is an unusual but important result, since MPMD receiver exploits multipath phenomenon in indoor wireless channels to increase the BER performance, hence the transmission rate in a UWB-MA system.

  3. Theory of Multiple Coulomb Scattering from Extended Nuclei

    DOE R&D Accomplishments Database

    Cooper, L. N.; Rainwater, J.

    1954-08-01

    Two independent methods are described for calculating the multiple scattering distribution for projected angle scattering resulting when very high energy charged particles traverse a thick scatterer. The results are compared with the theories of Moliere and Olbert.

  4. An extended signal control strategy for urban network traffic flow

    NASA Astrophysics Data System (ADS)

    Yan, Fei; Tian, Fuli; Shi, Zhongke

    2016-03-01

    Traffic flow patterns are in general repeated on a daily or weekly basis. To improve the traffic conditions by using the inherent repeatability of traffic flow, a novel signal control strategy for urban networks was developed via iterative learning control (ILC) approach. Rigorous analysis shows that the proposed learning control method can guarantee the asymptotic convergence. The impacts of the ILC-based signal control strategy on the macroscopic fundamental diagram (MFD) were analyzed by simulations on a test road network. The results show that the proposed ILC strategy can evenly distribute the accumulation in the network and improve the network mobility.

  5. Multiple Paternity in Urban Norway Rats: Extended Ranging for Mates.

    PubMed

    Glass, Gregory E; Klein, Sabra L; Norris, Douglas E; Gardner, Lynne C

    2016-05-01

    Norway rats are an abundant synanthropic species in urban settings and serve as reservoirs for many pathogens. Attempts to control their populations have met with little success. Recent genetic studies suggest that local populations are structured and few individuals move significant distances, but there is substantial gene flow. To understand these observations and their implications on control strategies, we genotyped 722 rats from 20 alleys in Baltimore to establish paternity for 180 embryos. Up to 88 males may have contributed to the litters. All litters were sired by ≥2 males, with an average of 4.9 (range 2-7) males. For dams and sires with known locations, most matings (71.7%; n = 46) occurred among animals from different alleys. The average distance between sires and dams was 114 meters (range 8-352 meters). In 10/17 (58.8%) litters, the majority of the identified sires were captured in different alleys than the females. Sires were significantly less related to females than were the males captured in the females' alleys. Although rats may generally restrict their movements, either receptive females and/or breeding males engage in mate-seeking behaviors that extend beyond movement patterns at other times. This geographically extends the sizes of local populations and buffers them from the impacts of control strategies that focus on local infestations. PMID:26885622

  6. Extended amplification of acoustic signals by amphibian burrows.

    PubMed

    Muñoz, Matías I; Penna, Mario

    2016-07-01

    Animals relying on acoustic signals for communication must cope with the constraints imposed by the environment for sound propagation. A resource to improve signal broadcast is the use of structures that favor the emission or the reception of sounds. We conducted playback experiments to assess the effect of the burrows occupied by the frogs Eupsophus emiliopugini and E. calcaratus on the amplitude of outgoing vocalizations. In addition, we evaluated the influence of these cavities on the reception of externally generated sounds potentially interfering with conspecific communication, namely, the vocalizations emitted by four syntopic species of anurans (E. emiliopugini, E. calcaratus, Batrachyla antartandica, and Pleurodema thaul) and the nocturnal owls Strix rufipes and Glaucidium nanum. Eupsophus advertisement calls emitted from within the burrows experienced average amplitude gains of 3-6 dB at 100 cm from the burrow openings. Likewise, the incoming vocalizations of amphibians and birds were amplified on average above 6 dB inside the cavities. The amplification of internally broadcast Eupsophus vocalizations favors signal detection by nearby conspecifics. Reciprocally, the amplification of incoming conspecific and heterospecific signals facilitates the detection of neighboring males and the monitoring of the levels of potentially interfering biotic noise by resident frogs, respectively. PMID:27209276

  7. A Pivotal Role of DELLAs in Regulating Multiple Hormone Signals.

    PubMed

    Davière, Jean-Michel; Achard, Patrick

    2016-01-01

    Plant phenotypic plasticity is controlled by diverse hormone pathways, which integrate and convey information from multiple developmental and environmental signals. Moreover, in plants many processes such as growth, development, and defense are regulated in similar ways by multiple hormones. Among them, gibberellins (GAs) are phytohormones with pleiotropic actions, regulating various growth processes throughout the plant life cycle. Previous work has revealed extensive interplay between GAs and other hormones, but the molecular mechanism became apparent only recently. Molecular and physiological studies have demonstrated that DELLA proteins, considered as master negative regulators of GA signaling, integrate multiple hormone signaling pathways through physical interactions with transcription factors or regulatory proteins from different families. In this review, we summarize the latest progress in GA signaling and its direct crosstalk with the main phytohormone signaling, emphasizing the multifaceted role of DELLA proteins with key components of major hormone signaling pathways. PMID:26415696

  8. Extended pseudo-screen migration with multiple reference velocities

    SciTech Connect

    Huang, Lian-Jie; Fehler, M.C.

    1997-11-01

    The pseudo-screen propagator is a kind of one way wave propagation based on the local Born approximation. The problem of the propagator is that it is difficult to calculate the scattered fields when the velocity perturbation is large; not to mention the accuracy of the propagator. We develop an extended pseudo-screen propagator by introducing different reference velocities in different regions of a medium to ensure the condition of small perturbation. The exploding reflector data for a 2D slice of the SEG/EAEG 3D salt model is generated by a finite difference scheme to test the feasibility of the method. The migration result demonstrates that the method can handle severe lateral velocity variations and provides high quality images for complex structures.

  9. Dynamic Stability and Gravitational Balancing of Multiple Extended Bodies

    NASA Technical Reports Server (NTRS)

    Quadrelli, Marco

    2008-01-01

    Feasibility of a non-invasive compensation scheme was analyzed for precise positioning of a massive extended body in free fall using gravitational forces influenced by surrounding source masses in close proximity. The N-body problem of classical mechanics is a paradigm used to gain insight into the physics of the equivalent N-body problem subject to control forces. The analysis addressed how a number of control masses move around the proof mass so that the proof mass position can be accurately and remotely compensated when exogenous disturbances are acting on it, while its sensitivity to gravitational waves remains unaffected. Past methods to correct the dynamics of the proof mass have considered active electrostatic or capacitive methods, but the possibility of stray capacitances on the surfaces of the proof mass have prompted the investigation of other alternatives, such as the method presented in this paper. While more rigorous analyses of the problem should be carried out, the data show that, by means of a combined feedback and feed-forward control approach, the control masses succeeded in driving the proof mass along the specified trajectory, which implies that the proof mass can, in principle, be balanced via gravitational forces only while external perturbations are acting on it. This concept involves the dynamic stability of a group of massive objects interacting gravitationally under active control, and can apply to drag-free control of spacecraft during missions, to successor gravitational wave space borne sensors, or to any application requiring flying objects to be precisely controlled in position and attitude relative to another body via gravitational interactions only.

  10. Algorithm for astronomical, extended source, signal-to-noise radio calculations

    NASA Technical Reports Server (NTRS)

    Jayroe, R. R.

    1984-01-01

    An algorithm was developed to simulate the expected signal-to-noise ratio as a function of observation time in the charge coupled device detector plane of an optical telescope located outside the Earth's atmosphere for an extended, uniform astronomical source embedded in a uniform cosmic background. By choosing the appropriate input values, the expected extended source signal-to-noise ratios can be computed for the Hubble Space Telescope using the Wide Field/Planetary Camera science instrument.

  11. Hexagonal multiple phase-and-amplitude-shift-keyed signal sets

    NASA Technical Reports Server (NTRS)

    Simon, M. K.; Smith, J. G.

    1973-01-01

    Selection of a particular signal set array for a bandwidth-constrained multiple phase-and-amplitude-shift-keyed (MPASK) communication system for a linear additive Gaussian noise channel requires consideration of factors such as average and/or peak power vs symbol error probability, signal amplitude dynamic range, simplicity of generation and detection, and number of bit errors per symbol error (Gray code properties). A simple technique is presented for generating and optimally detecting the honeycomb (hexagonal) signal set, i.e., the signal set that has the tightest sphere-packing properties. The symbol and bit error probability performance of this set is compared to other two-dimensional signal sets that have been investigated in the literature, and is shown to be slightly superior from an average power standpoint. The paper concludes with a comparison of all of these signal sets from the standpoint of the factors listed above.

  12. Automatic identification of resting state networks: an extended version of multiple template-matching

    NASA Astrophysics Data System (ADS)

    Guaje, Javier; Molina, Juan; Rudas, Jorge; Demertzi, Athena; Heine, Lizette; Tshibanda, Luaba; Soddu, Andrea; Laureys, Steven; Gómez, Francisco

    2015-12-01

    Functional magnetic resonance imaging in resting state (fMRI-RS) constitutes an informative protocol to investigate several pathological and pharmacological conditions. A common approach to study this data source is through the analysis of changes in the so called resting state networks (RSNs). These networks correspond to well-defined functional entities that have been associated to different low and high brain order functions. RSNs may be characterized by using Independent Component Analysis (ICA). ICA provides a decomposition of the fMRI-RS signal into sources of brain activity, but it lacks of information about the nature of the signal, i.e., if the source is artifactual or not. Recently, a multiple template-matching (MTM) approach was proposed to automatically recognize RSNs in a set of Independent Components (ICs). This method provides valuable information to assess subjects at individual level. Nevertheless, it lacks of a mechanism to quantify how much certainty there is about the existence/absence of each network. This information may be important for the assessment of patients with severely damaged brains, in which RSNs may be greatly affected as a result of the pathological condition. In this work we propose a set of changes to the original MTM that improves the RSNs recognition task and also extends the functionality of the method. The key points of this improvement is a standardization strategy and a modification of method's constraints that adds flexibility to the approach. Additionally, we also introduce an analysis to the trustworthiness measurement of each RSN obtained by using template-matching approach. This analysis consists of a thresholding strategy applied over the computed Goodness-of-Fit (GOF) between the set of templates and the ICs. The proposed method was validated on 2 two independent studies (Baltimore, 23 healthy subjects and Liege, 27 healthy subjects) with different configurations of MTM. Results suggest that the method will provide

  13. Notch signaling deregulation in multiple myeloma: A rational molecular target

    PubMed Central

    Garavelli, Silvia; Platonova, Natalia; Paoli, Alessandro; Basile, Andrea; Taiana, Elisa; Neri, Antonino; Chiaramonte, Raffaella

    2015-01-01

    Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches. PMID:26308486

  14. Regularized Embedded Multiple Kernel Dimensionality Reduction for Mine Signal Processing

    PubMed Central

    Li, Shuang; Liu, Bing; Zhang, Chen

    2016-01-01

    Traditional multiple kernel dimensionality reduction models are generally based on graph embedding and manifold assumption. But such assumption might be invalid for some high-dimensional or sparse data due to the curse of dimensionality, which has a negative influence on the performance of multiple kernel learning. In addition, some models might be ill-posed if the rank of matrices in their objective functions was not high enough. To address these issues, we extend the traditional graph embedding framework and propose a novel regularized embedded multiple kernel dimensionality reduction method. Different from the conventional convex relaxation technique, the proposed algorithm directly takes advantage of a binary search and an alternative optimization scheme to obtain optimal solutions efficiently. The experimental results demonstrate the effectiveness of the proposed method for supervised, unsupervised, and semisupervised scenarios. PMID:27247562

  15. Regularized Embedded Multiple Kernel Dimensionality Reduction for Mine Signal Processing.

    PubMed

    Li, Shuang; Liu, Bing; Zhang, Chen

    2016-01-01

    Traditional multiple kernel dimensionality reduction models are generally based on graph embedding and manifold assumption. But such assumption might be invalid for some high-dimensional or sparse data due to the curse of dimensionality, which has a negative influence on the performance of multiple kernel learning. In addition, some models might be ill-posed if the rank of matrices in their objective functions was not high enough. To address these issues, we extend the traditional graph embedding framework and propose a novel regularized embedded multiple kernel dimensionality reduction method. Different from the conventional convex relaxation technique, the proposed algorithm directly takes advantage of a binary search and an alternative optimization scheme to obtain optimal solutions efficiently. The experimental results demonstrate the effectiveness of the proposed method for supervised, unsupervised, and semisupervised scenarios. PMID:27247562

  16. Pentagone internalises glypicans to fine-tune multiple signalling pathways

    PubMed Central

    Norman, Mark; Vuilleumier, Robin; Springhorn, Alexander; Gawlik, Jennifer; Pyrowolakis, George

    2016-01-01

    Tight regulation of signalling activity is crucial for proper tissue patterning and growth. Here we investigate the function of Pentagone (Pent), a secreted protein that acts in a regulatory feedback during establishment and maintenance of BMP/Dpp morphogen signalling during Drosophila wing development. We show that Pent internalises the Dpp co-receptors, the glypicans Dally and Dally-like protein (Dlp), and propose that this internalisation is important in the establishment of a long range Dpp gradient. Pent-induced endocytosis and degradation of glypicans requires dynamin- and Rab5, but not clathrin or active BMP signalling. Thus, Pent modifies the ability of cells to trap and transduce BMP by fine-tuning the levels of the BMP reception system at the plasma membrane. In addition, and in accordance with the role of glypicans in multiple signalling pathways, we establish a requirement of Pent for Wg signalling. Our data propose a novel mechanism by which morphogen signalling is regulated. DOI: http://dx.doi.org/10.7554/eLife.13301.001 PMID:27269283

  17. Extended field-of-view and increased-signal 3D holographic illumination with time-division multiplexing

    PubMed Central

    Yang, Samuel J.; Allen, William E.; Kauvar, Isaac; Andalman, Aaron S.; Young, Noah P.; Kim, Christina K.; Marshel, James H.; Wetzstein, Gordon; Deisseroth, Karl

    2016-01-01

    Phase spatial light modulators (SLMs) are widely used for generating multifocal three-dimensional (3D) illumination patterns, but these are limited to a field of view constrained by the pixel count or size of the SLM. Further, with two-photon SLM-based excitation, increasing the number of focal spots penalizes the total signal linearly—requiring more laser power than is available or can be tolerated by the sample. Here we analyze and demonstrate a method of using galvanometer mirrors to time-sequentially reposition multiple 3D holograms, both extending the field of view and increasing the total time-averaged two-photon signal. We apply our approach to 3D two-photon in vivo neuronal calcium imaging. PMID:26699047

  18. Extended field-of-view and increased-signal 3D holographic illumination with time-division multiplexing.

    PubMed

    Yang, Samuel J; Allen, William E; Kauvar, Isaac; Andalman, Aaron S; Young, Noah P; Kim, Christina K; Marshel, James H; Wetzstein, Gordon; Deisseroth, Karl

    2015-12-14

    Phase spatial light modulators (SLMs) are widely used for generating multifocal three-dimensional (3D) illumination patterns, but these are limited to a field of view constrained by the pixel count or size of the SLM. Further, with two-photon SLM-based excitation, increasing the number of focal spots penalizes the total signal linearly--requiring more laser power than is available or can be tolerated by the sample. Here we analyze and demonstrate a method of using galvanometer mirrors to time-sequentially reposition multiple 3D holograms, both extending the field of view and increasing the total time-averaged two-photon signal. We apply our approach to 3D two-photon in vivo neuronal calcium imaging. PMID:26699047

  19. Multiple signal classification for self-mixing flowmetry.

    PubMed

    Nikolić, Milan; Lim, Yah Leng; Bertling, Karl; Taimre, Thomas; Rakić, Aleksandar D

    2015-03-20

    For the first time to our knowledge, we apply the multiple signal classification (MUSIC) algorithm to signals obtained from a self-mixing flow sensor. We find that MUSIC accurately extracts the fluid velocity and exhibits a markedly better signal-to-noise ratio (SNR) than the commonly used fast Fourier transform (FFT) method. We compare the performance of the MUSIC and FFT methods for three decades of scatterer concentration and fluid velocities from 0.5 to 50 mm/s. MUSIC provided better linearity than the FFT and was able to accurately function over a wider range of algorithm parameters. MUSIC exhibited excellent linearity and SNR even at low scatterer concentration, at which the FFT's SNR decreased to impractical levels. This makes MUSIC a particularly attractive method for flow measurement systems with a low density of scatterers such as microfluidic and nanofluidic systems and blood flow in capillaries. PMID:25968500

  20. High integrity carrier phase navigation using multiple civil GPS signals

    NASA Astrophysics Data System (ADS)

    Jung, Jaewoo

    2000-11-01

    A navigation system should guide users to their destinations accurately and reliably. Among the many available navigation aids, the Global Positioning System stands out due to its unique capabilities. It is a satellite-based navigation system which covers the entire Earth with horizontal accuracy of 20 meters for stand alone civil users. Today, the GPS provides only one civil signal, but two more signals will be available in the near future. GPS will provide a second signal at 1227.60 MHz (L2) and a third signal at 1176.45 MHz (Lc), in addition to the current signal at 1575.42 MHz (L1). The focus of this thesis is exploring the possibility of using beat frequencies of these signals to provide navigation aid to users with high accuracy and integrity. To achieve high accuracy, the carrier phase differential GPS is used. The integer ambiguity is resolved using the Cascade Integer Resolution (CIR), which is defined in this thesis. The CIR is an instantaneous, geometry-free integer resolution method utilizing beat frequencies of GPS signals. To insure high integrity, the probability of incorrect integer ambiguity resolution using the CIR is analyzed. The CIR can immediately resolve the Lc integer ambiguity up to 2.4 km from the reference receiver, the Widelane (L1-L2) integer ambiguity up to 22 km, and the Extra Widelane (L2-Lc) integer ambiguity from there on, with probability of incorrect integer resolution of 10-4 . The optimal use of algebraic combinations of multiple GPS signals are also investigated in this thesis. Finally, the gradient of residual differential ionospheric error is estimated to stimated to increase performance of the CIR.

  1. Multiple-channel optical signal processing with wavelength-waveform conversions, pulsewidth tunability, and signal regeneration.

    PubMed

    Nguyen Tan, Hung; Matsuura, Motoharu; Katafuchi, Tomoya; Kishi, Naoto

    2009-12-01

    A multiple-channel multiple-function optical signal processor (MCMF-OSP) including wavelength-waveform conversions, pulsewidth tunability, and signal regeneration is realized through AND logic gate based on optical parametric processing with a pulsewidth-tunable RZ clock pump. The proposed scheme simultaneously offers four signal processing functions which are useful in wavelength-division multiplexing (WDM) transmission systems, and at network nodes with the necessity for multiple-channel data processing. After the discussions on the concept of MCMF-OSP, a proof-of concept experiment is demonstrated on four 10 Gb/s nonreturn-to-zero (NRZ) data format channels using nonlinearities in semiconductor optical amplifier (SOA) and highly nonlinear fiber (HNLF). A wavelength and waveform conversions to return-to-zero (RZ) modulation format are obtained together with pulsewidth-tunable range from 20% to 80% duty cycles for all input signals. The converted signals inherit the timing and waveform of the RZ clock pump, thus resulting in a time regeneration and large tolerance to narrow-band optical filtering (NAOF) and fiber accumulated chromatic dispersion (CD). PMID:20052222

  2. Impact of noise in holography with extended references in the low signal regime.

    PubMed

    Boutu, W; Gauthier, D; Ge, X; Cassin, R; Ducousso, M; Gonzalez, A I; Iwan, B; Samaan, J; Wang, F; Kovačev, M; Merdji, H

    2016-03-21

    Signal-to-noise ratio is a key factor in lensless imaging, particularly for low diffraction signal experiments in the single shot regime. We present our recent study of the noise impact on holography with extended references. Experimental data have been measured in single shot acquisition using an intense coherent soft X-ray high harmonic source. The impact of hardware and software noise under various detection conditions is discussed. A final comparison between single shot and multi-shot regimes is given. PMID:27136823

  3. Interference signal frequency tracking for extracting phase in frequency scanning interferometry using an extended Kalman filter.

    PubMed

    Liu, Zhe; Liu, Zhigang; Deng, Zhongwen; Tao, Long

    2016-04-10

    Optical frequency scanning nonlinearity seriously affects interference signal phase extraction accuracy in frequency-scanning interferometry systems using external cavity diode lasers. In this paper, an interference signal frequency tracking method using an extended Kalman filter is proposed. The interferometric phase is obtained by integrating the estimated instantaneous frequency over time. The method is independent of the laser's optical frequency scanning nonlinearity. The method is validated through simulations and experiments. The experimental results demonstrate that the relative phase extraction error in the fractional part is <1.5% with the proposed method and the standard deviation of absolute distance measurement is <2.4  μm. PMID:27139864

  4. Estimation and detection of signals in multiplicative noise

    NASA Technical Reports Server (NTRS)

    Willsky, A. S.

    1974-01-01

    We define a class of detection-estimation problems on matrix Lie groups in which the observation noise is multiplicative in nature. By examining the differential versions of the hypotheses, which are bilinear, we are able to derive the relevant likelihood ratio formula and the associated optimal estimation equations for the signal given the observations and the assumption that the signal is present. These estimation equations are of interest in their own right, in that they represent a finite-dimensional optimal solution to a nonlinear estimation problem and consist of a Kalman-Bucy filter along with the on-line computation of the solution of the associated Riccati equation, which is driven by the observations. The usefulness of these results is illustrated via an example concerning the detection of an actuator failure in a rigid-body rotational control system.

  5. Extraction of quadrature phase information from multiple pulse NMR signals

    NASA Technical Reports Server (NTRS)

    Rhim, W.-K.; Burum, D. P.; Vaughan, R. W.

    1976-01-01

    A multiple pulse sequence (8-pulse sequence) used for high-resolution solid state NMR is analyzed with regard to the information available from each of the four wide sampling windows. It is demonstrated that full quadrature phase information can be obtained using only a single phase detector and that, for the commonly encountered situation where the spectral width is much less than the folding frequency, the signals from the various windows can be combined easily using standard complex Fourier transform software. An improvement in the signal-to-noise ratio equal to the square root of 3 is obtained over either standard single or quadrature phase detection schemes. Procedures for correcting spectral distortions are presented.

  6. Estimation and detection of signals in multiplicative noise

    NASA Technical Reports Server (NTRS)

    Willsky, A. S.

    1973-01-01

    A class of detection-estimation problems on matrix Lie groups is defined in which the observation noise is multiplicative in nature. By examining the differential versions of the hypotheses, which are bilinear in nature, it is possible to derive the relevant likelihood ratio formula and the associated optimal estimation equations for the signal given the observations and the assumption that the signal is present. These estimation equations are of interest in their own right, in that they represent a finite dimensional optimal solution to a nonlinear estimation problem and can be viewed as consisting of a Kalman-Bucy filter along with the on-line computation of the solution of the associated Riccati equation, which is driven by the observations. The usefulness of these results is illustrated via an example concerning the detection of an actuator failure in a rigid body rotational control system.

  7. Multiplicity and plasticity of natural killer cell signaling pathways

    PubMed Central

    Chiesa, Sabrina; Mingueneau, Michael; Fuseri, Nicolas; Malissen, Bernard; Raulet, David H.; Malissen, Marie; Vivier, Eric; Tomasello, Elena

    2006-01-01

    Natural killer (NK) cells express an array of activating receptors that associate with DAP12 (KARAP), CD3ζ, and/or FcRγ ITAM (immunoreceptor tyrosine-based activation motif)–bearing signaling subunits. In T and mast cells, ITAM-dependent signals are integrated by critical scaffolding elements such as LAT (linker for activation of T cells) and NTAL (non–T-cell activation linker). Using mice that are deficient for ITAM-bearing molecules, LAT or NTAL, we show that NK cell cytotoxicity and interferon-γ secretion are initiated by ITAM-dependent and -independent as well as LAT/NTAL-dependent and -independent pathways. The role of these various signaling circuits depends on the target cell as well as on the activation status of the NK cell. The multiplicity and the plasticity of the pathways that initiate NK cell effector functions contrast with the situation in T cells and B cells and provide an explanation for the resiliency of NK cell effector functions to various pharmacologic inhibitors and genetic mutations in signaling molecules. PMID:16291591

  8. Analysis and Design of Multiple-Antenna Cognitive Radios With Multiple Primary User Signals

    NASA Astrophysics Data System (ADS)

    Morales-Jimenez, David; Louie, Raymond H. Y.; McKay, Matthew R.; Chen, Yang

    2015-09-01

    We consider multiple-antenna signal detection of primary user transmission signals by a secondary user receiver in cognitive radio networks. The optimal detector is analyzed for the scenario where the number of primary user signals is no less than the number of receive antennas at the secondary user. We first derive exact expressions for the moments of the generalized likelihood ratio test (GLRT) statistic, yielding approximations for the false alarm and detection probabilities. We then show that the normalized GLRT statistic converges in distribution to a Gaussian random variable when the number of antennas and observations grow large at the same rate. Further, using results from large random matrix theory, we derive expressions to compute the detection probability without explicit knowledge of the channel, and then particularize these expressions for two scenarios of practical interest: 1) a single primary user sending spatially multiplexed signals, and 2) multiple spatially distributed primary users. Our analytical results are finally used to obtain simple design rules for the signal detection threshold.

  9. Integration of C/N-nutrient and multiple environmental signals into the ABA signaling cascade

    PubMed Central

    Lu, Yu; Yamaguchi, Junji; Sato, Takeo

    2015-01-01

    Due to their immobility, plants have developed sophisticated mechanisms to robustly monitor and appropriately respond to dynamic changes in nutrient availability. Carbon (C) and nitrogen (N) are especially important in regulating plant metabolism and development, thereby affecting crop productivity. In addition to their independent utilization, the ratio of C to N metabolites in the cell, referred to as the “C/N balance”, is important for the regulation of plant growth, although molecular mechanisms mediating C/N signaling remain unclear. Recently ABI1, a protein phosphatase type 2C (PP2C), was shown to be a regulator of C/N response in Arabidopsis plants. ABI1 functions as a negative regulator of abscisic acid (ABA) signal transduction. ABA is versatile phytohormone that regulates multiple aspects of plant growth and adaptation to environmental stress. This review highlights the regulation of the C/N response mediated by a non-canonical ABA signaling pathway that is independent of ABA biosynthesis, as well as recent findings on the direct crosstalk between multiple cellular signals and the ABA signaling cascade. PMID:26786013

  10. Extending lock-in methods: term isolation detection of nonlinear signals.

    PubMed

    Jarvis, Thomas W

    2016-08-01

    We show that components of a nonlinear signal can be measured using phase-sensitive detection at unconventional demodulation frequencies, allowing us to isolate individual terms from the signal. To demonstrate this technique, autocorrelation measurements of an ultrafast pulsed laser were performed using two-photon absorption. In this example, the isolation of individual autocorrelation terms may provide internal consistency checks to improve the precision and accuracy of pulse characterization. More generally, this scheme can be extended to a range of nonlinear measurements. As a demonstration, we analyze a three-photon autocorrelation model, showing that many nonlinear signals can be studied with this method. We anticipate that term isolation detection will find application in a broad range of experiments, such as multidimensional Fourier transform spectroscopy or coherent anti-Stokes Raman spectroscopy. PMID:27505362

  11. Reception of Multiple Telemetry Signals via One Dish Antenna

    NASA Technical Reports Server (NTRS)

    Mukai, Ryan; Vilnrotter, Victor

    2010-01-01

    A microwave aeronautical-telemetry receiver system includes an antenna comprising a seven-element planar array of receiving feed horns centered at the focal point of a paraboloidal dish reflector that is nominally aimed at a single aircraft or at multiple aircraft flying in formation. Through digital processing of the signals received by the seven feed horns, the system implements a method of enhanced cancellation of interference, such that it becomes possible to receive telemetry signals in the same frequency channel simultaneously from either or both of two aircraft at slightly different angular positions within the field of view of the antenna, even in the presence of multipath propagation. The present system is an advanced version of the system described in Spatio- Temporal Equalizer for a Receiving-Antenna Feed Array NPO-43077, NASA Tech Briefs, Vol. 34, No. 2 (February 2010), page 32. To recapitulate: The radio-frequency telemetry signals received by the seven elements of the array are digitized, converted to complex baseband form, and sent to a spatio-temporal equalizer that consists mostly of a bank of seven adaptive finite-impulse-response (FIR) filters (one for each element in the array) plus a unit that sums the outputs of the filters. The combination of the spatial diversity of the feedhorn array and the temporal diversity of the filter bank affords better multipath suppression performance than is achievable by means of temporal equalization alone. The FIR filter bank adapts itself in real time to enable reception of telemetry at a low bit error rate, even in the presence of frequency-selective multipath propagation like that commonly found at flight-test ranges. The combination of the array and the filter bank makes it possible to constructively add multipath incoming signals to the corresponding directly arriving signals, thereby enabling reductions in telemetry bit-error rates.

  12. Extended layerwise method for laminated composite plates with multiple delaminations and transverse cracks

    NASA Astrophysics Data System (ADS)

    Li, D. H.; Zhang, X.; Sze, K. Y.; Liu, Y.

    2016-07-01

    In this paper, the extended layerwise method (XLWM), which was developed for laminated composite beams with multiple delaminations and transverse cracks (Li et al. in Int J Numer Methods Eng 101:407-434, 2015), is extended to laminated composite plates. The strong and weak discontinuous functions along the thickness direction are adopted to simulate multiple delaminations and interlaminar interfaces, respectively, whilst transverse cracks are modeled by the extended finite element method (XFEM). The interaction integral method and maximum circumferential tensile criterion are used to calculate the stress intensity factor (SIF) and crack growth angle, respectively. The XLWM for laminated composite plates can accurately predicts the displacement and stress fields near the crack tips and delamination fronts. The thickness distribution of SIF and thus the crack growth angles in different layers can be obtained. These information cannot be predicted by using other existing shell elements enriched by XFEM. Several numerical examples are studied to demonstrate the capabilities of the XLWM in static response analyses, SIF calculations and crack growth predictions.

  13. An extended diffraction-enhanced imaging method for implementing multiple-image radiography

    NASA Astrophysics Data System (ADS)

    Chou, Cheng-Ying; Anastasio, Mark A.; Brankov, Jovan G.; Wernick, Miles N.; Brey, Eric M.; Connor, Dean M., Jr.; Zhong, Zhong

    2007-04-01

    Diffraction-enhanced imaging (DEI) is an analyser-based x-ray imaging method that produces separate images depicting the projected x-ray absorption and refractive properties of an object. Because the imaging model of DEI does not account for ultra-small-angle x-ray scattering (USAXS), the images produced in DEI can contain artefacts and inaccuracies in medical imaging applications. In this work, we investigate an extended DEI method for concurrent reconstruction of three images that depict an object's projected x-ray absorption, refraction and USAXS properties. The extended DEI method can be viewed as an implementation of the recently proposed multiple-image radiography paradigm. Validation studies are conducted by use of computer-simulated and synchrotron measurement data.

  14. All-optical code-division multiple-access applications: 2(n) extended-prime codes.

    PubMed

    Zhang, J G; Kwong, W C; Mann, S

    1997-09-10

    A new family of 2(n) codes, called 2(n) extended-prime codes, is proposed for all-optical code-division multiple-access networks. Such 2(n) codes are derived from so-called extended-prime codes so that their cross-correlation functions are not greater than 1, as opposed to 2 for recently proposed 2(n) prime codes. As a result, a larger number of active users can now be supported by the new codes for a given bit-error rate than can be by 2(n) prime codes, while power-efficient, waveguide-integrable all-serial coding and correlating configurations proposed for the 2(n) prime codes can still be employed. PMID:18259529

  15. The initial rise method extended to multiple trapping levels in thermoluminescent materials.

    PubMed

    Furetta, C; Guzmán, S; Ruiz, B; Cruz-Zaragoza, E

    2011-02-01

    The well known Initial Rise Method (IR) is commonly used to determine the activation energy when only one glow peak is presented and analysed in the phosphor materials. However, when the glow peak is more complex, a wide peak and some holders appear in the structure. The application of the Initial Rise Method is not valid because multiple trapping levels are considered and then the thermoluminescent analysis becomes difficult to perform. This paper shows the case of a complex glow curve structure as an example and shows that the calculation is also possible using the IR method. The aim of the paper is to extend the well known Initial Rise Method (IR) to the case of multiple trapping levels. The IR method is applied to minerals extracted from Nopal cactus and Oregano spices because the thermoluminescent glow curve's shape suggests a trap distribution instead of a single trapping level. PMID:21051238

  16. Multiple Signals Regulate PLC beta 3 in Human Myometrial Cells

    PubMed Central

    Zhong, Miao; Murtazina, Dilyara A.; Phillips, Jennifer; Ku, Chun-Ying; Sanborn, Barbara M.

    2008-01-01

    Summary The regulation of PLCB3-Serine1105 phosphorylation by both negative feedback and negative crosstalk facilitates the integration of multiple signaling pathways in myometrial cells. Phospholipase CB3 (PLCB3) Serine1105, a substrate for multiple protein kinases, represents a potential point of convergence of several signaling pathways in the myometrium. To explore this hypothesis, the regulation of PLCB3-Serine1105 phosphorylation (P-S1105) was studied in immortalized and primary human myometrial cells. CPT-cAMP and calcitonin gene-related peptide (CALCA) transiently increased P-S1105. Relaxin also stimulated P-S1105; this effect was partially blocked by the protein kinase A (PRKA) inhibitor Rp-8-CPT-cAMPS. Oxytocin, which stimulates Gαq-mediated pathways, also rapidly increased P-S1105, as did PGF2α and ATP. Oxytocin-stimulated phosphorylation was blocked by the protein kinase C (PRKC) inhibitor Go6976 and by pretreatment overnight with a phorbol ester. Cypermethrin, a PP2B phosphatase inhibitor, but not okadaic acid, a PP1/PP2A inhibitor, prolonged the effect of CALCA on P-S1105, whereas the reverse was the case for the oxytocin-stimulated increase in P-S1105. PLCB3 was the predominant PLC isoform expressed in the myometrial cells and PLCB3 shRNA constructs significantly attenuated oxytocin-stimulated increases in intracellular calcium. Oxytocin-induced phosphatidylinositol (PI) turnover was inhibited by CPT-cAMP and okadaic acid but enhanced by pretreatment with Go6976. CPT-cAMP inhibited oxytocin-stimulated PI turnover in the presence of overexpressed PLCB3, but not overexpressed PLCB3-S1105A. These data demonstrate that both negative crosstalk from the cAMP/PRKA pathway and a negative feedback loop in the oxytocin/G protein/PLCB pathway involving PRKC operate in myometrial cells and suggest that different protein phosphatases predominate in mediating P-S1105 dephosphorylation in these pathways. The integration of multiple signal components at the level

  17. The Expected Impact of Multiple Scattering on ATLID Signals

    NASA Astrophysics Data System (ADS)

    Donovan, D. P.

    2016-06-01

    ATLID stands for "ATmospheric LIDar" and is the lidar to be flown on the Earth Clouds and Radiation Explorer (EarthCARE) platform in 2018. ATLID is a High-Spectral Resolution (HSRL) system operating at 355nm with a narrower field-of-view and lower orbit than the CALIPSO lidar. In spite of the smaller footprint multiple-scattering (MS) will have an important impact on ATLID cloud signals and, in some aspects, the accurate treatment of MS will be more important for ATLID than CALIPSO. On the other hand, the relationship between integrated backscatter and integrated MS induced depolarization in water clouds will be similar between ATLID and CALIPSO indicating that a CALIPSO-like strategy for cloud-phase identification can be successfully applied to ATLID.

  18. Identifying causal variants at loci with multiple signals of association.

    PubMed

    Hormozdiari, Farhad; Kostem, Emrah; Kang, Eun Yong; Pasaniuc, Bogdan; Eskin, Eleazar

    2014-10-01

    Although genome-wide association studies have successfully identified thousands of risk loci for complex traits, only a handful of the biologically causal variants, responsible for association at these loci, have been successfully identified. Current statistical methods for identifying causal variants at risk loci either use the strength of the association signal in an iterative conditioning framework or estimate probabilities for variants to be causal. A main drawback of existing methods is that they rely on the simplifying assumption of a single causal variant at each risk locus, which is typically invalid at many risk loci. In this work, we propose a new statistical framework that allows for the possibility of an arbitrary number of causal variants when estimating the posterior probability of a variant being causal. A direct benefit of our approach is that we predict a set of variants for each locus that under reasonable assumptions will contain all of the true causal variants with a high confidence level (e.g., 95%) even when the locus contains multiple causal variants. We use simulations to show that our approach provides 20-50% improvement in our ability to identify the causal variants compared to the existing methods at loci harboring multiple causal variants. We validate our approach using empirical data from an expression QTL study of CHI3L2 to identify new causal variants that affect gene expression at this locus. CAVIAR is publicly available online at http://genetics.cs.ucla.edu/caviar/. PMID:25104515

  19. Identifying Causal Variants at Loci with Multiple Signals of Association

    PubMed Central

    Hormozdiari, Farhad; Kostem, Emrah; Kang, Eun Yong; Pasaniuc, Bogdan; Eskin, Eleazar

    2014-01-01

    Although genome-wide association studies have successfully identified thousands of risk loci for complex traits, only a handful of the biologically causal variants, responsible for association at these loci, have been successfully identified. Current statistical methods for identifying causal variants at risk loci either use the strength of the association signal in an iterative conditioning framework or estimate probabilities for variants to be causal. A main drawback of existing methods is that they rely on the simplifying assumption of a single causal variant at each risk locus, which is typically invalid at many risk loci. In this work, we propose a new statistical framework that allows for the possibility of an arbitrary number of causal variants when estimating the posterior probability of a variant being causal. A direct benefit of our approach is that we predict a set of variants for each locus that under reasonable assumptions will contain all of the true causal variants with a high confidence level (e.g., 95%) even when the locus contains multiple causal variants. We use simulations to show that our approach provides 20–50% improvement in our ability to identify the causal variants compared to the existing methods at loci harboring multiple causal variants. We validate our approach using empirical data from an expression QTL study of CHI3L2 to identify new causal variants that affect gene expression at this locus. CAVIAR is publicly available online at http://genetics.cs.ucla.edu/caviar/. PMID:25104515

  20. Estrogen Signaling Multiple Pathways to Impact Gene Transcription

    PubMed Central

    Marino, Maria; Galluzzo, Paola; Ascenzi, Paolo

    2006-01-01

    Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17β-estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-κB (NF-κB) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge. PMID:18369406

  1. Modelling tissue electrophysiology with multiple cell types: applications of the extended bidomain framework.

    PubMed

    Corrias, Alberto; Pathmanathan, Pras; Gavaghan, David J; Buist, Martin L

    2012-02-01

    The bidomain framework has been extensively used to model tissue electrophysiology in a variety of applications. One limitation of the bidomain model is that it describes the activity of only one cell type interacting with the extracellular space. If more than one cell type contributes to the tissue electrophysiology, then the bidomain model is not sufficient. Recently, evidence has suggested that this is the case for at least two important applications: cardiac and gastrointestinal tissue electrophysiology. In the heart, fibroblasts ubiquitously interact with myocytes and are believed to play an important role in the organ electrophysiology. Along the GI tract, interstitial cells of Cajal (ICC) generate electrical waves that are passed on to surrounding smooth muscle cells (SMC), which are interconnected with the ICC and with each other. Because of the contribution of more than one cell type to the overall organ electrophysiology, investigators in different fields have independently proposed similar extensions of the bidomain model to incorporate multiple cell types and tested it on simplified geometries. In this paper, we provide a general derivation of such an extended bidomain framework applicable to any tissue and provide a generic and efficient implementation applicable to any geometry. Proof-of-concept results of tissue electrophysiology on realistic 3D organ geometries using the extended bidomain framework are presented for the heart and the stomach. PMID:22222297

  2. Extending the Evaluation of a Computer System Used as a Microswitch for Word Utterances of Persons with Multiple Disabilities

    ERIC Educational Resources Information Center

    Lancioni, G. E.; O'Reilly, M. F.; Singh, N. N.; Sigafoos, J.; Oliva, D.; Montironi, G.; Savino, M.; Bosco, A.

    2005-01-01

    Background: Microswitches can be vital tools to help individuals with extensive multiple disabilities acquire control of environmental stimulation. This study was aimed at extending the evaluation of a computer system used as a microswitch for word utterances with three participants with multiple disabilities. Method: Sets of 7 or 12 word…

  3. Serotonergic neurons signal reward and punishment on multiple timescales

    PubMed Central

    Cohen, Jeremiah Y; Amoroso, Mackenzie W; Uchida, Naoshige

    2015-01-01

    Serotonin's function in the brain is unclear. One challenge in testing the numerous hypotheses about serotonin's function has been observing the activity of identified serotonergic neurons in animals engaged in behavioral tasks. We recorded the activity of dorsal raphe neurons while mice experienced a task in which rewards and punishments varied across blocks of trials. We ‘tagged’ serotonergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to light. We found three main features of serotonergic neuron activity: (1) a large fraction of serotonergic neurons modulated their tonic firing rates over the course of minutes during reward vs punishment blocks; (2) most were phasically excited by punishments; and (3) a subset was phasically excited by reward-predicting cues. By contrast, dopaminergic neurons did not show firing rate changes across blocks of trials. These results suggest that serotonergic neurons signal information about reward and punishment on multiple timescales. DOI: http://dx.doi.org/10.7554/eLife.06346.001 PMID:25714923

  4. Extending substructure based iterative solvers to multiple load and repeated analyses

    NASA Technical Reports Server (NTRS)

    Farhat, Charbel

    1993-01-01

    Direct solvers currently dominate commercial finite element structural software, but do not scale well in the fine granularity regime targeted by emerging parallel processors. Substructure based iterative solvers--often called also domain decomposition algorithms--lend themselves better to parallel processing, but must overcome several obstacles before earning their place in general purpose structural analysis programs. One such obstacle is the solution of systems with many or repeated right hand sides. Such systems arise, for example, in multiple load static analyses and in implicit linear dynamics computations. Direct solvers are well-suited for these problems because after the system matrix has been factored, the multiple or repeated solutions can be obtained through relatively inexpensive forward and backward substitutions. On the other hand, iterative solvers in general are ill-suited for these problems because they often must restart from scratch for every different right hand side. In this paper, we present a methodology for extending the range of applications of domain decomposition methods to problems with multiple or repeated right hand sides. Basically, we formulate the overall problem as a series of minimization problems over K-orthogonal and supplementary subspaces, and tailor the preconditioned conjugate gradient algorithm to solve them efficiently. The resulting solution method is scalable, whereas direct factorization schemes and forward and backward substitution algorithms are not. We illustrate the proposed methodology with the solution of static and dynamic structural problems, and highlight its potential to outperform forward and backward substitutions on parallel computers. As an example, we show that for a linear structural dynamics problem with 11640 degrees of freedom, every time-step beyond time-step 15 is solved in a single iteration and consumes 1.0 second on a 32 processor iPSC-860 system; for the same problem and the same parallel

  5. Tequila Regulates Insulin-Like Signaling and Extends Life Span in Drosophila melanogaster.

    PubMed

    Huang, Cheng-Wen; Wang, Horng-Dar; Bai, Hua; Wu, Ming-Shiang; Yen, Jui-Hung; Tatar, Marc; Fu, Tsai-Feng; Wang, Pei-Yu

    2015-12-01

    The aging process is a universal phenomenon shared by all living organisms. The identification of longevity genes is important in that the study of these genes is likely to yield significant insights into human senescence. In this study, we have identified Tequila as a novel candidate gene involved in the regulation of longevity in Drosophila melanogaster. We have found that a hypomorphic mutation of Tequila (Teq(f01792)), as well as cell-specific downregulation of Tequila in insulin-producing neurons of the fly, significantly extends life span. Tequila deficiency-induced life-span extension is likely to be associated with reduced insulin-like signaling, because Tequila mutant flies display several common phenotypes of insulin dysregulation, including reduced circulating Drosophila insulin-like peptide 2 (Dilp2), reduced Akt phosphorylation, reduced body size, and altered glucose homeostasis. These observations suggest that Tequila may confer life-span extension by acting as a modulator of Drosophila insulin-like signaling. PMID:26265729

  6. Efficient methods for joint estimation of multiple fundamental frequencies in music signals

    NASA Astrophysics Data System (ADS)

    Pertusa, Antonio; Iñesta, José M.

    2012-12-01

    This study presents efficient techniques for multiple fundamental frequency estimation in music signals. The proposed methodology can infer harmonic patterns from a mixture considering interactions with other sources and evaluate them in a joint estimation scheme. For this purpose, a set of fundamental frequency candidates are first selected at each frame, and several hypothetical combinations of them are generated. Combinations are independently evaluated, and the most likely is selected taking into account the intensity and spectral smoothness of its inferred patterns. The method is extended considering adjacent frames in order to smooth the detection in time, and a pitch tracking stage is finally performed to increase the temporal coherence. The proposed algorithms were evaluated in MIREX contests yielding state of the art results with a very low computational burden.

  7. A signal processing framework for simultaneous detection of multiple environmental contaminants

    NASA Astrophysics Data System (ADS)

    Chakraborty, Subhadeep; Manahan, Michael P.; Mench, Matthew M.

    2013-11-01

    The possibility of large-scale attacks using chemical warfare agents (CWAs) has exposed the critical need for fundamental research enabling the reliable, unambiguous and early detection of trace CWAs and toxic industrial chemicals. This paper presents a unique approach for the identification and classification of simultaneously present multiple environmental contaminants by perturbing an electrochemical (EC) sensor with an oscillating potential for the extraction of statistically rich information from the current response. The dynamic response, being a function of the degree and mechanism of contamination, is then processed with a symbolic dynamic filter for the extraction of representative patterns, which are then classified using a trained neural network. The approach presented in this paper promises to extend the sensing power and sensitivity of these EC sensors by augmenting and complementing sensor technology with state-of-the-art embedded real-time signal processing capabilities.

  8. Impact of extended-release dalfampridine on walking ability in patients with multiple sclerosis

    PubMed Central

    Hayes, Keith C

    2011-01-01

    Dalfampridine extended release (ER) 10 mg is an oral tablet form of the potassium (K+) channel-blocking compounded dalfampridine, also known as fampridine, and chemically 4-aminopyridine or 4-AP, which received regulatory approval in the United States for the treatment of walking in patients with multiple sclerosis (MS) in January 2010. Two pivotal Phase 3 clinical trials demonstrated significant improvements in walking in patients with the four primary forms of MS following administration of dalfampridine ER tablets 10 mg twice daily. The drug is thought to act by restoring conduction in focally demyelinated axons and by enhancing neurotransmission, thereby leading to improved neurological function. This review describes how dalfampridine represents a new pharmacotherapeutic approach to the clinical management of mobility impairment. It describes the mechanism of action and chemistry of dalfampridine ER, its pharmacokinetics, tolerability, and side effects, and the outcomes of multicenter trials showing its efficacy in improving walking speed. Clinician and patient global assessments, as well as patient self-assessment of the impact of MS on their gait disability, confirm clinically relevant benefit from the therapy. Patients tolerate the drug well and their improvement in terms of household and community ambulation, inferred from analysis of pooled data from several studies, is likely to translate into benefits in the performance of instrumental activities of daily living and a reduction in the neuropsychiatric burden of disease. PMID:21573085

  9. Multiple Running Speed Signals in Medial Entorhinal Cortex.

    PubMed

    Hinman, James R; Brandon, Mark P; Climer, Jason R; Chapman, G William; Hasselmo, Michael E

    2016-08-01

    Grid cells in medial entorhinal cortex (MEC) can be modeled using oscillatory interference or attractor dynamic mechanisms that perform path integration, a computation requiring information about running direction and speed. The two classes of computational models often use either an oscillatory frequency or a firing rate that increases as a function of running speed. Yet it is currently not known whether these are two manifestations of the same speed signal or dissociable signals with potentially different anatomical substrates. We examined coding of running speed in MEC and identified these two speed signals to be independent of each other within individual neurons. The medial septum (MS) is strongly linked to locomotor behavior, and removal of MS input resulted in strengthening of the firing rate speed signal, while decreasing the strength of the oscillatory speed signal. Thus, two speed signals are present in MEC that are differentially affected by disrupted MS input. PMID:27427460

  10. New genes that extend Caenorhabditis elegans' lifespan in response to reproductive signals.

    PubMed

    McCormick, Mark; Chen, Kan; Ramaswamy, Priya; Kenyon, Cynthia

    2012-04-01

    In Caenorhabditis elegans and Drosophila, removing germline stem cells increases lifespan. In C. elegans, this lifespan extension requires DAF-16, a FOXO transcription factor, and DAF-12, a nuclear hormone receptor. To better understand the regulatory relationships between DAF-16 and DAF-12, we used microarray analysis to identify downstream genes. We found that these two transcription factors influence the expression of distinct but overlapping sets of genes in response to loss of the germline. In addition, we identified several new genes that are required for loss of the germline to increase lifespan. One, phi-62, encodes a conserved, predicted RNA-binding protein. PHI-62 influences DAF-16-dependent transcription, possibly by collaborating with TCER-1, a putative transcription elongation factor, and FTT-2, a 14-3-3 protein known to bind DAF-16. Three other genes encode proteins involved in lipid metabolism; one is a triacylglycerol lipase, and another is an acyl-CoA reductase. These genes do not noticeably affect bulk fat storage levels; therefore, we propose a model in which they may influence production of a lifespan-extending signal or metabolite. PMID:22081913

  11. A fasting-responsive signaling pathway that extends life span in C. elegans.

    PubMed

    Uno, Masaharu; Honjoh, Sakiko; Matsuda, Mitsuhiro; Hoshikawa, Haruka; Kishimoto, Saya; Yamamoto, Tomohito; Ebisuya, Miki; Yamamoto, Takuya; Matsumoto, Kunihiro; Nishida, Eisuke

    2013-01-31

    Intermittent fasting is one of the most effective dietary restriction regimens that extend life span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, the mechanisms that sense and transduce the fasting stimulus remain largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we find that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting-induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acts as an activator of AP-1 and is activated in response to fasting. KGB-1 and AP-1 are involved in intermittent fasting-induced longevity. Fasting-induced upregulation of the components of the SCF E3 ubiquitin ligase complex via AP-1 and DAF-16 enhances protein ubiquitination and reduces protein carbonylation. Our results thus identify a fasting-responsive KGB-1/AP-1 signaling pathway, which, together with DAF-16, causes transcriptional changes that mediate longevity, partly through regulating proteostasis. PMID:23352664

  12. Healthspan and longevity can be extended by suppression of growth hormone signaling.

    PubMed

    Bartke, Andrzej

    2016-08-01

    Average and maximal lifespan are important biological characteristics of every species, but can be modified by mutations and by a variety of genetic, dietary, environmental, and pharmacological interventions. Mutations or disruption of genes required for biosynthesis or action of growth hormone (GH) produce remarkable extension of longevity in laboratory mice. Importantly, the long-lived GH-related mutants exhibit many symptoms of delayed and/or slower aging, including preservation of physical and cognitive functions and resistance to stress and age-related disease. These characteristics could be collectively described as "healthy aging" or extension of the healthspan. Extension of both the healthspan and lifespan in GH-deficient and GH-resistant mice appears to be due to multiple interrelated mechanisms. Some of these mechanisms have been linked to healthy aging and genetic predisposition to extended longevity in humans. Enhanced insulin sensitivity combined with reduced insulin levels, reduced adipose tissue, central nervous system inflammation, and increased levels of adiponectin represent such mechanisms. Further progress in elucidation of mechanisms that link reduced GH action to delayed and healthy aging should identify targets for lifestyle and pharmacological interventions that could benefit individuals as well as society. PMID:26909495

  13. Intracortical Multiplication of Thalamocortical Signals in Mouse Auditory Cortex

    PubMed Central

    Li, Ling-yun; Li, Ya-tang; Zhou, Mu; Tao, Huizhong W.; Zhang, Li I.

    2013-01-01

    Cortical processing of sensory information initiates from the transformation of thalamically-relayed signals. By optogenetically silencing intracortical circuits to isolate thalamic inputs to layer 4 neurons, we show that intracortical excitation linearly amplifies thalamocortical responses underlying frequency and direction selectivity with preserved spectral range and tuning, and prolongs the response duration. This signal pre-amplification and prolongation enhances the salience of thalamocortically-relayed information and ensures its robust, faithful and more persistent representation. PMID:23933752

  14. Signal Design for Improved Ranging Among Multiple Transceivers

    NASA Technical Reports Server (NTRS)

    Young, Lawrence; Tien, Jeffrey; Srinivasan, Jeffrey

    2004-01-01

    "Ultra-BOC" (where "BOC" signifies "binary offset carrier") is the name of an improved generic design of microwave signals to be used by a group of spacecraft flying in formation to measure ranges and bearings among themselves and to exchange telemetry needed for these measurements. Ultra-BOC could also be applied on Earth for diverse purposes -- for example, measuring relative positions of vehicles on highways for traffic-control purposes and determining the relative alignments of machines operating in mines and of construction machines and structures at construction sites. Ultra-BOC provides for rapid and robust acquisition of signals, even when signal-to-noise ratios are low. The design further provides that each spacecraft or other platform constantly strives to acquire and track the signals from the other platforms while simultaneously transmitting signals that provide full range, bearing, and telemetry service to the other platforms. In Ultra-BOC, unlike in other signal designs that have been considered for the same purposes, it is not necessary to maneuver the spacecraft or other platforms to obtain the data needed for resolving integer-carrier-cycle phase ambiguities.

  15. Multiple Stress Signals Induce p73β Accumulation1

    PubMed Central

    Lin, Kai Wei; Nam, Shin Yuen; Toh, Wen Hong; Dulloo, Iqbal; Sabapathy, Kanaga

    2004-01-01

    Abstract Although p73 is a structural and functional homologue of the tumor-suppressor gene p53, it is not mutated in many human cancers as p53. Besides, p73 was shown to be activated by only a subset of signals that activate p53, such as γ-irradiation and cisplatin, but not by other common genotoxic stress-inducing agents such as ultraviolet (UV) irradiation, although many of these signals are also capable of inducing p53-independent cell death. Using a p73-specific antibody, we confirmed that c-Abl is required for cisplatin-induced p73 upregulation, and further demonstrate that the p73 protein is upregulated by UV irradiation and other stress stimuli including sorbitol, hydrogen peroxide, nocodazol, and taxol. These stress signals upregulate both p73 mRNA and increases the stability of p73, indicating that p73 is regulated transcriptionally and posttranslationally. Cells stably expressing the dominant-negative p73 inhibitor protein (p73DD) and p73-/- fibroblasts are more resistant than control cells to apoptosis induced by these stress signals, suggesting that p73 contributes to apoptosis induction. Together, the data demonstrate that several stress signals can signal to p73 in vivo, which raises the possibility of eradicating cancers with an unmutated p73 gene by activating them with stress-inducing agents or their mimetics. PMID:15548364

  16. Extended Pausing by Humans on Multiple Fixed-Ratio Schedules with Varied Reinforcer Magnitude and Response Requirements

    ERIC Educational Resources Information Center

    Williams, Dean C.; Saunders, Kathryn J.; Perone, Michael

    2011-01-01

    We conducted three experiments to reproduce and extend Perone and Courtney's (1992) study of pausing at the beginning of fixed-ratio schedules. In a multiple schedule with unequal amounts of food across two components, they found that pigeons paused longest in the component associated with the smaller amount of food (the lean component), but only…

  17. The Multiple Signaling Systems Regulating Virulence in Pseudomonas aeruginosa

    PubMed Central

    Nadal Jimenez, Pol; Koch, Gudrun; Thompson, Jessica A.; Xavier, Karina B.; Cool, Robbert H.

    2012-01-01

    Summary: Cell-to-cell communication is a major process that allows bacteria to sense and coordinately react to the fluctuating conditions of the surrounding environment. In several pathogens, this process triggers the production of virulence factors and/or a switch in bacterial lifestyle that is a major determining factor in the outcome and severity of the infection. Understanding how bacteria control these signaling systems is crucial to the development of novel antimicrobial agents capable of reducing virulence while allowing the immune system of the host to clear bacterial infection, an approach likely to reduce the selective pressures for development of resistance. We provide here an up-to-date overview of the molecular basis and physiological implications of cell-to-cell signaling systems in Gram-negative bacteria, focusing on the well-studied bacterium Pseudomonas aeruginosa. All of the known cell-to-cell signaling systems in this bacterium are described, from the most-studied systems, i.e., N-acyl homoserine lactones (AHLs), the 4-quinolones, the global activator of antibiotic and cyanide synthesis (GAC), the cyclic di-GMP (c-di-GMP) and cyclic AMP (cAMP) systems, and the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), to less-well-studied signaling molecules, including diketopiperazines, fatty acids (diffusible signal factor [DSF]-like factors), pyoverdine, and pyocyanin. This overview clearly illustrates that bacterial communication is far more complex than initially thought and delivers a clear distinction between signals that are quorum sensing dependent and those relying on alternative factors for their production. PMID:22390972

  18. Effects of multiple scattering on scintillation of transionospheric radio signals

    NASA Technical Reports Server (NTRS)

    Liu, C. H.; Yeh, K. C.; Youakim, M. Y.; Wernik, A. W.

    1974-01-01

    Recent development in the optical scintillation theory has been adapted to the ionospheric geometry in order to study the ionospheric scintillation phenomenon in the presence of multiple scattering. Under approximations well satisfied in typical ionospheres for a frequency above about 20 MHz, the first through fourth moment equations have been derived and some analytic solutions given. The fourth moment equation has also been solved numerically. The numerical results show clearly the occurrence of focusing and saturation phenomena. The new multiple-scatter effects are emphasized.

  19. Elevated PI3K signaling drives multiple Breast Cancer subtypes

    PubMed Central

    Adams, Jessica R.; Schachter, Nathan F.; Liu, Jeff C.; Zacksenhaus, Eldad; Egan, Sean E.

    2011-01-01

    Most human breast tumors have mutations that elevate signaling through a key metabolic pathway that is induced by insulin and a number of growth factors. This pathway serves to activate an enzyme known as phosphatidylinositol 3' kinase (PI3K) as well as to regulate proteins that signal in response to lipid products of PI3K. The specific mutations that activate this pathway in breast cancer can occur in genes coding for tyrosine kinase receptors, adaptor proteins linked to PI3K, catalytic and regulatory subunits of PI3K, serine/threonine kinases that function downstream of PI3K, and also phosphatidylinositol phosphatase tumor suppressors that function to antagonize this pathway. While each genetic change results in net elevation of PI3K pathway signaling, and all major breast cancer subtypes show pathway activation, the specific mutation(s) involved in any one tumor may play an important role in defining tumor subtype, prognosis and even sensitivity to therapy. Here, we describe mouse models of breast cancer with elevated PI3K signaling, and how they may be used to guide development of novel therapeutics. PMID:21646685

  20. Adaptive frequency estimation by MUSIC (Multiple Signal Classification) method

    NASA Astrophysics Data System (ADS)

    Karhunen, Juha; Nieminen, Esko; Joutsensalo, Jyrki

    During the last years, the eigenvector-based method called MUSIC has become very popular in estimating the frequencies of sinusoids in additive white noise. Adaptive realizations of the MUSIC method are studied using simulated data. Several of the adaptive realizations seem to give in practice equally good results as the nonadaptive standard realization. The only exceptions are instantaneous gradient type algorithms that need considerably more samples to achieve a comparable performance. A new method is proposed for constructing initial estimates to the signal subspace. The method improves often dramatically the performance of instantaneous gradient type algorithms. The new signal subspace estimate can also be used to define a frequency estimator directly or to simplify eigenvector computation.

  1. Storage and switching of multiple optical signals among three channels

    SciTech Connect

    Song Xiaoli; Li Aijun; Wang Lei; Kang Zhihui; Kou Jun; Wang Chunliang; Jiang Yun; Gao Jinyue; Zhang Bing

    2009-05-15

    We experimentally and theoretically demonstrate that multioptical signals can be effectively stored and retrieved by fractional stimulated Raman adiabatic passage technique in a tripod-type four-level {sup 87}Rb atomic system. The optical pulses stored can be controllably released into two of the three different channels. The restored pulses have the same frequency, polarization, and propagation direction as the writing pulses. The experimental results fit very well with the numerical simulations.

  2. Code division multiple access signaling for modulated reflector technology

    DOEpatents

    Briles, Scott D.

    2012-05-01

    A method and apparatus for utilizing code division multiple access in modulated reflectance transmissions comprises the steps of generating a phase-modulated reflectance data bit stream; modifying the modulated reflectance data bit stream; providing the modified modulated reflectance data bit stream to a switch that connects an antenna to an infinite impedance in the event a "+1" is to be sent, or connects the antenna to ground in the event a "0" or a "-1" is to be sent.

  3. Multiple Functions of Endocannabinoid Signaling in the Brain

    PubMed Central

    Katona, István; Freund, Tamás F.

    2014-01-01

    Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters like glutamate or GABA, yet act in profoundly unconventional ways. We aim to illustrate how uncovering the molecular, anatomical and physiological characteristics of endocannabinoid signaling revealed new mechanistic insights into several fundamental phenomena in synaptic physiology. First, we summarize unexpected advances in the molecular complexity of biogenesis and inactivation of the two endocannabinoids, anandamide and 2-arachidonoylglycerol. Then we show how these new metabolic routes are integrated into well-known intracellular signaling pathways. These endocannabinoid-producing signalosomes operate in phasic and tonic modes thereby differentially governing homeostatic, short-term and long-term synaptic plasticity throughout the brain. Finally, we discuss how cell type- and synapse-specific refinement of endocannabinoid signaling may explain the characteristic behavioral effects of cannabinoids. PMID:22524785

  4. AMPylation of Rho GTPases Subverts Multiple Host Signaling Processes*

    PubMed Central

    Woolery, Andrew R.; Yu, Xiaobo; LaBaer, Joshua; Orth, Kim

    2014-01-01

    Rho GTPases are frequent targets of virulence factors as they are keystone signaling molecules. Herein, we demonstrate that AMPylation of Rho GTPases by VopS is a multifaceted virulence mechanism that counters several host immunity strategies. Activation of NFκB, Erk, and JNK kinase signaling pathways were inhibited in a VopS-dependent manner during infection with Vibrio parahaemolyticus. Phosphorylation and degradation of IKBα were inhibited in the presence of VopS as was nuclear translocation of the NFκB subunit p65. AMPylation also prevented the generation of superoxide by the phagocytic NADPH oxidase complex, potentially by inhibiting the interaction of Rac and p67. Furthermore, the interaction of GTPases with the E3 ubiquitin ligases cIAP1 and XIAP was hindered, leading to decreased degradation of Rac and RhoA during infection. Finally, we screened for novel Rac1 interactions using a nucleic acid programmable protein array and discovered that Rac1 binds to the protein C1QA, a protein known to promote immune signaling in the cytosol. Interestingly, this interaction was disrupted by AMPylation. We conclude that AMPylation of Rho Family GTPases by VopS results in diverse inhibitory consequences during infection beyond the most obvious phenotype, the collapse of the actin cytoskeleton. PMID:25301945

  5. MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis.

    PubMed

    Severin, Mary E; Lee, Priscilla W; Liu, Yue; Selhorst, Amanda J; Gormley, Matthew G; Pei, Wei; Yang, Yuhong; Guerau-de-Arellano, Mireia; Racke, Michael K; Lovett-Racke, Amy E

    2016-06-01

    Transforming growth factor beta (TGFβ) signalling is critical for regulatory T cell development and function, and regulatory T cell dysregulation is a common observation in autoimmune diseases, including multiple sclerosis. In a comprehensive miRNA profiling study of patients with multiple sclerosis naïve CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGFβ signalling pathway were identified, leading to the hypothesis that miRNAs may be responsible for the regulatory T cell defect observed in patients with multiple sclerosis. Patients with multiple sclerosis had reduced levels of TGFβ signalling components in their naïve CD4 T cells. The differentially expressed miRNAs negatively regulated the TGFβ pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGFβ-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGFβ signalling results in a reduced regulatory T cell repertoire insufficient to control autoimmunity, and patients with multiple sclerosis have a reduced regulatory T cell repertoire, these data indicate that the elevated expression of multiple TGFβ-targeting miRNAs in naïve CD4 T cells of patients with multiple sclerosis impairs TGFβ signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis. PMID:27190026

  6. Wireless sensor networks for monitoring physiological signals of multiple patients.

    PubMed

    Dilmaghani, R S; Bobarshad, H; Ghavami, M; Choobkar, S; Wolfe, C

    2011-08-01

    This paper presents the design of a novel wireless sensor network structure to monitor patients with chronic diseases in their own homes through a remote monitoring system of physiological signals. Currently, most of the monitoring systems send patients' data to a hospital with the aid of personal computers (PC) located in the patients' home. Here, we present a new design which eliminates the need for a PC. The proposed remote monitoring system is a wireless sensor network with the nodes of the network installed in the patients' homes. These nodes are then connected to a central node located at a hospital through an Internet connection. The nodes of the proposed wireless sensor network are created by using a combination of ECG sensors, MSP430 microcontrollers, a CC2500 low-power wireless radio, and a network protocol called the SimpliciTI protocol. ECG signals are first sampled by a small portable device which each patient carries. The captured signals are then wirelessly transmitted to an access point located within the patients' home. This connectivity is based on wireless data transmission at 2.4-GHz frequency. The access point is also a small box attached to the Internet through a home asynchronous digital subscriber line router. Afterwards, the data are sent to the hospital via the Internet in real time for analysis and/or storage. The benefits of this remote monitoring are wide ranging: the patients can continue their normal lives, they do not need a PC all of the time, their risk of infection is reduced, costs significantly decrease for the hospital, and clinicians can check data in a short time. PMID:23851949

  7. High sexual signalling rates of young individuals predict extended life span in male Mediterranean fruit flies.

    PubMed

    Papadopoulos, Nikos T; Katsoyannos, Byron I; Kouloussis, Nikos A; Carey, James R; Müller, Hans-Georg; Zhang, Ying

    2004-01-01

    In a laboratory study, we monitored the lifetime sexual signalling (advertisement) of wild male Mediterranean fruit flies, and we tested the hypothesis that high lifetime intensity of sexual signalling indicates high survival probabilities. Almost all males exhibited signalling and individual signalling rates were highly variable from the beginning of the adults' maturity and throughout their life span (average life span 62.3 days). Sexual signalling rates after day 10 (peak maturity) were consistently high until about 1 week before death. There was a positive relationship between daily signalling rates and life span, and an increase in signalling level by one unit over all times was associated with an approximately 50% decrease in mortality rate. Signalling rates early in adult life (day 6-20) were higher in the longest-lived than in the shortest-lived flies. These results support the hypothesis that intense sexual signalling indicates longer life span. We discuss the importance of age-specific behavioural studies for understanding the evolution of male life histories. PMID:14576929

  8. DOA estimation of coherent wideband signals based on extended TOPS algorithm

    NASA Astrophysics Data System (ADS)

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

    2015-12-01

    In this paper, we present a new direction of arrival (DOA) estimation algorithm for coherent wideband signals. This algorithm is based on the test of orthogonality of projected subspaces (TOPS) method which will fail to work in real environments where signals are highly correlated or coherent due to multipath propagation. In order to overcome the disadvantage, we combine spatial smoothing techniques with TOPS method so that the rank of covariance matrix is equal to the number of signal sources even signals received are coherent. Unlike other coherent wideband methods, such as the coherent signal subspace method (CSSM) and WAVES, the new method does not require any initial DOA estimation, thus avoiding errors brought by incorrect initial values. Simulations on computer and experiments in the anechoic chamber based on an 8-elements digital array radar test-bed operating at L & S band are carried out. Simulation and experimental results validate the effectiveness of proposed algorithm.

  9. Romidepsin targets multiple survival signaling pathways in malignant T cells.

    PubMed

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies. PMID:26473529

  10. Romidepsin targets multiple survival signaling pathways in malignant T cells

    PubMed Central

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies. PMID:26473529

  11. Photonic generation of a millimeter-wave signal based on sextuple-frequency multiplication.

    PubMed

    Zhang, Jian; Chen, Hongwei; Chen, Minghua; Wang, Tianliang; Xie, Shizhong

    2007-05-01

    A millimeter-wave signal with sextuple-frequency multiplication of a microwave source is obtained with two cascaded optical modulators, which are driven by the same microwave source with phase deviation of pi/2 introduced by an electrical phase shifter. Without any optical filter, a wideband continuously tunable millimeter-wave signal is easily generated. PMID:17410221

  12. Photonic generation of a millimeter-wave signal based on sextuple-frequency multiplication

    NASA Astrophysics Data System (ADS)

    Zhang, Jian; Chen, Hongwei; Chen, Minghua; Wang, Tianliang; Xie, Shizhong

    2007-05-01

    A millimeter-wave signal with sextuple-frequency multiplication of a microwave source is obtained with two cascaded optical modulators, which are driven by the same microwave source with phase deviation of π/2 introduced by an electrical phase shifter. Without any optical filter, a wideband continuously tunable millimeter-wave signal is easily generated.

  13. ASIC3 Channels Integrate Agmatine and Multiple Inflammatory Signals through the Nonproton Ligand Sensing Domain

    PubMed Central

    2010-01-01

    Background Acid-sensing ion channels (ASICs) have long been known to sense extracellular protons and contribute to sensory perception. Peripheral ASIC3 channels represent natural sensors of acidic and inflammatory pain. We recently reported the use of a synthetic compound, 2-guanidine-4-methylquinazoline (GMQ), to identify a novel nonproton sensing domain in the ASIC3 channel, and proposed that, based on its structural similarity with GMQ, the arginine metabolite agmatine (AGM) may be an endogenous nonproton ligand for ASIC3 channels. Results Here, we present further evidence for the physiological correlation between AGM and ASIC3. Among arginine metabolites, only AGM and its analog arcaine (ARC) activated ASIC3 channels at neutral pH in a sustained manner similar to GMQ. In addition to the homomeric ASIC3 channels, AGM also activated heteromeric ASIC3 plus ASIC1b channels, extending its potential physiological relevance. Importantly, the process of activation by AGM was highly sensitive to mild acidosis, hyperosmolarity, arachidonic acid (AA), lactic acid and reduced extracellular Ca2+. AGM-induced ASIC3 channel activation was not through the chelation of extracellular Ca2+ as occurs with increased lactate, but rather through a direct interaction with the newly identified nonproton ligand sensing domain. Finally, AGM cooperated with the multiple inflammatory signals to cause pain-related behaviors in an ASIC3-dependent manner. Conclusions Nonproton ligand sensing domain might represent a novel mechanism for activation or sensitization of ASIC3 channels underlying inflammatory pain-sensing under in vivo conditions. PMID:21143836

  14. Extending Learning Communities: New Technologies, Multiple Literacies, and Culture Blind Pedagogies

    ERIC Educational Resources Information Center

    Knight, Michelle G.; Dixon, Iris R.; Norton, Nadjwa E. L.; Bentley, Courtney

    2004-01-01

    Technologies such as videoconferencing used for distance education are creating ways for high schools to extend their learning communities to connect youth with professional communities of practice in ways that approximate the face-to-face interactions in traditional classrooms. These technologies are often touted as a way to augment course…

  15. Functional mapping of reaction norms to multiple environmental signals.

    PubMed

    Wu, Jiasheng; Zeng, Yanru; Huang, Jianqing; Hou, Wei; Zhu, Jun; Wu, Rongling

    2007-02-01

    Whether there are different genes involved in response to different environmental signals and how these genes interact to determine the final expression of the trait are of fundamental importance in agricultural and biological research. We present a statistical framework for mapping environment-induced genes (or quantitative trait loci, QTLs) of major effects on the expression of a trait that respond to changing environments. This framework is constructed with a maximum-likelihood-based mixture model, in which the mean and covariance structure of environment-induced responses is modelled. The means for responses to continuous environmental states, referred to as reaction norms, are approximated for different QTL genotypes by mathematical equations that were derived from fundamental biological principles or based on statistical goodness-of-fit to observational data. The residual covariance between different environmental states was modelled by autoregressive processes. Such an approach to studying the genetic control of reaction norms can be expected to be advantageous over traditional mapping approaches in which no biological principles and statistical structures are considered. We demonstrate the analytical procedure and power of this approach by modelling the photosynthetic rate process as a function of temperature and light irradiance. Our approach allows for testing how a QTL affects the reaction norm of photosynthetic rate to a specific environment and whether there exist different QTLs to mediate photosynthetic responses to temperature and light irradiance, respectively. PMID:17517157

  16. Concentric core optical fiber with multiple-mode signal transmission

    DOEpatents

    Muhs, Jeffrey D.

    1997-01-01

    A concentric core optical fiber provides for the simultaneous but independent transmission of signals over a single optical fiber. The concentric optical fiber is constructed of a single-mode or multimode inner optical fiber defined by a core and a cladding of a lower index of refraction than the core and an outer optical fiber defined by additional cladding concentrically disposed around the cladding and of an index of refraction lower than the first mentioned cladding whereby the latter functions as the core of the outer optical fiber. By employing such an optical fiber construction with a single-mode inner core or optical fiber, highly sensitive interferometric and stable less sensitive amplitude based sensors can be placed along the same length of a concentric core optical fiber. Also, by employing the concentric core optical fiber secure telecommunications can be achieved via the inner optical fiber since an intrusion of the concentric optical fiber will first cause a variation in the light being transmitted through the outer optical fiber and this variation of light being used to trigger a suitable alarm indicative of the intrusion.

  17. Concentric core optical fiber with multiple-mode signal transmission

    DOEpatents

    Muhs, J.D.

    1997-05-06

    A concentric core optical fiber provides for the simultaneous but independent transmission of signals over a single optical fiber. The concentric optical fiber is constructed of a single-mode or multimode inner optical fiber defined by a core and a cladding of a lower index of refraction than the core and an outer optical fiber defined by additional cladding concentrically disposed around the cladding and of an index of refraction lower than the first mentioned cladding whereby the latter functions as the core of the outer optical fiber. By employing such an optical fiber construction with a single-mode inner core or optical fiber, highly sensitive interferometric and stable less sensitive amplitude based sensors can be placed along the same length of a concentric core optical fiber. Also, by employing the concentric core optical fiber secure telecommunications can be achieved via the inner optical fiber since an intrusion of the concentric optical fiber will first cause a variation in the light being transmitted through the outer optical fiber and this variation of light being used to trigger a suitable alarm indicative of the intrusion. 3 figs.

  18. Novel approaches in Extended Principal Components Analysis to compare spatio-temporal patterns among multiple image time series

    NASA Astrophysics Data System (ADS)

    Neeti, N.; Eastman, R.

    2012-12-01

    Extended Principal Components Analysis (EPCA) aims to examine the patterns of variability shared among multiple image time series. Conventionally, this is done by virtually extending the spatial dimension of the time series by spatially concatenating the different time series and then performing S-mode PCA. In S-mode analysis, samples in space are the statistical variables and samples in time are the statistical observations. This paper introduces the concept of temporal concatenation of multiple image time series to perform EPCA. EPCA can also be done with T-mode orientation in which samples in time are the statistical variables and samples in space are the statistical observations. This leads to a total of four orientations in which EPCA can be carried out. This research explores these four orientations and their implications in investigating spatio-temporal relationships among multiple time series. This research demonstrates that EPCA carried out with temporal concatenation of the multiple time series with T-mode (tT) is able to identify similar spatial patterns among multiple time series. The conventional S-mode EPCA with spatial concatenation (sS) identifies similar temporal patterns among multiple time series. The other two modes, namely T-mode with spatial concatenation (sT) and S-mode with temporal concatenation (tS), are able to identify patterns which share consistent temporal phase relationships and consistent spatial phase relationships with each other, respectively. In a case study using three sets of precipitation time series data from GPCP, CMAP and NCEP-DOE, the results show that examination of all four modes provides an effective basis comparison of the series.

  19. Chloroplasts extend stromules independently and in response to internal redox signals.

    PubMed

    Brunkard, Jacob O; Runkel, Anne M; Zambryski, Patricia C

    2015-08-11

    A fundamental mystery of plant cell biology is the occurrence of "stromules," stroma-filled tubular extensions from plastids (such as chloroplasts) that are universally observed in plants but whose functions are, in effect, completely unknown. One prevalent hypothesis is that stromules exchange signals or metabolites between plastids and other subcellular compartments, and that stromules are induced during stress. Until now, no signaling mechanisms originating within the plastid have been identified that regulate stromule activity, a critical missing link in this hypothesis. Using confocal and superresolution 3D microscopy, we have shown that stromules form in response to light-sensitive redox signals within the chloroplast. Stromule frequency increased during the day or after treatment with chemicals that produce reactive oxygen species specifically in the chloroplast. Silencing expression of the chloroplast NADPH-dependent thioredoxin reductase, a central hub in chloroplast redox signaling pathways, increased chloroplast stromule frequency, whereas silencing expression of nuclear genes related to plastid genome expression and tetrapyrrole biosynthesis had no impact on stromules. Leucoplasts, which are not photosynthetic, also made more stromules in the daytime. Leucoplasts did not respond to the same redox signaling pathway but instead increased stromule formation when exposed to sucrose, a major product of photosynthesis, although sucrose has no impact on chloroplast stromule frequency. Thus, different types of plastids make stromules in response to distinct signals. Finally, isolated chloroplasts could make stromules independently after extraction from the cytoplasm, suggesting that chloroplast-associated factors are sufficient to generate stromules. These discoveries demonstrate that chloroplasts are remarkably autonomous organelles that alter their stromule frequency in reaction to internal signal transduction pathways. PMID:26150490

  20. Apparatus and method for measuring relative phase of signals in a multiple-echo system

    NASA Technical Reports Server (NTRS)

    Froggatt, Mark E. (Inventor)

    1998-01-01

    An apparatus and method for measuring the relative phase of echo signals in a multiple-echo system. A signal generator generates an exciting tone burst and subsequent tone bursts delayed in phase from the exciting tone burst. The exciting tone burst is gated into a transducer coupled to the multiple-echo system. Each subsequent tone burst is converted into a series of pulses. Each pulse triggers a sample/hold circuit to sample each echo signal. The samples of the echo signal are averaged and then compared to a reference value. The signal generator is controlled to vary the subsequent tone burst phase delay to determine for each echo signal a subsequent tone burst phase delay that causes the average of the samples of the echo signal to be substantially equal to the reference value wherein the determined subsequent tone burst phase delay is the phase delay of the echo signal with respect to the exciting tone burst. The control circuit then determines the difference in phase delay between echo signals to determine the relative phase delay of the echo signals.

  1. Structural Equation Modelling of Multiple Facet Data: Extending Models for Multitrait-Multimethod Data

    ERIC Educational Resources Information Center

    Bechger, Timo M.; Maris, Gunter

    2004-01-01

    This paper is about the structural equation modelling of quantitative measures that are obtained from a multiple facet design. A facet is simply a set consisting of a finite number of elements. It is assumed that measures are obtained by combining each element of each facet. Methods and traits are two such facets, and a multitrait-multimethod…

  2. Extending the Multiple-Goal Perspective to Tertiary Classroom Goal Structures

    ERIC Educational Resources Information Center

    James, Vennessa H.; Yates, Shirley M.

    2007-01-01

    The multiple-goal perspective has recently been applied to teacher behaviours in primary school classrooms through experimental intervention (Linnenbrink, 2005) and objective observation (Sideridis, 2005). However, there is evidence suggesting that rather than centered only on teacher behaviour, classroom goal structures are a whole class feature…

  3. Iterative signal separation based multiple phase estimation in digital holographic interferometry.

    PubMed

    Kulkarni, Rishikesh; Rastogi, Pramod

    2015-10-01

    We propose a new method for signal separation from a multicomponent interference field recorded in a digital holographic interferometry setup. The setup consisting of multiple object illuminating beams results in an interference field containing multiple signal components. The proposed method utilizes an amplitude discrimination criteria established by setting different intensities to the object illuminating beams in order to separate the signal components iteratively. The signal separation is performed in a small block of the interference field at a time. The augmentation of the block matrix with its own rows and columns is performed which has an effect of noise subspace inflation. This operation offers an improved noise robustness to the signal separation capability of the proposed method. The simulation and experimental results are provided to substantiate the applicability of the proposed method in multidimensional deformation measurement. PMID:26480195

  4. Photonic-assisted microwave signal multiplication and modulation using a silicon Mach-Zehnder modulator.

    PubMed

    Long, Yun; Zhou, Linjie; Wang, Jian

    2016-01-01

    Photonic generation of microwave signal is obviously attractive for many prominent advantages, such as large bandwidth, low loss, and immunity to electromagnetic interference. Based on a single integrated silicon Mach-Zehnder modulator (MZM), we propose and experimentally demonstrate a simple and compact photonic scheme to enable frequency-multiplicated microwave signal. Using the fabricated integrated MZM, we also demonstrate the feasibility of microwave amplitude-shift keying (ASK) modulation based on integrated photonic approach. In proof-of-concept experiments, 2-GHz frequency-doubled microwave signal is generated using a 1-GHz driving signal. 750-MHz/1-GHz frequency-tripled/quadrupled microwave signals are obtained with a driving signal of 250 MHz. In addition, a 50-Mb/s binary amplitude coded 1-GHz microwave signal is also successfully generated. PMID:26832305

  5. Photonic-assisted microwave signal multiplication and modulation using a silicon Mach-Zehnder modulator

    NASA Astrophysics Data System (ADS)

    Long, Yun; Zhou, Linjie; Wang, Jian

    2016-02-01

    Photonic generation of microwave signal is obviously attractive for many prominent advantages, such as large bandwidth, low loss, and immunity to electromagnetic interference. Based on a single integrated silicon Mach-Zehnder modulator (MZM), we propose and experimentally demonstrate a simple and compact photonic scheme to enable frequency-multiplicated microwave signal. Using the fabricated integrated MZM, we also demonstrate the feasibility of microwave amplitude-shift keying (ASK) modulation based on integrated photonic approach. In proof-of-concept experiments, 2-GHz frequency-doubled microwave signal is generated using a 1-GHz driving signal. 750-MHz/1-GHz frequency-tripled/quadrupled microwave signals are obtained with a driving signal of 250 MHz. In addition, a 50-Mb/s binary amplitude coded 1-GHz microwave signal is also successfully generated.

  6. Photonic-assisted microwave signal multiplication and modulation using a silicon Mach–Zehnder modulator

    PubMed Central

    Long, Yun; Zhou, Linjie; Wang, Jian

    2016-01-01

    Photonic generation of microwave signal is obviously attractive for many prominent advantages, such as large bandwidth, low loss, and immunity to electromagnetic interference. Based on a single integrated silicon Mach–Zehnder modulator (MZM), we propose and experimentally demonstrate a simple and compact photonic scheme to enable frequency-multiplicated microwave signal. Using the fabricated integrated MZM, we also demonstrate the feasibility of microwave amplitude-shift keying (ASK) modulation based on integrated photonic approach. In proof-of-concept experiments, 2-GHz frequency-doubled microwave signal is generated using a 1-GHz driving signal. 750-MHz/1-GHz frequency-tripled/quadrupled microwave signals are obtained with a driving signal of 250 MHz. In addition, a 50-Mb/s binary amplitude coded 1-GHz microwave signal is also successfully generated. PMID:26832305

  7. Recursive ideal observer detection of known M-ary signals in multiplicative and additive Gaussian noise.

    NASA Technical Reports Server (NTRS)

    Painter, J. H.; Gupta, S. C.

    1973-01-01

    This paper presents the derivation of the recursive algorithms necessary for real-time digital detection of M-ary known signals that are subject to independent multiplicative and additive Gaussian noises. The motivating application is minimum probability of error detection of digital data-link messages aboard civil aircraft in the earth reflection multipath environment. For each known signal, the detector contains one Kalman filter and one probability computer. The filters estimate the multipath disturbance. The estimates and the received signal drive the probability computers. Outputs of all the computers are compared in amplitude to give the signal decision. The practicality and usefulness of the detector are extensively discussed.

  8. Charge-signal multiplication mediated by urea wires inside Y-shaped carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Lv, Mei; He, Bing; Liu, Zengrong; Xiu, Peng; Tu, Yusong

    2014-07-01

    In previous studies, we reported molecular dynamics (MD) simulations showing that single-file water wires confined inside Y-shaped single-walled carbon nanotubes (Y-SWNTs) held strong and robust capability to convert and multiply charge signals [Y. S. Tu, P. Xiu, R. Z. Wan, J. Hu, R. H. Zhou, and H. P. Fang, Proc. Natl. Acad. Sci. U.S.A. 106, 18120 (2009); Y. Tu, H. Lu, Y. Zhang, T. Huynh, and R. Zhou, J. Chem. Phys. 138, 015104 (2013)]. It is fascinating to see whether the signal multiplication can be realized by other kinds of polar molecules with larger dipole moments (which make the experimental realization easier). In this article, we use MD simulations to study the urea-mediated signal conversion and multiplication with Y-SWNTs. We observe that when a Y-SWNT with an external charge of magnitude 1.0 e (the model of a signal at the single-electron level) is solvated in 1 M urea solutions, urea can induce drying of the Y-SWNT and fill its interiors in single-file, forming Y-shaped urea wires. The external charge can effectively control the dipole orientation of the urea wire inside the main channel (i.e., the signal can be readily converted), and this signal can further be multiplied into 2 (or more) output signals by modulating dipole orientations of urea wires in bifurcated branch channels of the Y-SWNT. This remarkable signal transduction capability arises from the strong dipole-induced ordering of urea wires under extreme confinement. We also discuss the advantage of urea as compared with water in the signal multiplication, as well as the robustness and biological implications of our findings. This study provides the possibility for multiplying signals by using urea molecules (or other polar organic molecules) with Y-shaped nanochannels and might also help understand the mechanism behind signal conduction in both physical and biological systems.

  9. Charge-signal multiplication mediated by urea wires inside Y-shaped carbon nanotubes

    SciTech Connect

    Lv, Mei; Liu, Zengrong; He, Bing; Xiu, Peng E-mail: ystu@shu.edu.cn; Tu, Yusong E-mail: ystu@shu.edu.cn

    2014-07-28

    In previous studies, we reported molecular dynamics (MD) simulations showing that single-file water wires confined inside Y-shaped single-walled carbon nanotubes (Y-SWNTs) held strong and robust capability to convert and multiply charge signals [Y. S. Tu, P. Xiu, R. Z. Wan, J. Hu, R. H. Zhou, and H. P. Fang, Proc. Natl. Acad. Sci. U.S.A. 106, 18120 (2009); Y. Tu, H. Lu, Y. Zhang, T. Huynh, and R. Zhou, J. Chem. Phys. 138, 015104 (2013)]. It is fascinating to see whether the signal multiplication can be realized by other kinds of polar molecules with larger dipole moments (which make the experimental realization easier). In this article, we use MD simulations to study the urea-mediated signal conversion and multiplication with Y-SWNTs. We observe that when a Y-SWNT with an external charge of magnitude 1.0 e (the model of a signal at the single-electron level) is solvated in 1 M urea solutions, urea can induce drying of the Y-SWNT and fill its interiors in single-file, forming Y-shaped urea wires. The external charge can effectively control the dipole orientation of the urea wire inside the main channel (i.e., the signal can be readily converted), and this signal can further be multiplied into 2 (or more) output signals by modulating dipole orientations of urea wires in bifurcated branch channels of the Y-SWNT. This remarkable signal transduction capability arises from the strong dipole-induced ordering of urea wires under extreme confinement. We also discuss the advantage of urea as compared with water in the signal multiplication, as well as the robustness and biological implications of our findings. This study provides the possibility for multiplying signals by using urea molecules (or other polar organic molecules) with Y-shaped nanochannels and might also help understand the mechanism behind signal conduction in both physical and biological systems.

  10. Human DNA Polymerase ϵ Is Able to Efficiently Extend from Multiple Consecutive Ribonucleotides*

    PubMed Central

    Göksenin, A. Yasemin; Zahurancik, Walter; LeCompte, Kimberly G.; Taggart, David J.; Suo, Zucai; Pursell, Zachary F.

    2012-01-01

    Replicative DNA polymerases (Pols) help to maintain the high fidelity of replication in large part through their strong selectivity against mispaired deoxyribonucleotides. It has recently been demonstrated that several replicative Pols from yeast have surprisingly low selectivity for deoxyribonucleotides over their analogous ribonucleotides. In human cells, ribonucleotides are found in great abundance over deoxyribonucleotides, raising the possibility that ribonucleotides are incorporated in the human genome at significant levels during normal cellular functions. To address this possibility, the ability of human DNA polymerase ϵ to incorporate ribonucleotides was tested. At physiological concentrations of nucleotides, human Pol ϵ readily inserts and extends from incorporated ribonucleotides. Almost half of inserted ribonucleotides escape proofreading by 3′ → 5′ exonuclease-proficient Pol ϵ, indicating that ribonucleotide incorporation by Pol ϵ is likely a significant event in human cells. Human Pol ϵ is also efficient at extending from primers terminating in up to five consecutive ribonucleotides. This efficient extension appears to result from reduced exonuclease activity on primers containing consecutive 3′-terminal ribonucleotides. These biochemical properties suggest that Pol ϵ is a likely source of ribonucleotides in human genomic DNA. PMID:23093410

  11. A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up.

    PubMed Central

    Francis, D A; Compston, D A; Batchelor, J R; McDonald, W I

    1987-01-01

    One hundred and one of 146 patients presenting with isolated idiopathic optic neuritis, previously reviewed in 1978, were reassessed clinically, and retyped for HLA antigens and Factor B alleles, after a mean follow-up of 11.6 years. Fifty eight patients (57%) had developed multiple sclerosis at the time of reassessment in the present study, of whom 51 (88%) had clinically definite disease. This compared with 40% of the original group, in 1978, of whom 62% then had clinically definite multiple sclerosis. When the life-table method of analysis was used, the probability of developing multiple sclerosis was 75%, 15 years after the initial episode of optic neuritis. The frequencies of HLA-DR2 and the recently defined D-region antigen, DQw1, were significantly increased in patients with isolated optic neuritis and those who subsequently developed multiple sclerosis compared with normal controls, but neither allele appears to influence progression from optic neuritis to multiple sclerosis. Patients with optic neuritis who were HLA-DR3 positive had an increased risk for the development of multiple sclerosis (RR = 2.8) and this risk was further enhanced when DR3 occurred in combination with DR2 (RR = 6.7). The overall increased risk of developing multiple sclerosis for patients with this combination was 26 times that for the normal population. When the patients' original tissue-typing was considered BT 101 no longer influenced conversion of optic neuritis to multiple sclerosis. This may partly be explained by improved methods of tissue-typing, since not all BT 101 patients were subsequently found to be positive for HLA-DR2 or HLA-DQw1 and vice versa and by extended follow-up as multiple sclerosis conversion in HLA-DR2 negative individuals increased with time. All 101 patients were typed for Factor B alleles. No significant differences in frequencies were found between individuals with isolated optic neuritis or those who progressed to multiple sclerosis compared with the

  12. PIF4 Integrates Multiple Environmental and Hormonal Signals for Plant Growth Regulation in Arabidopsis

    PubMed Central

    Choi, Hyunmo; Oh, Eunkyoo

    2016-01-01

    As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth. PMID:27432188

  13. PIF4 Integrates Multiple Environmental and Hormonal Signals for Plant Growth Regulation in Arabidopsis.

    PubMed

    Choi, Hyunmo; Oh, Eunkyoo

    2016-08-31

    As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth. PMID:27432188

  14. Differential rates of phenotypic introgression are associated with male behavioral responses to multiple signals.

    PubMed

    Greig, Emma I; Baldassarre, Daniel T; Webster, Michael S

    2015-10-01

    Sexual selection on multiple signals may lead to differential rates of signal introgression across hybrid zones if some signals contribute to reproductive isolation but others facilitate gene flow. Competition among males is one powerful form of sexual selection, but male behavioral responses to multiple traits have not been considered in a system where traits have introgressed differentially. Using playbacks, mounts, and a reciprocal experimental design, we tested the hypothesis that male responses to song and plumage in two subspecies of red-backed fairy-wren (Malurus melanocephalus) explain patterns of differential signal introgression (song has not introgressed, whereas plumage color has introgressed asymmetrically). We found that males of both subspecies discriminated symmetrically between subspecies' songs at a long range, but at a close range, we found that aggression was equal for both subspecies' plumage and songs. Taken together, our results suggest that male behavioral responses hinder the introgression of song, but allow for the observed asymmetrical introgression of plumage. Our results highlight how behavioral responses are a key component of signal evolution when recently divergent taxa come together, and how differential responses to multiple signals may lead to differential signal introgression and novel trait combinations. PMID:26292844

  15. Extending data worth methods to select multiple observations targeting specific hydrological predictions of interest

    NASA Astrophysics Data System (ADS)

    Vilhelmsen, Troels N.; Ferré, Ty P. A.

    2016-04-01

    Hydrological models are often developed to forecasting future behavior in response due to natural or human induced changes in stresses affecting hydrologic systems. Commonly, these models are conceptualized and calibrated based on existing data/information about the hydrological conditions. However, most hydrologic systems lack sufficient data to constrain models with adequate certainty to support robust decision making. Therefore, a key element of a hydrologic study is the selection of additional data to improve model performance. Given the nature of hydrologic investigations, it is not practical to select data sequentially, i.e. to choose the next observation, collect it, refine the model, and then repeat the process. Rather, for timing and financial reasons, measurement campaigns include multiple wells or sampling points. There is a growing body of literature aimed at defining the expected data worth based on existing models. However, these are almost all limited to identifying single additional observations. In this study, we present a methodology for simultaneously selecting multiple potential new observations based on their expected ability to reduce the uncertainty of the forecasts of interest. This methodology is based on linear estimates of the predictive uncertainty, and it can be used to determine the optimal combinations of measurements (location and number) established to reduce the uncertainty of multiple predictions. The outcome of the analysis is an estimate of the optimal sampling locations; the optimal number of samples; as well as a probability map showing the locations within the investigated area that are most likely to provide useful information about the forecasting of interest.

  16. π-Extended "Earring" Porphyrins with Multiple Cavities and Near-Infrared Absorption.

    PubMed

    Rao, Yutao; Kim, Taeyeon; Park, Kyu Hyung; Peng, Fulei; Liu, Lei; Liu, Yunmei; Wen, Bin; Liu, Shubin; Kirk, Steven Robert; Wu, Licheng; Chen, Bo; Ma, Ming; Zhou, Mingbo; Yin, Bangshao; Zhang, Yuexing; Kim, Dongho; Song, Jianxin

    2016-05-23

    β,β-tripyrrin-bridged earring porphyrins were synthesized through Suzuki-Miyaura cross coupling reactions. These porphyrinoids have multiple cavities and can accommodate two or three metal ions per molecule. The structures of the porphyrins have been elucidated by x-ray diffraction analysis, and feature curved π planes. The electronic spectra of the porphyrins exhibit near-infrared (NIR) absorptions and metal insertion leads to red-shifted and intensified absorption features. Electrochemical analysis and transient absorption measurements indicated that the porphyrins exhibit effective electronic communication between their central and peripheral moieties. PMID:27038255

  17. An approach for optimally extending mathematical models of signaling networks using omics data.

    PubMed

    Bianconi, Fortunato; Patiti, Federico; Baldelli, Elisa; Crino, Lucio; Valigi, Paolo

    2015-08-01

    Mathematical modeling is a key process in Systems Biology and the use of computational tools such as Cytoscape for omics data processing, need to be integrated in the modeling activity. In this paper we propose a new methodology for modeling signaling networks by combining ordinary differential equation models and a gene recommender system, GeneMANIA. We started from existing models, that are stored in the BioModels database, and we generated a query to use as input for the GeneMANIA algorithm. The output of the recommender system was then led back to the kinetic reactions that were finally added to the starting model. We applied the proposed methodology to EGFR-IGF1R signal transduction network, which plays an important role in translational oncology and cancer therapy of non small cell lung cancer. PMID:26737782

  18. Attention to Multiple Events Helps 2 1/2-Year-Olds Extend New Verbs

    PubMed Central

    Childers, Jane B.

    2013-01-01

    An important question in verb learning is how children extend new verbs to new situational contexts. In Study 1, 2 1/2-year-old children were shown a complex event followed by new events that preserved only the action from the initial event, only the result, or no new events. Children seeing events that preserved either the action or the result produced appropriate verb extensions at test while children without this information did not. In a follow-up study, children hearing new verbs produced more extensions than did children hearing nonlabeling speech. These studies suggest that attention to related events is helpful to young verb learners, perhaps because they structurally align these events (e.g., Gentner, 1983; 1989) during verb learning. PMID:24324284

  19. Parasites and health affect multiple sexual signals in male common wall lizards, Podarcis muralis

    NASA Astrophysics Data System (ADS)

    Martín, José; Amo, Luisa; López, Pilar

    2008-04-01

    Multiple advertising sexual traits may either advertise different characteristics of male condition or be redundant to reinforce reliability of signals. Research has focused on multiple visual traits. However, in animals that use different multiple additional sensory systems, such as chemoreception, different types of traits might have evolved to signal similar characteristics of a male quality using different sensory channels. We examined whether ventral coloration and chemicals in femoral gland secretions of male common wall lizards, Podarcis muralis, are affected by their health state (blood-parasite load and cell-mediated immune response). Our results indicated that less parasitized lizards had brighter and more yellowish ventral colorations and also femoral secretions with higher proportions of two esters of octadecenoic acid. In addition, lizards with a greater immune response had more saturated coloration and secretions with higher proportions of octadecenoic acid methyl ester. We suggest that these signals would be reliable because only healthier males seemed able to allocate more carotenoids to coloration and presumably costly chemicals to secretions. The use of multiple sensory channels may provide more opportunities to signal a male quality under different circumstances, but also may reinforce the reliability of the signal when both types of traits may be perceived simultaneously.

  20. Multiple logic functions from extended blockade region in a silicon quantum-dot transistor

    SciTech Connect

    Lee, Youngmin; Lee, Sejoon Im, Hyunsik; Hiramoto, Toshiro

    2015-02-14

    We demonstrate multiple logic-functions at room temperature on a unit device of the Si single electron transistor (SET). Owing to the formation of the multi-dot system, the device exhibits the enhanced Coulomb blockade characteristics (e.g., large peak-to-valley current ratio ∼200) that can improve the reliability of the SET-based logic circuits. The SET displays a unique feature useful for the logic applications; namely, the Coulomb oscillation peaks are systematically shifted by changing either of only the gate or the drain voltage. This enables the SET to act as a multi-functional one-transistor logic gate with AND, OR, NAND, and XOR functions.

  1. Pleiotropic effects of extended blockade of CSF1R signaling in adult mice

    PubMed Central

    Sauter, Kristin A.; Pridans, Clare; Sehgal, Anuj; Tsai, Yi Ting; Bradford, Barry M.; Raza, Sobia; Moffat, Lindsey; Gow, Deborah J.; Beard, Philippa M.; Mabbott, Neil A.; Smith, Lee B.; Hume, David A.

    2014-01-01

    We investigated the role of CSF1R signaling in adult mice using prolonged treatment with anti-CSF1R antibody. Mutation of the CSF1 gene in the op/op mouse produces numerous developmental abnormalities. Mutation of the CSF1R has an even more penetrant phenotype, including perinatal lethality, because of the existence of a second ligand, IL-34. These effects on development provide limited insight into functions of CSF1R signaling in adult homeostasis. The carcass weight and weight of several organs (spleen, kidney, and liver) were reduced in the treated mice, but overall body weight gain was increased. Despite the complete loss of Kupffer cells, there was no effect on liver gene expression. The treatment ablated OCL, increased bone density and trabecular volume, and prevented the decline in bone mass seen in female mice with age. The op/op mouse has a deficiency in pancreatic β cells and in Paneth cells in the gut wall. Only the latter was reproduced by the antibody treatment and was associated with increased goblet cell number but no change in villus architecture. Male op/op mice are infertile as a result of testosterone insufficiency. Anti-CSF1R treatment ablated interstitial macrophages in the testis, but there was no sustained effect on testosterone or LH. The results indicate an ongoing requirement for CSF1R signaling in macrophage and OCL homeostasis but indicate that most effects of CSF1 and CSF1R mutations are due to effects on development. PMID:24652541

  2. Cellerator: extending a computer algebra system to include biochemical arrows for signal transduction simulations

    NASA Technical Reports Server (NTRS)

    Shapiro, Bruce E.; Levchenko, Andre; Meyerowitz, Elliot M.; Wold, Barbara J.; Mjolsness, Eric D.

    2003-01-01

    Cellerator describes single and multi-cellular signal transduction networks (STN) with a compact, optionally palette-driven, arrow-based notation to represent biochemical reactions and transcriptional activation. Multi-compartment systems are represented as graphs with STNs embedded in each node. Interactions include mass-action, enzymatic, allosteric and connectionist models. Reactions are translated into differential equations and can be solved numerically to generate predictive time courses or output as systems of equations that can be read by other programs. Cellerator simulations are fully extensible and portable to any operating system that supports Mathematica, and can be indefinitely nested within larger data structures to produce highly scaleable models.

  3. Male-to-male transmission in extended pedigrees with multiple cases of autism

    SciTech Connect

    Hallmayer, J.; Spiker, D.; Lotspeich, L.

    1996-02-16

    Despite strong genetic influences in autism, the true mode of inheritance remains unknown. Sex differences in autism have been described in both singleton and multiplex families: boys outnumber girls by 3 or 4 to 1, and so a sex-linked mode of transmission must also be considered. The key characteristic of X-linkage is that all sons of affected men are unaffected (no male-to-male transmission). In the present study, which is part of an ongoing linkage project in autism, we describe 77 multiplex autism families, 11 of who are affected cousin or half-sibling families. By using these families, it is possible to trace the path of genetic transmission and observe whether the hypothesis of X-linkage is tenable. Of 11 extended pedigrees from 77 multiplex families, six show male-to-male transmission; in these families, X-linkage can be excluded as the genetic basis for their autism. The data from the other five families are compatible with either an autosomal or an X-linked mode of transmission. The key point to emerge, then, is that autism cannot be exclusively an X-linked disorder; there must be an autosomal mode of transmission at least in some families. Thus we must consider the alternative hypotheses that autism is either entirely autosomal, or it is genetically heterogeneous, involving at least one autosomal locus with gender-specific expression, as well as a possible locus on the X-chromosome. 28 refs., 1 fig.

  4. Single- and multiple-dose pharmacokinetics and dose proportionality of the psychotropic agent paliperidone extended release.

    PubMed

    Boom, Sandra; Talluri, Krishna; Janssens, Luc; Remmerie, Bart; De Meulder, Marc; Rossenu, Stefaan; van Osselaer, Nancy; Eerdekens, Marielle; Cleton, Adriaan

    2009-11-01

    Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D(2)- and serotonergic 5-HT(2A)-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations. Paliperidone is eliminated with a terminal half-life of approximately 24 hours. Steady state is achieved after 4 daily doses. Paliperidone ER exhibits time-invariant pharmacokinetics. It shows a 3.5-fold accumulation upon steady state, mainly caused by the controlled release characteristics of the formulation. Paliperidone ER displays dose proportionality over the dose range of 3 to 15 mg; the 90% confidence intervals of the pairwise dose comparisons are all included in the 80% to 125% bioequivalence limits. PMID:19713555

  5. A novel EMD selecting thresholding method based on multiple iteration for denoising LIDAR signal

    NASA Astrophysics Data System (ADS)

    Li, Meng; Jiang, Li-hui; Xiong, Xing-long

    2015-06-01

    Empirical mode decomposition (EMD) approach has been believed to be potentially useful for processing the nonlinear and non-stationary LIDAR signals. To shed further light on its performance, we proposed the EMD selecting thresholding method based on multiple iteration, which essentially acts as a development of EMD interval thresholding (EMD-IT), and randomly alters the samples of noisy parts of all the corrupted intrinsic mode functions to generate a better effect of iteration. Simulations on both synthetic signals and LIDAR signals from real world support this method.

  6. Code extraction from encoded signal in time-spreading optical code division multiple access.

    PubMed

    Si, Zhijian; Yin, Feifei; Xin, Ming; Chen, Hongwei; Chen, Minghua; Xie, Shizhong

    2010-01-15

    A vulnerability that allows eavesdroppers to extract the code from the waveform of the noiselike encoded signal of an isolated user in a standard time-spreading optical code division multiple access communication system using bipolar phase code is experimentally demonstrated. The principle is based on fine structure in the encoded signal. Each dip in the waveform corresponds to a transition of the bipolar code. Eavesdroppers can get the code by analyzing the chip numbers between any two transitions; then a decoder identical to the legal user's can be fabricated, and they can get the properly decoded signal. PMID:20081977

  7. Power-efficient method for IM-DD optical transmission of multiple OFDM signals.

    PubMed

    Effenberger, Frank; Liu, Xiang

    2015-05-18

    We propose a power-efficient method for transmitting multiple frequency-division multiplexed (FDM) orthogonal frequency-division multiplexing (OFDM) signals in intensity-modulation direct-detection (IM-DD) optical systems. This method is based on quadratic soft clipping in combination with odd-only channel mapping. We show, both analytically and experimentally, that the proposed approach is capable of improving the power efficiency by about 3 dB as compared to conventional FDM OFDM signals under practical bias conditions, making it a viable solution in applications such as optical fiber-wireless integrated systems where both IM-DD optical transmission and OFDM signaling are important. PMID:26074605

  8. When surfacers do not dive: multiple significance of extended surface times in marine turtles.

    PubMed

    Hochscheid, S; Bentivegna, F; Hamza, A; Hays, G C

    2010-04-01

    Marine turtles spend more than 90% of their life underwater and have been termed surfacers as opposed to divers. Nonetheless turtles have been reported occasionally to float motionless at the surface but the reasons for this behaviour are not clear. We investigated the location, timing and duration of extended surface times (ESTs) in 10 free-ranging loggerhead turtles (Caretta caretta) and the possible relationship to water temperature and diving activity recorded via satellite relay data loggers for 101-450 days. For one turtle that dived only in offshore areas, ESTs contributed 12% of the time whereas for the other turtles ESTs contributed 0.4-1.8% of the time. ESTs lasted on average 90 min but were mostly infrequent and irregular, excluding the involvement of a fundamental regulatory function. However, 82% of the ESTs occurred during daylight, mostly around noon, suggesting a dependence on solar radiation. For three turtles, there was an appreciable (7 degrees C to 10.5 degrees C) temperature decrease with depth for dives during periods when ESTs occurred frequently, suggesting a re-warming function of EST to compensate for decreased body temperatures, possibly to enhance digestive efficiency. A positive correlation between body mass and EST duration supported this explanation. By contrast, night-active turtles that exceeded their calculated aerobic dive limits in 7.6-16% of the dives engaged in nocturnal ESTs, probably for lactate clearance. This is the first evidence that loggerhead turtles may refrain from diving for at least two reasons, either to absorb solar radiation or to recover from anaerobic activity. PMID:20348345

  9. P wave detection in ECG signals using an extended Kalman filter: an evaluation in different arrhythmia contexts.

    PubMed

    Rahimpour, M; Mohammadzadeh Asl, B

    2016-07-01

    Monitoring atrial activity via P waves, is an important feature of the arrhythmia detection procedure. The aim of this paper is to present an algorithm for P wave detection in normal and some abnormal records by improving existing methods in the field of signal processing. In contrast to the classical approaches, which are completely blind to signal dynamics, our proposed method uses the extended Kalman filter, EKF25, to estimate the state variables of the equations modeling the dynamic of an ECG signal. This method is a modified version of the nonlinear dynamical model previously introduced for a generation of synthetic ECG signals and fiducial point extraction in normal ones. It is capable of estimating the separate types of activity of the heart with reasonable accuracy and performs well in the presence of morphological variations in the waveforms and ectopic beats. The MIT-BIH Arrhythmia and QT databases have been used to evaluate the performance of the proposed method. The results show that this method has Se  =  98.38% and Pr  =  96.74% in the overall records (considering normal and abnormal rhythms). PMID:27321699

  10. Multiple phase transitions in extended hard-core lattice gas models in two dimensions.

    PubMed

    Nath, Trisha; Rajesh, R

    2014-07-01

    We study the k-NN hard-core lattice gas model in which the first k next-nearest-neighbor sites of a particle are excluded from occupation by other particles on a two-dimensional square lattice. This model is the lattice version of the hard-disk system with increasing k corresponding to decreasing lattice spacing. While the hard-disk system is known to undergo a two-step freezing process with increasing density, the lattice model has been known to show only one transition. Here, based on Monte Carlo simulations and high-density expansions of the free energy and density, we argue that for k = 4,10,11,14,⋯, the lattice model undergoes multiple transitions with increasing density. Using Monte Carlo simulations, we confirm the same for k = 4,...,11. This, in turn, resolves an existing puzzle as to why the 4-NN model has a continuous transition against the expectation of a first-order transition. PMID:25122264

  11. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways

    PubMed Central

    Ren, Fangfang; Wang, Bing; Yue, Tao; Yun, Eun-Young; Ip, Y. Tony; Jiang, Jin

    2010-01-01

    Intestinal stem cells (ISCs) in the Drosophila adult midgut are essential for maintaining tissue homeostasis and replenishing lost cells in response to tissue damage. Here we demonstrate that the Hippo (Hpo) signaling pathway, an evolutionarily conserved pathway implicated in organ size control and tumorigenesis, plays an essential role in regulating ISC proliferation. Loss of Hpo signaling in either midgut precursor cells or epithelial cells stimulates ISC proliferation. We provide evidence that loss of Hpo signaling in epithelial cells increases the production of cytokines of the Upd family and multiple EGFR ligands that activate JAK-STAT and EGFR signaling pathways in ISCs to stimulate their proliferation, thus revealing a unique non–cell-autonomous role of Hpo signaling in blocking ISC proliferation. Finally, we show that the Hpo pathway mediator Yorkie (Yki) is also required in precursor cells for injury-induced ISC proliferation in response to tissue-damaging reagent DSS. PMID:21078993

  12. High-power optical millimeter-wave signal generation with tunable frequency multiplication factor

    NASA Astrophysics Data System (ADS)

    Han, Yi-shi; Zheng, Zhenyu; Luo, Zhixiao; Min, Zhixuan; Xu, Ou; Liu, Jie

    2015-01-01

    This work demonstrates a simple and novel scheme for millimeter-wave (MMW) signal generation using optical multi-sidebands (OMSB) modulation. In the proposed methods, several pairs of optical sidebands can be generated by employing parallel phase modulators driven by a low frequency radio frequency (RF) signal. The optical sidebands will beat at a photodetector (PD) to generate high frequency MMW signal with tunable frequency multiplication factor, such as frequency octupling, 12-tupling, 16-tupling and 18-tupling. Since no optical filters or DC bias are used, the MMW signal has the evident character of high-power output. A generalized analytic expression and simulation verification for generating the frequency multi-tupling MMW signal are developed. The influences caused by non-ideal factors are discussed in detail, and undesired power ratios versus non-ideal factors are plotted and analyzed.

  13. Error detection and correction for a multiple frequency quaternary phase shift keyed signal

    NASA Astrophysics Data System (ADS)

    Hopkins, Kevin S.

    1989-06-01

    A multiple frequency quaternary phased shift (MFQPSK) signaling system was developed and experimentally tested in a controlled environment. In order to insure that the quality of the received signal is such that information recovery is possible, error detection/correction (EDC) must be used. Various EDC coding schemes available are reviewed and their application to the MFQPSK signal system is analyzed. Hamming, Golay, Bose-Chaudhuri-Hocquenghem (BCH), Reed-Solomon (R-S) block codes as well as convolutional codes are presented and analyzed in the context of specific MFQPSK system parameters. A computer program was developed in order to compute bit error probabilities as a function of signal to noise ratio. Results demonstrate that various EDC schemes are suitable for the MFQPSK signal structure, and that significant performance improvements are possible with the use of certain error correction codes.

  14. Elastic extended images and velocity-sensitive objective functions using multiple reflections and transmissions

    NASA Astrophysics Data System (ADS)

    Ravasi, Matteo; Vasconcelos, Ivan; Curtis, Andrew; Meles, Giovanni

    2015-08-01

    One interpretation of a seismic image is the instantaneous scattered wave response of a colocated pseudo-source and pseudo-receiver at each point in the subsurface model. If there is no model perturbation at a point then there will be no instantaneous scattered wave so nothing will be imaged; if something is imaged then there must be a perturbation at that location. By extension, so-called extended images (EIs) represent the full spatio-temporal response between offset subsurface pseudo-sources and pseudo-receivers which can be used to constrain elastic properties around each image point. However, one-sided illumination of the subsurface (from the Earth's surface), errors in the initial velocity model estimate, and the use of a linearized, single-scattering assumption (as is usual in seismic imaging) cause errors in EI gathers such as missing events, incorrect amplitudes, and spurious energy. By creating elastic (P-to-P and P-to-S) EIs in a synthetic example of subsalt imaging, we demonstrate the advantages of incorporating multiply scattered waves correctly by non-linear imaging, and of including transmitted waves by using two-sided receiver arrays, and discuss how the recently developed autofocussing methods could provide us with the various required subsurface wavefields. Pre- and post-imaging f-k filtering procedures are introduced to further improve the quality of the EIs by (explicitly or implicitly) limiting the directions of waves arriving at the subsurface pseudo-source and receiver survey line. These filters suppress strong linear events that arise from the erroneous interaction of near-horizontally propagating waves which are not naturally accounted for due to the lack of sources and receivers on either side of the imaging target. Finally, we analyse the sensitivity of elastic P-to-P EIs to errors in the migration velocity models and show that events in the EI are shifted in opposite directions when constructed using reflection or transmission data. In

  15. [Extending therapeutic possibilities in relapsing-remitting multiple sclerosis: dimethyl fumarate].

    PubMed

    Matolcsi, Judit; Rózsa, Csilla

    2015-01-30

    Dimethyl fumarate (DMF) is a novel oral therapy that has recently been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Dimethyl fumarate shows anti-inflammatory and cytoprotective properties that are thought to be mediated primarily via activation of the nuclear factor (erythroid-derived 2)-like 2- Nrf2 transcriptional pathway, which up-regulates the genes involved in the cellular response to oxidative stress. The drug was evaluated in 2 large, randomized, double-blind, multicentric, multinational, 2-year, phase III clinical trials. The DEFINE and CONFIRM trials, conducted with over 2600 adult patients suffering from RRMS, unequivocally confirmed the efficacy of DMF (2 x 240 mg daily) in reducing the annualized relapse rate (ARR) and reducing the proportion of patients with MS relapse at 2 years. Significantly reduced sustained disability progression was observed with the drug versus placebo in DEFINE, while the same tendency was seen in CONFIRM. The MRI results of the studies were also convincing: DMF significantly reduced the number of new/enlarging T2-hyperintense lesions and the number of Gd-enhancing lesions compared to placebo. Dimethyl fumarate was generally well tolerated and no safety concern has been raised. Adverse events that occurred most frequently included flushing and gastrointestinal events. The long-term efficacy and tolerability of dimethyl fumarate is currently being investigated in the ENDORSE trial, with interim results demonstrating the same results as the two previous studies. In conclusion, although further, mostly comparative data are needed to fully establish the relative efficacy and tolerability of dimethyl fumarate compared with other therapies, dimethyl-fumarate is a valuable addition to the therapeutic options available for RRMS. PMID:25842911

  16. A coherent digital demodulator for multiple signal formats and widely varying data rates

    NASA Technical Reports Server (NTRS)

    Mcguffin, Bruce F.

    1989-01-01

    The Tracking and Data Relay Satellite System (TDRSS) uses four ground station demodulators for K-band signals with data rates from 1 kb/s to 300 Mb/s. The author discusses the feasibility of replacing these demodulators with a single digital demodulator that may be reconfigured by altering stored parameters to accommodate all signal formats and data rates. This implementation will reduce total ground station cost and facilitate automation of ground station operation. Analysis of system performance concentrates on the carrier tracking loop. Analytic and simulation results relate system performance to parameter values and signal format as data rate and power vary independently on the In-phase and quadrature channels. It is demonstrated that a single digital demodulator can support TDRSS-compatible signals at data rates conservatively extending from 1K symbols/s to 10M symbols/s, using off-the-shelf hardware with 6 or more bits of accuracy.

  17. Detection of geodesic acoustic mode oscillations, using multiple signal classification analysis of Doppler backscattering signal on Tore Supra

    NASA Astrophysics Data System (ADS)

    Vermare, L.; Hennequin, P.; Gürcan, Ö. D.; the Tore Supra Team

    2012-06-01

    This paper presents the first observation of geodesic acoustic modes (GAMs) on Tore Supra plasmas. Using the Doppler backscattering system, the oscillations of the plasma flow velocity, localized between r/a = 0.85 and r/a = 0.95, and with a frequency, typically around 10 kHz, have been observed at the plasma edge in numerous discharges. When the additional heating power is varied, the frequency is found to scale with Cs/R. The MUltiple SIgnal Classification (MUSIC) algorithm is employed to access the temporal evolution of the perpendicular velocity of density fluctuations. The method is presented in some detail, and is validated and compared against standard methods, such as the conventional fast Fourier transform method, using a synthetic signal. It stands out as a powerful data analysis method to follow the Doppler frequency with a high temporal resolution, which is important in order to extract the dynamics of GAMs.

  18. NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking.

    PubMed

    Pleil, Kristen E; Rinker, Jennifer A; Lowery-Gionta, Emily G; Mazzone, Christopher M; McCall, Nora M; Kendra, Alexis M; Olson, David P; Lowell, Bradford B; Grant, Kathleen A; Thiele, Todd E; Kash, Thomas L

    2015-04-01

    Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders. PMID:25751534

  19. NPY Signaling Inhibits Extended Amygdala CRF Neurons to Suppress Binge Alcohol Drinking

    PubMed Central

    Pleil, Kristen E.; Rinker, Jennifer A.; Lowery-Gionta, Emily G.; Mazzone, Christopher M.; McCall, Nora M.; Kendra, Alexis M.; Olson, David P.; Lowell, Bradford B.; Grant, Kathleen A.; Thiele, Todd E.; Kash, Thomas L.

    2015-01-01

    Summary paragraph Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies including alcohol abuse, and anxiety1–4. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin–releasing factor (CRF). The central actions of NPY and CRF play opposing functional roles in the regulation of emotional and reward–seeking behaviors; therefore, dysfunctional interactions between these peptidergic systems could play a role in the development of these pathologies. Here, we used converging physiological, pharmacological, and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a novel, Gi-mediated, PKA-dependent postsynaptic mechanism. Further, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of novel therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders. PMID:25751534

  20. Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues

    PubMed Central

    Bordeleau, Francois; Reinhart-King, Cynthia A.

    2016-01-01

    There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors. PMID:27508074

  1. Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues.

    PubMed

    Bordeleau, Francois; Reinhart-King, Cynthia A

    2016-01-01

    There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors. PMID:27508074

  2. Raman signal enhancement by multiple beam excitation and its application for the detection of chemicals

    SciTech Connect

    Gupta, Sakshi; Ahmad, Azeem; Mehta, Dalip S.; Gambhir, Vijayeta; Reddy, Martha N.

    2015-08-31

    In a typical Raman based sensor, a single laser beam is used for exciting the sample and the backscattered or forward scattered light is collected using collection optics and is analyzed by a spectrometer. We have investigated that by means of exciting the sample with multiple beams, i.e., by dividing the same input power of the single beam into two or three or more beams and exciting the sample from different angles, the Raman signal enhances significantly. Due to the presence of multiple beams passing through the same volume of the sample, an interference pattern is formed and the volume of interaction of excitation beams with the sample increases. By means of this geometry, the enhancement in the Raman signal is observed and it was found that the signal strength increases linearly with the increase in number of excitation beams. Experimental results of this scheme for excitation of the samples are reported for explosive detection at a standoff distance.

  3. NMDA Receptors Multiplicatively Scale Visual Signals and Enhance Directional Motion Discrimination in Retinal Ganglion Cells.

    PubMed

    Poleg-Polsky, Alon; Diamond, Jeffrey S

    2016-03-16

    Postsynaptic responses in many CNS neurons are typically small and variable, often making it difficult to distinguish physiologically relevant signals from background noise. To extract salient information, neurons are thought to integrate multiple synaptic inputs and/or selectively amplify specific synaptic activation patterns. Here, we present evidence for a third strategy: directionally selective ganglion cells (DSGCs) in the mouse retina multiplicatively scale visual signals via a mechanism that requires both nonlinear NMDA receptor (NMDAR) conductances in DSGC dendrites and directionally tuned inhibition provided by the upstream retinal circuitry. Postsynaptic multiplication enables DSGCs to discriminate visual motion more accurately in noisy visual conditions without compromising directional tuning. These findings demonstrate a novel role for NMDARs in synaptic processing and provide new insights into how synaptic and network features interact to accomplish physiologically relevant neural computations. PMID:26948896

  4. [Quality of neuronal signal registered in the monkey motor cortex with chronically implanted multiple microwires].

    PubMed

    Bondar', I V; Vasil'eva, L N; Badakva, A M; Miller, N V; Zobova, L N; Roshchin, V Iu

    2014-01-01

    Disconnection of central and peripheral parts of motor system leads to severe forms of disability. However, current research of brain-computer interfaces will solve the problem of rehabilitation of patients with motor disorders in future. Chronic recordings of single-unit activity in specialized areas of cerebral cortex could provide appropriate control signal for effectors with multiple degrees of freedom. In present article we evaluated the quality of chronic single-unit recordings in the primary motor cortex of awake behaving monkeys obtained with bundles of multiple microwires. Action potentials of proper quality were recorded from single units during three months. In some cases up to 7 single units could be extracted on a channel. Recording quality stabilized after 40 days since electrodes were implanted. Ultimately, functionality of multiple electrodes bundle makes it highly usable and reliable instrument for obtaining of control neurophysiologic signal from populations of neurons for brain-computer interfaces. PMID:25710068

  5. Triple signal amplification using gold nanoparticles, bienzyme and platinum nanoparticles functionalized graphene as enhancers for simultaneous multiple electrochemical immunoassay.

    PubMed

    Jia, Xinle; Chen, Xia; Han, Jingman; Ma, Jie; Ma, Zhanfang

    2014-03-15

    Here we demonstrated an ultrasensitive electrochemical immunoassay employing graphene, platinum nanoparticles (PtNPs), glucose oxidase (GOD) and horseradish peroxidase (HRP) as enhancers to simultaneously detect carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP). This immunosensor is based on the observation that multiple-labeled antibodies (thionine-labeled anti-CEA and ferrocene-labeled anti-AFP) recognition event yielded a distinct voltammetric peak through "sandwich" immunoreaction, whose position and size reflected the identity and level of the corresponding antigen. Greatly enhanced sensitivity for cancer markers is based on a triple signal amplification strategy. Experimental results revealed that the immunoassay enabled simultaneous determination of CEA and AFP in a single run with wide working ranges of 0.01-100 ng mL(-1). The detection limits reached 1.64 pg mL(-1) for CEA and 1.33 pg mL(-1) for AFP. No obvious cross-talk was observed during the experiment. In addition, through the analysis of clinical serum samples, the proposed method received a good correlation with ELISA as a reference. The signal amplification strategy could be easily modified and extended to detect other multiple targets. PMID:24113435

  6. Recruitment-dance signals draw larger audiences when honey bee colonies have multiple patrilines

    PubMed Central

    Mattila, H. R.; Seeley, T. D.

    2010-01-01

    Honey bee queens (Apis mellifera) who mate with multiple males produce colonies that are filled with numerous genetically distinct patrilines of workers. A genetically diverse colony benefits from an enhanced foraging effort, fuelled in part by an increase in the number of recruitment signals that are produced by foragers. However, the influence of patriline diversity on the attention paid to these signals by audiences of potentially receptive workers remains unexplored. To determine whether recruitment dances performed by foragers in multiple-patriline colonies attract a greater number of dance followers than dances in colonies that lack patriline diversity, we trained workers from multiple- and single-patriline colonies to forage in a greenhouse and monitored their dance-following activity back in the hives. On average, more workers followed a dance if it was performed in a multiple-patriline colony rather than a single-patriline colony (33% increase), and for a greater number of dance circuits per follower. Furthermore, dance-following workers in multiple-patriline colonies were more likely to exit their hive after following a dance, although this did not translate to a difference in colony-level exit rates between treatment types. Recruiting nest mates to profitable food sources through dance communication is critical to a colony’s foraging success and long-term fitness; polyandrous queens produce colonies that benefit not only from increased recruitment signalling, but also from the generation of larger and more attentive audiences of signal receivers. This study highlights the importance of integrating responses of both signal senders and receivers to understand more fully the success of animal-communication systems. PMID:21350596

  7. Cosmetics as a feature of the extended human phenotype: modulation of the perception of biologically important facial signals.

    PubMed

    Etcoff, Nancy L; Stock, Shannon; Haley, Lauren E; Vickery, Sarah A; House, David M

    2011-01-01

    Research on the perception of faces has focused on the size, shape, and configuration of inherited features or the biological phenotype, and largely ignored the effects of adornment, or the extended phenotype. Research on the evolution of signaling has shown that animals frequently alter visual features, including color cues, to attract, intimidate or protect themselves from conspecifics. Humans engage in conscious manipulation of visual signals using cultural tools in real time rather than genetic changes over evolutionary time. Here, we investigate one tool, the use of color cosmetics. In two studies, we asked viewers to rate the same female faces with or without color cosmetics, and we varied the style of makeup from minimal (natural), to moderate (professional), to dramatic (glamorous). Each look provided increasing luminance contrast between the facial features and surrounding skin. Faces were shown for 250 ms or for unlimited inspection time, and subjects rated them for attractiveness, competence, likeability and trustworthiness. At 250 ms, cosmetics had significant positive effects on all outcomes. Length of inspection time did not change the effect for competence or attractiveness. However, with longer inspection time, the effect of cosmetics on likability and trust varied by specific makeup looks, indicating that cosmetics could impact automatic and deliberative judgments differently. The results suggest that cosmetics can create supernormal facial stimuli, and that one way they may do so is by exaggerating cues to sexual dimorphism. Our results provide evidence that judgments of facial trustworthiness and attractiveness are at least partially separable, that beauty has a significant positive effect on judgment of competence, a universal dimension of social cognition, but has a more nuanced effect on the other universal dimension of social warmth, and that the extended phenotype significantly influences perception of biologically important signals at first

  8. Cosmetics as a Feature of the Extended Human Phenotype: Modulation of the Perception of Biologically Important Facial Signals

    PubMed Central

    Etcoff, Nancy L.; Stock, Shannon; Haley, Lauren E.; Vickery, Sarah A.; House, David M.

    2011-01-01

    Research on the perception of faces has focused on the size, shape, and configuration of inherited features or the biological phenotype, and largely ignored the effects of adornment, or the extended phenotype. Research on the evolution of signaling has shown that animals frequently alter visual features, including color cues, to attract, intimidate or protect themselves from conspecifics. Humans engage in conscious manipulation of visual signals using cultural tools in real time rather than genetic changes over evolutionary time. Here, we investigate one tool, the use of color cosmetics. In two studies, we asked viewers to rate the same female faces with or without color cosmetics, and we varied the style of makeup from minimal (natural), to moderate (professional), to dramatic (glamorous). Each look provided increasing luminance contrast between the facial features and surrounding skin. Faces were shown for 250 ms or for unlimited inspection time, and subjects rated them for attractiveness, competence, likeability and trustworthiness. At 250 ms, cosmetics had significant positive effects on all outcomes. Length of inspection time did not change the effect for competence or attractiveness. However, with longer inspection time, the effect of cosmetics on likability and trust varied by specific makeup looks, indicating that cosmetics could impact automatic and deliberative judgments differently. The results suggest that cosmetics can create supernormal facial stimuli, and that one way they may do so is by exaggerating cues to sexual dimorphism. Our results provide evidence that judgments of facial trustworthiness and attractiveness are at least partially separable, that beauty has a significant positive effect on judgment of competence, a universal dimension of social cognition, but has a more nuanced effect on the other universal dimension of social warmth, and that the extended phenotype significantly influences perception of biologically important signals at first

  9. Bmi-1 extends the life span of normal human oral keratinocytes by inhibiting the TGF-{beta} signaling

    SciTech Connect

    Kim, Reuben H.; Lieberman, Mark B.; Lee, Rachel; Shin, Ki-Hyuk; Mehrazarin, Shebli; Oh, Ju-Eun; Park, No-Hee; Kang, Mo K.

    2010-10-01

    We previously demonstrated that Bmi-1 extended the in vitro life span of normal human oral keratinocytes (NHOK). We now report that the prolonged life span of NHOK by Bmi-1 is, in part, due to inhibition of the TGF-{beta} signaling pathway. Serial subculture of NHOK resulted in replicative senescence and terminal differentiation and activation of TGF-{beta} signaling pathway. This was accompanied with enhanced intracellular and secreted TGF-{beta}1 levels, phosphorylation of Smad2/3, and increased expression of p15{sup INK4B} and p57{sup KIP2}. An ectopic expression of Bmi-1 in NHOK (HOK/Bmi-1) decreased the level of intracellular and secreted TGF-{beta}1 induced dephosphorylation of Smad2/3, and diminished the level of p15{sup INK4B} and p57{sup KIP2}. Moreover, Bmi-1 expression led to the inhibition of TGF-{beta}-responsive promoter activity in a dose-specific manner. Knockdown of Bmi-1 in rapidly proliferating HOK/Bmi-1 and cancer cells increased the level of phosphorylated Smad2/3, p15{sup INK4B}, and p57{sup KIP2}. In addition, an exposure of senescent NHOK to TGF-{beta} receptor I kinase inhibitor or anti-TGF-{beta} antibody resulted in enhanced replicative potential of cells. Taken together, these data suggest that Bmi-1 suppresses senescence of cells by inhibiting the TGF-{beta} signaling pathway in NHOK.

  10. Signal processing for the detection of multiple imperfection echoes drowned in the structural noise.

    PubMed

    Drai, R; Benammar, A; Benchaala, A

    2004-04-01

    In this work, we propose to develop algorithms based on the split spectrum processing method associated with the multi-steps method based on "Group delay moving entropy" (GDME) allowing detecting and locating multiple imperfection echoes drowned in the structural noise of materials. In fact, GDME is based on the fact that defect echoes have a constant group delay while the noise has a random group delay. The investigation is performed with 4 known defect echoes with different characteristics (position, center frequency and bandwidth). The defect echo frequency is varied around the frequency of the input signal in order to evaluate, by signal to noise ratio calculation, the robustness of the detection method. The grain noise signal is generated first, by a simple clutter model which consider the noise, in the time domain, as the superimposed of signal coming from backscaterers in the medium and second, experimentally by a material with coarse grains. PMID:15047392

  11. Prediction of multiple resonance characteristics by an extended resistor-inductor-capacitor circuit model for plasmonic metamaterials absorbers in infrared.

    PubMed

    Xu, Xiaolun; Li, Yongqian; Wang, Binbin; Zhou, Zili

    2015-10-01

    The resonance characteristics of plasmonic metamaterials absorbers (PMAs) are strongly dependent on geometric parameters. A resistor-inductor-capacitor (RLC) circuit model has been extended to predict the resonance wavelengths and the bandwidths of multiple magnetic polaritons modes in PMAs. For a typical metallic-dielectric-metallic structure absorber working in the infrared region, the developed model describes the correlation between the resonance characteristics and the dimensional sizes. In particular, the RLC model is suitable for not only the fundamental resonance mode, but also for the second- and third-order resonance modes. The prediction of the resonance characteristics agrees fairly well with those calculated by the finite-difference time-domain simulation and the experimental results. The developed RLC model enables the facilitation of designing multi-band PMAs for infrared radiation detectors and thermal emitters. PMID:26421549

  12. Signaling system for multiple-access laser communications and interference protection.

    PubMed

    Riza, N A; Hershey, J E; Hassan, A A

    1993-04-10

    Signaling by spatial coding is proposed for asynchronous multiple-access free-space optical communications and interference mitigation. The large spatial bandwidth (e.g., 10(6) pixels) of each laser transmitter aperture is utilized for user coding, while the transmitter temporal bandwidth is preserved for information signals. Signal recovery is based on incoherent optical detection, spatial sampling, and electronic or optical matched filtering of the remotely received transmit optical beam Fresnel or Fraunhofer diffraction pattern. The proposed signaling method is appropriate for multiple-access free-space laser links involving multiple transmitters that use a common receiver. With electronic filtering, low-to-medium (e.g., 3 Mbits/s) data-rate users are appropriate. With a lenslet-array-based incoherent optical correlator, higher (e.g., 100 Mbits/s) data rates can be achieved. Improved interference protection is achieved cby spatially distributed bit-duration-based processing. Preliminary simulation results are carried out to demonstrate operating principles. PMID:20820331

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

    PubMed

    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

    2016-02-01

    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

  14. Treatment of Acute Renal Failure Secondary to Multiple Myeloma with Chemotherapy and Extended High Cut-Off Hemodialysis

    PubMed Central

    Hutchison, Colin A.; Bradwell, Arthur R.; Cook, Mark; Basnayake, Kolitha; Basu, Supratik; Harding, Stephen; Hattersley, John; Evans, Neil D.; Chappel, Mike J.; Sampson, Paul; Foggensteiner, Lukas; Adu, Dwomoa; Cockwell, Paul

    2009-01-01

    Background and objectives: Extended hemodialysis using a high cut-off dialyzer (HCO-HD) removes large quantities of free light chains in patients with multiple myeloma. However, the clinical utility of this method is uncertain. This study assessed the combination of chemotherapy and HCO-HD on serum free light chain concentrations and renal recovery in patients with myeloma kidney (cast nephropathy) and dialysis-dependent acute renal failure. Design, setting, participants, & measurements: An open-label study of the relationship between free light chain levels and clinical outcomes in 19 patients treated with standard chemotherapy regimens and HCO-HD. Results: There were sustained early reductions in serum free light chain concentrations (median 85% [range 50 to 97]) in 13 patients. These 13 patients became dialysis independent at a median of 27 d (range 13 to 120). Six patients had chemotherapy interrupted because of early infections and did not achieve sustained early free light chain reductions; one of these patients recovered renal function (at 105 d) the remaining 5 patients did not recover renal function. Patients who recovered renal function had a significantly improved survival (P < 0.012). Conclusion: In dialysis-dependent acute renal failure secondary to myeloma kidney, patients who received uninterrupted chemotherapy and extended HCO-HD had sustained reductions in serum free light chain concentrations and recovered independent renal function. PMID:19339414

  15. Intracellular calcium signals display an avalanche-like behavior over multiple lengthscales

    PubMed Central

    Lopez, Lucía; Piegari, Estefanía; Sigaut, Lorena; Ponce Dawson, Silvina

    2012-01-01

    Many natural phenomena display “self-organized criticality” (SOC), (Bak et al., 1987). This refers to spatially extended systems for which patterns of activity characterized by different lengthscales can occur with a probability density that follows a power law with pattern size. Differently from power laws at phase transitions, systems displaying SOC do not need the tuning of an external parameter. Here we analyze intracellular calcium (Ca2+) signals, a key component of the signaling toolkit of almost any cell type. Ca2+ signals can either be spatially restricted (local) or propagate throughout the cell (global). Different models have suggested that the transition from local to global signals is similar to that of directed percolation. Directed percolation has been associated, in turn, to the appearance of SOC. In this paper we discuss these issues within the framework of simple models of Ca2+ signal propagation. We also analyze the size distribution of local signals (“puffs”) observed in immature Xenopus Laevis oocytes. The puff amplitude distribution obtained from observed local signals is not Gaussian with a noticeable fraction of large size events. The experimental distribution of puff areas in the spatio-temporal record of the image has a long tail that is approximately log-normal. The distribution can also be fitted with a power law relationship albeit with a smaller goodness of fit. The power law behavior is encountered within a simple model that includes some coupling among individual signals for a wide range of parameter values. An analysis of the model shows that a global elevation of the Ca2+ concentration plays a major role in determining whether the puff size distribution is long-tailed or not. This suggests that Ca2+-clearing from the cytosol is key to determine whether IP3-mediated Ca2+ signals can display a SOC-like behavior or not. PMID:22969730

  16. Intracellular calcium signals display an avalanche-like behavior over multiple lengthscales.

    PubMed

    Lopez, Lucía; Piegari, Estefanía; Sigaut, Lorena; Ponce Dawson, Silvina

    2012-01-01

    Many natural phenomena display "self-organized criticality" (SOC), (Bak et al., 1987). This refers to spatially extended systems for which patterns of activity characterized by different lengthscales can occur with a probability density that follows a power law with pattern size. Differently from power laws at phase transitions, systems displaying SOC do not need the tuning of an external parameter. Here we analyze intracellular calcium (Ca(2+)) signals, a key component of the signaling toolkit of almost any cell type. Ca(2+) signals can either be spatially restricted (local) or propagate throughout the cell (global). Different models have suggested that the transition from local to global signals is similar to that of directed percolation. Directed percolation has been associated, in turn, to the appearance of SOC. In this paper we discuss these issues within the framework of simple models of Ca(2+) signal propagation. We also analyze the size distribution of local signals ("puffs") observed in immature Xenopus Laevis oocytes. The puff amplitude distribution obtained from observed local signals is not Gaussian with a noticeable fraction of large size events. The experimental distribution of puff areas in the spatio-temporal record of the image has a long tail that is approximately log-normal. The distribution can also be fitted with a power law relationship albeit with a smaller goodness of fit. The power law behavior is encountered within a simple model that includes some coupling among individual signals for a wide range of parameter values. An analysis of the model shows that a global elevation of the Ca(2+) concentration plays a major role in determining whether the puff size distribution is long-tailed or not. This suggests that Ca(2+)-clearing from the cytosol is key to determine whether IP(3)-mediated Ca(2+) signals can display a SOC-like behavior or not. PMID:22969730

  17. Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context

    SciTech Connect

    Joslin, Elizabeth J.; Shankaran, Harish; Opresko, Lee K.; Bollinger, Nikki; Lauffenburger, Douglas A.; Wiley, H. S.

    2010-05-10

    Transactivation of the epidermal growth factor receptor (EGFR) has been proposed to be a mechanism by which a variety of cellular inputs can be integrated into a single signaling pathway, but the regulatory topology of this important system is unclear. To understand the transactivation circuit, we first created a “non-binding” reporter for ligand shedding. We then quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR into the extracellular signal regulated kinase (ERK) cascade in human mammary epithelial cells. We found that transactivation is mediated by a recursive autocrine circuit where ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. The time from shedding to ERK activation is fast (<5 min) whereas the recursive feedback is slow (>15 min). Simulations showed that this delay in positive feedback greatly enhanced system stability and robustness. Our results indicate that the transactivation circuit is constructed so that the magnitude of ERK signaling is governed by the sum of multiple direct inputs, while recursive, autocrine ligand shedding controls signal duration.

  18. Analytical multiple scattering correction to the Mie theory: Application to the analysis of the lidar signal

    NASA Technical Reports Server (NTRS)

    Flesia, C.; Schwendimann, P.

    1992-01-01

    The contribution of the multiple scattering to the lidar signal is dependent on the optical depth tau. Therefore, the radar analysis, based on the assumption that the multiple scattering can be neglected is limited to cases characterized by low values of the optical depth (tau less than or equal to 0.1) and hence it exclude scattering from most clouds. Moreover, all inversion methods relating lidar signal to number densities and particle size must be modified since the multiple scattering affects the direct analysis. The essential requests of a realistic model for lidar measurements which include the multiple scattering and which can be applied to practical situations follow. (1) Requested are not only a correction term or a rough approximation describing results of a certain experiment, but a general theory of multiple scattering tying together the relevant physical parameter we seek to measure. (2) An analytical generalization of the lidar equation which can be applied in the case of a realistic aerosol is requested. A pure analytical formulation is important in order to avoid the convergency and stability problems which, in the case of numerical approach, are due to the large number of events that have to be taken into account in the presence of large depth and/or a strong experimental noise.

  19. Extending the eigCG algorithm to nonsymmetric Lanczos for linear systems with multiple right-hand sides

    SciTech Connect

    Abdel-Rehim, A M; Stathopoulos, Andreas; Orginos, Kostas

    2014-08-01

    The technique that was used to build the EigCG algorithm for sparse symmetric linear systems is extended to the nonsymmetric case using the BiCG algorithm. We show that, similarly to the symmetric case, we can build an algorithm that is capable of computing a few smallest magnitude eigenvalues and their corresponding left and right eigenvectors of a nonsymmetric matrix using only a small window of the BiCG residuals while simultaneously solving a linear system with that matrix. For a system with multiple right-hand sides, we give an algorithm that computes incrementally more eigenvalues while solving the first few systems and then uses the computed eigenvectors to deflate BiCGStab for the remaining systems. Our experiments on various test problems, including Lattice QCD, show the remarkable ability of EigBiCG to compute spectral approximations with accuracy comparable to that of the unrestarted, nonsymmetric Lanczos. Furthermore, our incremental EigBiCG followed by appropriately restarted and deflated BiCGStab provides a competitive method for systems with multiple right-hand sides.

  20. The Relative Kinematics of Galaxy Emission and Multiple Gas Phases in z~0.5 Extended Galaxy Halos

    NASA Astrophysics Data System (ADS)

    Churchill, Christopher

    2010-09-01

    Evidence abounds from quasar absorption line data that the extended gaseous halos of galaxies comprise multiple phases {densities, temperatures, ionization conditions}. Developing a comprehensive and deeper understanding of the origin and persistence of extended galaxy halos, and their role in galaxy evolution, requires that these multiple phases be observed and analyzed. However, such studies that incorporate the host galaxies are virtually non-existent. The new COS instrument opens a new window in which the forest of FUV lines arising in neutral, low, AND high ionization halo gas can be probed with high resolution and sensitivity for multiple chemical species. For intermediate redshift galaxies, these lines are free of Ly-alpha forest contamination. We propose to obtain G160M COS/FUV high resolution spectra of the two quasars Q0454-220 {J0456-2159} and Q1038+064 {4c 06.41} in order to measure the neutral hydrogen Ly-beta, gamma, and delta transitions and the OVI 1031,1038 doublet and CII 1036 and CIII 977 transitions {as well as a few others that fall on the spectral format} in three intervening z 0.45 intervening gaseous halos. We augment the proposed observations with a similar pending COS spectrum {scheduled May 2010, PID 11667, PI Churchill} of the quasar TON 153, which will provide the multiphase absorption kinematics for two additional gaseous halos at z 0.67. The proposed observations will bring our final sample size to five.For these five systems, we have quantified the host galaxy morphologies {WFCP-2/HST images}, measured the galaxy emission lines and rotation curves {ESI/Keck spectra}, and analyzed the MgII 2796,2803 and FeII multiplet absorption {HIRES/Keck spectra}. Our goal is to undertake a comprehensive analysis of the multiphase physical conditions in these five galaxy-absorber pairs. We aim to perform the first ever quantitative comparison of the relative relationships between neutral, low, and high ionization absorbing halo gas kinematics with

  1. Damped oscillations in a multiple delayed feedback NF-[Formula: see text]B signaling module.

    PubMed

    Yu, Wen-Ting; Tang, Jun; Ma, Jun; Luo, Jin-Ming; Yang, Xian-Qing

    2015-12-01

    The NF-[Formula: see text]B signaling system regulates a number of cellular processes. Recent studies with simplified models found a damped function of the dual delayed feedback NF-[Formula: see text]B signaling module. We use a computational model to investigate how multiple delayed feedback aids achieving damping oscillation in the system and how internal noise can influence the damping function. A curve-fitting method (CFM) is introduced to quantify the damped oscillation. Our results show that (1) the structure of multiple delayed feedback, containing double or triple significantly delayed feedback, determines achieving damped oscillation. (2) Internal noise could aid the system to achieve damped oscillation under almost all circumstances. PMID:26290058

  2. Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates

    PubMed Central

    Baker, Jillian G.; Hill, Stephen J.

    2007-01-01

    Antagonist affinity measurements have traditionally been considered important in characterizing the cell-surface receptors present in a particular cell or tissue. A central assumption has been that antagonist affinity is constant for a given receptor–antagonist interaction, regardless of the agonist used to stimulate that receptor or the downstream response that is measured. As a consequence, changes in antagonist affinity values have been taken as initial evidence for the presence of novel receptor subtypes. Emerging evidence suggests, however, that receptors can possess multiple binding sites and the same receptor can show different antagonist affinity measurements under distinct experimental conditions. Here, we discuss several mechanisms by which antagonists have different affinities for the same receptor as a consequence of allosterism, coupling to different G proteins, multiple (but non-interacting) receptor sites, and signal-pathway-dependent pharmacology (where the pharmacology observed varies depending on the signalling pathway measured). PMID:17629959

  3. Signal Increase on Unenhanced T1-Weighted Images in the Rat Brain After Repeated, Extended Doses of Gadolinium-Based Contrast Agents

    PubMed Central

    Jost, Gregor; Lenhard, Diana Constanze; Sieber, Martin Andrew; Lohrke, Jessica; Frenzel, Thomas; Pietsch, Hubertus

    2016-01-01

    but statistically not significant CN/Po signal intensity ratio. No increased CN/Po signal intensity ratios were determined in the MRI scans of rats that received macrocyclic GBCAs gadobutrol and gadoterate meglumine or saline. The ratio of signal intensity in GP/Th was not elevated in any group injected with GBCAs or saline. Enhanced signal intensities of CSF spaces were observed in the postcontrast fluid-attenuated inversion recovery images of all animals receiving GBCAs but not for saline. Conclusions In this animal study in rats, increased signal intensity in the CN was found up to 24 days after multiple, extended doses of linear GBCAs. However, in contrast to clinical reports, the signal enhancement in the GP was not reproduced, demonstrating the limitations of this animal experiment. The elevated signal intensities remained persistent over the entire observation period. In contrast, no changes of signal intensities in either the CN or the GP were observed for macrocyclic GBCAs. However, all GBCAs investigated were able to pass the blood-CSF barrier in rats to a certain, not yet quantified extent. PMID:26606548

  4. An extended U2AF65–RNA-binding domain recognizes the 3′ splice site signal

    PubMed Central

    Agrawal, Anant A.; Salsi, Enea; Chatrikhi, Rakesh; Henderson, Steven; Jenkins, Jermaine L.; Green, Michael R.; Ermolenko, Dmitri N.; Kielkopf, Clara L.

    2016-01-01

    How the essential pre-mRNA splicing factor U2AF65 recognizes the polypyrimidine (Py) signals of the major class of 3′ splice sites in human gene transcripts remains incompletely understood. We determined four structures of an extended U2AF65–RNA-binding domain bound to Py-tract oligonucleotides at resolutions between 2.0 and 1.5 Å. These structures together with RNA binding and splicing assays reveal unforeseen roles for U2AF65 inter-domain residues in recognizing a contiguous, nine-nucleotide Py tract. The U2AF65 linker residues between the dual RNA recognition motifs (RRMs) recognize the central nucleotide, whereas the N- and C-terminal RRM extensions recognize the 3′ terminus and third nucleotide. Single-molecule FRET experiments suggest that conformational selection and induced fit of the U2AF65 RRMs are complementary mechanisms for Py-tract association. Altogether, these results advance the mechanistic understanding of molecular recognition for a major class of splice site signals. PMID:26952537

  5. Reduced Ssy1-Ptr3-Ssy5 (SPS) Signaling Extends Replicative Life Span by Enhancing NAD+ Homeostasis in Saccharomyces cerevisiae*

    PubMed Central

    Tsang, Felicia; James, Christol; Kato, Michiko; Myers, Victoria; Ilyas, Irtqa; Tsang, Matthew; Lin, Su-Ju

    2015-01-01

    Attenuated nutrient signaling extends the life span in yeast and higher eukaryotes; however, the mechanisms are not completely understood. Here we identify the Ssy1-Ptr3-Ssy5 (SPS) amino acid sensing pathway as a novel longevity factor. A null mutation of SSY5 (ssy5Δ) increases replicative life span (RLS) by ∼50%. Our results demonstrate that several NAD+ homeostasis factors play key roles in this life span extension. First, expression of the putative malate-pyruvate NADH shuttle increases in ssy5Δ cells, and deleting components of this shuttle, MAE1 and OAC1, largely abolishes RLS extension. Next, we show that Stp1, a transcription factor of the SPS pathway, directly binds to the promoter of MAE1 and OAC1 to regulate their expression. Additionally, deletion of SSY5 increases nicotinamide riboside (NR) levels and phosphate-responsive (PHO) signaling activity, suggesting that ssy5Δ increases NR salvaging. This increase contributes to NAD+ homeostasis, partially ameliorating the NAD+ deficiency and rescuing the short life span of the npt1Δ mutant. Moreover, we observed that vacuolar phosphatase, Pho8, is partially required for ssy5Δ-mediated NR increase and RLS extension. Together, our studies present evidence that supports SPS signaling is a novel NAD+ homeostasis factor and ssy5Δ-mediated life span extension is likely due to concomitantly increased mitochondrial and vacuolar function. Our findings may contribute to understanding the molecular basis of NAD+ metabolism, cellular life span, and diseases associated with NAD+ deficiency and aging. PMID:25825491

  6. Reduced Ssy1-Ptr3-Ssy5 (SPS) signaling extends replicative life span by enhancing NAD+ homeostasis in Saccharomyces cerevisiae.

    PubMed

    Tsang, Felicia; James, Christol; Kato, Michiko; Myers, Victoria; Ilyas, Irtqa; Tsang, Matthew; Lin, Su-Ju

    2015-05-15

    Attenuated nutrient signaling extends the life span in yeast and higher eukaryotes; however, the mechanisms are not completely understood. Here we identify the Ssy1-Ptr3-Ssy5 (SPS) amino acid sensing pathway as a novel longevity factor. A null mutation of SSY5 (ssy5Δ) increases replicative life span (RLS) by ∼50%. Our results demonstrate that several NAD(+) homeostasis factors play key roles in this life span extension. First, expression of the putative malate-pyruvate NADH shuttle increases in ssy5Δ cells, and deleting components of this shuttle, MAE1 and OAC1, largely abolishes RLS extension. Next, we show that Stp1, a transcription factor of the SPS pathway, directly binds to the promoter of MAE1 and OAC1 to regulate their expression. Additionally, deletion of SSY5 increases nicotinamide riboside (NR) levels and phosphate-responsive (PHO) signaling activity, suggesting that ssy5Δ increases NR salvaging. This increase contributes to NAD(+) homeostasis, partially ameliorating the NAD(+) deficiency and rescuing the short life span of the npt1Δ mutant. Moreover, we observed that vacuolar phosphatase, Pho8, is partially required for ssy5Δ-mediated NR increase and RLS extension. Together, our studies present evidence that supports SPS signaling is a novel NAD(+) homeostasis factor and ssy5Δ-mediated life span extension is likely due to concomitantly increased mitochondrial and vacuolar function. Our findings may contribute to understanding the molecular basis of NAD(+) metabolism, cellular life span, and diseases associated with NAD(+) deficiency and aging. PMID:25825491

  7. Packet communications in satellites with multiple-beam antennas and signal processing

    NASA Technical Reports Server (NTRS)

    Davies, R.; Chethik, F.; Penick, M.

    1980-01-01

    A communication satellite with a multiple-beam antenna and onboard signal processing is considered for use in a 'message-switched' data relay system. The signal processor may incorporate demodulation, routing, storage, and remodulation of the data. A system user model is established and key functional elements for the signal processing are identified. With the throughput and delay requirements as the controlled variables, the hardware complexity, operational discipline, occupied bandwidth, and overall user end-to-end cost are estimated for (1) random-access packet switching; and (2) reservation-access packet switching. Other aspects of this network (eg, the adaptability to channel switched traffic requirements) are examined. For the given requirements and constraints, the reservation system appears to be the most attractive protocol.

  8. Spectral and temporal properties of optical signals with multiple sinusoidal phase modulations.

    PubMed

    Dorrer, C

    2014-02-10

    Optical signals generated by multiple sinusoidal temporal phase modulations (multi-FMs) applied to a monochromatic field are studied from the viewpoint of their optical spectrum and temporal modulations arising from spectral impairments. Statistical analysis based on the central limit theorem shows that the signals' optical spectrum converges to a normal distribution as the number of modulations increases, allowing one to predict the frequency range containing a given fraction of the total energy with the associated cumulative density function. The conversion of frequency modulation to amplitude modulation is analyzed and simulated for arbitrary multi-FM signals. These developments are of theoretical and practical importance for high-energy laser systems, where optical pulses are phase modulated in the front end to smooth out the on-target beam profile and prevent potentially catastrophic damage to optical components. PMID:24663283

  9. Following the trail of lipids: Signals initiated by PI3K function at multiple cellular membranes.

    PubMed

    Naguib, Adam

    2016-01-01

    Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] is the signaling currency of the phosphoinositide 3-kinase (PI3K)/AKT pathway; transduction through this axis depends on this signaling lipid. Formation of PtdIns(3,4,5)P3 is dictated not only by PI3K activation but also by the localization and access of PI3K to its substrate PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate). PI3K/AKT-mediated signaling is antagonized by PtdIns(3,4,5)P3 dephosphorylation. Although previously typically considered an event associated with the plasma membrane, it is now appreciated that the formation and metabolism of PtdIns(3,4,5)P3 occur on multiple membranes with distinct kinetics. Modulated activity of phosphatidylinositol lipid kinases and phosphatases contributes to intricately orchestrated lipid gradients that define the signaling status of the pathway at multiple sites within the cell. PMID:27188443

  10. Genotype to Phenotype Maps: Multiple Input Abiotic Signals Combine to Produce Growth Effects via Attenuating Signaling Interactions in Maize

    PubMed Central

    Makumburage, G. Buddhika; Richbourg, H. Lee; LaTorre, Kalindi D.; Capps, Andrew; Chen, Cuixen; Stapleton, Ann E.

    2013-01-01

    The complexity of allele interactions constrains crop improvement and the prediction of disease susceptibility. Additive allele effects are the foundation for selection in animal and plant breeding, and complex genetic and environmental interactions contribute to inefficient detection of desirable loci. Manipulation and modeling of other sources of variation, such as environmental variables, have the potential to improve our prediction of phenotype from genotype. As an example of our approach to analysis of the network linking environmental input to alleles, we mapped the genetic architecture of single and combined abiotic stress responses in two maize mapping populations and compared the observed genetic architecture patterns to simple theoretical predictions. Comparisons of single and combined stress effects on growth and biomass traits exhibit patterns of allele effects that suggest attenuating interactions among physiological signaling steps in drought and ultraviolet radiation stress responses. The presence of attenuating interactions implies that shared QTL found in sets of environments could be used to group environment types and identify underlying environmental similarities, and that patterns of stress-dependent genetic architecture should be studied as a way to prioritize prebreeding populations. A better understanding of whole-plant interactor pathways and genetic architecture of multiple-input environmental signaling has the potential to improve the prediction of genomic value in plant breeding and crop modeling. PMID:24142926

  11. A Homozygous B3GAT3 Mutation Causes a Severe Syndrome with Multiple Fractures, Extending the Number of Linkeropathy Syndromes

    PubMed Central

    Jones, Kelly L.; Schwarze, Ulrike; Adam, Margaret P.; Byers, Peter H.; Mefford, Heather C.

    2015-01-01

    Linkeropathies are a group of syndromes characterized by short stature, radio-ulnar synostosis, decreased bone density, congenital contractures and dislocations, joint laxity, broad digits, brachycephaly, small mouth, prominent eyes, short or webbed neck, congenital heart defects and mild developmental delay. Linkeropathies are due to enzymatic defects in the synthesis of the common linker region that joins the core proteins to their glycosaminoglycan side chains. The enzyme glucuronyltransferase 1, encoded by B3GAT3, adds the last of the four saccharides that comprise the linker region. Mutations in B3GAT3 have been reported in two unrelated families with the same homozygous mutation (c.830G>A, p.Arg277Gln). We report a patient with a novel homozygous B3GAT3 (c.667G>A, p.Gly223Ser) mutation and a history of multiple fractures, blue sclerae, and glaucoma. Our patient is a 12 month old boy born to consanguineous parents and, like previously reported patients, he has bilateral radio-ulnar synostosis, severe osteopenia, an increased gap between first and second toes, bilateral club feet, and atrial and ventricular septal defects. He also the additional features of bilateral glaucoma, hypertelorism, upturned nose with anteverted nares, a small chest, a diaphragmatic hernia, multiple fractures, arachnodactyly, overlapping fingers with ulnar deviation, lymphedema, hypotonia, hearing loss, and perinatal cerebral infarction with bilateral supra- and infratentorial subdural hematomas. We provide a clinical report to highlight the extended phenotypic range of B3GAT3 mutations and a comparative overview of the phenotypic features of the linkeropathies associated with mutations in XYLT1, B4GALT7, B3GALT6, and B3GAT3. PMID:26086840

  12. Multiple Model-Informed Open-Loop Control of Uncertain Intracellular Signaling Dynamics

    PubMed Central

    Perley, Jeffrey P.; Mikolajczak, Judith; Harrison, Marietta L.; Buzzard, Gregery T.; Rundell, Ann E.

    2014-01-01

    Computational approaches to tune the activation of intracellular signal transduction pathways both predictably and selectively will enable researchers to explore and interrogate cell biology with unprecedented precision. Techniques to control complex nonlinear systems typically involve the application of control theory to a descriptive mathematical model. For cellular processes, however, measurement assays tend to be too time consuming for real-time feedback control and models offer rough approximations of the biological reality, thus limiting their utility when considered in isolation. We overcome these problems by combining nonlinear model predictive control with a novel adaptive weighting algorithm that blends predictions from multiple models to derive a compromise open-loop control sequence. The proposed strategy uses weight maps to inform the controller of the tendency for models to differ in their ability to accurately reproduce the system dynamics under different experimental perturbations (i.e. control inputs). These maps, which characterize the changing model likelihoods over the admissible control input space, are constructed using preexisting experimental data and used to produce a model-based open-loop control framework. In effect, the proposed method designs a sequence of control inputs that force the signaling dynamics along a predefined temporal response without measurement feedback while mitigating the effects of model uncertainty. We demonstrate this technique on the well-known Erk/MAPK signaling pathway in T cells. In silico assessment demonstrates that this approach successfully reduces target tracking error by 52% or better when compared with single model-based controllers and non-adaptive multiple model-based controllers. In vitro implementation of the proposed approach in Jurkat cells confirms a 63% reduction in tracking error when compared with the best of the single-model controllers. This study provides an experimentally

  13. Multiple model-informed open-loop control of uncertain intracellular signaling dynamics.

    PubMed

    Perley, Jeffrey P; Mikolajczak, Judith; Harrison, Marietta L; Buzzard, Gregery T; Rundell, Ann E

    2014-04-01

    Computational approaches to tune the activation of intracellular signal transduction pathways both predictably and selectively will enable researchers to explore and interrogate cell biology with unprecedented precision. Techniques to control complex nonlinear systems typically involve the application of control theory to a descriptive mathematical model. For cellular processes, however, measurement assays tend to be too time consuming for real-time feedback control and models offer rough approximations of the biological reality, thus limiting their utility when considered in isolation. We overcome these problems by combining nonlinear model predictive control with a novel adaptive weighting algorithm that blends predictions from multiple models to derive a compromise open-loop control sequence. The proposed strategy uses weight maps to inform the controller of the tendency for models to differ in their ability to accurately reproduce the system dynamics under different experimental perturbations (i.e. control inputs). These maps, which characterize the changing model likelihoods over the admissible control input space, are constructed using preexisting experimental data and used to produce a model-based open-loop control framework. In effect, the proposed method designs a sequence of control inputs that force the signaling dynamics along a predefined temporal response without measurement feedback while mitigating the effects of model uncertainty. We demonstrate this technique on the well-known Erk/MAPK signaling pathway in T cells. In silico assessment demonstrates that this approach successfully reduces target tracking error by 52% or better when compared with single model-based controllers and non-adaptive multiple model-based controllers. In vitro implementation of the proposed approach in Jurkat cells confirms a 63% reduction in tracking error when compared with the best of the single-model controllers. This study provides an experimentally

  14. Sprouty genes prevent excessive FGF signalling in multiple cell types throughout development of the cerebellum

    PubMed Central

    Yu, Tian; Yaguchi, Yuichiro; Echevarria, Diego; Martinez, Salvador; Basson, M. Albert

    2011-01-01

    Fibroblast growth factors (FGFs) and regulators of the FGF signalling pathway are expressed in several cell types within the cerebellum throughout its development. Although much is known about the function of this pathway during the establishment of the cerebellar territory during early embryogenesis, the role of this pathway during later developmental stages is still poorly understood. Here, we investigated the function of sprouty genes (Spry1, Spry2 and Spry4), which encode feedback antagonists of FGF signalling, during cerebellar development in the mouse. Simultaneous deletion of more than one of these genes resulted in a number of defects, including mediolateral expansion of the cerebellar vermis, reduced thickness of the granule cell layer and abnormal foliation. Analysis of cerebellar development revealed that the anterior cerebellar neuroepithelium in the early embryonic cerebellum was expanded and that granule cell proliferation during late embryogenesis and early postnatal development was reduced. We show that the granule cell proliferation deficit correlated with reduced sonic hedgehog (SHH) expression and signalling. A reduction in Fgfr1 dosage during development rescued these defects, confirming that the abnormalities are due to excess FGF signalling. Our data indicate that sprouty acts both cell autonomously in granule cell precursors and non-cell autonomously to regulate granule cell number. Taken together, our data demonstrate that FGF signalling levels have to be tightly controlled throughout cerebellar development in order to maintain the normal development of multiple cell types. PMID:21693512

  15. A comparison of particle filters and multiple-hypothesis extended Kalman filters for bearings-only tracking

    NASA Astrophysics Data System (ADS)

    Zaugg, David A.; Samuel, Alphonso A.; Waagen, Donald E.; Schmitt, Harry A.

    2004-07-01

    Bearings-only tracking is widely used in the defense arena. Its value can be exploited in systems using optical sensors and sonar, among others. Non-linearity and non-Gaussian prior statistics are among the complications of bearings-only tracking. Several filters have been used to overcome these obstacles, including particle filters and multiple hypothesis extended Kalman filters (MHEKF). Particle filters can accommodate a wide range of distributions and do not need to be linearized. Because of this they seem ideally suited for this problem. A MHEKF can only approximate the prior distribution of a bearings-only tracking scenario and needs to be linearized. However, the likelihood distribution maintained for each MHEKF hypothesis demonstrates significant memory and lends stability to the algorithm, potentially enhancing tracking convergence. Also, the MHEKF is insensitive to outliers. For the scenarios under investigation, the sensor platform is tracking a moving and a stationary target. The sensor is allowed to maneuver in an attempt to maximize tracking performance. For these scenarios, we compare and contrast the acquisition time and mean-squared tracking error performance characteristics of particle filters and MHEKF via Monte Carlo simulation.

  16. A robust state-of-charge estimator for multiple types of lithium-ion batteries using adaptive extended Kalman filter

    NASA Astrophysics Data System (ADS)

    Xiong, Rui; Gong, Xianzhi; Mi, Chunting Chris; Sun, Fengchun

    2013-12-01

    This paper presents a novel data-driven based approach for the estimation of the state of charge (SoC) of multiple types of lithium ion battery (LiB) cells with adaptive extended Kalman filter (AEKF). A modified second-order RC network based battery model is employed for the state estimation. Based on the battery model and experimental data, the SoC variation per mV voltage for different types of battery chemistry is analyzed and the parameters are identified. The AEKF algorithm is then employed to achieve accurate data-driven based SoC estimation, and the multi-parameter, closed loop feedback system is used to achieve robustness. The accuracy and convergence of the proposed approach is analyzed for different types of LiB cells, including convergence behavior of the model with a large initial SoC error. The results show that the proposed approach has good accuracy for different types of LiB cells, especially for C/LFP LiB cell that has a flat open circuit voltage (OCV) curve. The experimental results show good agreement with the estimation results with maximum error being less than 3%.

  17. Application of differential analysis of VLF signals for seismic-ionospheric precursor detection from multiple receivers

    NASA Astrophysics Data System (ADS)

    Skeberis, Christos; Zaharis, Zaharias; Xenos, Thomas; Contadakis, Michael; Stratakis, Dimitrios; Tommaso, Maggipinto; Biagi, Pier Francesco

    2015-04-01

    This study investigates the application of differential analysis on VLF signals emitted from a single transmitter and received by multiple stations in order to filter and detect disturbances that can be attributed to seismic-ionospheric precursor phenomena. The cross-correlation analysis applied on multiple VLF signals provides a way of discerning the nature of a given disturbance and accounts for more widespread geomagnetic interferences compared to local precursor phenomena. For the purpose of this paper, data acquired in Thessaloniki (40.59N, 22,78E) and in Heraklion (35.31N, 25.10E) from the VLF station in Tavolara, Italy (ICV station Lat. 40.923, Lon. 9.731) for a period of four months (September 2014 - December 2014) are used. The receivers have been developed by Elettronika Srl and are part of the International Network for Frontier Research on Earthquake Precursors (INFREP). A normalization process and an improved variant of the Hilbert-Huang transform are initially applied to the received VLF signals. The signals derived from the first two Intrinsic Mode Functions (IMF1 and IMF2) undergo a cross-correlation analysis and, in this way, time series from the two receivers can be compared. The efficacy of the processing method and the results produced by the proposed process are then discussed. Finally, results are presented along with an evaluation of the discrimination and detection capabilities of the method on disturbances of the received signals. Based upon the results, the merits of such a processing method are discussed to further improve the current method by using differential analysis to better classify between different disturbances but, more importantly, discriminate between points of interest in the provided spectra. This could provide an improved method of detecting disturbances attributed to seismic-ionospheric precursor phenomena and also contribute to a real-time method for correlating seismic activity with the observed disturbances.

  18. Robust algorithm to locate heart beats from multiple physiological waveforms by individual signal detector voting.

    PubMed

    Galeotti, Loriano; Scully, Christopher G; Vicente, Jose; Johannesen, Lars; Strauss, David G

    2015-08-01

    Alarm fatigue is a top medical device hazard in patient monitoring that could be reduced by merging physiological information from multiple sensors, minimizing the impact of a single sensor failing. We developed a heart beat detection algorithm that utilizes multi-modal physiological signals (e.g. electrocardiogram, blood pressure, stroke volume, photoplethysmogram and electro-encephalogram) by merging the heart beats obtained from signal-specific detectors. We used the PhysioNet/Computing in Cardiology Challenge 2014 training set to develop the algorithm, and we refined it with a mix of signals from the multiparameter intelligent monitoring in intensive care (MIMIC II) database and artificially disrupted waveforms. The algorithm had an average sensitivity of 95.67% and positive predictive value (PPV) of 92.28% when applied to the PhysioNet/Computing in Cardiology Challenge 2014 200 record training set. On a refined dataset obtained by removing 5 records with arrhythmias and inconsistent reference annotations we obtained an average sensitivity of 97.43% and PPV of 94.17%. Algorithm performance was assessed with the Physionet Challenge 2014 test set that consisted of 200 records (each up to 10 min length) containing multiple physiological signals and reference annotations verified by the PhysioNet/Computing in Cardiology Challenge 2014 organizers. Our algorithm had a sensitivity of 92.74% and PPV of 87.37% computed over all annotated beats, and a record average sensitivity of 91.08%, PPV of 86.96% and an overall score (average of all 4 measures) of 89.53%. Our algorithm is an example of a data fusion approach that can improve patient monitoring and reduce false alarms by reducing the effect of individual signal failures. PMID:26218439

  19. Parishin from Gastrodia elata Extends the Lifespan of Yeast via Regulation of Sir2/Uth1/TOR Signaling Pathway

    PubMed Central

    Lin, Yanfei; Sun, Yujuan; Weng, Yufang; Xiang, Lan; Qi, Jianhua

    2016-01-01

    Parishin is a phenolic glucoside isolated from Gastrodia elata, which is an important traditional Chinese medicine; this glucoside significantly extended the replicative lifespan of K6001 yeast at 3, 10, and 30 μM. To clarify its mechanism of action, assessment of oxidative stress resistance, superoxide dismutase (SOD) activity, malondialdehyde (MDA), and reactive oxygen species (ROS) assays, replicative lifespans of sod1, sod2, uth1, and skn7 yeast mutants, and real-time quantitative PCR (RT-PCR) analysis were conducted. The significant increase of cell survival rate in oxidative stress condition was observed in parishin-treated groups. Silent information regulator 2 (Sir2) gene expression and SOD activity were significantly increased after treating parishin in normal condition. Meanwhile, the levels of ROS and MDA in yeast were significantly decreased. The replicative lifespans of sod1, sod2, uth1, and skn7 mutants of K6001 yeast were not affected by parishin. We also found that parishin could decrease the gene expression of TORC1, ribosomal protein S26A (RPS26A), and ribosomal protein L9A (RPL9A) in the target of rapamycin (TOR) signaling pathway. Gene expression levels of RPS26A and RPL9A in uth1, as well as in uth1, sir2 double mutants, were significantly lower than those of the control group. Besides, TORC1 gene expression in uth1 mutant of K6001 yeast was inhibited significantly. These results suggested that parishin exhibited antiaging effects via regulation of Sir2/Uth1/TOR signaling pathway. PMID:27429709

  20. Parishin from Gastrodia elata Extends the Lifespan of Yeast via Regulation of Sir2/Uth1/TOR Signaling Pathway.

    PubMed

    Lin, Yanfei; Sun, Yujuan; Weng, Yufang; Matsuura, Akira; Xiang, Lan; Qi, Jianhua

    2016-01-01

    Parishin is a phenolic glucoside isolated from Gastrodia elata, which is an important traditional Chinese medicine; this glucoside significantly extended the replicative lifespan of K6001 yeast at 3, 10, and 30 μM. To clarify its mechanism of action, assessment of oxidative stress resistance, superoxide dismutase (SOD) activity, malondialdehyde (MDA), and reactive oxygen species (ROS) assays, replicative lifespans of sod1, sod2, uth1, and skn7 yeast mutants, and real-time quantitative PCR (RT-PCR) analysis were conducted. The significant increase of cell survival rate in oxidative stress condition was observed in parishin-treated groups. Silent information regulator 2 (Sir2) gene expression and SOD activity were significantly increased after treating parishin in normal condition. Meanwhile, the levels of ROS and MDA in yeast were significantly decreased. The replicative lifespans of sod1, sod2, uth1, and skn7 mutants of K6001 yeast were not affected by parishin. We also found that parishin could decrease the gene expression of TORC1, ribosomal protein S26A (RPS26A), and ribosomal protein L9A (RPL9A) in the target of rapamycin (TOR) signaling pathway. Gene expression levels of RPS26A and RPL9A in uth1, as well as in uth1, sir2 double mutants, were significantly lower than those of the control group. Besides, TORC1 gene expression in uth1 mutant of K6001 yeast was inhibited significantly. These results suggested that parishin exhibited antiaging effects via regulation of Sir2/Uth1/TOR signaling pathway. PMID:27429709

  1. Analytical expressions for the gate utilization factors of passive multiplicity counters including signal build-up

    SciTech Connect

    Croft, Stephen; Evans, Louise G; Schear, Melissa A

    2010-01-01

    In the realm of nuclear safeguards, passive neutron multiplicity counting using shift register pulse train analysis to nondestructively quantify Pu in product materials is a familiar and widely applied technique. The approach most commonly taken is to construct a neutron detector consisting of {sup 3}He filled cylindrical proportional counters embedded in a high density polyethylene moderator. Fast neutrons from the item enter the moderator and are quickly slowed down, on timescales of the order of 1-2 {micro}s, creating a thermal population which then persists typically for several 10's {micro}s and is sampled by the {sup 3}He detectors. Because the initial transient is of comparatively short duration it has been traditional to treat it as instantaneous and furthermore to approximate the subsequent capture time distribution as exponential in shape. With these approximations simple expressions for the various Gate Utilization Factors (GUFs) can be obtained. These factors represent the proportion of time correlated events i.e. Doubles and Triples signal present in the pulse train that is detected by the coincidence gate structure chosen (predelay and gate width settings of the multiplicity shift register). More complicated expressions can be derived by generalizing the capture time distribution to multiple time components or harmonics typically present in real systems. When it comes to applying passive neutron multiplicity methods to extremely intense (i.e. high emission rate and highly multiplying) neutron sources there is a drive to use detector types with very fast response characteristics in order to cope with the high rates. In addition to short pulse width, detectors with a short capture time profile are also desirable so that a short coincidence gate width can be set in order to reduce the chance or Accidental coincidence signal. In extreme cases, such as might be realized using boron loaded scintillators, the dieaway time may be so short that the build

  2. Multiple Shh signaling centers participate in fungiform papilla and taste bud formation and maintenance

    PubMed Central

    Liu, H-X; Ermilov, A; Grachtchouk, M; Li, L; Gumucio, DL; Dlugosz, AA; Mistretta, CM

    2014-01-01

    The adult fungiform taste papilla is a complex of specialized cell types residing in the stratified squamous tongue epithelium. This unique sensory organ includes taste buds, papilla epithelium and lateral walls that extend into underlying connective tissue to surround a core of lamina propria cells. Fungiform papillae must contain long-lived, sustaining or stem cells and short-lived, maintaining or transit amplifying cells that support the papilla and specialized taste buds. Shh signaling has established roles in supporting fungiform induction, development and patterning. However, for a full understanding of how Shh transduced signals act in tongue, papilla and taste bud formation and maintenance, it is necessary to know where and when the Shh ligand and pathway components are positioned. We used immunostaining, in situ hybridization and mouse reporter strains for Shh, Ptch1, Gli1 and Gli2-expression and proliferation markers to identify cells that participate in hedgehog signaling. Whereas there is a progressive restriction in location of Shh ligand-expressing cells, from placode and apical papilla cells to taste bud cells only, a surrounding population of Ptch1 and Gli1 responding cells is maintained in signaling centers throughout papilla and taste bud development and differentiation. The Shh signaling targets are in regions of active cell proliferation. Using genetic-inducible lineage tracing for Gli1-expression, we found that Shh-responding cells contribute not only to maintenance of filiform and fungiform papillae, but also to taste buds. A requirement for normal Shh signaling in fungiform papilla, taste bud and filiform papilla maintenance was shown by Gli2 constitutive activation. We identified proliferation niches where Shh signaling is active and suggest that epithelial and mesenchymal compartments harbor potential stem and/or progenitor cell zones. In all, we report a set of hedgehog signaling centers that regulate development and maintenance of taste

  3. Which is the best intrinsic motivation signal for learning multiple skills?

    PubMed

    Santucci, Vieri G; Baldassarre, Gianluca; Mirolli, Marco

    2013-01-01

    Humans and other biological agents are able to autonomously learn and cache different skills in the absence of any biological pressure or any assigned task. In this respect, Intrinsic Motivations (i.e., motivations not connected to reward-related stimuli) play a cardinal role in animal learning, and can be considered as a fundamental tool for developing more autonomous and more adaptive artificial agents. In this work, we provide an exhaustive analysis of a scarcely investigated problem: which kind of IM reinforcement signal is the most suitable for driving the acquisition of multiple skills in the shortest time? To this purpose we implemented an artificial agent with a hierarchical architecture that allows to learn and cache different skills. We tested the system in a setup with continuous states and actions, in particular, with a kinematic robotic arm that has to learn different reaching tasks. We compare the results of different versions of the system driven by several different intrinsic motivation signals. The results show (a) that intrinsic reinforcements purely based on the knowledge of the system are not appropriate to guide the acquisition of multiple skills, and (b) that the stronger the link between the IM signal and the competence of the system, the better the performance. PMID:24273511

  4. 2D wax-printed paper substrates with extended solvent supply capabilities allow enhanced ion signal in paper spray ionization.

    PubMed

    Damon, Deidre E; Maher, Yosef S; Yin, Mengzhen; Jjunju, Fred P M; Young, Iain S; Taylor, Stephen; Maher, Simon; Badu-Tawiah, Abraham K

    2016-06-21

    Paper-based microfluidic channels were created from solid wax printing, and the resultant 2D wax-printed paper substrates were used for paper spray (PS) mass spectrometry (MS) analysis of small organic compounds. Controlling fluid flow at the tip of the wax-printed paper triangles enabled the use of lower spray voltages (0.5-1 kV) and extended signal lifetime (10 minutes) in PS-MS. High sensitivity (sub ng mL(-1) levels) and quantitation precision (<10% RSD) have been achieved in the analysis of illicit drugs in 4 μL of raw urine (fresh and dry), as well as corrosion inhibitors and pesticides in water samples. The reported study encourages the future development of disposable 3D microfluidic paper-based analytical devices, which function with simple operation but capable of on-chip analyte detection by MS; such a device can replace the traditional complex laboratory procedures for MS analysis to enable on-site in situ sampling with portable mass spectrometers. PMID:27121269

  5. Targeting Apoptosis and Multiple Signaling Pathways with Icariside II in Cancer Cells

    PubMed Central

    Khan, Muhammad; Maryam, Amara; Qazi, Javed Iqbal; Ma, Tonghui

    2015-01-01

    Cancer is the second leading cause of deaths worldwide. Despite concerted efforts to improve the current therapies, the prognosis of cancer remains dismal. Highly selective or specific blocking of only one of the signaling pathways has been associated with limited or sporadic responses. Using targeted agents to inhibit multiple signaling pathways has emerged as a new paradigm for anticancer treatment. Icariside II, a flavonol glycoside, is one of the major components of Traditional Chinese Medicine Herba epimedii and possesses multiple biological and pharmacological properties including anti-inflammatory, anti-osteoporosis, anti-oxidant, anti-aging, and anticancer activities. Recently, the anticancer activity of Icariside II has been extensively investigated. Here, in this review, our aim is to give our perspective on the current status of Icariside II, and discuss its natural sources, anticancer activity, molecular targets and the mechanisms of action with specific emphasis on apoptosis pathways which may help the further design and conduct of preclinical and clinical trials. Icariside II has been found to induce apoptosis in various human cancer cell lines of different origin by targeting multiple signaling pathways including STAT3, PI3K/AKT, MAPK/ERK, COX-2/PGE2 and β-Catenin which are frequently deregulated in cancers, suggesting that this collective activity rather than just a single effect may play an important role in developing Icariside II into a potential lead compound for anticancer therapy. This review suggests that Icariside II provides a novel opportunity for treatment of cancers, but additional investigations and clinical trials are still required to fully understand the mechanism of therapeutic effects to further validate it in anti-tumor therapy. PMID:26221076

  6. Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways.

    PubMed

    Basu, Srijani; Kaw, Sheetal; D'Souza, Lucas; Vaidya, Tushar; Bal, Vineeta; Rath, Satyajit; George, Anna

    2016-08-01

    CD40 signaling during B cell activation is known to inhibit terminal differentiation and promote memory generation. Blimp-1 is essential for efficient plasma cell (PC) generation, and although CD40 signaling is known to inhibit Blimp-1 induction during B cell activation, the mechanisms involved have been unclear. We report that CD40 signaling induces miR-125b that targets Blimp-1 transcripts, and increases amounts of the ubiquitin ligase Hrd1 that targets BLIMP-1 protein for proteasomal degradation. CD40 signaling also inhibits the early unfolded protein response (UPR) of activated B cells that precedes the induction of terminal differentiation, and Hrd1 feeds into this pathway by targeting the core UPR component IRE-1α. Strikingly, CD40 signaling in the absence of BCR- or TLR-ligation also repressed Blimp-1 transcripts, suggesting that noncognate ligation of CD40 via T-B interactions may repress Blimp-1 in vivo. In support of this, we find that naive B cells purified from CD40-CD154 interaction-deficient mice express higher amounts of Blimp-1 and lower amounts of microRNAs and Hrd1. Higher basal amounts of Blimp-1 in naive CD40(-/-) B cells correlate with an increased tendency of the cells to undergo terminal differentiation upon LPS stimulation. Conversely, a 24-h exposure to CD40 ligation during LPS stimulation of wild-type B cells is sufficient to inhibit PC generation. The data show that CD40-mediated inhibition of PC generation is via engagement of multiple pathways that involve repression of Blimp-1 and inhibition of the UPR that prepares cells to become professional secretors. They also show that constitutive CD40 signaling in vivo involving bystander T-B interactions can calibrate B cell differentiation outcomes. PMID:27342845

  7. TGF-β signaling is altered in the peripheral blood of subjects with multiple sclerosis

    PubMed Central

    Meoli, Elise M.; Oh, Unsong; Grant, Christian W.; Jacobson, Steven

    2016-01-01

    Multiple sclerosis (MS) is a central nervous system inflammatory disorder with evidence of peripheral immune dysregulation. Abnormalities of the immune suppressive cytokine TGF-β have been reported, but not fully defined, in MS. Through a pathway-focused expression profiling of the peripheral blood, we found abnormalities of TGF-βRII, SMAD4 and SMAD7 expression in subjects with MS, and reduction in the levels of TGF-β regulated genes, indicating an overall reduction in TGF-β signaling in MS. The response to exogenous TGF-β was intact, however, indicating an extrinsic defect of TGF-β signaling in MS. These results indicate that TGF-β control is diminished in MS. PMID:21093933

  8. Gigabit Ethernet signal transmission using asynchronous optical code division multiple access.

    PubMed

    Ma, Philip Y; Fok, Mable P; Shastri, Bhavin J; Wu, Ben; Prucnal, Paul R

    2015-12-15

    We propose and experimentally demonstrate a novel architecture for interfacing and transmitting a Gigabit Ethernet (GbE) signal using asynchronous incoherent optical code division multiple access (OCDMA). This is the first such asynchronous incoherent OCDMA system carrying GbE data being demonstrated to be working among multi-users where each user is operating with an independent clock/data rate and is granted random access to the network. Three major components, the GbE interface, the OCDMA transmitter, and the OCDMA receiver are discussed in detail. The performance of the system is studied and characterized through measuring eye diagrams, bit-error rate and packet loss rate in real-time file transfer. Our Letter also addresses the near-far problem and realizes asynchronous transmission and detection of signal. PMID:26670529

  9. A different approach to use narrowband super-resolution multiple signal classification algorithm on wideband sources.

    PubMed

    Asgari, Mohammad; Soltani, Nasim Yahya; Riahi, Ali

    2010-01-01

    There are varieties of wideband direction-of-arrival (DOA) estimation algorithms. Their structure comprises a number of narrowband ones, each performs in one frequency in a given bandwidth, and then different responses should be combined in a proper way to yield true DOAs. Hence, wideband algorithms are always complex and so non-real-time. This paper investigates a method to derive a flat response of narrowband multiple signal classification (MUSIC) [R. O. Schmidt, IEEE Trans. Antennas Propag., 34, 276-280 (1986)] algorithm in the whole frequencies of given band. Therefore, required conditions of applying narrowband algorithm on wideband impinging signals will be given through a concrete analysis. It could be found out that array sensor locations are able to compensate the frequency variations to reach a flat response of DOAs in a specified wideband frequency. PMID:20058975

  10. Multidimensional signal exploration using multiple correspondence analysis. An example of a load lifting study.

    PubMed

    Loslever, Pierre; Bouilland, Stéphane

    2003-09-01

    Most empirical studies concerning rehabilitation yield numerous multidimensional signals (dozens of time variables are obtained for dozens of empirical situations). The purpose of this paper is to suggest a statistical analysis procedure based on: 1) space-time fuzzy windowing; 2) signal behavior characterization within the windows using membership value averages (MVA); and 3) MVA analysis using the multiple correspondence analysis (MCA). A load lifting study provided an example of 78 multidimensional signals including 89 time variables (forces, energy indicators, linear and angular positions, speeds, and accelerations). The main goal of MCA was to compare and contrast biomechanical signals from two lifting modes: "free" and "isokinetic." In the first mode, three loads were tested--light, medium, and heavy. In the second, three speeds were tested--slow, medium, and fast. Thirteen male individuals without disabilities participated in this study. The MCA showed that most of the free load-lifting strategies cannot be used in isokinetic lifting because the constraints of the subject and the environment are different. In addition, as the level of difficulty increases, free lifting became more economical while isokinetic lifting became less economical. These results would appear to indicate that movement strategies used for free lifting cannot be learned using an isokinetic machine during rehabilitation sessions for chronic low back pain. MCA was also suggested as a tool for comparing patients with control individuals. To achieve this aim, the notion of "supplementary data" was introduced. PMID:14518795

  11. FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling

    PubMed Central

    Zhou, Siru; Xie, Yangli; Tang, Junzhou; Huang, Junlan; Huang, Qizhao; Xu, Wei; Wang, Zuqiang; Luo, Fengtao; Wang, Quan; Chen, Hangang; Du, Xiaolan; Shen, Yue; Chen, Di; Chen, Lin

    2015-01-01

    Most cartilaginous tumors are formed during skeletal development in locations adjacent to growth plates, suggesting that they arise from disordered endochondral bone growth. Fibroblast growth factor receptor (FGFR)3 signaling plays essential roles in this process; however, the role of FGFR3 in cartilaginous tumorigenesis is not known. In this study, we found that postnatal chondrocyte-specific Fgfr3 deletion induced multiple chondroma-like lesions, including enchondromas and osteochondromas, adjacent to disordered growth plates. The lesions showed decreased extracellular signal-regulated kinase (ERK) activity and increased Indian hedgehog (IHH) expression. The same was observed in Fgfr3-deficient primary chondrocytes, in which treatment with a mitogen-activated protein kinase (MEK) inhibitor increased Ihh expression. Importantly, treatment with an inhibitor of IHH signaling reduced the occurrence of chondroma-like lesions in Fgfr3-deficient mice. This is the first study reporting that the loss of Fgfr3 function leads to the formation of chondroma-like lesions via downregulation of MEK/ERK signaling and upregulation of IHH, suggesting that FGFR3 has a tumor suppressor-like function in chondrogenesis. PMID:26091072

  12. Environmental signals elicit multiple responses in dorsal telencephalic progenitors by threshold-dependent mechanisms.

    PubMed

    Lillien, Laura; Gulacsi, Alexandra

    2006-07-01

    Environmental signals including epidermal growth factor family members, Shh, fibroblast growth factor, and bone morphogenetic protein (BMP) can affect multiple processes during the development of the central nervous system, raising questions about the mechanisms that determine how these pleiotropic signals are interpreted to elicit appropriate responses at specific times and locations. Here we address the idea that different thresholds of stimulation determine how progenitors in the dorsal telencephalon interpret these signals. One mechanism for achieving different thresholds of signaling is illustrated by the developmental increase in the level of epidermal growth factor receptor (EGFR) expression among a subset of progenitors in the late embryonic telencephalon. Another mechanism is illustrated by the antagonistic interaction of BMP with Shh, which can influence EGFR expression and neuron subtype choice. We focus on the similarities and differences in the control of these responses and address the possibility that the gamma-aminobutyric acidergic neuron specification might be linked to progenitor expression of a higher level of EGFRs. PMID:16766711

  13. Implementation of linear sensory signaling via multiple coordinated mechanisms at central vestibular nerve synapses

    PubMed Central

    McElvain, Lauren E.; Faulstich, Michael; Jeanne, James M.; Moore, Jeffrey D.; du Lac, Sascha

    2015-01-01

    Summary Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate-coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations. PMID:25704949

  14. Multiple functionally redundant signals mediate targeting to the apicoplast in the apicomplexan parasite Toxoplasma gondii.

    PubMed

    Harb, Omar S; Chatterjee, Bithi; Fraunholz, Martin J; Crawford, Michael J; Nishi, Manami; Roos, David S

    2004-06-01

    Most species of the protozoan phylum Apicomplexa harbor an endosymbiotic organelle--the apicoplast--acquired when an ancestral parasite engulfed a eukaryotic plastid-containing alga. Several hundred proteins are encoded in the parasite nucleus and are posttranslationally targeted to the apicoplast by a distinctive bipartite signal. The N-terminal 20 to 30 amino acids of nucleus-encoded apicoplast targeted proteins function as a classical signal sequence, mediating entry into the secretory pathway. Cleavage of the signal sequence exposes a transit peptide of variable length (50 to 200 amino acids) that is required for directing proteins to the apicoplast. Although these peptides are enriched in basic amino acids, their structural and functional characteristics are not well understood, which hampers the identification of apicoplast proteins that may constitute novel chemotherapeutic targets. To identify functional domains for a model apicoplast transit peptide, we generated more than 80 deletions and mutations throughout the transit peptide of Toxoplasma gondii ferredoxin NADP+ reductase (TgFNR) and examined the ability of these altered transit peptides to mediate proper targeting and processing of a fluorescent protein reporter. These studies revealed the presence of numerous functional domains. Processing can take place at multiple sites in the protein sequence and may occur outside of the apicoplast lumen. The TgFNR transit peptide contains at least two independent and functionally redundant targeting signals, each of which contains a subdomain that is required for release from or proper sorting within the endoplasmic reticulum. Certain deletion constructs traffic to multiple locations, including the apicoplast periphery, the rhoptries, and the parasitophorous vacuole, suggesting a common thread for targeting to these specialized compartments. PMID:15189987

  15. Extended Analysis of a Genome-Wide Association Study in Primary Sclerosing Cholangitis Detects Multiple Novel Risk Loci

    PubMed Central

    Folseraas, Trine; Melum, Espen; Rausch, Philipp; Juran, Brian D.; Ellinghaus, Eva; Shiryaev, Alexey; Laerdahl, Jon K.; Ellinghaus, David; Schramm, Christoph; Weismüller, Tobias J.; Gotthardt, Daniel Nils; Hov, Johannes Roksund; Clausen, Ole Petter; Weersma, Rinse K.; Janse, Marcel; Boberg, Kirsten Muri; Björnsson, Einar; Marschall, Hanns-Ulrich; Cleynen, Isabelle; Rosenstiel, Philip; Holm, Kristian; Teufel, Andreas; Rust, Christian; Gieger, Christian; Wichmann, H-Erich; Bergquist, Annika; Ryu, Euijung; Ponsioen, Cyriel Y.; Runz, Heiko; Sterneck, Martina; Vermeire, Severine; Beuers, Ulrich; Wijmenga, Cisca; Schrumpf, Erik; Manns, Michael P.; Lazaridis, Konstantinos N.; Schreiber, Stefan; Baines, John F.; Franke, Andre; Karlsen, Tom H.

    2012-01-01

    Background & Aims A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (Preplication<0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; Pcombined=2.1×10−8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (Prepl<0.05). FUT2 at chromosome 19q13 (rs602662; Pcomb=1.9×10−6, rs281377; Pcomb = 2.1×10−6 and rs601338; Pcomb=2.7×10−6) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influences biliary microbial community composition in PSC patients. Conclusions We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence from microbiota on biliary pathology in PSC. PMID:22521342

  16. A Randomized Crossover Trial of Dalfampridine Extended Release for Effect on Ambulatory Activity in People with Multiple Sclerosis

    PubMed Central

    Simnad, Virginia I.

    2016-01-01

    Background: Dalfampridine extended release (D-ER) is indicated to improve walking in people with multiple sclerosis (MS) as demonstrated by an increase in walking speed. This study assessed the effects of D-ER on accelerometer-based measures in people with MS, including intensity of walking and total amount of walking during daily activities. Methods: In this double-blind placebo-controlled crossover study, people with MS-related walking difficulty were randomized (1:1) to receive 4 weeks of D-ER 10 mg twice daily and 4 weeks of placebo in either order separated by a 2-week washout. Participants wore accelerometers for 7 days at baseline and week 3 of each on-drug period. The primary outcome was the peak activity index (PAI), defined as the most intense 30 individual minutes of the day (strides per minute). Secondary outcomes included daily step count, 6-Minute Walk Test (6MWT), Timed Up and Go (TUG) test, and patient-reported outcomes. A mixed-effects repeated-measures statistical model was used. Results: Forty-three participants were randomized (mean Expanded Disability Status Scale score, 5.17). Least squares mean (standard error) change from baseline on the PAI was 0.6 (0.54) strides/min on D-ER and 0.3 (0.55) strides/min on placebo and in daily step count was 148.7 (222.4) on D-ER and 128.0 (225.4) on placebo. Other accelerometer-based measures and the 6MWT showed no significant differences between D-ER and placebo. The TUG test (P = .042) favored D-ER. There were no serious adverse events. Conclusions: Dalfampridine did not show an effect on accelerometer-measured ambulatory activity in people with MS-related walking difficulty. More work is needed to confirm these results. PMID:27551241

  17. Multiple target tracking and classification improvement using data fusion at node level using acoustic signals

    NASA Astrophysics Data System (ADS)

    Damarla, T. R.; Whipps, Gene

    2005-05-01

    Target tracking and classification using passive acoustic signals is difficult at best as the signals are contaminated by wind noise, multi-path effects, road conditions, and are generally not deterministic. In addition, microphone characteristics, such as sensitivity, vary with the weather conditions. The problem is further compounded if there are multiple targets, especially if some are measured with higher signal-to-noise ratios (SNRs) than the others and they share spectral information. At the U. S. Army Research Laboratory we have conducted several field experiments with a convoy of two, three, four and five vehicles traveling on different road surfaces, namely gravel, asphalt, and dirt roads. The largest convoy is comprised of two tracked vehicles and three wheeled vehicles. Two of the wheeled vehicles are heavy trucks and one is a light vehicle. We used a super-resolution direction-of-arrival estimator, specifically the minimum variance distortionless response, to compute the bearings of the targets. In order to classify the targets, we modeled the acoustic signals emanated from the targets as a set of coupled harmonics, which are related to the engine-firing rate, and subsequently used a multivariate Gaussian classifier. Independent of the classifier, we find tracking of wheeled vehicles to be intermittent as the signals from vehicles with high SNR dominate the much quieter wheeled vehicles. We used several fusion techniques to combine tracking and classification results to improve final tracking and classification estimates. We will present the improvements (or losses) made in tracking and classification of all targets. Although improvements in the estimates for tracked vehicles are not noteworthy, significant improvements are seen in the case of wheeled vehicles. We will present the fusion algorithm used.

  18. Epithelial SCAP/INSIG/SREBP Signaling Regulates Multiple Biological Processes during Perinatal Lung Maturation

    PubMed Central

    Bridges, James P.; Schehr, Angelica; Wang, Yanhua; Huo, Liya; Besnard, Valérie; Ikegami, Machiko; Whitsett, Jeffrey A.; Xu, Yan

    2014-01-01

    Pulmonary surfactant is required for lung function at birth and throughout postnatal life. Defects in the surfactant system are associated with common pulmonary disorders including neonatal respiratory distress syndrome and acute respiratory distress syndrome in children and adults. Lipogenesis is essential for the synthesis of pulmonary surfactant by type II epithelial cells lining the alveoli. This study sought to identify the role of pulmonary epithelial SREBP, a transcriptional regulator of cellular lipid homeostasis, during a critical time period of perinatal lung maturation in the mouse. Genome wide mRNA expression profiling of lung tissue from transgenic mice with epithelial-specific deletions of Scap (ScapΔ/Δ, resulting in inactivation of SREBP signaling) or Insig1 and Insig2 (Insig1/2Δ/Δ, resulting in activation of SREBP signaling) was assessed. Differentially expressed genes responding to SREBP perturbations were identified and subjected to functional enrichment analysis, pathway mapping and literature mining to predict upstream regulators and transcriptional networks regulating surfactant lipid homeostasis. Through comprehensive data analysis and integration, time dependent effects of epithelial SCAP/INSIG/SREBP deletion and defined SCAP/INSIG/SREBP-associated genes, bioprocesses and downstream pathways were identified. SREBP signaling influences epithelial development, cell death and cell proliferation at E17.5, while primarily influencing surfactant physiology, lipid/sterol synthesis, and phospholipid transport after birth. SREBP signaling integrated with the Wnt/β-catenin and glucocorticoid receptor signaling pathways during perinatal lung maturation. SREBP regulates perinatal lung lipogenesis and maturation through multiple mechanisms by interactions with distinct sets of regulatory partners. PMID:24806461

  19. Carotenoid-based bill colour is an integrative signal of multiple parasite infection in blackbird

    NASA Astrophysics Data System (ADS)

    Biard, Clotilde; Saulnier, Nicolas; Gaillard, Maria; Moreau, Jérôme

    2010-11-01

    In the study of parasite-mediated sexual selection, there has been controversial evidence for the prediction that brighter males should have fewer parasites. Most of these studies have focused on one parasite species. Our aim was to investigate the expression of carotenoid-based coloured signals in relation to patterns of multiple parasite infections, to determine whether colour reflects parasite load of all parasite species, or whether different relationships might be found when looking at each parasite species independently. We investigated the relationship between bill colour, body mass and plasma carotenoids and parasite load (feather chewing lice, blood parasite Plasmodium sp., intestinal parasites cestodes and coccidia) in the blackbird ( Turdus merula). Bill colour on its own appeared to be a poor predictor of parasite load when investigating its relationships with individual parasite species. Variation in parasite intensities at the community level was summarised using principal component analysis to derive synthetic indexes of relative parasite species abundance and absolute parasite load. The relative abundance of parasite species was strongly related to bill colour, plasma carotenoid levels and body mass: birds with relatively more cestodes and chewing lice and relatively less Plasmodium and coccidia had a more colourful bill, circulated more carotenoids and were heavier. These results suggest that bill colour more accurately reflects the relative intensities of parasite infection, rather than one-by-one relationships with parasites or absolute parasite burden. Investigating patterns of multiple parasite infection would thus improve our understanding of the information conveyed by coloured signals on parasite load.

  20. Asymmetric signal amplification for simultaneous SERS detection of multiple cancer markers with significantly different levels.

    PubMed

    Ye, Sujuan; Wu, Yanying; Zhai, Xiaomo; Tang, Bo

    2015-08-18

    Simultaneous detection of cancer biomarkers holds great promise for the early diagnosis of different cancers. However, in the presence of high-concentration biomarkers, the signals of lower-expression biomarkers are overlapped. Existing techniques are not suitable for simultaneously detecting multiple biomarkers at concentrations with significantly different orders of magnitude. Here, we propose an asymmetric signal amplification method for simultaneously detecting multiple biomarkers with significantly different levels. Using the bifunctional probe, a linear amplification mode responds to high-concentration markers, and quadratic amplification mode responds to low-concentration markers. With the combined biobarcode probe and hybridization chain reaction (HCR) amplification method, the detection limits of microRNA (miRNA) and ATP via surface-enhanced Raman scattering (SERS) detection are 0.15 fM and 20 nM, respectively, with a breakthrough of detection concentration difference over 11 orders of magnitude. Furthermore, successful determination of miRNA and ATP in cancer cells supports the practicability of the assay. This methodology promises to open an exciting new avenue for the detection of various types of biomolecules. PMID:26218034

  1. Incident signal power comparison for localization of concurrent multiple acoustic sources.

    PubMed

    Salvati, Daniele; Canazza, Sergio

    2014-01-01

    In this paper, a method to solve the localization of concurrent multiple acoustic sources in large open spaces is presented. The problem of the multisource localization in far-field conditions is to correctly associate the direction of arrival (DOA) estimated by a network array system to the same source. The use of systems implementing a Bayesian filter is a traditional approach to address the problem of localization in multisource acoustic scenario. However, in a real noisy open space the acoustic sources are often discontinuous with numerous short-duration events and thus the filtering methods may have difficulty to track the multiple sources. Incident signal power comparison (ISPC) is proposed to compute DOAs association. ISPC is based on identifying the incident signal power (ISP) of the sources on a microphone array using beamforming methods and comparing the ISP between different arrays using spectral distance (SD) measurement techniques. This method solves the ambiguities, due to the presence of simultaneous sources, by identifying sounds through a minimization of an error criterion on SD measures of DOA combinations. The experimental results were conducted in an outdoor real noisy environment and the ISPC performance is reported using different beamforming techniques and SD functions. PMID:24701179

  2. Incident Signal Power Comparison for Localization of Concurrent Multiple Acoustic Sources

    PubMed Central

    2014-01-01

    In this paper, a method to solve the localization of concurrent multiple acoustic sources in large open spaces is presented. The problem of the multisource localization in far-field conditions is to correctly associate the direction of arrival (DOA) estimated by a network array system to the same source. The use of systems implementing a Bayesian filter is a traditional approach to address the problem of localization in multisource acoustic scenario. However, in a real noisy open space the acoustic sources are often discontinuous with numerous short-duration events and thus the filtering methods may have difficulty to track the multiple sources. Incident signal power comparison (ISPC) is proposed to compute DOAs association. ISPC is based on identifying the incident signal power (ISP) of the sources on a microphone array using beamforming methods and comparing the ISP between different arrays using spectral distance (SD) measurement techniques. This method solves the ambiguities, due to the presence of simultaneous sources, by identifying sounds through a minimization of an error criterion on SD measures of DOA combinations. The experimental results were conducted in an outdoor real noisy environment and the ISPC performance is reported using different beamforming techniques and SD functions. PMID:24701179

  3. Andrographolide inhibits multiple myeloma cells by inhibiting the TLR4/NF-κB signaling pathway.

    PubMed

    Gao, Hui; Wang, Jianrong

    2016-02-01

    Andrographolide is an active component from the extract of Andrographis paniculata [(Burm.f) Nees], a medicinal plant from the Acanthaceae family. Pharmacological studies have revealed that andrographolide possesses anti-bacterial, anti-inflammatory, anti-viral, immune regulatory and hepatoprotective properties, and is efficacious in the treatment of cardiovascular diseases, while exhibiting low toxicity and low cost. The present study aimed to determine the inhibitory effects of andrographolide on the growth of multiple myeloma (MM) cells and its possible impact on the Toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling pathway. Cell proliferation was detected using an MTT assay, cellular apoptosis was measured using flow cytometry, and caspase-9/3 activation were assessed using colorimetric assay kits. Furthermore, TLR4 and NF-κB protein expression was determined by western blot analysis. The results revealed that andrographolide reduced the proliferation, while increasing cellular apoptosis and caspase-9/3 activation of MM cells, in addition to downregulating the expression of TLR4 and NF-κB protein. Of note, TLR4- or NF-κB-targeting small-interfering (si)RNA enhanced the andrographolide-induced inhibition of cell proliferation and induction of apoptosis of MM cells. The results of the present study therefore suggested that andrographolide inhibited multiple myeloma cells via the TLR4/NF-κB signaling pathway. PMID:26707811

  4. Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

    PubMed Central

    Ren, Fangfang; Shi, Qing; Chen, Yongbin; Jiang, Alice; Ip, Y Tony; Jiang, Huaqi; Jiang, Jin

    2013-01-01

    Intestinal stem cells (ISCs) in the Drosophila adult midgut are essential for maintaining tissue homeostasis, and their proliferation and differentiation speed up in order to meet the demand for replenishing the lost cells in response to injury. Several signaling pathways including JAK-STAT, EGFR and Hippo (Hpo) pathways have been implicated in damage-induced ISC proliferation, but the mechanisms that integrate these pathways have remained elusive. Here, we demonstrate that the Drosophila homolog of the oncoprotein Myc (dMyc) functions downstream of these signaling pathways to mediate their effects on ISC proliferation. dMyc expression in precursor cells is stimulated in response to tissue damage, and dMyc is essential for accelerated ISC proliferation and midgut regeneration. We show that tissue damage caused by dextran sulfate sodium feeding stimulates dMyc expression via the Hpo pathway, whereas bleomycin feeding activates dMyc through the JAK-STAT and EGFR pathways. We provide evidence that dMyc expression is transcriptionally upregulated by multiple signaling pathways, which is required for optimal ISC proliferation in response to tissue damage. We have also obtained evidence that tissue damage can upregulate dMyc expression post-transcriptionally. Finally, we show that a basal level of dMyc expression is required for ISC maintenance, proliferation and lineage differentiation during normal tissue homeostasis. PMID:23896988

  5. Multiple signals modulate the activity of the complex sensor kinase TodS

    PubMed Central

    Silva-Jiménez, Hortencia; Ortega, Álvaro; García-Fontana, Cristina; Ramos, Juan Luis; Krell, Tino

    2015-01-01

    The reason for the existence of complex sensor kinases is little understood but thought to lie in the capacity to respond to multiple signals. The complex, seven-domain sensor kinase TodS controls in concert with the TodT response regulator the expression of the toluene dioxygenase pathway in Pseudomonas putida F1 and DOT-T1E. We have previously shown that some aromatic hydrocarbons stimulate TodS activity whereas others behave as antagonists. We show here that TodS responds in addition to the oxidative agent menadione. Menadione but no other oxidative agent tested inhibited TodS activity in vitro and reduced PtodX expression in vivo. The menadione signal is incorporated by a cysteine-dependent mechanism. The mutation of the sole conserved cysteine of TodS (C320) rendered the protein insensitive to menadione. We evaluated the mutual opposing effects of toluene and menadione on TodS autophosphorylation. In the presence of toluene, menadione reduced TodS activity whereas toluene did not stimulate activity in the presence of menadione. It was shown by others that menadione increases expression of glucose metabolism genes. The opposing effects of menadione on glucose and toluene metabolism may be partially responsible for the interwoven regulation of both catabolic pathways. This work provides mechanistic detail on how complex sensor kinases integrate different types of signal molecules. PMID:24986263

  6. Activation of multiple signaling modules is critical in angiotensin IV-induced lung endothelial cell proliferation.

    PubMed

    Li, Yong D; Block, Edward R; Patel, Jawaharlal M

    2002-10-01

    Signaling events involving angiotensin IV (ANG IV)-mediated pulmonary artery endothelial cell (PAEC) proliferation were examined. ANG IV significantly increased upstream phosphatidylinositide (PI) 3-kinase (PI3K), PI-dependent kinase-1 (PDK-1), extracellular signal-related kinases (ERK1/2), and protein kinase B-alpha/Akt (PKB-alpha) activities, as well as downstream p70 ribosomal S6 kinase (p70S6K) activities and/or phosphorylation of these proteins. ANG IV also significantly increased 5-bromo-2'-deoxy-uridine incorporation into newly synthesized DNA in a concentration- and time-dependent manner. Pretreatment of cells with wortmannin and LY-294002, inhibitors of PI3K, or rapamycin, an inhibitor of the mammalian target of rapamycin kinase and p70S6K, diminished the ANG IV-mediated activation of PDK-1 and PKB-alpha as well as phosphorylation of p70S6K. Although an inhibitor of mitogen-activated protein kinase kinase, PD-98059, but not rapamycin, blocked ANG IV-induced phosphorylation of ERK1/2, both PD-98059 and rapamycin independently caused partial reduction in ANG IV-mediated cell proliferation. However, simultaneous treatment with PD-98059 and rapamycin resulted in total inhibition of ANG IV-induced cell proliferation. These results demonstrate that ANG IV-induced DNA synthesis is regulated in a coordinated fashion involving multiple signaling modules in PAEC. PMID:12225947

  7. Simultaneous Reconstruction of Multiple Signaling Pathways via the Prize-Collecting Steiner Forest Problem

    PubMed Central

    Tuncbag, Nurcan; Braunstein, Alfredo; Pagnani, Andrea; Huang, Shao-Shan Carol; Chayes, Jennifer; Borgs, Christian; Zecchina, Riccardo

    2013-01-01

    Abstract Signaling and regulatory networks are essential for cells to control processes such as growth, differentiation, and response to stimuli. Although many “omic” data sources are available to probe signaling pathways, these data are typically sparse and noisy. Thus, it has been difficult to use these data to discover the cause of the diseases and to propose new therapeutic strategies. We overcome these problems and use “omic” data to reconstruct simultaneously multiple pathways that are altered in a particular condition by solving the prize-collecting Steiner forest problem. To evaluate this approach, we use the well-characterized yeast pheromone response. We then apply the method to human glioblastoma data, searching for a forest of trees, each of which is rooted in a different cell-surface receptor. This approach discovers both overlapping and independent signaling pathways that are enriched in functionally and clinically relevant proteins, which could provide the basis for new therapeutic strategies. Although the algorithm was not provided with any information about the phosphorylation status of receptors, it identifies a small set of clinically relevant receptors among hundreds present in the interactome. PMID:23383998

  8. Inhibition of CXCR2 signaling promotes recovery in models of Multiple Sclerosis

    PubMed Central

    Kerstetter, AE; Padovani-Claudio, DA; Bai, L; Miller, RH

    2009-01-01

    Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination/remyelination episodes that ultimately fail. Chemokines and their receptors have been implicated in both myelination and remyelination failure. Chemokines regulate migration, proliferation and differentiation of immune and neural cells during development and pathology. Previous studies have demonstrated that the absence of the chemokine receptor CXCR2 results in both disruption of early oligodendrocyte development and long term structural alterations in myelination. Histological studies suggest CXCL1, the primary ligand for CXCR2, is upregulated around the peripheral areas of demyelination suggesting this receptor/ligand combination modulates responses to injury. Here we show that in focal LPC induced demyelinating lesions, localized inhibition of CXCR2 signaling reduced lesion size and enhanced remyelination while systemic treatments were relatively less effective. Treatment of spinal cord cultures with CXCR2 antagonists reduced CXCL1 induced A2B5+ cell proliferation and increased differentiation of myelin producing cells. More critically, treatment of myelin oligodendrocyte glycoprotein peptide 35-55-induced EAE mice, an animal model of multiple sclerosis, with small molecule antagonists against CXCR2 results in increased functionality, decreased lesion load, and enhanced remyelination. Our findings demonstrate the importance of antagonizing CXCR2 in enhancing myelin repair by reducing lesion load and functionality in models of multiple sclerosis and thus provide a therapeutic target for demyelinating diseases. PMID:19616545

  9. Sensitive detection of multiple mycotoxins by SPRi with gold nanoparticles as signal amplification tags.

    PubMed

    Hu, Weihua; Chen, Hongming; Zhang, Huanhuan; He, Guangli; Li, Xin; Zhang, Xiaoxing; Liu, Yang; Li, Chang Ming

    2014-10-01

    Detection of multiple toxic mycotoxins is of importance in food quality control. Surface plasmon resonance imaging (SPRi) is an advanced tool for simultaneously multiple detections with accuracy; however, it suffers from limited sensitivity due to the instrumental constraint and small sizes of mycotoxins with only one epitope for an insensitive competitive immunoassay. In this work a gold nanoparticle (AuNP)-enhanced SPRi chip is designed to sensitively detect multiple mycotoxins using a competitive immunoassay format. The sensing surface is constructed by uniformly attaching dense mycotoxin antigens on poly[oligo(ethylene glycol) methacrylate-co-glycidyl methacrylate] (POEGMA-co-GMA) brush modified SPRi gold chip. After competitive binding in a sample solution containing respective monoclonal antibodies, secondary antibody-conjugated AuNPs are employed to bind with the captured monoclonal antibodies for further amplification of the SPRi signal. Highly specific and sensitive simultaneous detection is achieved for three typical mycotoxins including Aflatoxin B1 (AFB1), Ochratoxin A (OTA) and Zearalenone (ZEN) with low detection limits of 8, 30 and 15 pg mL(-1) and dynamic ranges covering three orders of magnitude. PMID:24992296

  10. Safety profile of dalfampridine extended release in multiple sclerosis: 5-year postmarketing experience in the United States

    PubMed Central

    Jara, Michele; Aquilina, Thomas; Aupperle, Peter; Rabinowicz, Adrian L

    2015-01-01

    Background Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine outside the US), 10 mg twice daily, was approved by the US Food and Drug Administration (FDA) in January 2010 to improve walking in people with multiple sclerosis, as determined by an increase in walking speed. Objective To provide a descriptive analysis of reported adverse events (AEs) for commercially available dalfampridine-ER from March 2010 through March 31, 2015. Methods Five-year postmarketing data for dalfampridine-ER were available from the exposure of approximately 107,000 patients in the US (103,700 patient-years). Commonly reported AEs (≥2% of all reported AEs) and serious AEs were determined. The incidence of reported seizures was determined and the events were further investigated. Results Among the 107,000 patients exposed to dalfampridine-ER (70% female; mean age 52.1), the most common AEs were dizziness (3.7%), insomnia (3.2%), balance disorder (3%), fall (2.4%), headache (2.4%), nausea (2.1%), and urinary tract infection (2%). Other common AEs were drug ineffectiveness (5.8%), gait disturbance (4.6%), and inappropriate dosing (3.1%). Serious AEs included rare anaphylactic reactions (five cases) and drug hypersensitivity reactions (eight cases). A total of 657 seizure cases were reported (6.3/1,000 patient-years); of these, 324 were medically confirmed (3.1/1,000 patient-years). Incidence of reported seizures was stable over time. Duration of treatment prior to a seizure ranged from a single dose to >4 years; 12% of the seizures occurred within a week of starting treatment. Conclusion The 5-year US postmarketing safety data of dalfampridine-ER is consistent with the safety profile observed in clinical trials. Incidence of reported seizures remained stable over time. Since commercial availability in March 2010, a warning regarding the risk of anaphylaxis and severe allergic reactions was added to the US prescribing information

  11. Treatment patterns and health care resource utilization associated with dalfampridine extended release in multiple sclerosis: a retrospective claims database analysis

    PubMed Central

    Guo, Amy; Grabner, Michael; Palli, Swetha Rao; Elder, Jessica; Sidovar, Matthew; Aupperle, Peter; Krieger, Stephen

    2016-01-01

    Background Although previous studies have demonstrated the clinical benefits of dalfampridine extended release (D-ER) tablets in patients with multiple sclerosis (MS), there are limited real-world data on D-ER utilization and associated outcomes in patients with MS. Purpose The objective of this study was to evaluate treatment patterns, budget impact, and health care resource utilization (HRU) associated with D-ER use in a real-world setting. Methods A retrospective claims database analysis was conducted using the HealthCore Integrated Research DatabaseSM. Adherence (measured by medication possession ratio, or [MPR]) and persistence (measured by days between initial D-ER claim and discontinuation or end of follow-up) were evaluated over 1-year follow-up. Budget impact was calculated as cost per member per month (PMPM) over the available follow-up period. D-ER and control cohorts were propensity-score matched on baseline demographics, comorbidities, and MS-related resource utilization to compare walking-impairment-related HRU over follow-up. Results Of the 2,138 MS patients identified, 1,200 were not treated with D-ER (control) and 938 were treated with D-ER. Patients were aged 51 years on average and 74% female. Approximately 82.6% of D-ER patients were adherent (MPR >80%). The estimated budget impact range of D-ER was $0.014–$0.026 PMPM. Propensity-score-matched D-ER and controls yielded 479 patients in each cohort. Postmatching comparison showed that the D-ER cohort was associated with fewer physician (21.5% vs 62.4%, P<0.0001) and other outpatient visits (22.8% vs 51.4%, P<0.0001) over the 12-month follow-up. Changes in HRU from follow-up to baseline were lower in the D-ER cohort for metrics including walking-impairment-related hospitalizations and emergency department visits. Conclusion The majority of D-ER patients were adherent to treatment. D-ER utilization was associated with fewer walking-impairment-related physician and outpatient visits, with lower HRU

  12. Hedgehog signaling is required at multiple stages of zebrafish tooth development

    PubMed Central

    2010-01-01

    Background The accessibility of the developing zebrafish pharyngeal dentition makes it an advantageous system in which to study many aspects of tooth development from early initiation to late morphogenesis. In mammals, hedgehog signaling is known to be essential for multiple stages of odontogenesis; however, potential roles for the pathway during initiation of tooth development or in later morphogenesis are incompletely understood. Results We have identified mRNA expression of the hedgehog ligands shha and the receptors ptc1 and ptc2 during zebrafish pharyngeal tooth development. We looked for, but did not detect, tooth germ expression of the other known zebrafish hedgehog ligands shhb, dhh, ihha, or ihhb, suggesting that as in mammals, only Shh participates in zebrafish tooth development. Supporting this idea, we found that morphological and gene expression evidence of tooth initiation is eliminated in shha mutant embryos, and that morpholino antisense oligonucleotide knockdown of shha, but not shhb, function prevents mature tooth formation. Hedgehog pathway inhibition with the antagonist compound cyclopamine affected tooth formation at each stage in which we applied it: arresting development at early stages and disrupting mature tooth morphology when applied later. These results suggest that hedgehog signaling is required continuously during odontogenesis. In contrast, over-expression of shha had no effect on the developing dentition, possibly because shha is normally extensively expressed in the zebrafish pharyngeal region. Conclusion We have identified previously unknown requirements for hedgehog signaling for early tooth initiation and later morphogenesis. The similarity of our results with data from mouse and other vertebrates suggests that despite gene duplication and changes in the location of where teeth form, the roles of hedgehog signaling in tooth development have been largely conserved during evolution. PMID:21118524

  13. Male satin bowerbirds (Ptilonorhynchus violaceus) compensate for sexual signal loss by enhancing multiple display features

    NASA Astrophysics Data System (ADS)

    Bravery, Benjamin D.; Goldizen, Anne W.

    2007-06-01

    Numerous studies have focussed on the relationship between female choice and the multiple exaggerated sexual traits of males. However, little is known about the ability of males to actively enhance specific components of their display in response to the loss of one component. We investigated the capacity of male satin bowerbirds (Ptilonorhynchus violaceus) to respond to the loss of one of their sexual signals by performing an experiment in which we removed decorations at their bowers. We found that males compensated for decoration loss by increasing bower construction behaviour and decreasing their latency to bower painting. These results are novel because they suggest that males can assess the quality of their own display and make decisions about how to augment their displays. We discuss these results in the context of previous studies of mate choice in satin bowerbirds, as both of the supplementary behaviours we observed are known correlates of male mating success.

  14. First initial community-acquired meningitis due to extended-spectrum beta-lactamase producing Escherichia coli complicated with multiple aortic mycotic aneurysms.

    PubMed

    Weyrich, Pierre; Ettahar, Nicolas; Legout, Laurence; Meybeck, Agnes; Leroy, Olivier; Senneville, Eric

    2012-01-01

    We report the first case of extended-spectrum beta-lactamase producing E. coli community-acquired meningitis complicated with multiple aortic mycotic aneurysms. Because of the acute aneurysm expansion with possible impending rupture on 2 abdominal CT scan, the patient underwent prompt vascular surgery and broad spectrum antibiotic therapy but he died of a hemorrhagic shock. Extended-spectrum beta-lactamase producing E. coli was identified from both blood and cerebrospinal fluid culture before vascular treatment. The present case report does not however change the guidelines of Gram negative bacteria meningitis in adults. PMID:22321435

  15. A modular cell-based biosensor using engineered genetic logic circuits to detect and integrate multiple environmental signals.

    PubMed

    Wang, Baojun; Barahona, Mauricio; Buck, Martin

    2013-02-15

    Cells perceive a wide variety of cellular and environmental signals, which are often processed combinatorially to generate particular phenotypic responses. Here, we employ both single and mixed cell type populations, pre-programmed with engineered modular cell signalling and sensing circuits, as processing units to detect and integrate multiple environmental signals. Based on an engineered modular genetic AND logic gate, we report the construction of a set of scalable synthetic microbe-based biosensors comprising exchangeable sensory, signal processing and actuation modules. These cellular biosensors were engineered using distinct signalling sensory modules to precisely identify various chemical signals, and combinations thereof, with a quantitative fluorescent output. The genetic logic gate used can function as a biological filter and an amplifier to enhance the sensing selectivity and sensitivity of cell-based biosensors. In particular, an Escherichia coli consortium-based biosensor has been constructed that can detect and integrate three environmental signals (arsenic, mercury and copper ion levels) via either its native two-component signal transduction pathways or synthetic signalling sensors derived from other bacteria in combination with a cell-cell communication module. We demonstrate how a modular cell-based biosensor can be engineered predictably using exchangeable synthetic gene circuit modules to sense and integrate multiple-input signals. This study illustrates some of the key practical design principles required for the future application of these biosensors in broad environmental and healthcare areas. PMID:22981411

  16. Expression of multiple sexual signals by fathers and sons in the East-Mediterranean barn swallow: are advertising strategies heritable?

    PubMed

    Vortman, Yoni; Safran, Rebecca J; Reiner Brodetzki, Tali; Dor, Roi; Lotem, Arnon

    2015-01-01

    The level of expression of sexually selected traits is generally determined by genes, environment and their interaction. In species that use multiple sexual signals which may be costly to produce, investing in the expression of one sexual signal may limit the expression of the other, favoring the evolution of a strategy for resource allocation among signals. As a result, even when the expression of sexual signals is condition dependent, the relative level of expression of each signal may be heritable. We tested this hypothesis in the East-Mediterranean barn swallow (Hirundo rustica transitiva), in which males have been shown to express two uncorrelated sexual signals: red-brown ventral coloration, and long tail streamers. We show that variation in both signals may partially be explained by age, as well as by paternal origin (genetic father-son regressions), but that the strongest similarity between fathers and sons is the relative allocation towards one trait or the other (relative expression index), rather than the expression of the traits themselves. These results suggest that the expression of one signal is not independent of the other, and that genetic strategies for resource allocation among sexual signals may be selected for during the evolution of multiple sexual signals. PMID:25679206

  17. Expression of Multiple Sexual Signals by Fathers and Sons in the East-Mediterranean Barn Swallow: Are Advertising Strategies Heritable?

    PubMed Central

    Vortman, Yoni; Safran, Rebecca J.; Reiner Brodetzki, Tali; Dor, Roi; Lotem, Arnon

    2015-01-01

    The level of expression of sexually selected traits is generally determined by genes, environment and their interaction. In species that use multiple sexual signals which may be costly to produce, investing in the expression of one sexual signal may limit the expression of the other, favoring the evolution of a strategy for resource allocation among signals. As a result, even when the expression of sexual signals is condition dependent, the relative level of expression of each signal may be heritable. We tested this hypothesis in the East-Mediterranean barn swallow (Hirundo rustica transitiva), in which males have been shown to express two uncorrelated sexual signals: red-brown ventral coloration, and long tail streamers. We show that variation in both signals may partially be explained by age, as well as by paternal origin (genetic father-son regressions), but that the strongest similarity between fathers and sons is the relative allocation towards one trait or the other (relative expression index), rather than the expression of the traits themselves. These results suggest that the expression of one signal is not independent of the other, and that genetic strategies for resource allocation among sexual signals may be selected for during the evolution of multiple sexual signals. PMID:25679206

  18. Performance of a novel multiple-signal luminescence sediment tracing method

    NASA Astrophysics Data System (ADS)

    Reimann, Tony

    2014-05-01

    Optically Stimulated Luminescence (OSL) is commonly used for dating sediments. Luminescence signals build up due to exposure of mineral grains to natural ionizing radiation, and are reset when these grains are exposed to (sun)light during sediment transport and deposition. Generally, luminescence signals can be read in two ways, potentially providing information on the burial history (dating) or the transport history (sediment tracing) of mineral grains. In this study we use a novel luminescence measurement procedure (Reimann et al., submitted) that simultaneously monitors six different luminescence signals from the same sub-sample (aliquot) to infer the transport history of sand grains. Daylight exposure experiments reveal that each of these six signals resets (bleaches) at a different rate, thus allowing to trace the bleaching history of the sediment in six different observation windows. To test the feasibility of luminescence sediment tracing in shallow-marine coastal settings we took eight sediment samples from the pilot mega-nourishment Zandmotor in Kijkduin (South-Holland). This site provides relatively controlled conditions as the morphological evolution of this nourishment is densely monitored (Stive et al., 2013). After sampling the original nourishment source we took samples along the seaward facing contour of the spit that was formed from August 2011 (start of nourishment) to June 2012 (sampling). It is presumed that these samples originate from the source and were transported and deposited within the first year after construction. The measured luminescence of a sediment sample was interpolated onto the daylight bleaching curve of each signal to assign the Equivalent Exposure Time (EET) to a sample. The EET is a quantitative measure of the full daylight equivalent a sample was exposed to during sediment transport, i.e. the higher the EET the longer the sample has been transported or the more efficient it has been exposed to day-light during sediment

  19. Multiple Signaling Pathways Contribute to the Thrombin-induced Secretory Phenotype in Vascular Smooth Muscle Cells

    PubMed Central

    Jeong, Ji Young; Son, Younghae; Kim, Bo-Young; Eo, Seong-Kug; Rhim, Byung-Yong

    2015-01-01

    We attempted to investigate molecular mechanisms underlying phenotypic change of vascular smooth muscle cells (VSMCs) by determining signaling molecules involved in chemokine production. Treatment of human aortic smooth muscle cells (HAoSMCs) with thrombin resulted not only in elevated transcription of the (C-C motif) ligand 11 (CCL11) gene but also in enhanced secretion of CCL11 protein. Co-treatment of HAoSMCs with GF109230X, an inhibitor of protein kinase C, or GW5074, an inhibitor of Raf-1 kinase, caused inhibition of ERK1/2 phosphorylation and significantly attenuated expression of CCL11 at transcriptional and protein levels induced by thrombin. Both Akt phosphorylation and CCL11 expression induced by thrombin were attenuated in the presence of pertussis toxin (PTX), an inhibitor of Gi protein-coupled receptor, or LY294002, a PI3K inhibitor. In addition, thrombin-induced production of CCL11 was significantly attenuated by pharmacological inhibition of Akt or MEK which phosphorylates ERK1/2. These results indicate that thrombin is likely to promote expression of CCL11 via PKC/Raf-1/ERK1/2 and PTX-sensitive protease-activated receptors/PI3K/Akt pathways in HAoSMCs. We propose that multiple signaling pathways are involved in change of VSMCs to a secretory phenotype. PMID:26557022

  20. Multiple Signaling Pathways Contribute to the Thrombin-induced Secretory Phenotype in Vascular Smooth Muscle Cells.

    PubMed

    Jeong, Ji Young; Son, Younghae; Kim, Bo-Young; Eo, Seong-Kug; Rhim, Byung-Yong; Kim, Koanhoi

    2015-11-01

    We attempted to investigate molecular mechanisms underlying phenotypic change of vascular smooth muscle cells (VSMCs) by determining signaling molecules involved in chemokine production. Treatment of human aortic smooth muscle cells (HAoSMCs) with thrombin resulted not only in elevated transcription of the (C-C motif) ligand 11 (CCL11) gene but also in enhanced secretion of CCL11 protein. Co-treatment of HAoSMCs with GF109230X, an inhibitor of protein kinase C, or GW5074, an inhibitor of Raf-1 kinase, caused inhibition of ERK1/2 phosphorylation and significantly attenuated expression of CCL11 at transcriptional and protein levels induced by thrombin. Both Akt phosphorylation and CCL11 expression induced by thrombin were attenuated in the presence of pertussis toxin (PTX), an inhibitor of Gi protein-coupled receptor, or LY294002, a PI3K inhibitor. In addition, thrombin-induced production of CCL11 was significantly attenuated by pharmacological inhibition of Akt or MEK which phosphorylates ERK1/2. These results indicate that thrombin is likely to promote expression of CCL11 via PKC/Raf-1/ERK1/2 and PTX-sensitive protease-activated receptors/PI3K/Akt pathways in HAoSMCs. We propose that multiple signaling pathways are involved in change of VSMCs to a secretory phenotype. PMID:26557022

  1. The PKC-NFκB Signaling Pathway Induces APOBEC3B Expression in Multiple Human Cancers

    PubMed Central

    Leonard, Brandon; McCann, Jennifer L.; Starrett, Gabriel J.; Kosyakovsky, Leah; Luengas, Elizabeth M.; Molan, Amy M.; Burns, Michael B.; McDougle, Rebecca M.; Parker, Peter J.; Brown, William L.; Harris, Reuben S.

    2015-01-01

    Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in many cancers. HPV infection accounts for APOBEC3B upregulation in cervical and head/neck cancers, but the mechanisms underlying non-viral malignancies are unclear. In this study, we investigated the signal transduction pathways responsible for APOBEC3B upregulation. Activation of protein kinase C (PKC) by the diacylglycerol (DAG) mimic phorbol-myristic acid (PMA) resulted in specific and dose-responsive increases in APOBEC3B expression and activity, which could then be strongly suppressed by PKC or NFκB inhibition. PKC activation caused the recruitment of RELB, but not RELA, to the APOBEC3B promoter implicating non-canonical NFκB signaling. Notably, PKC was required for APOBEC3B upregulation in cancer cell lines derived from multiple tumor types. By revealing how APOBEC3B is upregulated in many cancers, our findings suggest that PKC and NFκB inhibitors may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes such as drug resistance and metastases. PMID:26420215

  2. γ-Tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways

    PubMed Central

    Yap, W N; Chang, P N; Han, H Y; Lee, D T W; Ling, M T; Wong, Y C; Yap, Y L

    2008-01-01

    Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of γ-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G1 cell population. Examination of the pro-survival genes revealed that the γ-tocotrienol-induced cell death was associated with suppression of NF-κB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, γ-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of γ-tocotrienol. Interestingly, γ-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and γ-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with γ-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of γ-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of γ-tocotrienol against PCa cells. PMID:19002171

  3. Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma.

    PubMed

    Hunsucker, Sally A; Magarotto, Valeria; Kuhn, Deborah J; Kornblau, Steven M; Wang, Michael; Weber, Donna M; Thomas, Sheeba K; Shah, Jatin J; Voorhees, Peter M; Xie, Hong; Cornfeld, Mark; Nemeth, Jeffrey A; Orlowski, Robert Z

    2011-03-01

    Signalling through the interleukin (IL)-6 pathway induces proliferation and drug resistance of multiple myeloma cells. We therefore sought to determine whether the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could enhance the activity of melphalan, and to examine some of the mechanisms underlying this interaction. Siltuximab increased the cytotoxicity of melphalan in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to melphalan. These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs co-cultured with a human-derived stromal cell line. Siltuximab with melphalan enhanced activation of caspase-8, caspase-9, and the downstream effector caspase-3 compared with either of the single agents. This increased induction of cell death occurred in association with enhanced Bak activation. Neutralization of IL-6 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced anti-proliferative effects against primary plasma cells derived from patients with myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis. These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies. PMID:21241278

  4. Distinct Signaling Mechanisms in Multiple Developmental Pathways by the SCRAMBLED Receptor of Arabidopsis1[OPEN

    PubMed Central

    Kwak, Su-Hwan; Woo, Sooah; Lee, Myeong Min; Schiefelbein, John

    2014-01-01

    SCRAMBLED (SCM), a leucine-rich repeat receptor-like kinase in Arabidopsis (Arabidopsis thaliana), is required for positional signaling in the root epidermis and for tissue/organ development in the shoot. To further understand SCM action, we generated a series of kinase domain variants and analyzed their ability to complement scm mutant defects. We found that the SCM kinase domain, but not kinase activity, is required for its role in root epidermal patterning, supporting the view that SCM is an atypical receptor kinase. We also describe a previously uncharacterized role for SCM in fruit dehiscence, because mature siliques from scm mutants fail to open properly. Interestingly, the kinase domain of SCM appears to be dispensable for this developmental process. Furthermore, we found that most of the SCM kinase domain mutations dramatically inhibit inflorescence development. Because this process is not affected in scm null mutants, it is likely that SCM acts redundantly to regulate inflorescence size. The importance of distinct kinase residues for these three developmental processes provides an explanation for the maintenance of the conserved kinase domain in the SCM protein, and it may generally explain its conservation in other atypical kinases. Furthermore, these results indicate that individual leucine-rich repeat receptor-like kinases may participate in multiple pathways using distinct signaling mechanisms to mediate diverse cellular communication events. PMID:25136062

  5. Multiple signal amplification electrogenerated chemiluminescence biosensors for sensitive protein kinase activity analysis and inhibition.

    PubMed

    Wang, Zonghua; Yan, Zhiyong; Sun, Na; Liu, Yang

    2015-06-15

    A novel electrogenerated chemiluminescence (ECL) biosensor was built for the detection of kinase activity based on multiple signal amplification nanoprobes. In this strategy, the Xanthine oxidase (XOD) and 5'-phosphate group end DNA conjugated AuNPs was integrated with the phosphorylated peptide by Zr(4+). The XOD on gold nanoparticles can catalyze dissolved oxygen to produce H2O2 in the presence of hypoxanthine (HA) which acts as a coreactor for luminol ECL reaction. In addition, due to the excellent catalytic activity of gold nanoparticle toward luminol ECL reaction and its large surface area that can accommodate large number of XOD and DNA on the surface, the ECL signal of luminol was significantly amplified, affording a highly sensitive ECL analysis of kinase activity. The as-proposed biosensor presents a low detection limit of 0.09 U mL(-1) for protein kinase A (PKA) activity, wide linear range (from 0.1 to 10 U mL(-1)) and excellent stability even in serum samples. This biosensor can also be applied for quantitative kinase inhibitor evaluation. The robust ECL biosensor provides a valuable tool for the high throughput assay in the applications of clinic diagnostic and therapeutic. PMID:25682506

  6. Physical basis for signal separation for remote sensing of multiple high energy radiation sources

    NASA Astrophysics Data System (ADS)

    Richards, J.; Jain, V. K.

    2015-08-01

    In `radiation remote sensing' multiple unknown high energy sources are generally involved. The detectors, upon sensing the corresponding mixed signals, must separate their contributions blindly for further analysis. A practical way to perform this separation could be through the Independent Component Analysis algorithm. However, the challenge faced is that theoretically there is no correlation among events, even those arising from the same source - thereby disabling meaningful ICA analysis. We overcome this hurdle by use of a thin barrier and by providing wide detector pulses. The radiation events that interact with the barrier take a longer time to reach the detector due to their increased path length. They also lose some energy, which makes them increasingly prone to capture in the barrier once they have scattered. These observations are confirmed through Monte-Carlo simulations upon Gamma-ray sources. Normalized crosscovariance up to 0.22 was found, but is actually controllable through appropriate selection of the detector shaping-pulse width. Experiments on a physical setup confirm these findings. Finally, the application of the ICA approach is demonstrated to demix, or separate, the individual contributions of the sources to the observed detector signals.

  7. The impact of relative intensity noise on the signal in multiple reference optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Neuhaus, Kai; Subhash, Hrebesh; Alexandrov, Sergey; Dsouza, Roshan; Hogan, Josh; Wilson, Carol; Leahy, Martin; Slepneva, Svetlana; Huyet, Guillaume

    2016-03-01

    Multiple reference optical coherence tomography (MR-OCT) applies a unique low-cost solution to enhance the scanning depth of standard time domain OCT by inserting an partial mirror into the reference arm of the interferometric system. This novel approach achieves multiple reflections for different layers and depths of an sample with minimal effort of engineering and provides an excellent platform for low-cost OCT systems based on well understood production methods for micro-mechanical systems such as CD/DVD pick-up systems. The direct integration of a superluminescent light-emitting diode (SLED) is a preferable solution to reduce the form- factor of an MR-OCT system. Such direct integration exposes the light source to environmental conditions that can increase fluctuations in heat dissipation and vibrations and affect the noise characteristics of the output spectrum. This work describes the impact of relative intensity noise (RIN) on the quality of the interference signal of MR-OCT related to a variety of environmental conditions, such as temperature.

  8. Identification and characterization of multiple conserved nuclear localization signals within adenovirus E1A

    SciTech Connect

    Marshall, Kris S.; Cohen, Michael J.; Fonseca, Greg J.; Todorovic, Biljana; King, Cason R.; Yousef, Ahmed F.; Zhang, Zhiying; Mymryk, Joe S.

    2014-04-15

    The human adenovirus 5 (HAdV-5) E1A protein has a well defined canonical nuclear localization signal (NLS) located at its C-terminus. We used a genetic assay in the yeast Saccharomyces cerevisiae to demonstrate that the canonical NLS is present and functional in the E1A proteins of each of the six HAdV species. This assay also detects a previously described non-canonical NLS within conserved region 3 and a novel active NLS within the N-terminal/conserved region 1 portion of HAdV-5 E1A. These activities were also present in the E1A proteins of each of the other five HAdV species. These results demonstrate that, despite substantial differences in primary sequence, HAdV E1A proteins are remarkably consistent in that they contain one canonical and two non-canonical NLSs. By utilizing independent mechanisms, these multiple NLSs ensure nuclear localization of E1A in the infected cell. - Highlights: • HAdV E1A uses multiple mechanisms for nuclear import. • We identified an additional non-canonical NLS in the N-terminal/CR1 portion of E1A. • The new NLS does not contact importin-alpha directly. • All NLSs are functionally conserved in the E1A proteins of all 6 HAdV species.

  9. Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways.

    PubMed

    Pandey, Manoj K; Kale, Vijay P; Song, Chunhua; Sung, Shen-shu; Sharma, Arun K; Talamo, Giampaolo; Dovat, Sinisa; Amin, Shantu G

    2014-10-01

    Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1α/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation, but rather GA suppresses CXCR4 mRNA expression by inhibiting nuclear factor-kappa B (NF-κB) DNA binding. This was further confirmed by quantitative chromatin immunoprecipitation assay, as GA inhibits p65 binding at the CXCR4 promoter. GA suppressed SDF-1α-induced chemotaxis of MM cells and downstream signaling of CXCR4 by inhibiting phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA abrogated the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. In addition, we found that MM cells induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Importantly, suppression of osteoclastogenesis by GA was mediated through IL-6 inhibition. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and has a strong potential to suppress osteoclastogenesis mediated by MM cells. PMID:25034231

  10. Optical telecommunications system and signal analysis using data-entropy and multiple-centroid data-scatter

    NASA Astrophysics Data System (ADS)

    Egan, J.; McMillan, N. D.; Denieffe, D.; Riedel, S.; Doyle, G.; Farrell, G.

    2005-09-01

    The data-entropy quality-budget developed by the authors is used as an alternative to the conventional power budget. The traditional power budget approach is not capable of providing a full analysis of a system with different noise types and specifically providing a measure of signal quality. The quality-budget addressed this issue by applying its dimensionless 'bit measure' to integrate the analysis of all types of losses. A data-entropy visualisation is produced for each set of points in a reference and test signal. This data-entropy signal is a measure of signal disorder and reflects the power loss and types of signal degradation experienced by the test signal. To analyse the differences between two signals an algorithm known as phase-coherent data-scatter (PCDS) is used to assess levels of attenuation, dispersion, jitter, etc. Practical analysis of telecommunications signals using the new multiple-centroid (MC) PCDS is presented here for the first time. MC-PCDS is then used to analyse differences between sets of data-entropy signals and digital signals. The theory behind MC data-scatter is discussed and its advantages for the quantification of signal degradations are assessed. Finally, a brief consideration is given to the use of pattern recognition algorithms to measure optical signal degrading factors.

  11. Visual Signals Vertically Extend the Perceptual Span in Searching a Text: A Gaze-Contingent Window Study

    ERIC Educational Resources Information Center

    Cauchard, Fabrice; Eyrolle, Helene; Cellier, Jean-Marie; Hyona, Jukka

    2010-01-01

    This study investigated the effect of visual signals on perceptual span in text search and the kinds of signal information that facilitate the search. Participants were asked to find answers to specific questions in chapter-length texts in either a normal or a window condition, where the text disappeared beyond a vertical 3 degrees gaze-contingent…

  12. Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release

    PubMed Central

    Lee, Sang-Hun; Ledri, Marco; Tóth, Blanka; Marchionni, Ivan; Henstridge, Christopher M.; Dudok, Barna; Kenesei, Kata; Barna, László; Szabó, Szilárd I.; Renkecz, Tibor; Oberoi, Michelle; Watanabe, Masahiko; Limoli, Charles L.; Horvai, George; Soltesz, Ivan

    2015-01-01

    Persistent CB1 cannabinoid receptor activity limits neurotransmitter release at various synapses throughout the brain. However, it is not fully understood how constitutively active CB1 receptors, tonic endocannabinoid signaling, and its regulation by multiple serine hydrolases contribute to the synapse-specific calibration of neurotransmitter release probability. To address this question at perisomatic and dendritic GABAergic synapses in the mouse hippocampus, we used a combination of paired whole-cell patch-clamp recording, liquid chromatography/tandem mass spectrometry, stochastic optical reconstruction microscopy super-resolution imaging, and immunogold electron microscopy. Unexpectedly, application of the CB1 antagonist and inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide], but not the neutral antagonist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-5,6-dihydro-4H-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], significantly increased synaptic transmission between CB1-positive perisomatic interneurons and CA1 pyramidal neurons. JZL184 (4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate), a selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 (N-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide) elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic

  13. Knee-clicks and visual traits indicate fighting ability in eland antelopes: multiple messages and back-up signals

    PubMed Central

    Bro-Jørgensen, Jakob; Dabelsteen, Torben

    2008-01-01

    Background Given the costs of signalling, why do males often advertise their fighting ability to rivals using several signals rather than just one? Multiple signalling theories have developed largely in studies of sexual signals, and less is known about their applicability to intra-sexual communication. We here investigate the evolutionary basis for the intricate agonistic signalling system in eland antelopes, paying particular attention to the evolutionary phenomenon of loud knee-clicking. Results A principal components analysis separated seven male traits into three groups. The dominant frequency of the knee-clicking sound honestly indicated body size, a main determinant of fighting ability. In contrast, the dewlap size increased with estimated age rather than body size, suggesting that, by magnifying the silhouette of older bulls disproportionately, the dewlap acts as an indicator of age-related traits such as fighting experience. Facemask darkness, frontal hairbrush size and body greyness aligned with a third underlying variable, presumed to be androgen-related aggression. A longitudinal study provided independent support of these findings. Conclusion The results show that the multiple agonistic signals in eland reflect three separate components of fighting ability: (1) body size, (2) age and (3) presumably androgen-related aggression, which is reflected in three backup signals. The study highlights how complex agonistic signalling systems can evolve through the simultaneous action of several selective forces, each of which favours multiple signals. Specifically, loud knee-clicking is discovered to be an honest signal of body size, providing an exceptional example of the potential for non-vocal acoustic communication in mammals. PMID:18986518

  14. Robust myoelectric signal detection based on stochastic resonance using multiple-surface-electrode array made of carbon nanotube composite paper

    NASA Astrophysics Data System (ADS)

    Shirata, Kento; Inden, Yuki; Kasai, Seiya; Oya, Takahide; Hagiwara, Yosuke; Kaeriyama, Shunichi; Nakamura, Hideyuki

    2016-04-01

    We investigated the robust detection of surface electromyogram (EMG) signals based on the stochastic resonance (SR) phenomenon, in which the response to weak signals is optimized by adding noise, combined with multiple surface electrodes. Flexible carbon nanotube composite paper (CNT-cp) was applied to the surface electrode, which showed good performance that is comparable to that of conventional Ag/AgCl electrodes. The SR-based EMG signal system integrating an 8-Schmitt-trigger network and the multiple-CNT-cp-electrode array successfully detected weak EMG signals even when the subject’s body is in the motion, which was difficult to achieve using the conventional technique. The feasibility of the SR-based EMG detection technique was confirmed by demonstrating its applicability to robot hand control.

  15. Fluorescent multiple staining and CASA system to assess boar sperm viability and membranes integrity in short and long-term extenders

    PubMed Central

    Lange-Consiglio, A.; Meucci, A.; Cremonesi, F.

    2013-01-01

    The aim of this study was to assess the effect on boar spermatozoa quality of in vitro storage in short and long-term extenders by fluorescent multiple staining (FMS) and computer assisted semen analyzer (CASA). Fresh ejaculates from three healthy, sexually mature boars were diluted with equal volumes of six short-term or three long-term commercial extenders and stored at 19°C for 6 days (short-term) or 12 days (long-term). The integrity of spermatozoa membranes was analyzed by FMS using propidium iodide, 5,5’,6,6’-tetrachloro-1,1’,3,3’ tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) and fluorescein isothiocyanate-conjugated peanut agglutinin (PNA). The results obtained from this staining were compared with spermatozoa motility assessed by CASA. Our study showed that the number of viable spermatozoa with non-reacted acrosomes and intact mitochondria was positively correlated with the rate of motile spermatozoa (r2>0.9) irrespective of the extender used. In all extenders the number of motile spermatozoa significantly decreased as preservation period increased (P<0.05). FMS test is a potent indicator of sperm motility because it analyses mitochondrial integrity independently from observable alterations in motility. The best performing extenders were BTS for short-term storage and TRI-x-Cell for long-term storage. PMID:26623308

  16. Signaling Interplay between Bone Marrow Adipose Tissue and Multiple Myeloma cells

    PubMed Central

    Falank, Carolyne; Fairfield, Heather; Reagan, Michaela R.

    2016-01-01

    In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutation) (2). In multiple myeloma (MM), a destructive cancer of the plasma cell that grows predominantly in the bone marrow (BM), it is clear that all these hallmarks and characteristics are in play, contributing to tumor initiation, drug resistance, disease progression, and relapse. Bone marrow adipose tissue (BMAT) is a newly recognized contributor to MM oncogenesis and disease progression, potentially affecting MM cell metabolism, immune action, inflammation, and influences on angiogenesis. In this review, we discuss the confirmed and hypothetical contributions of BMAT to MM development and disease progression. BMAT has been understudied due to technical challenges and a previous lack of appreciation for the endocrine function of this tissue. In this review, we define the dynamic, responsive, metabolically active BM adipocyte. We then describe how BMAT influences MM in terms of: lipids/metabolism, hypoxia/angiogenesis, paracrine or endocrine signaling, and bone disease. We then discuss the connection between BMAT and systemic inflammation and potential treatments to inhibit the feedback loops between BM adipocytes and MM cells that support MM progression. We aim for researchers to use this review to guide and help prioritize their experiments to develop better treatments or a cure for cancers, such as MM, that associate with and may depend on BMAT. PMID:27379019

  17. Signaling Interplay between Bone Marrow Adipose Tissue and Multiple Myeloma cells.

    PubMed

    Falank, Carolyne; Fairfield, Heather; Reagan, Michaela R

    2016-01-01

    In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutation) (2). In multiple myeloma (MM), a destructive cancer of the plasma cell that grows predominantly in the bone marrow (BM), it is clear that all these hallmarks and characteristics are in play, contributing to tumor initiation, drug resistance, disease progression, and relapse. Bone marrow adipose tissue (BMAT) is a newly recognized contributor to MM oncogenesis and disease progression, potentially affecting MM cell metabolism, immune action, inflammation, and influences on angiogenesis. In this review, we discuss the confirmed and hypothetical contributions of BMAT to MM development and disease progression. BMAT has been understudied due to technical challenges and a previous lack of appreciation for the endocrine function of this tissue. In this review, we define the dynamic, responsive, metabolically active BM adipocyte. We then describe how BMAT influences MM in terms of: lipids/metabolism, hypoxia/angiogenesis, paracrine or endocrine signaling, and bone disease. We then discuss the connection between BMAT and systemic inflammation and potential treatments to inhibit the feedback loops between BM adipocytes and MM cells that support MM progression. We aim for researchers to use this review to guide and help prioritize their experiments to develop better treatments or a cure for cancers, such as MM, that associate with and may depend on BMAT. PMID:27379019

  18. Altered signaling for mitochondrial and myofibrillar biogenesis in skeletal muscles of patients with multiple sclerosis.

    PubMed

    Hansen, Dominique; Wens, Inez; Vandenabeele, Frank; Verboven, Kenneth; Eijnde, Bert O

    2015-07-01

    Patients with multiple sclerosis (pwMS) experience muscle weakness and lowered muscle oxidative capacity. To explore the etiology for the development of such muscle phenotype we studied skeletal muscle adenosine monophosphate (AMP)-activated protein kinase phosphorylation (phospho-AMPKα, governing mitochondrial biogenesis) and mammalian target of rapamycin phosphorylation (phospho-mTOR, governing myofibrillar biogenesis) in pwMS. After assessment of body composition, muscle strength, exercise tolerance, and muscle fiber type, muscle phospho-AMPKα and phospho-mTOR were assessed in 14 pwMS and 10 healthy controls (part 1). Next, an endurance exercise bout was executed by 9 pwMS and 7 healthy subjects, with assessment of changes in muscle phospho-AMPKα and phospho-mTOR (part 2). Increased basal muscle phospho-AMPKα and phospho-mTOR were present in MS (P < 0.01) and independently related to MS. Correlations between muscle phospho-AMPKα or phospho-mTOR and whole-body fat mass, peak oxygen uptake, and expanded disability status scale (P < 0.05) were found. After endurance exercise muscle phospho-AMPKα and phospho-mTOR remained increased in pwMS (P < 0.01). Muscle signaling cascades for mitochondrial and myofibrillar biogenesis are altered in MS and related to the impairment and disability level. These findings indicate a link between muscle signaling cascades and the level of disability and impairment, and thus may open a new area for the development of novel therapies for peripheral muscle impairment in MS. PMID:25666356

  19. Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma.

    PubMed

    Carapuça, Elisabete F; Gemenetzidis, Emilios; Feig, Christine; Bapiro, Tashinga E; Williams, Michael D; Wilson, Abigail S; Delvecchio, Francesca R; Arumugam, Prabhu; Grose, Richard P; Lemoine, Nicholas R; Richards, Frances M; Kocher, Hemant M

    2016-07-01

    Stromal targeting for pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming an attractive option, due to the lack of efficacy of standard chemotherapy and increased knowledge about PDAC stroma. We postulated that the addition of stromal therapy may enhance the anti-tumour efficacy of chemotherapy. Gemcitabine and all-trans retinoic acid (ATRA) were combined in a clinically applicable regimen, to target cancer cells and pancreatic stellate cells (PSCs) respectively, in 3D organotypic culture models and genetically engineered mice (LSL-Kras(G12D) (/+) ;LSL-Trp53(R172H) (/+) ;Pdx-1-Cre: KPC mice) representing the spectrum of PDAC. In two distinct sets of organotypic models as well as KPC mice, we demonstrate a reduction in cancer cell proliferation and invasion together with enhanced cancer cell apoptosis when ATRA is combined with gemcitabine, compared to vehicle or either agent alone. Simultaneously, PSC activity (as measured by deposition of extracellular matrix proteins such as collagen and fibronectin) and PSC invasive ability were both diminished in response to combination therapy. These effects were mediated through a range of signalling cascades (Wnt, hedgehog, retinoid, and FGF) in cancer as well as stellate cells, affecting epithelial cellular functions such as epithelial-mesenchymal transition, cellular polarity, and lumen formation. At the tissue level, this resulted in enhanced tumour necrosis, increased vascularity, and diminished hypoxia. Consequently, there was an overall reduction in tumour size. The enhanced effect of stromal co-targeting (ATRA) alongside chemotherapy (gemcitabine) appears to be mediated by dampening multiple signalling cascades in the tumour-stroma cross-talk, rather than ablating stroma or targeting a single pathway. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID:27061193

  20. Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms

    PubMed Central

    Verweij, Marieke C.; Wellish, Mary; Whitmer, Travis; Malouli, Daniel; Lapel, Martin; Jonjić, Stipan; Haas, Juergen G.; DeFilippis, Victor R.; Mahalingam, Ravi; Früh, Klaus

    2015-01-01

    Varicella zoster virus (VZV) causes chickenpox in humans and, subsequently, establishes latency in the sensory ganglia from where it reactivates to cause herpes zoster. Infection of rhesus macaques with simian varicella virus (SVV) recapitulates VZV pathogenesis in humans thus representing a suitable animal model for VZV infection. While the type I interferon (IFN) response has been shown to affect VZV replication, the virus employs counter mechanisms to prevent the induction of anti-viral IFN stimulated genes (ISG). Here, we demonstrate that SVV inhibits type I IFN-activated signal transduction via the JAK-STAT pathway. SVV-infected rhesus fibroblasts were refractory to IFN stimulation displaying reduced protein levels of IRF9 and lacking STAT2 phosphorylation. Since previous work implicated involvement of the VZV immediate early gene product ORF63 in preventing ISG-induction we studied the role of SVV ORF63 in generating resistance to IFN treatment. Interestingly, SVV ORF63 did not affect STAT2 phosphorylation but caused IRF9 degradation in a proteasome-dependent manner, suggesting that SVV employs multiple mechanisms to counteract the effect of IFN. Control of SVV ORF63 protein levels via fusion to a dihydrofolate reductase (DHFR)-degradation domain additionally confirmed its requirement for viral replication. Our results also show a prominent reduction of IRF9 and inhibition of STAT2 phosphorylation in VZV-infected cells. In addition, cells expressing VZV ORF63 blocked IFN-stimulation and displayed reduced levels of the IRF9 protein. Taken together, our data suggest that varicella ORF63 prevents ISG-induction both directly via IRF9 degradation and indirectly via transcriptional control of viral proteins that interfere with STAT2 phosphorylation. SVV and VZV thus encode multiple viral gene products that tightly control IFN-induced anti-viral responses. PMID:25973608

  1. Multiple Nuclear Localization Signals Mediate Nuclear Localization of the GATA Transcription Factor AreA

    PubMed Central

    Hunter, Cameron C.; Siebert, Kendra S.; Downes, Damien J.; Wong, Koon Ho; Kreutzberger, Sara D.; Fraser, James A.; Clarke, David F.; Hynes, Michael J.; Davis, Meryl A.

    2014-01-01

    The Aspergillus nidulans GATA transcription factor AreA activates transcription of nitrogen metabolic genes in response to nitrogen limitation and is known to accumulate in the nucleus during nitrogen starvation. Sequence analysis of AreA revealed multiple nuclear localization signals (NLSs), five putative classical NLSs conserved in fungal AreA orthologs but not in the Saccharomyces cerevisiae functional orthologs Gln3p and Gat1p, and one putative noncanonical RRX33RXR bipartite NLS within the DNA-binding domain. In order to identify the functional NLSs in AreA, we constructed areA mutants with mutations in individual putative NLSs or combinations of putative NLSs and strains expressing green fluorescent protein (GFP)-AreA NLS fusion genes. Deletion of all five classical NLSs individually or collectively did not affect utilization of nitrogen sources or AreA-dependent gene expression and did not prevent AreA nuclear localization. Mutation of the bipartite NLS conferred the inability to utilize alternative nitrogen sources and abolished AreA-dependent gene expression likely due to effects on DNA binding but did not prevent AreA nuclear localization. Mutation of all six NLSs simultaneously prevented AreA nuclear accumulation. The bipartite NLS alone strongly directed GFP to the nucleus, whereas the classical NLSs collaborated to direct GFP to the nucleus. Therefore, AreA contains multiple conserved NLSs, which show redundancy and together function to mediate nuclear import. The noncanonical bipartite NLS is conserved in GATA factors from Aspergillus, yeast, and mammals, indicating an ancient origin. PMID:24562911

  2. Therapeutic Impact of Sphingosine 1-phosphate Receptor Signaling in Multiple Sclerosis.

    PubMed

    Candido, Kristina; Soufi, Henry; Bandyopadhyay, Mausumi; Dasgupta, Subhajit

    2016-01-01

    Multiple sclerosis (MS) is a female predominant autoimmune demyelinating disease of central nervous system. The proper etiology is not clear. The existing therapies with interferon beta (Betaseron, Rebif), glatiramer acetate (copolymer 1, copaxone) are found to be promising for MS patients. The alpha-4 integrin antagonist monoclonal antibody Natalizumab has been found to decrease brain inflammation in relapsing-remitting MS via inhibition of alpha-4 beta- 1 integrinmediated mode of action of antigen -primed T cells to enter into central nervous system through blood brain barrier. The advancement of drug development introduced prospects of CD52 monoclonal antibody Alemtuzumab and CD20 monoclonal antibody Rituximab in MS therapy. The benefit versus risk ratios of these therapeutic monoclonal antibodies are currently under clinical trial. The ongoing researches demonstrated the importance of HMG-CoA reductase inhibitor statins, NF-κBp65 inhibitor NBD peptide, and antagonist of poly-ADP-ribose polymerase (PARP) in experimental autoimmune encephalomyelitis (EAE), animal model for MS. Recently, the clinical trials indicated the therapeutic prospect of G-protein coupled sphingosine 1-phosphate receptor (S1PR) in MS patients. Recent studies showed remyelination through selective activation of oligodendrocyte progenitor cells. In the context, role of S1PR-mediated signals following interaction with natural ligand S1P and agonist Fingolimod (FTY720) gain profound therapeutic importance in prevention of demyelination in MS brain. The S1PR agonist Fingolimod (FTY 720) has recently been approved by Food and Drug Administration for MS therapy. In the review, we provided an insight on S1PR mode of action in the aspect of treatment of autoimmune disorder, re-myelination and regeneration of axons in damaged central nervous system in multiple sclerosis. PMID:26156414

  3. The use of digital technology in finding multiple paths to solve and extend an equilateral triangle task

    NASA Astrophysics Data System (ADS)

    Santos-Trigo, Manuel; Reyes-Rodriguez, Aaron

    2016-01-01

    Mathematical tasks are crucial elements for teachers to orient, foster and assess students' processes to comprehend and develop mathematical knowledge. During the process of working and solving a task, searching for or discussing multiple solution paths becomes a powerful strategy for students to engage in mathematical thinking. A simple task that involves the construction of an equilateral triangle is used to present and discuss multiple solution approaches that rely on a variety of concepts and ways of reasoning. To this end, the use of a Dynamic Geometry System (GeoGebra) became instrumental in constructing and exploring dynamic models of the task. These model explorations provided a means to generate novel mathematical results.

  4. The Use of Digital Technology in Finding Multiple Paths to Solve and Extend an Equilateral Triangle Task

    ERIC Educational Resources Information Center

    Santos-Trigo, Manuel; Reyes-Rodriguez, Aaron

    2016-01-01

    Mathematical tasks are crucial elements for teachers to orient, foster and assess students' processes to comprehend and develop mathematical knowledge. During the process of working and solving a task, searching for or discussing multiple solution paths becomes a powerful strategy for students to engage in mathematical thinking. A simple task that…

  5. Multiple Signaling Pathways of the Insulin-Like Growth Factor 1 Receptor in Protection from Apoptosis

    PubMed Central

    Peruzzi, Francesca; Prisco, Marco; Dews, Michael; Salomoni, Paolo; Grassilli, Emanuela; Romano, Gaetano; Calabretta, Bruno; Baserga, Renato

    1999-01-01

    The type 1 insulin-like growth factor receptor (IGF-1R), activated by its ligands, protects several cell types from a variety of apoptotic injuries. The main signaling pathway for IGF-1R-mediated protection from apoptosis has been previously elucidated and rests on the activation of phosphatidylinositol 3-kinase, Akt/protein kinase B, and the phosphorylation and inactivation of BAD, a member of the Bcl-2 family of proteins. In 32D cells (a murine hemopoietic cell line devoid of insulin receptor substrate 1 [IRS-1]), the IGF-1R activates alternative pathways for protection from apoptosis induced by withdrawal of interleukin-3. One of these pathways leads to the activation of mitogen-activated protein kinase, while a third pathway results in the mitochondrial translocation of Raf and depends on the integrity of a group of serines in the C terminus of the receptor that are known to interact with 14.3.3 proteins. All three pathways, however, result in BAD phosphorylation. The presence of multiple antiapoptotic pathways may explain the remarkable efficacy of the IGF-1R in protecting cells from apoptosis. PMID:10490655

  6. Angiogenic activity of sesamin through the activation of multiple signal pathways

    SciTech Connect

    Chung, Byung-Hee; Lee, Jung Joon; Kim, Jong-Dai; Jeoung, Dooil; Lee, Hansoo; Choe, Jongseon; Ha, Kwon-Soo; Kwon, Young-Geun; Kim, Young-Myeong

    2010-01-01

    The natural product sesamin has been known to act as a potent antioxidant and prevent endothelial dysfunction. We here found that sesamin increased in vitro angiogenic processes, such as endothelial cell proliferation, migration, and tube formation, as well as neovascularization in an animal model. This compound elicited the activation of multiple angiogenic signal modulators, such as ERK, Akt, endothelial nitric oxide synthase (eNOS), NO production, FAK, and p38 MAPK, but not Src. The MEK inhibitor PD98059 and the PI3K inhibitor Wortmannin specifically inhibited sesamin-induced activation of the ERK and Akt/eNOS pathways. These inhibitors reduced angiogenic events, with high specificity for MEK/ERK-dependent cell proliferation and migration and PI3K/Akt-mediated tube formation. Moreover, inhibition of p38 MAPK effectively inhibited sesamin-induced cell migration. The angiogenic activity of sesamin was not associated with VEGF expression. Furthermore, this compound did not induce vascular permeability and upregulated ICAM-1 and VCAM-1 expression, which are hallmarks of vascular inflammation. These results suggest that sesamin stimulates angiogenesis in vitro and in vivo through the activation of MEK/ERK-, PI3K/Akt/eNOS-, p125{sup FAK}-, and p38 MAPK-dependent pathways, without increasing vascular inflammation, and may be used for treating ischemic diseases and tissue regeneration.

  7. Female preference for multiple condition-dependent components of a sexually selected signal.

    PubMed

    Scheuber, Hannes; Jacot, Alain; Brinkhof, Martin W G

    2004-12-01

    Theoretical models explain the evolution of multi-cue mate-choice decisions from a trade-off between benefits owing to improved assessment of potential mates and costs linked to the use of multiple signals. However, empirical support for these basic assumptions is lacking. In field crickets (Gryllus campestris) we experimentally investigated the female preference to variation in two key components of the male calling song: carrier frequency and chirp rate. Previous studies have revealed carrier frequency and chirp rate as reliable indicators of male quality that reflect past condition and current condition, respectively. In a two-way choice experiment, females significantly preferred test songs of lower carrier frequency and higher chirp rate, but prioritized the carrier frequency over the chirp rate. Hence, the static long-term indicator of mate quality was weighted more than the dynamic short-term one. Our results thus indicate that females integrate information from independent condition-dependent cues to discriminate between available males in mate-choice decisions. PMID:15590595

  8. Female preference for multiple condition-dependent components of a sexually selected signal.

    PubMed Central

    Scheuber, Hannes; Jacot, Alain; Brinkhof, Martin W. G.

    2004-01-01

    Theoretical models explain the evolution of multi-cue mate-choice decisions from a trade-off between benefits owing to improved assessment of potential mates and costs linked to the use of multiple signals. However, empirical support for these basic assumptions is lacking. In field crickets (Gryllus campestris) we experimentally investigated the female preference to variation in two key components of the male calling song: carrier frequency and chirp rate. Previous studies have revealed carrier frequency and chirp rate as reliable indicators of male quality that reflect past condition and current condition, respectively. In a two-way choice experiment, females significantly preferred test songs of lower carrier frequency and higher chirp rate, but prioritized the carrier frequency over the chirp rate. Hence, the static long-term indicator of mate quality was weighted more than the dynamic short-term one. Our results thus indicate that females integrate information from independent condition-dependent cues to discriminate between available males in mate-choice decisions. PMID:15590595

  9. Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells.

    PubMed

    Edwards, Shanique K E; Han, Yeming; Liu, Yingying; Kreider, Benjamin Z; Liu, Yan; Grewal, Sukhdeep; Desai, Anand; Baron, Jacqueline; Moore, Carissa R; Luo, Chang; Xie, Ping

    2016-02-01

    Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations. PMID:26740054

  10. Saccharomyces cerevisiae vacuolar H+-ATPase regulation by disassembly and reassembly: one structure and multiple signals.

    PubMed

    Parra, Karlett J; Chan, Chun-Yuan; Chen, Jun

    2014-06-01

    Vacuolar H(+)-ATPases (V-ATPases) are highly conserved ATP-driven proton pumps responsible for acidification of intracellular compartments. V-ATPase proton transport energizes secondary transport systems and is essential for lysosomal/vacuolar and endosomal functions. These dynamic molecular motors are composed of multiple subunits regulated in part by reversible disassembly, which reversibly inactivates them. Reversible disassembly is intertwined with glycolysis, the RAS/cyclic AMP (cAMP)/protein kinase A (PKA) pathway, and phosphoinositides, but the mechanisms involved are elusive. The atomic- and pseudo-atomic-resolution structures of the V-ATPases are shedding light on the molecular dynamics that regulate V-ATPase assembly. Although all eukaryotic V-ATPases may be built with an inherent capacity to reversibly disassemble, not all do so. V-ATPase subunit isoforms and their interactions with membrane lipids and a V-ATPase-exclusive chaperone influence V-ATPase assembly. This minireview reports on the mechanisms governing reversible disassembly in the yeast Saccharomyces cerevisiae, keeping in perspective our present understanding of the V-ATPase architecture and its alignment with the cellular processes and signals involved. PMID:24706019

  11. Vector Time-Series from Multiple Aperture Interferometry in Regions with Small Deformation Signals

    NASA Astrophysics Data System (ADS)

    Wortham, C.; Zebker, H. A.

    2012-12-01

    We estimate 3-D deformation from the June 2007 eruption along the East Rift Zone (ERZ) of Kilauea Volcano, Hawaii, using new extensions to InSAR small baseline subset (SBAS) analysis. Given the east-west orientation of the ERZ, a large component of the deformation is in the north-south direction with velocities on the order of 19 cm/yr for dates spanning the event and 4 cm/yr following the eruption. Similarly, we see deflation at the Kilauea caldera on the order of 7 cm/yr, with deformation in the east, north, and up directions. We use multiple geometries from ALOS/PALSAR and a modified SBAS algorithm to estimate all three components of the time-series. Ascending and descending geometries give measurements in the east and up directions, and we use multiple aperture InSAR (MAI) to estimate the along-track deformation. The azimuthal MAI method adds the missing component from the InSAR observations. However, due to aperture splitting, these MAI measurements are highly sensitive to phase errors and are only useful in areas with large signals. Given the pre and post-eruption velocities of the Hawaii data set, most MAI interferograms have very low SNR. Furthermore, the acquisition times of ascending and descending geometries differ by weeks or months. With at most two observations at each time step, the resulting system of equations is highly underdetermined. Both the low MAI SNR and rank deficiency of the inversion complicate the time-series estimation. We present our extension of SBAS time-series to vector deformation in which multiple radar geometries are combined in the geodetic domain. We show that by using ascending and descending acquisitions, along with their corresponding MAI measurements, accurate, three-dimensional time-series are possible, despite the time offset between each radar geometry. In combining these data sets, the temporal resolution of the time-series is increased, however, as a consequence of the lower MAI SNR, the spatial coverage from viable

  12. Computer modeling of multiple-channel input signals and intermodulation losses caused by nonlinear traveling wave tube amplifiers

    NASA Technical Reports Server (NTRS)

    Stankiewicz, N.

    1982-01-01

    The multiple channel input signal to a soft limiter amplifier as a traveling wave tube is represented as a finite, linear sum of Gaussian functions in the frequency domain. Linear regression is used to fit the channel shapes to a least squares residual error. Distortions in output signal, namely intermodulation products, are produced by the nonlinear gain characteristic of the amplifier and constitute the principal noise analyzed in this study. The signal to noise ratios are calculated for various input powers from saturation to 10 dB below saturation for two specific distributions of channels. A criterion for the truncation of the series expansion of the nonlinear transfer characteristic is given. It is found that he signal to noise ratios are very sensitive to the coefficients used in this expansion. Improper or incorrect truncation of the series leads to ambiguous results in the signal to noise ratios.

  13. Asynchronous detection of optical code division multiple access signals using a bandwidth-efficient and wavelength-aware receiver.

    PubMed

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

    2010-04-01

    We experimentally demonstrate what we believe to be a novel detection scheme for interfacing asynchronous optical code division multiple access (CDMA) signals with an electronic clock and data recovery system that operates only at the baseband bandwidth. This allows using a large optical bandwidth expansion factor in which the optical chip rate is much larger than the bandwidth of the optoelectronic receiver. The received optical CDMA signal is launched into a four-wave-mixing-based wavelength-aware all-optical front end that rejects multiaccess interference, followed by an amplitude-noise suppression stage comprised of a semiconductor optical amplifier. The clean signal is then converted into a non-return-to-zero-like signal by a baseband receiver. Using the proposed detection scheme, asynchronous transmission and detection of optical CDMA signals is implemented. With the novel detection scheme, the classic CDMA near-far problem is mitigated, and error-free detection is easily obtained. PMID:20364229

  14. Reconstruction of extended Petri nets from time series data and its application to signal transduction and to gene regulatory networks

    PubMed Central

    2011-01-01

    Background Network inference methods reconstruct mathematical models of molecular or genetic networks directly from experimental data sets. We have previously reported a mathematical method which is exclusively data-driven, does not involve any heuristic decisions within the reconstruction process, and deliveres all possible alternative minimal networks in terms of simple place/transition Petri nets that are consistent with a given discrete time series data set. Results We fundamentally extended the previously published algorithm to consider catalysis and inhibition of the reactions that occur in the underlying network. The results of the reconstruction algorithm are encoded in the form of an extended Petri net involving control arcs. This allows the consideration of processes involving mass flow and/or regulatory interactions. As a non-trivial test case, the phosphate regulatory network of enterobacteria was reconstructed using in silico-generated time-series data sets on wild-type and in silico mutants. Conclusions The new exact algorithm reconstructs extended Petri nets from time series data sets by finding all alternative minimal networks that are consistent with the data. It suggested alternative molecular mechanisms for certain reactions in the network. The algorithm is useful to combine data from wild-type and mutant cells and may potentially integrate physiological, biochemical, pharmacological, and genetic data in the form of a single model. PMID:21762503

  15. Population pharmacokinetics of methylphenidate hydrochloride extended-release multiple-layer beads in pediatric subjects with attention deficit hyperactivity disorder

    PubMed Central

    Teuscher, Nathan S; Adjei, Akwete; Findling, Robert L; Greenhill, Laurence L; Kupper, Robert J; Wigal, Sharon

    2015-01-01

    A new multilayer-bead formulation of extended-release methylphenidate hydrochloride (MPH-MLR) has been evaluated in pharmacokinetic studies in healthy adults and in Phase III efficacy/safety studies in children and adolescents with attention deficit hyperactivity disorder (ADHD). Using available data in healthy adults, a two-input, one-compartment, first-order elimination population pharmacokinetic model was developed using nonlinear mixed-effect modeling. The model was then extended to pediatric subjects, and was found to adequately describe plasma concentration–time data for this population. A pharmacokinetic/pharmacodynamic model was also developed using change from baseline in the ADHD Rating Scale (ADHD-RS)-IV total scores from a pediatric Phase III trial and simulated plasma concentration–time data. During simulations for each MPH-MLR dose level (10–80 mg), increased body weight resulted in decreased maximum concentration. Additionally, as maximum concentration increased, ADHD-RS-IV total score improved (decreased). Knowledge of the relationship between dose, body weight, and clinical response following the administration of MPH-MLR in children and adolescents may be useful for clinicians selecting initial dosing of MPH-MLR. Additional study is needed to confirm these results. PMID:26060393

  16. Simultaneous multiple-depths en-face optical coherence tomography using multiple signal excitation of acousto-optic deflectors.

    PubMed

    Zurauskas, Mantas; Rogers, John; Podoleanu, Adrian Gh

    2013-01-28

    We present a novel low-coherence interferometer configuration, equipped with acousto-optic deflectors that can be used to simultaneously acquire up to eight time domain optical coherence tomography en-face images. The capabilities of the configuration are evaluated in terms of depth resolution, signal to noise ratio and crosstalk. Then the configuration is employed to demonstrate simultaneous en-face optical coherence tomography imaging at five different depths in a specimen of armadillidium vulgare. PMID:23389175

  17. Stretchable Multichannel Electromyography Sensor Array Covering Large Area for Controlling Home Electronics with Distinguishable Signals from Multiple Muscles.

    PubMed

    Kim, Namyun; Lim, Taehoon; Song, Kwangsun; Yang, Sung; Lee, Jongho

    2016-08-17

    Physiological signals provide important information for biomedical applications and, more recently, in the form of wearable electronics for active interactions between bodies and external environments. Multiple physiological sensors are often required to map distinct signals from multiple points over large areas for more diverse applications. In this paper, we present a reusable, multichannel, surface electromyography (EMG) sensor array that covers multiple muscles over relatively large areas, with compliant designs that provide different levels of stiffness for repetitive uses, without backing layers. Mechanical and electrical characteristics along with distinct measurements from different muscles demonstrate the feasibility of the concept. The results should be useful to actively control devices in the environment with one array of wearable sensors, as demonstrated with home electronics. PMID:27500864

  18. Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers.

    PubMed

    Hayes, Michael P; Roman, David L

    2016-05-01

    Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling networks by terminating signals produced by active Gα subunits. RGS17, a member of the RZ subfamily of RGS proteins, is typically only expressed in appreciable amounts in the human central nervous system, but previous works have shown that RGS17 expression is selectively upregulated in a number of malignancies, including lung, breast, prostate, and hepatocellular carcinoma. In addition, this upregulation of RGS17 is associated with a more aggressive cancer phenotype, as increased proliferation, migration, and invasion are observed. Conversely, decreased RGS17 expression diminishes the response of ovarian cancer cells to agents commonly used during chemotherapy. These somewhat contradictory roles of RGS17 in cancer highlight the need for selective, high-affinity inhibitors of RGS17 to use as chemical probes to further the understanding of RGS17 biology. Based on current evidence, these compounds could potentially have clinical utility as novel chemotherapeutics in the treatment of lung, prostate, breast, and liver cancers. Recent advances in screening technologies to identify potential inhibitors coupled with increasing knowledge of the structural requirements of RGS-Gα protein-protein interaction inhibitors make the future of drug discovery efforts targeting RGS17 promising. This review highlights recent findings related to RGS17 as both a canonical and atypical RGS protein, its role in various human disease states, and offers insights on small molecule inhibition of RGS17. PMID:26928451

  19. Extending the Convergence of Canonical WNT Signaling and Classic Cancer Pathways for Treatment of Malignant Peripheral Nerve Sheath Tumors

    PubMed Central

    Reilly, Karlyne M.

    2016-01-01

    Summary Malignant peripheral nerve sheath tumors (MPNSTs) are incurable tumors of the Schwann cell lineage that progress unpredictably from benign plexiform neurofibromas (PNFs). In this issue of Cancer Discovery Watson and colleagues (1) use an insertional mutagenesis screen combined with network analysis to identify the canonical Wnt signaling pathway as an important potential biomarker of tumor progression and target for combination therapy in MPNSTs. PMID:23749527

  20. The application of multiple biophysical cues to engineer functional neocartilage for treatment of osteoarthritis. Part II: signal transduction.

    PubMed

    Brady, Mariea A; Waldman, Stephen D; Ethier, C Ross

    2015-02-01

    The unique mechanoelectrochemical environment of cartilage has motivated researchers to investigate the effect of multiple biophysical cues, including mechanical, magnetic, and electrical stimulation, on chondrocyte biology. It is well established that biophysical stimuli promote chondrocyte proliferation, differentiation, and maturation within "biological windows" of defined dose parameters, including mode, frequency, magnitude, and duration of stimuli (see companion review Part I: Cellular Response). However, the underlying molecular mechanisms and signal transduction pathways activated in response to multiple biophysical stimuli remain to be elucidated. Understanding the mechanisms of biophysical signal transduction will deepen knowledge of tissue organogenesis, remodeling, and regeneration and aiding in the treatment of pathologies such as osteoarthritis. Further, this knowledge will provide the tissue engineer with a potent toolset to manipulate and control cell fate and subsequently develop functional replacement cartilage. The aim of this article is to review chondrocyte signal transduction pathways in response to mechanical, magnetic, and electrical cues. Signal transduction does not occur along a single pathway; rather a number of parallel pathways appear to be activated, with calcium signaling apparently common to all three types of stimuli, though there are different modes of activation. Current tissue engineering strategies, such as the development of "smart" functionalized biomaterials that enable the delivery of growth factors or integration of conjugated nanoparticles, may further benefit from targeting known signal transduction pathways in combination with external biophysical cues. PMID:25065615

  1. Quantitative solid-state 13C NMR with signal enhancement by multiple cross polarization

    NASA Astrophysics Data System (ADS)

    Johnson, Robert L.; Schmidt-Rohr, Klaus

    2014-02-01

    A simple new method is presented that yields quantitative solid-state magic-angle spinning (MAS) 13C NMR spectra of organic materials with good signal-to-noise ratios. It achieves long (>10 ms) cross polarization (CP) from 1H without significant magnetization losses due to relaxation and with a moderate duty cycle of the radio-frequency irradiation, by multiple 1-ms CP periods alternating with 1H spin-lattice relaxation periods that repolarize the protons. The new method incorporates previous techniques that yield less distorted CP/MAS spectra, such as a linear variation (“ramp”) of the radio-frequency field strength, and it overcomes their main limitation, which is T1ρ relaxation of the spin-locked 1H magnetization. The ramp of the radio-frequency field strength and the asymptotic limit of cross polarization makes the spectral intensity quite insensitive to the exact field strengths used. The new multiCP pulse sequence is a “drop-in” replacement for previous CP methods and produces no additional data-processing burden. Compared to the only reliable quantitative 13C NMR method for unlabeled solids previously available, namely direct-polarization NMR, the measuring time is reduced by more than a factor of 50, enabling higher-throughput quantitative NMR studies. The new multiCP technique is validated with 14-kHz MAS on amino-acid derivatives, plant matter, a highly aromatic humic acid, and carbon materials made by low-temperature pyrolysis.

  2. The extended Beer-Lambert theory for ray tracing modeling of LED chip-scaled packaging application with multiple luminescence materials

    NASA Astrophysics Data System (ADS)

    Yuan, Cadmus C. A.

    2015-12-01

    Optical ray tracing modeling applied Beer-Lambert method in the single luminescence material system to model the white light pattern from blue LED light source. This paper extends such algorithm to a mixed multiple luminescence material system by introducing the equivalent excitation and emission spectrum of individual luminescence materials. The quantum efficiency numbers of individual material and self-absorption of the multiple luminescence material system are considered as well. By this combination, researchers are able to model the luminescence characteristics of LED chip-scaled packaging (CSP), which provides simple process steps and the freedom of the luminescence material geometrical dimension. The method will be first validated by the experimental results. Afterward, a further parametric investigation has been then conducted.

  3. The KLT (Karhunen-Loève Transform) to extend SETI searches to broad-band and extremely feeble signals

    NASA Astrophysics Data System (ADS)

    Maccone, Claudio

    2010-12-01

    The KLT (acronym for Karhunen-Loève Transform) is a mathematical algorithm superior to the classical FFT in many regards: The KLT can filter signals out of the background noise over both wide and narrow bands. This is in sharp contrast to the FFT that rigorously applies to narrow-band signals only. The KLT can be applied to random functions that are non-stationary in time, i.e. whose autocorrelation is a function of the two independent variables t1 and t2 separately. Again, this is a sheer advantage of the KLT over the FFT, inasmuch as the FFT rigorously applies to stationary processes only, i.e. processes whose autocorrelation is a function of the absolute value of the difference of t1 and t2 only. The KLT can detect signals embedded in noise to unbelievably small values of the Signal-to-Noise Ratio (SNR), like 10 -3 or so. This particular feature of the KLT is studied in detail in this paper. An excellent filtering algorithm like the KLT, however, comes with a cost that one must be ready to pay for especially in SETI: its computational burden is much higher than for the FFT. In fact, it can be shown that no fast KLT transform can possibly exist and, for an autocorrelation matrix of size N, the calculations must be of the order of N2, rather than N log( N). Nevertheless, for moderate values of N (in the hundreds), the KLT dominates over the FFT, as shown by the numerical simulations. Finally, an important and recent (2007-2008) development in the KLT theory, called the "Bordered Autocorrelation Method" (BAM), is presented. This BAM-KLT method gets around the difficulty of the N2 brunt calculations and ends up in the following unexpected theorem: the KLT of a feeble sinusoidal carrier embedded into a lot of white stationary noise is given by the Fourier transform of the derivative of the largest KLT eigenvalue with respect to the bordering index. This basic result is fully proved analytically in the final sections of this paper by virtue of a new theorem

  4. Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells

    SciTech Connect

    Voss, Kelsey; Amaya, Moushimi; Mueller, Claudius; Roberts, Brian; Kehn-Hall, Kylene; Bailey, Charles; Petricoin, Emanuel; Narayanan, Aarthi

    2014-11-15

    New World alphaviruses belonging to the family Togaviridae are classified as emerging infectious agents and Category B select agents. Our study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. Infection of human cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Ag-126-mediated inhibition of VEEV was due to potential effects on early and late stages of the infectious process. While expression of viral proteins was down-regulated in Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear distribution of capsid. Finally, Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses. - Highlights: • VEEV infection activated multiple components of the ERK signaling cascade. • Inhibition of ERK activation using Ag-126 inhibited VEEV multiplication. • Activation of ERK by Ceramide C6 increased infectious titers of TC-83. • Ag-126 inhibited virulent strains of all New World alphaviruses. • Ag-126 treatment increased percent survival of infected cells.

  5. Viral binding-induced signaling drives a unique and extended intracellular trafficking pattern during infection of primary monocytes.

    PubMed

    Kim, Jung Heon; Collins-McMillen, Donna; Caposio, Patrizia; Yurochko, Andrew D

    2016-08-01

    We initiated experiments to examine the infection of monocytes postentry. New data show that human cytomegalovirus (HCMV) DNA is detected in the nucleus beginning only at 3 d postinfection in monocytes, compared with 30 min postinfection in fibroblasts and endothelial cells, suggesting that HCMV nuclear translocation in monocytes is distinct from that seen in other cell types. We now show that HCMV is initially retained in early endosomes and then moves sequentially to the trans-Golgi network (TGN) and recycling endosomes before nuclear translocation. HCMV is retained initially as a mature particle before deenvelopment in recycling endosomes. Disruption of the TGN significantly reduced nuclear translocation of viral DNA, and HCMV nuclear translocation in infected monocytes was observed only when correct gH/gL/UL128-131/integrin/c-Src signaling occurred. Taken together, our findings show that viral binding of the gH/gL/UL128-131 complex to integrins and the ensuing c-Src signaling drive a unique nuclear translocation pattern that promotes productive infection and avoids viral degradation, suggesting that it represents an additional viral evasion/survival strategy. PMID:27432979

  6. Multiple-Trellis-Coded Modulation

    NASA Technical Reports Server (NTRS)

    Divsalar, D.; Simon, M. K.

    1990-01-01

    Theoretical gain over simple multiple-phase-shift keying at least 2 to 3 decibels. Multiple-trellis-coded modulation scheme combined with M-ary modulation shows theoretically to yield asymptotic gains in performance over uncoded multiple-phase-shift keying, while employing symmetric multiple-phase-shift signal constellations and avoiding code catastrophe. Suitable for satellite and terrestrial-mobile/satellite communications or other communications requiring burst-error correction. Extended to such higher dimensional modulations as quadrature amplitude modulation.

  7. Statistics of cellular signal transduction as a race to the nucleus by multiple random walkers in compartment/phosphorylation space

    PubMed Central

    Lu, Ting; Shen, Tongye; Zong, Chenghang; Hasty, Jeff; Wolynes, Peter G.

    2006-01-01

    Cellular signal transduction often involves a reaction network of phosphorylation and transport events arranged with a ladder topology. If we keep track of the location of the phosphate groups describing an abstract state space, a simple model of signal transduction involving enzymes can be mapped on to a problem of how multiple biased random walkers compete to reach their target in the nucleus yielding a signal. Here, the first passage time probability and the survival probability for multiple walkers can be used to characterize the response of the network. The statistics of the first passage through the network has an asymmetric distribution with a long tail arising from the hierarchical structure of the network. This distribution implies a significant difference between the mean and the most probable signal transduction time. The response patterns for various external inputs generated by our model agree with recent experiments. In addition, the model predicts that there is an optimal phosphorylation enzyme concentration for rapid signal transduction. PMID:17071742

  8. Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity.

    PubMed

    Valvezan, Alexander J; Zhang, Fang; Diehl, J Alan; Klein, Peter S

    2012-02-01

    Glycogen synthase kinase-3 (GSK-3) is essential for many signaling pathways and cellular processes. As Adenomatous Polyposis Coli (APC) functions in many of the same processes, we investigated a role for APC in the regulation of GSK-3-dependent signaling. We find that APC directly enhances GSK-3 activity. Furthermore, knockdown of APC mimics inhibition of GSK-3 by reducing phosphorylation of glycogen synthase and by activating mTOR, revealing novel roles for APC in the regulation of these enzymes. Wnt signaling inhibits GSK-3 through an unknown mechanism, and this results in both stabilization of β-catenin and activation of mTOR. We therefore hypothesized that Wnts may regulate GSK-3 by disrupting the interaction between APC and the Axin-GSK-3 complex. We find that Wnts rapidly induce APC dissociation from Axin, correlating with β-catenin stabilization. Furthermore, Axin interaction with the Wnt co-receptor LRP6 causes APC dissociation from Axin. We propose that APC regulates multiple signaling pathways by enhancing GSK-3 activity, and that Wnts induce APC dissociation from Axin to reduce GSK-3 activity and activate downstream signaling. APC regulation of GSK-3 also provides a novel mechanism for Wnt regulation of multiple downstream effectors, including β-catenin and mTOR. PMID:22184111

  9. Multiple feature extraction and classification of electroencephalograph signal for Alzheimers' with spectrum and bispectrum

    NASA Astrophysics Data System (ADS)

    Wang, Ruofan; Wang, Jiang; Li, Shunan; Yu, Haitao; Deng, Bin; Wei, Xile

    2015-01-01

    In this paper, we have combined experimental neurophysiologic recording and statistical analysis to investigate the nonlinear characteristic and the cognitive function of the brain. Spectrum and bispectrum analyses are proposed to extract multiple effective features of electroencephalograph (EEG) signals from Alzheimer's disease (AD) patients and further applied to distinguish AD patients from the normal controls. Spectral analysis based on autoregressive Burg method is first used to quantify the power distribution of EEG series in the frequency domain. Compared to the control group, the relative power spectral density of AD group is significantly higher in the theta frequency band, while lower in the alpha frequency bands. In addition, median frequency of spectrum is decreased, and spectral entropy ratio of these two frequency bands undergoes drastic changes at the P3 electrode in the central-parietal brain region, implying that the electrophysiological behavior in AD brain is much slower and less irregular. In order to explore the nonlinear high order information, bispectral analysis which measures the complexity of phase-coupling is further applied to P3 electrode in the whole frequency band. It is demonstrated that less bispectral peaks appear and the amplitudes of peaks fall, suggesting a decrease of non-Gaussianity and nonlinearity of EEG in ADs. Notably, the application of this method to five brain regions shows higher concentration of the weighted center of bispectrum and lower complexity reflecting phase-coupling by bispectral entropy. Based on spectrum and bispectrum analyses, six efficient features are extracted and then applied to discriminate AD from the normal in the five brain regions. The classification results indicate that all these features could differentiate AD patients from the normal controls with a maximum accuracy of 90.2%. Particularly, different brain regions are sensitive to different features. Moreover, the optimal combination of

  10. Seasonal Climate Signals in Multiple Tree-Ring Parameters: A Pilot Study of Pinus ponderosa in the Columbia River Basin

    NASA Astrophysics Data System (ADS)

    Dannenberg, M.; Wise, E. K.; Keung, J. H.

    2014-12-01

    Proxy-based reconstructions of past climate have played an integral role in assessments of historical climate change, and tree-ring widths (TRW) have a long history of use in this paleoclimate research due to their annual resolution, widespread availability, and sensitivity of growth processes to variation in temperature and water availability. Increasingly, studies have shown that additional tree-ring metrics—including earlywood and latewood widths (EW and LW, respectively), maximum latewood density, and the intensity of reflected blue light from latewood (BI)—can provide additional information on seasonal climatic variability that is not present in TRW alone due to different processes that affect growth in different parts of the growing season. Studies of these additional tree-ring metrics highlight their utility in climate reconstructions, but to date they have mostly been limited to a few tree species and regions. Here, we extend the range of previous studies on alternative tree-ring metrics by evaluating the seasonal climate signals in TRW, EW, LW, and BI of Pinus ponderosa at six semiarid sites surrounding the Columbia River basin in the U.S. Pacific Northwest (PNW). Cores from each site were cross-dated and EW, LW, and TRW were measured using standard dendrochronological procedures. BI was obtained using a high-resolution flatbed scanner and CooRecorder software. To evaluate the unique climate processes and seasonalities contributing to different dendrochronological metrics, monthly temperature and precipitation from each site were obtained from the PRISM climate model and were correlated with each of the tree-ring metrics using the MATLAB program SEASCORR. We also evaluate the potential of using multiple tree-ring metrics (rather than a single proxy) in reconstructions of precipitation in the PNW. Initial results suggest that 1) tree growth at each site is water-limited but with substantial differences among the sites in the strength and seasonality of

  11. Involvement of Peripheral Nerves in the Transgenic PLP-α-Syn Model of Multiple System Atrophy: Extending the Phenotype

    PubMed Central

    Kuzdas-Wood, Daniela; Irschick, Regina; Theurl, Markus; Malsch, Philipp; Mair, Norbert; Mantinger, Christine; Wanschitz, Julia; Klimaschewski, Lars; Poewe, Werner; Stefanova, Nadia; Wenning, Gregor K.

    2015-01-01

    Multiple system atrophy (MSA) is a fatal, rapidly progressive neurodegenerative disease with (oligodendro-)glial cytoplasmic α-synuclein (α-syn) inclusions (GCIs). Peripheral neuropathies have been reported in up to 40% of MSA patients, the cause remaining unclear. In a transgenic MSA mouse model featuring GCI-like inclusion pathology based on PLP-promoter driven overexpression of human α-syn in oligodendroglia motor and non-motor deficits are associated with MSA-like neurodegeneration. Since α-syn is also expressed in Schwann cells we aimed to investigate whether peripheral nerves are anatomically and functionally affected in the PLP-α-syn MSA mouse model. Results To this end, heat/cold as well as mechanical sensitivity tests were performed. Furthermore, in vivo and ex vivo nerve conduction and the G-ratios of the sciatic nerve were analyzed, and thermosensitive ion channel mRNA expression in dorsal root ganglia (DRG) was assessed. The presence of human α-syn in Schwann cells was associated with subtle behavioral impairments. The G-ratio of the sciatic nerve, the conduction velocity of myelinated and unmyelinated primary afferents and the expression of thermosensitive ion channels in the sensory neurons, however, were similar to wildtype mice. Conclusion Our results suggest that the PNS appears to be affected by Schwann cell α-syn deposits in the PLP-α-syn MSA mouse model. However, there was no consistent evidence for functional PNS perturbations resulting from such α-syn aggregates suggesting a more central cause of the observed behavioral abnormalities. Nonetheless, our results do not exclude a causal role of α-syn in the pathogenesis of MSA associated peripheral neuropathy. PMID:26496712

  12. Destruction complex function in the Wnt signaling pathway of Drosophila requires multiple interactions between Adenomatous polyposis coli 2 and Armadillo.

    PubMed

    Kunttas-Tatli, Ezgi; Zhou, Meng-Ning; Zimmerman, Sandra; Molinar, Olivia; Zhouzheng, Fangyuan; Carter, Krista; Kapur, Megha; Cheatle, Alys; Decal, Richard; McCartney, Brooke M

    2012-03-01

    The tumor suppressor Adenomatous polyposis coli (APC) negatively regulates Wnt signaling through its activity in the destruction complex. APC binds directly to the main effector of the pathway, β-catenin (βcat, Drosophila Armadillo), and helps to target it for degradation. In vitro studies demonstrated that a nonphosphorylated 20-amino-acid repeat (20R) of APC binds to βcat through the N-terminal extended region of a 20R. When phosphorylated, the phospho-region of an APC 20R also binds βcat and the affinity is significantly increased. These distinct APC-βcat interactions suggest different models for the sequential steps of destruction complex activity. However, the in vivo role of 20R phosphorylation and extended region interactions has not been rigorously tested. Here we investigated the functional role of these molecular interactions by making targeted mutations in Drosophila melanogaster APC2 that disrupt phosphorylation and extended region interactions and deletion mutants missing the Armadillo binding repeats. We tested the ability of these mutants to regulate Wnt signaling in APC2 null and in APC2 APC1 double-null embryos. Overall, our in vivo data support the role of phosphorylation and extended region interactions in APC2's destruction complex function, but suggest that the extended region plays a more significant functional role. Furthermore, we show that the Drosophila 20Rs with homology to the vertebrate APC repeats that have the highest affinity for βcat are functionally dispensable, contrary to biochemical predictions. Finally, for some mutants, destruction complex function was dependent on APC1, suggesting that APC2 and APC1 may act cooperatively in the destruction complex. PMID:22174073

  13. A calmodulin-binding/CGCG box DNA-binding protein family involved in multiple signaling pathways in plants

    NASA Technical Reports Server (NTRS)

    Yang, Tianbao; Poovaiah, B. W.

    2002-01-01

    We reported earlier that the tobacco early ethylene-responsive gene NtER1 encodes a calmodulin-binding protein (Yang, T., and Poovaiah, B. W. (2000) J. Biol. Chem. 275, 38467-38473). Here we demonstrate that there is one NtER1 homolog as well as five related genes in Arabidopsis. These six genes are rapidly and differentially induced by environmental signals such as temperature extremes, UVB, salt, and wounding; hormones such as ethylene and abscisic acid; and signal molecules such as methyl jasmonate, H(2)O(2), and salicylic acid. Hence, they were designated as AtSR1-6 (Arabidopsis thaliana signal-responsive genes). Ca(2+)/calmodulin binds to all AtSRs, and their calmodulin-binding regions are located on a conserved basic amphiphilic alpha-helical motif in the C terminus. AtSR1 targets the nucleus and specifically recognizes a novel 6-bp CGCG box (A/C/G)CGCG(G/T/C). The multiple CGCG cis-elements are found in promoters of genes such as those involved in ethylene signaling, abscisic acid signaling, and light signal perception. The DNA-binding domain in AtSR1 is located on the N-terminal 146 bp where all AtSR1-related proteins share high similarity but have no similarity to other known DNA-binding proteins. The calmodulin-binding nuclear proteins isolated from wounded leaves exhibit specific CGCG box DNA binding activities. These results suggest that the AtSR gene family encodes a family of calmodulin-binding/DNA-binding proteins involved in multiple signal transduction pathways in plants.

  14. Sensitive SERS detection of DNA methyltransferase by target triggering primer generation-based multiple signal amplification strategy.

    PubMed

    Li, Ying; Yu, Chuanfeng; Han, Huixia; Zhao, Caisheng; Zhang, Xiaoru

    2016-07-15

    A novel and sensitive surface-enhanced Raman scattering (SERS) method is proposed for the assay of DNA methyltransferase (MTase) activity and evaluation of inhibitors by developing a target triggering primer generation-based multiple signal amplification strategy. By using of a duplex substrate for Dam MTase, two hairpin templates and a Raman probe, multiple signal amplification mode is achieved. Once recognized by Dam MTase, the duplex substrate can be cleaved by Dpn I endonuclease and two primers are released for triggering the multiple signal amplification reaction. Consequently, a wide dynamic range and remarkably high sensitivity are obtained under isothermal conditions. The detection limit is 2.57×10(-4)UmL(-1). This assay exhibits an excellent selectivity and is successfully applied in the screening of inhibitors for Dam MTase. In addition, this novel sensing system is potentially universal as the recognition element can be conveniently designed for other target analytes by changing the substrate of DNA MTase. PMID:26926592

  15. Global Transcription Profiling Reveals Multiple Sugar Signal Transduction Mechanisms in ArabidopsisW⃞

    PubMed Central

    Price, John; Laxmi, Ashverya; St. Martin, Steven K.; Jang, Jyan-Chyun

    2004-01-01

    Complex and interconnected signaling networks allow organisms to control cell division, growth, differentiation, or programmed cell death in response to metabolic and environmental cues. In plants, it is known that sugar and nitrogen are critical nutrient signals; however, our understanding of the molecular mechanisms underlying nutrient signal transduction is very limited. To begin unraveling complex sugar signaling networks in plants, DNA microarray analysis was used to determine the effects of glucose and inorganic nitrogen source on gene expression on a global scale in Arabidopsis thaliana. In whole seedling tissue, glucose is a more potent signal in regulating transcription than inorganic nitrogen. In fact, other than genes associated with nitrate assimilation, glucose had a greater effect in regulating nitrogen metabolic genes than nitrogen itself. Glucose also regulated a broader range of genes, including genes associated with carbohydrate metabolism, signal transduction, and metabolite transport. In addition, a large number of stress responsive genes were also induced by glucose, indicating a role of sugar in environmental responses. Cluster analysis revealed significant interaction between glucose and nitrogen in regulating gene expression because glucose can modulate the effects of nitrogen and vise versa. Intriguingly, cycloheximide treatment appeared to disrupt glucose induction more than glucose repression, suggesting that de novo protein synthesis is an intermediary event required before most glucose induction can occur. Cross talk between sugar and ethylene signaling may take place on the transcriptional level because several ethylene biosynthetic and signal transduction genes are repressed by glucose, and the repression is largely unaffected by cycloheximide. Collectively, our global expression data strongly support the idea that glucose and inorganic nitrogen act as both metabolites and signaling molecules. PMID:15273295

  16. Demonstration of digital phase-sensitive boosting to extend signal reach for long-haul WDM systems using optical phase-conjugated copy.

    PubMed

    Tian, Yue; Huang, Yue-Kai; Zhang, Shaoliang; Prucnal, Paul R; Wang, Ting

    2013-02-25

    We demonstrate a hybrid optical/digital phase-sensitive boosting (PSB) technique for long-haul wavelength division multiplexing (WDM) transmission systems. The approach uses four-wave mixing (FWM) to generate a phase-conjugated idler alongside the original signal. At the receiver, the signal and idler are jointly detected, and the phases of the idler symbols are conjugated and summed with the signal symbols to suppress noise and nonlinear phase distortion. The proposed hybrid PSB scheme is independent of modulation format and does not require an optical phase-locked loop to achieve phase matching required by conventional phase-sensitive amplifiers. Our simulation and experimental results of 112-Gb/s dual-polarization quadrature phase-shift-keying (DP-QPSK) transmission confirmed the principle of the PSB scheme, attaining a Q-factor improvement of 2.4 dB over conventional single-channel transmission after 4,800 km of dispersion-managed fiber (DMF) link at the expense of 50% reduction in spectral efficiency and extending the system reach by 60% to 7,680 km. PMID:23482044

  17. Multiple logistic regression model of signalling practices of drivers on urban highways

    NASA Astrophysics Data System (ADS)

    Puan, Othman Che; Ibrahim, Muttaka Na'iya; Zakaria, Rozana

    2015-05-01

    Giving signal is a way of informing other road users, especially to the conflicting drivers, the intention of a driver to change his/her movement course. Other users are exposed to hazard situation and risks of accident if the driver who changes his/her course failed to give signal as required. This paper describes the application of logistic regression model for the analysis of driver's signalling practices on multilane highways based on possible factors affecting driver's decision such as driver's gender, vehicle's type, vehicle's speed and traffic flow intensity. Data pertaining to the analysis of such factors were collected manually. More than 2000 drivers who have performed a lane changing manoeuvre while driving on two sections of multilane highways were observed. Finding from the study shows that relatively a large proportion of drivers failed to give any signals when changing lane. The result of the analysis indicates that although the proportion of the drivers who failed to provide signal prior to lane changing manoeuvre is high, the degree of compliances of the female drivers is better than the male drivers. A binary logistic model was developed to represent the probability of a driver to provide signal indication prior to lane changing manoeuvre. The model indicates that driver's gender, type of vehicle's driven, speed of vehicle and traffic volume influence the driver's decision to provide a signal indication prior to a lane changing manoeuvre on a multilane urban highway. In terms of types of vehicles driven, about 97% of motorcyclists failed to comply with the signal indication requirement. The proportion of non-compliance drivers under stable traffic flow conditions is much higher than when the flow is relatively heavy. This is consistent with the data which indicates a high degree of non-compliances when the average speed of the traffic stream is relatively high.

  18. Perivascular innervation: A multiplicity of roles in vasomotor control and myoendothelial signaling

    PubMed Central

    Westcott, Erika B.; Segal, Steven S.

    2013-01-01

    The control of vascular resistance and tissue perfusion reflect coordinated changes in the diameter of feed arteries and the arteriolar networks they supply. Against a background of myogenic tone and metabolic demand, vasoactive signals originating from perivascular sympathetic and sensory nerves are integrated with endothelium-derived signals to produce vasodilation or vasoconstriction. PVNs release adrenergic, cholinergic, peptidergic, purinergic, and nitrergic neurotransmitters that lead to SMC contraction or relaxation via their actions on SMCs, ECs, or other PVNs. ECs release autacoids that can have opposing actions on SMCs. Respective cell layers are connected directly to each other through GJs at discrete sites via MEJs projecting through holes in the IEL. Whereas studies of intercellular communication in the vascular wall have centered on endothelium-derived signals that govern SMC relaxation, attention has increasingly focused on signaling from SMCs to ECs. Thus, via MEJs, neurotransmission from PVNs can evoke distinct responses from ECs subsequent to acting on SMCs. To integrate this emerging area of investigation in light of vasomotor control, the present review synthesizes current understanding of signaling events that originate within SMCs in response to perivascular neurotransmission in light of EC feedback. Though often ignored in studies of the resistance vasculature, PVNs are integral to blood flow control and can provide a physiological stimulus for myoendothelial communication. Greater understanding of these underlying signaling events and how they may be affected by aging and disease will provide new approaches for selective therapeutic interventions. PMID:23289720

  19. Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment.

    PubMed

    Strunk, Ann-Kathrin; Ciesek, Sandra; Schmidt, Julius J; Kühn, Christian; Hoeper, Marius M; Welte, Tobias; Kielstein, Jan T

    2016-01-01

    The dosing of drugs in critically ill patients undergoing renal replacement therapy is based on limited data. We report for the first time single- and multiple-dose pharmacokinetics of ethambutol (EMB), which is cleared renally to 80%, and rifampicin (RIF), which is cleared renally to <30%, in a patient requiring both extracorporeal membrane oxygenation (ECMO) and renal replacement therapy. Extended dialysis removed a considerable amount of both EMB and RIF, with a dialyser plasma clearance ranging between 37 and 95 ml/min for EMB and between 39 and 53 ml/min for RIF. The EMB peak level (3h after a 2-h infusion) using a dose of 1000 mg/day on the first day of treatment was 2.3mg/l, which is in the low therapeutic range (2-5mg/l). Doubling the dose to 2000 mg/day resulted in peak levels slightly to markedly above the recommended range. There was no detectable effect of the ECMO membrane on the removal of both drugs. After an initial dose as for patients without renal impairment (15 mg/kg/day), therapeutic drug monitoring should be used to guide EMB dosing in patients undergoing extended daily dialysis. PMID:26518065

  20. Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types.

    PubMed

    Chartier, Cecile; Raval, Janak; Axelrod, Fumiko; Bond, Chris; Cain, Jennifer; Dee-Hoskins, Cristina; Ma, Shirley; Fischer, Marcus M; Shah, Jalpa; Wei, Jie; Ji, May; Lam, Andrew; Stroud, Michelle; Yen, Wan-Ching; Yeung, Pete; Cancilla, Belinda; O'Young, Gilbert; Wang, Min; Kapoun, Ann M; Lewicki, John; Hoey, Timothy; Gurney, Austin

    2016-02-01

    Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. PMID:26719531

  1. Application of the multiple signal classification (MUSIC) method for one-pulse burst-echo Doppler sonar data

    NASA Astrophysics Data System (ADS)

    Iwata, Tetsuo; Goto, Yoji; Susaki, Hironori

    2001-12-01

    In order to estimate ship velocity, we have applied the multiple signal classification (MUSIC) method to one-pulse burst-echo Doppler sonar data. The MUSIC method enabled us to estimate the Doppler frequency shift precisely under a low-signal-to-noise ratio (SNR) situation even from a one-pulse burst-echo signal with small data points. In simulation experiments, a signal frequency component of f = 16 Hz could be extracted from N = 128 data-point data under a 40% Gaussian-distributed additive noise with a sampling frequency fs = 2048 Hz. From actual one-pulse burst-echo signal data of N = 128 points, a Doppler frequency shift of Δf = 1.45 kHz, corresponding to a ship velocity 1.76 knots, was clearly detected, the frequency resolution of which was almost impossible to attain by the conventional Fourier transform (FFT) method. We found that the MUSIC method was useful especially for estimating the ship velocity at a very low speed.

  2. A parallel unbalanced digitization architecture to reduce the dynamic range of multiple signals

    NASA Astrophysics Data System (ADS)

    Vallérian, Mathieu; HuÅ£u, Florin; Villemaud, Guillaume; Miscopein, Benoît; Risset, Tanguy

    2016-05-01

    Technologies employed in urban sensor networks are permanently evolving, and thus the gateways employed to collect data in such kind of networks have to be very flexible in order to be compliant with the new communication standards. A convenient way to do that is to digitize all the received signals in one shot and then to digitally perform the signal processing, as it is done in software-defined radio (SDR). All signals can be emitted with very different features (bandwidth, modulation type, and power level) in order to respond to the various propagation conditions. Their difference in terms of power levels is a problem when digitizing them together, as no current commercial analog-to-digital converter (ADC) can provide a fine enough resolution to digitize this high dynamic range between the weakest possible signal in the presence of a stronger signal. This paper presents an RF front end receiver architecture capable of handling this problem by using two ADCs of lower resolutions. The architecture is validated through a set of simulations using Keysight's ADS software. The main validation criterion is the bit error rate comparison with a classical receiver.

  3. Control of IL-17 receptor signaling and tissue inflammation by the p38α–MKP-1 signaling axis in a mouse model of multiple sclerosis

    PubMed Central

    Vogel, Peter; Chi, Hongbo

    2015-01-01

    T helper 17 (TH17) cells are CD4+ T cells that secrete the proinflammatory cytokine interleukin-17 (IL-17) and that play a key pathogenic role in autoimmune diseases. Through inducible and tissue-specific deletion systems, we described the temporal and cell type–specific roles of the mitogen-activated protein kinase (MAPK) p38α in mediating TH17 cell–induced tissue inflammation. Inducible deletion of Mapk14 (which encodes p38α) after the onset of experimental autoimmune encephalomyelitis (EAE), a murine model for human multiple sclerosis, protected mice from inflammation. Furthermore, the severity of EAE was markedly reduced in mice with specific loss of p38α in neuroectoderm-derived cells, including astrocytes, an effect that was associated with defective production of chemokines and decreased infiltration of the target tissue by immune cells. p38α linked IL-17 receptor (IL-17R) signaling to the expression of genes encoding proinflammatory chemokines and cytokines. Mice that lacked MAPK phosphatase 1 (MKP-1), an inhibitor of p38α, had exacerbated EAE and enhanced expression of IL-17R–dependent genes. Our results suggest that the p38α–MKP-1 signaling axis links IL-17R signaling in tissue-resident cells to autoimmune inflammation dependent on infiltrating TH17 cells. PMID:25737586

  4. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

    PubMed Central

    Amin Al Olama, Ali; Dadaev, Tokhir; Hazelett, Dennis J.; Li, Qiuyan; Leongamornlert, Daniel; Saunders, Edward J.; Stephens, Sarah; Cieza-Borrella, Clara; Whitmore, Ian; Benlloch Garcia, Sara; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schumacher, Fredrick; Haiman, Christopher A.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; Mcdonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokołorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Park, Jong Y.; Sellers, Thomas; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Clements, Judith A.; Spurdle, Amanda; Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Govindasami, Koveela; Guy, Michelle; Lophatonanon, Artitaya; Muir, Kenneth; Viñuela, Ana; Brown, Andrew A.; Freedman, Mathew; Conti, David V.; Easton, Douglas; Coetzee, Gerhard A.; Eeles, Rosalind A.; Kote-Jarai, Zsofia

    2015-01-01

    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region. PMID:26025378

  5. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans.

    PubMed

    Amin Al Olama, Ali; Dadaev, Tokhir; Hazelett, Dennis J; Li, Qiuyan; Leongamornlert, Daniel; Saunders, Edward J; Stephens, Sarah; Cieza-Borrella, Clara; Whitmore, Ian; Benlloch Garcia, Sara; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schumacher, Fredrick; Haiman, Christopher A; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; Mcdonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokołorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Park, Jong Y; Sellers, Thomas; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Clements, Judith A; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Govindasami, Koveela; Guy, Michelle; Lophatonanon, Artitaya; Muir, Kenneth; Viñuela, Ana; Brown, Andrew A; Freedman, Mathew; Conti, David V; Easton, Douglas; Coetzee, Gerhard A; Eeles, Rosalind A; Kote-Jarai, Zsofia

    2015-10-01

    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region. PMID:26025378

  6. Pituitary Adenylate Cyclase-activating Polypeptide (PACAP)/PAC1HOP1 Receptor Activation Coordinates Multiple Neurotrophic Signaling Pathways

    PubMed Central

    May, Victor; Lutz, Eve; MacKenzie, Christopher; Schutz, Kristin C.; Dozark, Kate; Braas, Karen M.

    2010-01-01

    MAPK and Akt pathways are predominant mediators of trophic signaling for many neuronal systems. Among the vasoactive intestinal peptide/secretin/glucagon family of related peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) binding to specific PAC1 receptor isoforms can engage multiple signaling pathways and promote neuroprotection through mechanisms that are not well understood. Using a primary sympathetic neuronal system, the current studies demonstrate that PACAP activation of PAC1HOP1 receptors engages both MAPK and Akt neurotrophic pathways in an integrated program to facilitate neuronal survival after growth factor withdrawal. PACAP not only stimulated prosurvival ERK1/2 and ERK5 activation but also abrogated SAPK/JNK and p38 MAPK signaling in parallel. In contrast to the potent and rapid effects of PACAP in ERK1/2 phosphorylation, PACAP stimulated Akt phosphorylation in a late phase of PAC1HOP1 receptor signaling. From inhibitor and immunoprecipitation analyses, the PACAP/PAC1HOP1 receptor-mediated Akt responses did not represent transactivation mechanisms but appeared to depend on Gαq/phosphatidylinositol 3-kinase γ activity and vesicular internalization pathways. Phosphatidylinositol 3-kinase γ-selective inhibitors blocked PACAP-stimulated Akt phosphorylation in primary neuronal cultures and in PAC1HOP1-overexpressing cell lines; RNA interference-mediated knockdown of the receptor effectors attenuated PACAP-mediated Akt activation. Similarly, perturbation of endocytic pathways also blocked Akt phosphorylation. Between ERK and Akt pathways, PACAP-stimulated Akt signaling was the primary cascade that attenuated cultured neuron apoptosis after growth factor withdrawal. The partitioning of PACAP-mediated Akt signaling in endosomes may be a key mechanism contributing to the high spatial and temporal specificity in signal transduction necessary for survival pathways. PMID:20093365

  7. Objective evaluation of speech signal quality by the prediction of multiple foreground diagnostic acceptability measure attributes.

    PubMed

    Sen, Deep; Lu, W

    2012-05-01

    A methodology is described to objectively diagnose the quality of speech signals by predicting the perceptual detectability of a selected set of distortions. The distortions are a statistically selected subset of the broad number of distortions used in diagnostic acceptability measure (DAM) testing. The justification for such a methodology is established from the analysis of a set of speech signals representing a broad set of distortions and their respective DAM scores. At the heart of the ability to isolate and diagnose the perceptibility of the individual distortions is a physiologically motivated cochlear model. The philosophy and methodology is thus distinct from traditional objective measures that are typically designed to predict mean opinion scores (MOS) using well versed functional psychoacoustic models. Even so, a weighted sum of these objectively predicted set of distortions is able to predict accurate and robust MOS scores, even when the reference speech signals have been subject to the Lombard effect. PMID:22559381

  8. A sequential method for passive detection, characterization, and localization of multiple low probability of intercept LFMCW signals

    NASA Astrophysics Data System (ADS)

    Hamschin, Brandon M.

    A method for passive Detection, Characterization, and Localization (DCL) of multiple low power, Linear Frequency Modulated Continuous Wave (LFMCW) (i.e., Low Probability of Intercept (LPI)) signals is proposed. We demonstrate, via simulation, laboratory, and outdoor experiments, that the method is able to detect and correctly characterize the parameters that define two simultaneous LFMCW signals with probability greater than 90% when the signal to noise ratio is -10 dB or greater. While this performance is compelling, it is far from the Cramer-Rao Lower Bound (CRLB), which we derive, and the performance of the Maximum Likelihood Estimator (MLE), whose performance we simulate. The loss in performance relative to the CRLB and the MLE is the price paid for computational tractability. The LFMCW signal is the focus of this work because of its common use in modern, low-cost radar systems. In contrast to other detection and characterization approaches, such as the MLE and those based on the Wigner-Ville Transform (WVT) or the Wigner-Ville Hough Transform (WVHT), our approach does not begin with a parametric model of the received signal that is specified directly in terms of its LFMCW constituents. Rather, we analyze the signal over time intervals that are short, non-overlapping, and contiguous by modeling it within these intervals as a sum of a small number sinusoidal (i.e., harmonic) components with unknown frequencies, deterministic but unknown amplitudes, unknown order (i.e., number of harmonic components), and unknown noise autocorrelation function. It is this model of the data that makes the solution computationally feasible, but also what leads to a degradation in performance since estimates are not based on the full time series. By modeling the signal in this way, we reliably detect the presence of multiple LFMCW signals in colored noise without the need for prewhitening, efficiently estimate (i.e. , characterize) their parameters, provide estimation error

  9. Nosocomial outbreak of septicaemia in neonatal intensive care unit due to extended spectrum β-lactamase producing Klebsiella pneumoniae showing multiple mechanisms of drug resistance.

    PubMed

    Rastogi, V; Nirwan, P S; Jain, S; Kapil, A

    2010-01-01

    A total of 14 phenotypically similar clinical isolates of Klebsiella pneumoniae, resistant to multiple drugs including cefotaxime and ceftazidime, were isolated from blood of neonates admitted to neonatal intensive care unit (NICU) within a short span of 10 days. Alarmed at the possibility of occurrence of outbreak, a thorough investigation was done. Microbiological sampling of the NICU and labour room (LR) environment yielded 12 K. pneumoniae isolates. The presence of extended spectrum β-lactamase (ESBL) in the clinical and environmental strains was detected by double-disk synergy test (DDST), CLSI phenotypic confirmatory disk diffusion test (PCDDT) and E-test ESBL strips. Amp-C screen (disk) test was done to determine Amp-C β-lactamase production. 100% clinical strains, 57% NICU strains and 80% LR strains were ESBL positive. 57% clinical, 43% NICU and 20% LR strains were Amp-C screen positive. Polymerase chain reaction (PCR) of representative ESBL positive (10 clinical and 5 environmental) strains showed CTX gene and TEM and/or SHV gene in all. K. pneumoniae showing multiple mechanisms of drug resistance was responsible for the outbreak. PMID:20966575

  10. Integrating Multiple Types of Data for Signaling Research: Challenges and Opportunities

    SciTech Connect

    Wiley, H. S.

    2011-02-15

    New technologies promise to provide unprecedented amounts of information that can provide a foundation for creating predictive models of cell signaling pathways. To be useful, however, this information must be integrated into a coherent framework. In addition, the sheer volume of data gathered from the new technologies requires computational approaches for its analysis. Unfortunately, there are many barriers to data integration and analysis, mostly because of a lack of adequate data standards and their inconsistent use by scientists. However, solving the fundamental issues of data sharing will enable the investigation of entirely new areas of cell signaling research.

  11. A low-cost, high-performance, digital signal processor-based lock-in amplifier capable of measuring multiple frequency sweeps simultaneously

    SciTech Connect

    Sonnaillon, Maximiliano Osvaldo; Bonetto, Fabian Jose

    2005-02-01

    A high-performance digital lock-in amplifier implemented in a low-cost digital signal processor (DSP) board is described. This lock in is capable of measuring simultaneously multiple frequencies that change in time as frequency sweeps (chirps). The used 32-bit DSP has enough computing power to generate N=3 simultaneous reference signals and accurately measure the N=3 responses, operating as three lock ins connected in parallel to a linear system. The lock in stores the measured values in memory until they are downloaded to the a personal computer (PC). The lock in works in stand-alone mode and can be programmed and configured through the PC serial port. Downsampling and multiple filter stages were used in order to obtain a sharp roll off and a long time constant in the filters. This makes measurements possible in presence of high-noise levels. Before each measurement, the lock in performs an autocalibration that measures the frequency response of analog output and input circuitry in order to compensate for the departure from ideal operation. Improvements from previous lock-in implementations allow measuring the frequency response of a system in a short time. Furthermore, the proposed implementation can measure how the frequency response changes with time, a characteristic that is very important in our biotechnological application. The number of simultaneous components that the lock in can generate and measure can be extended, without reprogramming, by only using other DSPs of the same family that are code compatible and work at higher clock frequencies.

  12. Signal-on electrochemical detection of antibiotics at zeptomole level based on target-aptamer binding triggered multiple recycling amplification.

    PubMed

    Wang, Hongzhi; Wang, Yu; Liu, Su; Yu, Jinghua; Guo, Yuna; Xu, Ying; Huang, Jiadong

    2016-06-15

    In the work, a signal-on electrochemical DNA sensor based on multiple amplification for ultrasensitive detection of antibiotics has been reported. In the presence of target, the ingeniously designed hairpin probe (HP1) is opened and the polymerase-assisted target recycling amplification is triggered, resulting in autonomous generation of secondary target. It is worth noting that the produced secondary target could not only hybridize with other HP1, but also displace the Helper from the electrode. Consequently, methylene blue labeled HP2 forms a "close" probe structure, and the increase of signal is monitored. The increasing current provides an ultrasensitive electrochemical detection for antibiotics down to 1.3 fM. To our best knowledge, such work is the first report about multiple recycling amplification combing with signal-on sensing strategy, which has been utilized for quantitative determination of antibiotics. It would be further used as a general strategy associated with more analytical techniques toward the detection of a wide spectrum of analytes. Thus, it holds great potential for the development of ultrasensitive biosensing platform for the applications in bioanalysis, disease diagnostics, and clinical biomedicine. PMID:26878484

  13. Multiple inductive signals are involved in the development of the ctenophore Mnemiopsis leidyi

    NASA Technical Reports Server (NTRS)

    Henry, J. Q.; Martindale, M. Q.

    2001-01-01

    Ctenophores possess eight longitudinally arrayed rows of comb plate cilia. Previous intracellular cell lineage analysis has shown that these comb rows are derived from two embryonic lineages, both daughters of the four e(1) micromeres (e(11) and e(12)) and a single daughter of the four m(1) micromeres (the m(12) micromeres). Although isolated e(1) micromeres will spontaneously generate comb plates, cell deletion experiments have shown that no comb plates appear during embryogenesis following the removal of e(1) descendents. Thus, the m(1) lineage requires the inductive interaction of the e(1) lineage to contribute to comb plate formation. Here we show that, although m(12) cells are normally the only m(1) derivatives to contribute to comb plate formation, m(11) cells are capable of generating comb plates in the absence m(12) cells. The reason that m(11) cells do not normally make comb rows may be attributable either to their more remote location relative to critical signaling centers (e.g., e(1) descendants) or to inhibitory signals that may be provided by other nearby cells such as sister cells m(12). In addition, we show that the signals provided by the e(1) lineage are not sufficient for m(1)-derived comb plate formation. Signals provided by endomesodermal progeny of either the E or the M lineages (the 3E or 2M macromeres) are also required. Copyright 2001 Academic Press.

  14. Comprehending Multiple Documents on Scientific Controversies: Effects of Reading Goals and Signaling Rhetorical Relationships

    ERIC Educational Resources Information Center

    Stadtler, Marc; Scharrer, Lisa; Skodzik, Timo; Bromme, Rainer

    2014-01-01

    Understanding conflicts between sources is an inherent part of science text comprehension. We examined whether readers' memories for conflicts and their situational interpretation of conflicts would be affected by reading goals and lexical cue phrases that signal rhetorical relationships. To this end, 198 undergraduates read multiple…

  15. MULTIPLE TRANSCRIPTION-FACTOR GENES ARE EARLY TARGETS OF PHYTOCHROME A SIGNALING

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The phytochrome family of sensory photoreceptors directs adaptational changes in gene expression in response to environmental light signals. Using oligonucleotide microarrays to measure expression profiles in wild-type and phytochrome A (phyA) null-mutant Arabidopsis seedlings, we have shown that 10...

  16. Membrane-anchored Plakoglobins Have Multiple Mechanisms of Action in Wnt Signaling

    PubMed Central

    Klymkowsky, Michael W.; Williams, Bart O.; Barish, Grant D.; Varmus, Harold E.; Vourgourakis, Yanni E.

    1999-01-01

    In Wnt signaling, β-catenin and plakoglobin transduce signals to the nucleus through interactions with TCF-type transcription factors. However, when plakoglobin is artificially engineered to restrict it to the cytoplasm by fusion with the transmembrane domain of connexin (cnxPg), it efficiently induces a Wnt-like axis duplication phenotype in Xenopus. In Xenopus embryos, maternal XTCF3 normally represses ventral expression of the dorsalizing gene Siamois. Two models have been proposed to explain the Wnt-like activity of cnxPg: 1) that cnxPg inhibits the machinery involved in the turnover of cytosolic β-catenin, which then accumulates and inhibits maternal XTCF3, and 2) that cnxPg directly acts to inhibit XTCF3 activity. To distinguish between these models, we created a series of N-terminal deletion mutations of cnxPg and examined their ability to induce an ectopic axis in Xenopus, activate a TCF-responsive reporter (OT), stabilize β-catenin, and colocalize with components of the Wnt signaling pathway. cnxPg does not colocalize with the Wnt pathway component Dishevelled, but it does lead to the redistribution of APC and Axin, two proteins involved in the regulation of β-catenin turnover. Expression of cnxPg increases levels of cytosolic β-catenin; however, this effect does not completely explain its signaling activity. Although cnxPg and Wnt-1 stabilize β-catenin to similar extents, cnxPg activates OT to 10- to 20-fold higher levels than Wnt-1. Moreover, although LEF1 and TCF4 synergize with β-catenin and plakoglobin to activate OT, both suppress the signaling activity of cnxPg. In contrast, XTCF3 suppresses the signaling activity of both β-catenin and cnxPg. Both exogenous XLEF1 and XTCF3 are sequestered in the cytoplasm of Xenopus cells by cnxPg. Based on these data, we conclude that, in addition to its effects on β-catenin, cnxPg interacts with other components of the Wnt pathway, perhaps TCFs, and that these interactions contribute to its signaling

  17. The HAMP Signal Relay Domain Adopts Multiple Conformational States through Collective Piston and Tilt Motions

    PubMed Central

    Zhu, Lizhe; Bolhuis, Peter G.; Vreede, Jocelyne

    2013-01-01

    The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP. PMID:23468603

  18. Brain source localization: A new method based on MUltiple SIgnal Classification algorithm and spatial sparsity of the field signal for electroencephalogram measurements

    NASA Astrophysics Data System (ADS)

    Vergallo, P.; Lay-Ekuakille, A.

    2013-08-01

    Brain activity can be recorded by means of EEG (Electroencephalogram) electrodes placed on the scalp of the patient. The EEG reflects the activity of groups of neurons located in the head, and the fundamental problem in neurophysiology is the identification of the sources responsible of brain activity, especially if a seizure occurs and in this case it is important to identify it. The studies conducted in order to formalize the relationship between the electromagnetic activity in the head and the recording of the generated external field allow to know pattern of brain activity. The inverse problem, that is given the sampling field at different electrodes the underlying asset must be determined, is more difficult because the problem may not have a unique solution, or the search for the solution is made difficult by a low spatial resolution which may not allow to distinguish between activities involving sources close to each other. Thus, sources of interest may be obscured or not detected and known method in source localization problem as MUSIC (MUltiple SIgnal Classification) could fail. Many advanced source localization techniques achieve a best resolution by exploiting sparsity: if the number of sources is small as a result, the neural power vs. location is sparse. In this work a solution based on the spatial sparsity of the field signal is presented and analyzed to improve MUSIC method. For this purpose, it is necessary to set a priori information of the sparsity in the signal. The problem is formulated and solved using a regularization method as Tikhonov, which calculates a solution that is the better compromise between two cost functions to minimize, one related to the fitting of the data, and another concerning the maintenance of the sparsity of the signal. At the first, the method is tested on simulated EEG signals obtained by the solution of the forward problem. Relatively to the model considered for the head and brain sources, the result obtained allows to

  19. Wogonin inhibits multiple myeloma-stimulated angiogenesis via c-Myc/VHL/HIF-1α signaling axis

    PubMed Central

    Wang, Xiao-Ping; An, Teng; Tao, Lei; Zhou, Yu-Xin; Huang, Yu-Jie; Chen, Bao-An; Li, Zhi-Yu; You, Qi-Dong; Guo, Qing-Long; Wu, Zhao-Qiu

    2016-01-01

    Angiogenesis is associated with the progression of multiple myeloma (MM). Wogonin is an active mono-flavonoid with remarkable antitumor activity. However, its impact on MM-stimulated angiogenesis remains largely unknown. Here, we demonstrated that wogonin decreased expression and secretion of pro-angiogenic factors in MM cells via c-Myc/HIF-1α signaling axis, reducing MM-stimulated angiogenesis and MM cell proliferation in vivo. Overexpression of c-Myc in MM cells disrupted the balance between VHL SUMOylation and ubiquitination, and thus inhibited proteasome-mediated HIF-1α degradation. Impaired function of VHL ubiquitination complex in c-Myc-overexpressing cells was fully reversed by wogonin treatment via increasing HIF-1α-VHL interaction and promoting HIF-1α degradation. Collectively, our in vitro and in vivo studies reveal for the first time that wogonin represses MM-stimulated angiogenesis and tumor progression via c-Myc/VHL/HIF-1α signaling axis. PMID:26735336

  20. The high risk HPV16 L2 minor capsid protein has multiple transport signals that mediate its nucleocytoplasmic traffic

    SciTech Connect

    Mamoor, Shahan; Onder, Zeynep; Karanam, Balasubramanyam; Kwak, Kihyuck; Bordeaux, Jennifer; Crosby, Lauren; Roden, Richard B.S.; Moroianu, Junona

    2012-01-20

    In this study we examined the transport signals contributing to HPV16 L2 nucleocytoplasmic traffic using confocal microscopy analysis of enhanced green fluorescent protein-L2 (EGFP-L2) fusions expressed in HeLa cells. We confirmed that both nuclear localization signals (NLSs), the nNLS (1MRHKRSAKRTKR12) and cNLS (456RKRRKR461), previously characterized in vitro (Darshan et al., 2004), function independently in vivo. We discovered that a middle region rich in arginine residues (296SRRTGIRYSRIGNKQTLRTRS316) functions as a nuclear retention sequence (NRS), as mutagenesis of critical arginine residues within this NRS reduced the fraction of L2 in the nucleus despite the presence of both NLSs. Significantly, the infectivity of HPV16 pseudoviruses containing either RR297AA or RR297EE within the L2 NRS was strongly reduced both in HaCaT cells and in a murine challenge model. Experiments using Ratjadone A nuclear export inhibitor and mutation-localization analysis lead to the discovery of a leucine-rich nuclear export signal ({sub 462}LPYFFSDVSL) mediating 16L2 nuclear export. These data indicate that HPV16 L2 nucleocytoplasmic traffic is dependent on multiple functional transport signals.

  1. O-GlcNAcylation of master growth repressor DELLA by SECRET AGENT modulates multiple signaling pathways in Arabidopsis.

    PubMed

    Zentella, Rodolfo; Hu, Jianhong; Hsieh, Wen-Ping; Matsumoto, Peter A; Dawdy, Andrew; Barnhill, Benjamin; Oldenhof, Harriëtte; Hartweck, Lynn M; Maitra, Sushmit; Thomas, Stephen G; Cockrell, Shelley; Boyce, Michael; Shabanowitz, Jeffrey; Hunt, Donald F; Olszewski, Neil E; Sun, Tai-Ping

    2016-01-15

    The DELLA family of transcription regulators functions as master growth repressors in plants by inhibiting phytohormone gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also play a central role in mediating cross-talk between GA and other signaling pathways via antagonistic direct interactions with key transcription factors. However, how these crucial protein-protein interactions can be dynamically regulated during plant development remains unclear. Here, we show that DELLAs are modified by the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) SECRET AGENT (SEC) in Arabidopsis. O-GlcNAcylation of the DELLA protein REPRESSOR OF ga1-3 (RGA) inhibits RGA binding to four of its interactors-PHYTOCHROME-INTERACTING FACTOR3 (PIF3), PIF4, JASMONATE-ZIM DOMAIN1, and BRASSINAZOLE-RESISTANT1 (BZR1)-that are key regulators in light, jasmonate, and brassinosteroid signaling pathways, respectively. Consistent with this, the sec-null mutant displayed reduced responses to GA and brassinosteroid and showed decreased expression of several common target genes of DELLAs, BZR1, and PIFs. Our results reveal a direct role of OGT in repressing DELLA activity and indicate that O-GlcNAcylation of DELLAs provides a fine-tuning mechanism in coordinating multiple signaling activities during plant development. PMID:26773002

  2. O-GlcNAcylation of master growth repressor DELLA by SECRET AGENT modulates multiple signaling pathways in Arabidopsis

    PubMed Central

    Zentella, Rodolfo; Hu, Jianhong; Hsieh, Wen-Ping; Matsumoto, Peter A.; Dawdy, Andrew; Barnhill, Benjamin; Oldenhof, Harriëtte; Hartweck, Lynn M.; Maitra, Sushmit; Thomas, Stephen G.; Cockrell, Shelley; Boyce, Michael; Shabanowitz, Jeffrey; Hunt, Donald F.; Olszewski, Neil E.; Sun, Tai-ping

    2016-01-01

    The DELLA family of transcription regulators functions as master growth repressors in plants by inhibiting phytohormone gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also play a central role in mediating cross-talk between GA and other signaling pathways via antagonistic direct interactions with key transcription factors. However, how these crucial protein–protein interactions can be dynamically regulated during plant development remains unclear. Here, we show that DELLAs are modified by the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) SECRET AGENT (SEC) in Arabidopsis. O-GlcNAcylation of the DELLA protein REPRESSOR OF ga1-3 (RGA) inhibits RGA binding to four of its interactors—PHYTOCHROME-INTERACTING FACTOR3 (PIF3), PIF4, JASMONATE-ZIM DOMAIN1, and BRASSINAZOLE-RESISTANT1 (BZR1)—that are key regulators in light, jasmonate, and brassinosteroid signaling pathways, respectively. Consistent with this, the sec-null mutant displayed reduced responses to GA and brassinosteroid and showed decreased expression of several common target genes of DELLAs, BZR1, and PIFs. Our results reveal a direct role of OGT in repressing DELLA activity and indicate that O-GlcNAcylation of DELLAs provides a fine-tuning mechanism in coordinating multiple signaling activities during plant development. PMID:26773002

  3. Simultaneous decomposition of multiple hyperspectral data sets: signal recovery of unknown fluorophores in the retinal pigment epithelium.

    PubMed

    Smith, R Theodore; Post, Robert; Johri, Ansh; Lee, Michele D; Ablonczy, Zsolt; Curcio, Christine A; Ach, Thomas; Sajda, Paul

    2014-12-01

    Upon excitation with different wavelengths of light, biological tissues emit distinct but related autofluorescence signals. We used non-negative matrix factorization (NMF) to simultaneously decompose co-registered hyperspectral emission data from human retinal pigment epithelium/Bruch's membrane specimens illuminated with 436 and 480 nm light. NMF analysis was initialized with Gaussian mixture model fits and constrained to provide identical abundance images for the two excitation wavelengths. Spectra recovered this way were smoother than those obtained separately; fluorophore abundances more clearly localized within tissue compartments. These studies provide evidence that leveraging multiple co-registered hyperspectral emission data sets is preferential for identifying biologically relevant fluorophore information. PMID:25574430

  4. Experimental demonstration of multiple pulse nonlinear optoacoustic signal generation and control.

    PubMed

    Blackmon, Fletcher; Antonelli, Lynn

    2005-01-01

    Generating underwater acoustic signals from a remote, aerial location by use of a high-energy pulsed infrared laser has been demonstrated. The laser beam is directed from the air and focused onto the water surface, where the optical energy was converted into a propagating acoustic wave. Sound pressure levels of 185 dB re microPa (decibel re microPa) were consistently recorded under freshwater laboratory conditions at laser-pulse repetition rates of up to 1000 pulses/s. The nonlinear optoacoustic transmission concept is outlined, and the experimental results from investigation of the time-domain and frequency-domain characteristics of the generated underwater sound are provided. A high repetition rate, high-energy per pulse laser was used in this test under freshwater laboratory conditions. A means of deterministically controlling the spectrum of the underwater acoustic signal was investigated and demonstrated by varying the laser-pulse repetition rate. PMID:15662891

  5. Chemical Signals of Synthetic Disaccharide Derivatives Dominate Rhamnolipids at Controlling Multiple Bacterial Activities.

    PubMed

    Singh, Nischal; Shetye, Gauri S; Zheng, Hewen; Sun, Jiayue; Luk, Yan-Yeung

    2016-01-01

    Microbes secrete molecules that modify their environment. Here, we demonstrate a class of synthetic disaccharide derivatives (DSDs) that mimics and dominates the activity of naturally secreted rhamnolipids by Pseudomonas aeruginosa. The DSDs exhibit the dual function of activating and inhibiting the swarming motility through a concentration-dependent activity reversal that is characteristic of signaling molecules. Whereas DSDs tethered with a saturated farnesyl group exhibit inhibition of both biofilm formation and swarming motility, with higher activities than rhamnolipids, a saturated farnesyl tethered with a sulfonate group only inhibits swarming motility but promote biofilm formation. These results identified important structural elements for controlling swarming motility, biofilm formation, and bacterial adhesion and suggest an effective chemical approach to control intertwined signaling processes that are important for biofilm formation and motilities. PMID:26511780

  6. Multiple signaling pathways control nitrogen-mediated root elongation in maize

    PubMed Central

    Chen, Fanjun; Zhang, Fusuo

    2008-01-01

    Response of root system architecture to nutrient availability is an essential way for plants to adapt to soil environments. Nitrogen can affect root development either as a result of changes in the external concentration, or through changes in the internal nutrient status of the plant. Low soil N stimulates root elongation in maize. Recent evidence suggests that plant hormones auxin and cytokinin, as well as NO signaling pathway, are involved in the regulation of root elongation by low nitrogen nutrition. PMID:19704443

  7. Crosstalk between signaling pathways provided by single and multiple protein phosphorylation sites

    PubMed Central

    Nishi, Hafumi; Demir, Emek; Panchenko, Anna R.

    2014-01-01

    Cellular fate depends on the spatio-temporal separation and integration of signaling processes which can be provided by phosphorylation events. In this study we identify the crucial points in signaling crosstalk which can be triggered by discrete phosphorylation events on a single target protein. We integrated the data on individual human phosphosites with the evidence on their corresponding kinases, the functional consequences on phosphorylation on activity of the target protein and corresponding pathways. Our results show that there is a substantial fraction of phosphosites that can play critical roles in crosstalk between alternative or redundant pathways and regulatory outcome of phosphorylation can be linked to a type of phosphorylated residue. These regulatory phosphosites can serve as hubs in the signal flow and their functional roles are directly connected to their specific properties. Namely, phosphosites with similar regulatory functions are phosphorylated by the same kinases and participate in regulation of similar biochemical pathways. Such sites are more likely to cluster in sequence and space unlike sites with antagonistic outcomes of their phosphorylation on a target protein. In addition we found that in silico phosphorylation of sites with similar functional consequences have comparable outcomes on a target protein stability. An important role of phosphorylation sites in biological crosstalk is evident from the analysis of their evolutionary conservation. PMID:25451034

  8. Multispecific Drug Transporter Slc22a8 (Oat3) Regulates Multiple Metabolic and Signaling Pathways

    PubMed Central

    Wu, Wei; Jamshidi, Neema; Eraly, Satish A.; Liu, Henry C.; Bush, Kevin T.; Palsson, Bernhard O.

    2013-01-01

    Multispecific drug transporters of the solute carrier and ATP-binding cassette families are highly conserved through evolution, but their true physiologic role remains unclear. Analyses of the organic anion transporter 3 (OAT3; encoded by Slc22a8/Oat3, originally Roct) knockout mouse have confirmed its critical role in the renal handling of common drugs (e.g., antibiotics, antivirals, diuretics) and toxins. Previous targeted metabolomics of the knockout of the closely related Oat1 have demonstrated a central metabolic role, but the same approach with Oat3 failed to reveal a similar set of endogenous substrates. Nevertheless, the Oat3 knockout is the only Oat described so far with a physiologically significant phenotype, suggesting the disturbance of metabolic or signaling pathways. Here we analyzed global gene expression in Oat3 knockout tissue, which implicated OAT3 in phase I and phase II metabolism (drug metabolizing enzymes or DMEs), as well as signaling pathways. Metabolic reconstruction with the recently developed “mouse Recon1” supported the involvement of Oat3 in the aforementioned pathways. Untargeted metabolomics were used to determine whether the predicted metabolic alterations could be confirmed. Many significant changes were observed; several metabolites were tested for direct interaction with mOAT3, whereas others were supported by published data. Oat3 thus appears critical for the handling of phase I (hydroxylation) and phase II (glucuronidation) metabolites. Oat3 also plays a role in bioenergetic pathways (e.g., the tricarboxylic acid cycle), as well as those involving vitamins (e.g., folate), steroids, prostaglandins, gut microbiome products, uremic toxins, cyclic nucleotides, amino acids, glycans, and possibly hyaluronic acid. The data seemingly consistent with the Remote Sensing and Signaling Hypothesis (Ahn and Nigam, 2009; Wu et al., 2011), also suggests that Oat3 is essential for the handling of dietary flavonoids and antioxidants. PMID

  9. Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells.

    PubMed

    Boutin, Alisa; Neumann, Susanne; Gershengorn, Marvin C

    2016-05-01

    It has been shown that the TSH receptor (TSHR) couples to a number of different signaling pathways, although the Gs-cAMP pathway has been considered primary. Here, we measured the effects of TSH on bone marker mRNA and protein expression in preosteoblast-like U2OS cells stably expressing TSHRs. We determined which signaling cascades are involved in the regulation of IL-11, osteopontin (OPN), and alkaline phosphatase (ALPL). We demonstrated that TSH-induced up-regulation of IL-11 is primarily mediated via the Gs pathway as IL-11 was up-regulated by forskolin (FSK), an adenylyl cyclase activator, and inhibited by protein kinase A inhibitor H-89 and by silencing of Gαs by small interfering RNA. OPN levels were not affected by FSK, but its up-regulation was inhibited by TSHR/Gi-uncoupling by pertussis toxin. Pertussis toxin decreased p38 MAPK kinase phosphorylation, and a p38 inhibitor and small interfering RNA knockdown of p38α inhibited OPN induction by TSH. Up-regulation of ALPL expression required high doses of TSH (EC50 = 395nM), whereas low doses (EC50 = 19nM) were inhibitory. FSK-stimulated cAMP production decreased basal ALPL expression, whereas protein kinase A inhibition by H-89 and silencing of Gαs increased basal levels of ALPL. Knockdown of Gαq/11 and a protein kinase C inhibitor decreased TSH-stimulated up-regulation of ALPL, whereas a protein kinase C activator increased ALPL levels. A MAPK inhibitor and silencing of ERK1/2 inhibited TSH-stimulated ALPL expression. We conclude that TSH regulates expression of different bone markers via distinct signaling pathways. PMID:26950201

  10. Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells

    PubMed Central

    Boutin, Alisa; Neumann, Susanne

    2016-01-01

    It has been shown that the TSH receptor (TSHR) couples to a number of different signaling pathways, although the Gs-cAMP pathway has been considered primary. Here, we measured the effects of TSH on bone marker mRNA and protein expression in preosteoblast-like U2OS cells stably expressing TSHRs. We determined which signaling cascades are involved in the regulation of IL-11, osteopontin (OPN), and alkaline phosphatase (ALPL). We demonstrated that TSH-induced up-regulation of IL-11 is primarily mediated via the Gs pathway as IL-11 was up-regulated by forskolin (FSK), an adenylyl cyclase activator, and inhibited by protein kinase A inhibitor H-89 and by silencing of Gαs by small interfering RNA. OPN levels were not affected by FSK, but its up-regulation was inhibited by TSHR/Gi-uncoupling by pertussis toxin. Pertussis toxin decreased p38 MAPK kinase phosphorylation, and a p38 inhibitor and small interfering RNA knockdown of p38α inhibited OPN induction by TSH. Up-regulation of ALPL expression required high doses of TSH (EC50 = 395nM), whereas low doses (EC50 = 19nM) were inhibitory. FSK-stimulated cAMP production decreased basal ALPL expression, whereas protein kinase A inhibition by H-89 and silencing of Gαs increased basal levels of ALPL. Knockdown of Gαq/11 and a protein kinase C inhibitor decreased TSH-stimulated up-regulation of ALPL, whereas a protein kinase C activator increased ALPL levels. A MAPK inhibitor and silencing of ERK1/2 inhibited TSH-stimulated ALPL expression. We conclude that TSH regulates expression of different bone markers via distinct signaling pathways. PMID:26950201

  11. p38 and Extracellular Signal-Regulated Kinases Regulate the Myogenic Program at Multiple Steps

    PubMed Central

    Wu, Zhenguo; Woodring, Pamela J.; Bhakta, Kunjan S.; Tamura, Kumiko; Wen, Fang; Feramisco, James R.; Karin, Michael; Wang, Jean Y. J.; Puri, Pier Lorenzo

    2000-01-01

    The extracellular signals which regulate the myogenic program are transduced to the nucleus by mitogen-activated protein kinases (MAPKs). We have investigated the role of two MAPKs, p38 and extracellular signal-regulated kinase (ERK), whose activities undergo significant changes during muscle differentiation. p38 is rapidly activated in myocytes induced to differentiate. This activation differs from those triggered by stress and cytokines, because it is not linked to Jun–N-terminal kinase stimulation and is maintained during the whole process of myotube formation. Moreover, p38 activation is independent of a parallel promyogenic pathway stimulated by insulin-like growth factor 1. Inhibition of p38 prevents the differentiation program in myogenic cell lines and human primary myocytes. Conversely, deliberate activation of endogenous p38 stimulates muscle differentiation even in the presence of antimyogenic cues. Much evidence indicates that p38 is an activator of MyoD: (i) p38 kinase activity is required for the expression of MyoD-responsive genes, (ii) enforced induction of p38 stimulates the transcriptional activity of a Gal4-MyoD fusion protein and allows efficient activation of chromatin-integrated reporters by MyoD, and (iii) MyoD-dependent myogenic conversion is reduced in mouse embryonic fibroblasts derived from p38α−/− embryos. Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphorylation. With MEF2C, selective phosphorylation of one residue (Thr293) is a tissue-specific activating signal in differentiating myocytes. Finally, ERK shows a biphasic activation profile, with peaks of activity in undifferentiated myoblasts and postmitotic myotubes. Importantly, activation of ERK is inhibitory toward myogenic transcription in myoblasts but contributes to the activation of myogenic transcription and regulates postmitotic responses (i.e., hypertrophic growth) in myotubes. PMID

  12. Enhancement of signal denoising and multiple fault signatures detecting in rotating machinery using dual-tree complex wavelet transform

    NASA Astrophysics Data System (ADS)

    Wang, Yanxue; He, Zhengjia; Zi, Yanyang

    2010-01-01

    In order to enhance the desired features related to some special type of machine fault, a technique based on the dual-tree complex wavelet transform (DTCWT) is proposed in this paper. It is demonstrated that DTCWT enjoys better shift invariance and reduced spectral aliasing than second-generation wavelet transform (SGWT) and empirical mode decomposition by means of numerical simulations. These advantages of the DTCWT arise from the relationship between the two dual-tree wavelet basis functions, instead of the matching of the used single wavelet basis function to the signal being analyzed. Since noise inevitably exists in the measured signals, an enhanced vibration signals denoising algorithm incorporating DTCWT with NeighCoeff shrinkage is also developed. Denoising results of vibration signals resulting from a crack gear indicate the proposed denoising method can effectively remove noise and retain the valuable information as much as possible compared to those DWT- and SGWT-based NeighCoeff shrinkage denoising methods. As is well known, excavation of comprehensive signatures embedded in the vibration signals is of practical importance to clearly clarify the roots of the fault, especially the combined faults. In the case of multiple features detection, diagnosis results of rolling element bearings with combined faults and an actual industrial equipment confirm that the proposed DTCWT-based method is a powerful and versatile tool and consistently outperforms SGWT and fast kurtogram, which are widely used recently. Moreover, it must be noted, the proposed method is completely suitable for on-line surveillance and diagnosis due to its good robustness and efficient algorithm.

  13. Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells.

    PubMed

    Voss, Kelsey; Amaya, Moushimi; Mueller, Claudius; Roberts, Brian; Kehn-Hall, Kylene; Bailey, Charles; Petricoin, Emanuel; Narayanan, Aarthi

    2014-11-01

    New World alphaviruses belonging to the family Togaviridae are classified as emerging infectious agents and Category B select agents. Our study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. Infection of human cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Ag-126-mediated inhibition of VEEV was due to potential effects on early and late stages of the infectious process. While expression of viral proteins was down-regulated in Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear distribution of capsid. Finally, Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses. PMID:25261871

  14. Methoxychlor affects multiple hormone signaling pathways in the largemouth bass (Micropterus salmoides) liver

    PubMed Central

    Martyniuk, Christopher J.; Spade, Daniel J.; Blum, Jason L.; Kroll, Kevin J.; Denslow, Nancy D.

    2011-01-01

    Methoxychlor (MXC) is an organochlorine pesticide that has been shown to have estrogenic activity by activating estrogen receptors and inducing vitellogenin production in male fish. Previous studies report that exposure to MXC induces changes in mRNA abundance of reproductive genes in the liver and testes of largemouth bass (Micropterus salmoides). The objective of the present study was to better characterize the mode of action of MXC by measuring the global transcriptomic response in the male largemouth liver using an oligonucleotide microarray. Microarray analysis identified highly significant changes in the expression of 37 transcripts (p<0.001) (20 induced and 17 decreased) in the liver after MXC injection and a total of 900 expression changes (p<0.05) in transcripts with high homology to known genes. Largemouth bass estrogen receptor alpha (esr1) and androgen receptor (ar) were among the transcripts that were increased in the liver after MXC treatment. Functional enrichment analysis identified the molecular functions of steroid binding and androgen receptor activity as well as steroid hormone receptor activity as being significantly over-represented gene ontology terms. Pathway analysis identified c-fos signaling as being putatively affected through both estrogen and androgen signaling. This study provides evidence that MXC elicits transcriptional effects through the estrogen receptor as well as androgen receptor-mediated pathways in the liver. PMID:21276474

  15. PDE4D phosphorylation: A coincidence detector integrating multiple signaling pathways.

    PubMed

    Mika, Delphine; Conti, Marco

    2016-07-01

    In Eukaryotes, more than 100 different phosphodiesterase (PDE) proteins serve to fine-tune cyclic nucleotide (cAMP and cGMP) signals and contribute to specificity of signaling. In mammals, PDEs are divided into 11 families, of which PDE4 represents the largest family. Four genes (pde4a, pde4b, pde4c and pde4d) encode for this class of enzymes in mammals and give rise to more than 20 variants. Within this family of genes, PDE4D was discovered on the basis of its regulatory properties and its induction by hormones and cAMP. PDE4D has often been used as the prototype PDE4 and large body of work has been generated on the biochemical, pharmacological, and physiological properties of this enzyme. This review covers the regulation of PDE4D by phosphorylation, the impact of this regulation in the context of the structure of this protein, and the functional consequences of this complex pattern of posttranslational modifications. PMID:26562185

  16. Long-term music training tunes how the brain temporally binds signals from multiple senses.

    PubMed

    Lee, Hweeling; Noppeney, Uta

    2011-12-20

    Practicing a musical instrument is a rich multisensory experience involving the integration of visual, auditory, and tactile inputs with motor responses. This combined psychophysics-fMRI study used the musician's brain to investigate how sensory-motor experience molds temporal binding of auditory and visual signals. Behaviorally, musicians exhibited a narrower temporal integration window than nonmusicians for music but not for speech. At the neural level, musicians showed increased audiovisual asynchrony responses and effective connectivity selectively for music in a superior temporal sulcus-premotor-cerebellar circuitry. Critically, the premotor asynchrony effects predicted musicians' perceptual sensitivity to audiovisual asynchrony. Our results suggest that piano practicing fine tunes an internal forward model mapping from action plans of piano playing onto visible finger movements and sounds. This internal forward model furnishes more precise estimates of the relative audiovisual timings and hence, stronger prediction error signals specifically for asynchronous music in a premotor-cerebellar circuitry. Our findings show intimate links between action production and audiovisual temporal binding in perception. PMID:22114191

  17. Multiple cases of striking genetic similarity between alternate electric fish signal morphs in sympatry.

    PubMed

    Arnegard, Matthew E; Bogdanowicz, Steven M; Hopkins, Carl D

    2005-02-01

    Striking trait polymorphisms are worthy of study in natural populations because they can often shed light on processes of phenotypic divergence and specialization, adaptive evolution, and (in some cases) the early stages of speciation. We examined patterns of genetic variation within and between populations of mormyrid fishes that are morphologically cryptic in sympatry but produce alternate types of electric organ discharge (EOD). Other species in a large group containing a clade of these morphologically cryptic EOD types produce stereotyped, species-typical EOD waveforms thought to function in mate recognition. First, for six populations from Gabon's Brienomyrus species flock, we confirm that forms of electric fish that exhibit distinctive morphologies and unique EOD waveforms (i.e., good reference species) are reproductively isolated from coexisting congeners. These sympatric species deviate from genetic panmixia across five microsatellite loci. Given this result, we examined three focal pairs of syntopic and morphologically cryptic EOD waveform types that are notable exceptions to the pattern of robust genetic partitioning among unique waveform classes within assemblages. These exceptional pairs constitute a monophyletic group within the Brienomyrus flock known as the magnostipes complex. One member of each pair (type I) produces a head-negative EOD, while the other member (either type II or type III, depending on location) produces a longer duration EOD differing in waveform from type I. We show that signal development in these pairs begins with juveniles of all magnostipes-complex morphs emitting head-positive EODs resembling those of type II adults. Divergence of EOD waveforms occurs with growth such that there are two discrete and fixed signal types in morphologically indistinguishable adults at each of several localities. Strong microsatellite partitioning between allopatric samples of any of these morphologically cryptic signal types suggests that

  18. G-protein Signaling Components GCR1 and GPA1 Mediate Responses to Multiple Abiotic Stresses in Arabidopsis

    PubMed Central

    Chakraborty, Navjyoti; Singh, Navneet; Kaur, Kanwaljeet; Raghuram, Nandula

    2015-01-01

    G-protein signaling components have been implicated in some individual stress responses in Arabidopsis, but have not been comprehensively evaluated at the genetic and biochemical level. Stress emerged as the largest functional category in our whole transcriptome analyses of knock-out mutants of GCR1 and/or GPA1 in Arabidopsis (Chakraborty et al., 2015a,b). This led us to ask whether G-protein signaling components offer converging points in the plant's response to multiple abiotic stresses. In order to test this hypothesis, we carried out detailed analysis of the abiotic stress category in the present study, which revealed 144 differentially expressed genes (DEGs), spanning a wide range of abiotic stresses, including heat, cold, salt, light stress etc. Only 10 of these DEGs are shared by all the three mutants, while the single mutants (GCR1/GPA1) shared more DEGs between themselves than with the double mutant (GCR1-GPA1). RT-qPCR validation of 28 of these genes spanning different stresses revealed identical regulation of the DEGs shared between the mutants. We also validated the effects of cold, heat and salt stresses in all the 3 mutants and WT on % germination, root and shoot length, relative water content, proline content, lipid peroxidation and activities of catalase, ascorbate peroxidase and superoxide dismutase. All the 3 mutants showed evidence of stress tolerance, especially to cold, followed by heat and salt, in terms of all the above parameters. This clearly shows the role of GCR1 and GPA1 in mediating the plant's response to multiple abiotic stresses for the first time, especially cold, heat and salt stresses. This also implies a role for classical G-protein signaling pathways in stress sensitivity in the normal plants of Arabidopsis. This is also the first genetic and biochemical evidence of abiotic stress tolerance rendered by knock-out mutation of GCR1 and/or GPA1. This suggests that G-protein signaling pathway could offer novel common targets for the

  19. Development of Multi-Field of view-Multiple-Scattering-Polarization Lidar : analysis of angular resolved backscattered signals

    NASA Astrophysics Data System (ADS)

    Makino, T.; Okamoto, H.; Sato, K.; Tanaka, K.; Nishizawa, T.; Sugimoto, N.; Matsui, I.; Jin, Y.; Uchiyama, A.; Kudo, R.

    2014-12-01

    We have developed a new type of ground-based lidar, Multi-Field of view-Multiple-Scattering-Polarization Lidar (MFMSPL), to analyze multiple scattering contribution due to low-level clouds. One issue of the ground based lidar is the limitation of optical thickness of about 3 due to the strong attenuation in the lidar signals so that only the cloud bottom part can be observed. In order to overcome the problem, we have proposed the MFMSPL that has been designed to observe similar degree of multiple scattering contribution expected from space-borne lidar CALIOP on CALIPSO satellite. The system consists of eight detectors; four telescopes for parallel channels and four for perpendicular channels. The four pairs of telescope have been mounted with four different off-beam angles, ranging from -5 to 35mrad, where the angle is defined as the one between the direction of laser beam and the direction of telescope. Consequently, similar large foot print (100m) as CALIOP can be achieved in the MFMSPL observations when the altitude of clouds is located at about 1km. The use of multi-field of views enables to measure depolarization ratio from optically thick clouds. The outer receivers attached with larger angles generally detect backscattered signals from clouds located at upper altitudes due to the enhanced multiple scattering compared with the inner receiver that detects signals only from cloud bottom portions. Therefore the information of cloud microphysics from optically thicker regions is expected by the MFMSPL observations compared with the conventional lidar with small FOV. The MFMSPL have been continuously operated in Tsukuba, Japan since June 2014.Initial analyses have indicated expected performances from the theoretical estimation by backward Monte-Carlo simulations. The depolarization ratio from deeper part of the clouds detected by the receiver with large off-beam angle showed much larger values than those from the one with small angle. The calibration procedures

  20. Seasonal climate signals from multiple tree ring metrics: A case study of Pinus ponderosa in the upper Columbia River Basin

    NASA Astrophysics Data System (ADS)

    Dannenberg, Matthew P.; Wise, Erika K.

    2016-04-01

    Projected changes in the seasonality of hydroclimatic regimes are likely to have important implications for water resources and terrestrial ecosystems in the U.S. Pacific Northwest. The tree ring record, which has frequently been used to position recent changes in a longer-term context, typically relies on signals embedded in the total ring width of tree rings. Additional climatic inferences at a subannual temporal scale can be made using alternative tree ring metrics such as earlywood and latewood widths and the density of tree ring latewood. Here we examine seasonal precipitation and temperature signals embedded in total ring width, earlywood width, adjusted latewood width, and blue intensity chronologies from a network of six Pinus ponderosa sites in and surrounding the upper Columbia River Basin of the U.S. Pacific Northwest. We also evaluate the potential for combining multiple tree ring metrics together in reconstructions of past cool- and warm-season precipitation. The common signal among all metrics and sites is related to warm-season precipitation. Earlywood and latewood widths differ primarily in their sensitivity to conditions in the year prior to growth. Total and earlywood widths from the lowest elevation sites also reflect cool-season moisture. Effective correlation analyses and composite-plus-scale tests suggest that combining multiple tree ring metrics together may improve reconstructions of warm-season precipitation. For cool-season precipitation, total ring width alone explains more variance than any other individual metric or combination of metrics. The composite-plus-scale tests show that variance-scaled precipitation reconstructions in the upper Columbia River Basin may be asymmetric in their ability to capture extreme events.

  1. Remote sensing of ice phenomena from orbit by signal correlation of multiple receiver responses

    NASA Technical Reports Server (NTRS)

    Stacey, J. M.; Johnston, E. J.

    1983-01-01

    The method of signal correlation of microwave responses as applied to the measurement of Earth-surface ice temperatures from orbit is explained and summarized. Ice temperatures are estimated by a correlation function that is derived from the processes of a forward stepwise correlator. Subsets of the post-detected outputs of microwave receiving channels are combined in a multivariate cross-correlation function which operates as a spatial filter and serves to improve the spatial resolution of the thermal gradients in ice structures. The correlator is designed to selectively identify the correlative components among the microwave responses and to strongly suppress or cancel the non-correlative components appearing in the post-detected outputs.

  2. Cucurbitacin-E inhibits multiple cancer cells proliferation through attenuation of Wnt/β-catenin signaling.

    PubMed

    Feng, Hui; Zang, Li; Zhao, Zhen-Xia; Kan, Quan-Cheng

    2014-06-01

    Recent studies suggest that the use of cucurbitacins could inhibit cancer cell progression. In the current study, the authors analyzed the effect of cucurbitacin-E (CuE) in cancer cells using A549, Hep3B, and SW480 cells. The authors found that CuE inhibited cell proliferation and modulated the expression of cell cycle regulators in these cells. Moreover, the authors found that CuE inhibited Wnt/β-catenin signaling activation through upregulation of tumor suppressor Menin. Indeed, ablation of Menin using small interfering RNA (siRNA) oligos attenuated the antiproliferative roles of CuE. Taken together, the results of this study provide a novel mechanism that may contribute to the antineoplastic effects of CuE in cancer cells. PMID:24885795

  3. Naringenin suppresses TPA-induced tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.

    PubMed

    Yen, Hung-Rong; Liu, Ching-Ju; Yeh, Chia-Chou

    2015-06-25

    Naringenin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong anti-proliferative properties and the ability to induce apoptosis in hepatoma cell lines. However, there are no reports describing its effects on the invasion and metastasis of hepatoma cell lines, and the detailed molecular mechanisms of its effects are still unclear. In this study, we investigated the mechanisms underlying naringenin-mediated inhibition of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (HepG2, Huh-7, and HA22T) and murine embryonic liver cells (BNL CL2). Naringenin suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κB (NF-κB) activity. It suppressed TPA-induced AP-1 activity through inhibiting the phosphorylation of the extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and it suppressed TPA-induced inhibition of NF-κB nuclear translocation through IκB. Additionally, it suppressed TPA-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1. These data suggest that naringenin suppresses the invasiveness and metastatic potential of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PMID:25866363

  4. Estimation of source location and ground impedance using a hybrid multiple signal classification and Levenberg-Marquardt approach

    NASA Astrophysics Data System (ADS)

    Tam, Kai-Chung; Lau, Siu-Kit; Tang, Shiu-Keung

    2016-07-01

    A microphone array signal processing method for locating a stationary point source over a locally reactive ground and for estimating ground impedance is examined in detail in the present study. A non-linear least square approach using the Levenberg-Marquardt method is proposed to overcome the problem of unknown ground impedance. The multiple signal classification method (MUSIC) is used to give the initial estimation of the source location, while the technique of forward backward spatial smoothing is adopted as a pre-processer of the source localization to minimize the effects of source coherence. The accuracy and robustness of the proposed signal processing method are examined. Results show that source localization in the horizontal direction by MUSIC is satisfactory. However, source coherence reduces drastically the accuracy in estimating the source height. The further application of Levenberg-Marquardt method with the results from MUSIC as the initial inputs improves significantly the accuracy of source height estimation. The present proposed method provides effective and robust estimation of the ground surface impedance.

  5. Multiple organelle-targeting signals in the N-terminal portion of peroxisomal membrane protein PMP70.

    PubMed

    Iwashita, Shohei; Tsuchida, Masashi; Tsukuda, Miwa; Yamashita, Yukari; Emi, Yoshikazu; Kida, Yuichiro; Komori, Masayuki; Kashiwayama, Yoshinori; Imanaka, Tsuneo; Sakaguchi, Masao

    2010-04-01

    Most membrane proteins are recognized by a signal recognition particle and are cotranslationally targeted to the endoplasmic reticulum (ER) membrane, whereas almost all peroxisomal membrane proteins are posttranslationally targeted to the destination. Here we examined organelle-targeting properties of the N-terminal portions of the peroxisomal isoform of the ABC transporter PMP70 (ABCD3) using enhanced green fluorescent protein (EGFP) fusion. When the N-terminal 80 amino acid residue (N80)-segment preceding transmembrane segment (TM) 1 was deleted and the TM1-TM2 region was fused to EGFP, the TM1 segment induced ER-targeting and integration in COS cells. When the N80-segment was fused to EGFP, the fusion protein was targeted to the outer mitochondrial membrane. When both the N80-segment and the following TM1-TM2 region were present, the fusion located exclusively to the peroxisome. The full-length PMP70 molecule was clearly located in the ER in the absence of the N80-segment, even when multiple peroxisome-targeting signals were retained. We concluded that the TM1 segment possesses a sufficient ER-targeting function and that the N80-segment is critical for suppressing the ER-targeting function to allow the TM1-TM2 region to localize to the peroxisome. Cooperation of the organelle-targeting signals enables PMP70 to correctly target to peroxisomal membranes. PMID:20007743

  6. Modulation of the Tumor Metastatic Microenvironment and Multiple Signal Pathways by Prunella vulgaris in Human Hepatocellular Carcinoma.

    PubMed

    Su, Yu-Chieh; Lin, I-Hsin; Siao, Yu-Miao; Liu, Ching-Ju; Yeh, Chia-Chou

    2016-01-01

    Prunella vulgaris (PV) is a traditional Chinese medicine that has been used clinically for centuries in Asian countries to treat herpetic keratitis. In previous studies, PV was shown to suppress TPA-induced activation of MMP-9 and inhibit cell invasion and migration in hepatoma cell lines. However, the detailed molecular mechanism underlying these effects is still unclear. In this study, we investigated the mechanisms underlying PV-mediated inhibition of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (Huh-7 and HA22T). PV suppressed VEGF and MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) activity. PV suppressed TPA-induced AP-1 activity by inhibiting phosphorylation of the extracellular signal-related kinase (ERK), downregulating p38 signaling pathways, and suppressing TPA-induced inhibition of NF-[Formula: see text]B nuclear translocation through I[Formula: see text]B. PV suppressed TPA-induced activation of ERK/phosphatidylinositol-3-kinase/Akt upstream of NF-[Formula: see text]B and AP-1. These data suggest that PV modifies the metastatic microenvironment of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PV thus may have the therapeutic potential to inhibit the migration and invasion of HCC and act as potential agent for systemic therapies. PMID:27222069

  7. Concurrent activation of multiple vasoactive signaling pathways in vasoconstriction caused by tubuloglomerular feedback: a quantitative assessment.

    PubMed

    Schnermann, Jurgen

    2015-01-01

    Tubuloglomerular feedback (TGF) describes the negative relationship between (a) NaCl concentration at the macula densa and (b) glomerular filtration rate or glomerular capillary pressure. TGF-induced vasoconstriction of the afferent arteriole results from the enhanced effect of several vasoconstrictors with an effect size sequence of adenosine = 20-HETE > angiotensin II > thromboxane = superoxide > renal nerves > ATP. TGF-mediated vasoconstriction is limited by the simultaneous release of several vasodilators with an effect size sequence of nitric oxide > carbon monoxide = kinins > adenosine. The sum of the constrictor effects exceeds that of the dilator effects by the magnitude of the TGF response. The validity of the additive model used in this analysis can be tested by determining the effect of combined inhibition of some or all agents contributing to TGF. Multiple independent contributors to TGF are consistent with the variability of TGF and of the factors contributing to TGF resetting. PMID:25668021

  8. Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways

    PubMed Central

    GAO, JIAN-LI; LV, GUI-YUAN; HE, BAI-CHENG; ZHANG, BING-QIANG; ZHANG, HONGYU; WANG, NING; WANG, CHONG-ZHI; DU, WEI; YUAN, CHUN-SU; HE, TONG-CHUAN

    2013-01-01

    Plant-derived active constituents and their semi-synthetic or synthetic analogs have served as major sources of anticancer drugs. 20(S)-protopanaxadiol (PPD) is a metabolite of ginseng saponin of both American ginseng (Panax quinquefolius L.) and Asian ginseng (Panax ginseng C.A. Meyer). We previously demonstrated that ginsenoside Rg3, a glucoside precursor of PPD, exhibits anti-proliferative effects on HCT116 cells and reduces tumor size in a xenograft model. Our subsequent study indicated that PPD has more potent antitumor activity than that of Rg3 in vitro although the mechanism underlying the anticancer activity of PPD remains to be defined. Here, we investigated the mechanism underlying the anticancer activity of PPD in human cancer cells in vitro and in vivo. PPD was shown to inhibit growth and induce cell cycle arrest in HCT116 cells. The in vivo studies indicate that PPD inhibits xenograft tumor growth in athymic nude mice bearing HCT116 cells. The xenograft tumor size was significantly reduced when the animals were treated with PPD (30 mg/kg body weight) for 3 weeks. When the expression of previously identified Rg3 targets, A kinase (PRKA) anchor protein 8 (AKAP8L) and phosphatidylinositol transfer protein α (PITPNA), was analyzed, PPD was shown to inhibit the expression of PITPNA while upregulating AKAP8L expression in HCT116 cells. Pathway-specific reporter assays indicated that PPD effectively suppressed the NF-κB, JNK and MAPK/ERK signaling pathways. Taken together, our results suggest that the anticancer activity of PPD in colon cancer cells may be mediated through targeting NF-κB, JNK and MAPK/ERK signaling pathways, although the detailed mechanisms underlying the anticancer mode of PPD action need to be fully elucidated. PMID:23633038

  9. Modulation of Cell Metabolic Pathways and Oxidative Stress Signaling Contribute to Acquired Melphalan Resistance in Multiple Myeloma Cells

    PubMed Central

    Zub, Kamila Anna; de Sousa, Mirta Mittelstedt Leal; Sarno, Antonio; Sharma, Animesh; Demirovic, Aida; Rao, Shalini; Young, Clifford; Aas, Per Arne; Ericsson, Ida; Sundan, Anders; Jensen, Ole Nørregaard; Slupphaug, Geir

    2015-01-01

    Alkylating agents are widely used chemotherapeutics in the treatment of many cancers, including leukemia, lymphoma, multiple myeloma, sarcoma, lung, breast and ovarian cancer. Melphalan is the most commonly used chemotherapeutic agent against multiple myeloma. However, despite a 70–80% initial response rate, virtually all patients eventually relapse due to the emergence of drug-resistant tumour cells. By using global proteomic and transcriptomic profiling on melphalan sensitive and resistant RPMI8226 cell lines followed by functional assays, we discovered changes in cellular processes and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further explored to elucidate their potential to overcome melphalan resistance. PMID:25769101

  10. Relevancies of multiple-interaction events and signal-to-noise ratio for Anger-logic based PET detector designs

    NASA Astrophysics Data System (ADS)

    Peng, Hao

    2015-10-01

    A fundamental challenge for PET block detector designs is to deploy finer crystal elements while limiting the number of readout channels. The standard Anger-logic scheme including light sharing (an 8 by 8 crystal array coupled to a 2×2 photodetector array with an optical diffuser, multiplexing ratio: 16:1) has been widely used to address such a challenge. Our work proposes a generalized model to study the impacts of two critical parameters on spatial resolution performance of a PET block detector: multiple interaction events and signal-to-noise ratio (SNR). The study consists of the following three parts: (1) studying light output profile and multiple interactions of 511 keV photons within crystal arrays of different crystal widths (from 4 mm down to 1 mm, constant height: 20 mm); (2) applying the Anger-logic positioning algorithm to investigate positioning/decoding uncertainties (i.e., "block effect") in terms of peak-to-valley ratio (PVR), with light sharing, multiple interactions and photodetector SNR taken into account; and (3) studying the dependency of spatial resolution on SNR in the context of modulation transfer function (MTF). The proposed model can be used to guide the development and evaluation of a standard Anger-logic based PET block detector including: (1) selecting/optimizing the configuration of crystal elements for a given photodetector SNR; and (2) predicting to what extent additional electronic multiplexing may be implemented to further reduce the number of readout channels.

  11. SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling

    SciTech Connect

    Xu, Jun; Sun, Hui-Yan; Xiao, Feng-Jun; Wang, Hua; Yang, Yang; Wang, Lu; Gao, Chun-Ji; Guo, Zi-Kuan; Wu, Chu-Tse; Wang, Li-Sheng

    2015-05-01

    SUMO/sentrin specific protease 1 (Senp1) is an important regulation protease in the protein sumoylation, which affects the cell cycle, proliferation and differentiation. The role of Senp1 mediated protein desumoylation in pathophysiological progression of multiple myeloma is unknown. In this study, we demonstrated that Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. Lentivirus-mediated Senp1 knockdown triggers apoptosis and reduces viability, proliferation and colony forming ability of MM cells. The NF-κB family members including P65 and inhibitor protein IkBα play important roles in regulation of MM cell survival and proliferation. We further demonstrated that Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation, leading to inactivation of NF-kB signaling in MM cells. These results delineate a key role for Senp1in IL-6 induced proliferation and survival of MM cells, suggesting it may be a potential new therapeutic target in MM. - Highlights: • Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. • Senp1 knockdown triggers apoptosis and reduces proliferation of MM cells. • Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation.

  12. Mosaic analysis of extended auricle1 (eta1) suggests that a two-way signaling pathway is involved in positioning the blade/sheath boundary in Zea mays.

    PubMed

    Osmont, Karen S; Sadeghian, Nasim; Freeling, Michael

    2006-07-01

    The maize leaf develops in a simple, stereotypical manner; therefore, it serves as a basic model to understand the processes involved in forming developmental boundaries. extended auricle1 (eta1) is a pleiotropic maize mutant that affects proximodistal leaf development. Mutant eta1 individuals display basipetal displacement of the blade/sheath boundary and the boundary between auricle and blade is not clearly delineated, leading to an undulating auricle. SEM analysis shows that eta1 is required for proper placement of the blade/sheath boundary on the adaxial leaf surface. Examination of vascular and cellular organization indicates that eta1 affects not only placement of the blade/sheath boundary, but also differentiation of cell types within the blade/sheath boundary. Genetic mosaic analysis was used to determine the effect of eta1 mutant tissue on wild-type leaf development and to resolve the site and timing of the Eta1+ gene product. Interestingly, sectors of eta1 tissue affect the placement of the blade/sheath boundary even in wild-type tissue. These results suggest that a two-way signaling pathway may be involved in the positioning of the blade/sheath boundary. Based on these data, we propose a model for Eta1+ function in the maize leaf. PMID:16684518

  13. The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death

    USGS Publications Warehouse

    Hodge, D.L.; Subleski, J.J.; Reynolds, D.A.; Buschman, M.D.; Schill, W.B.; Burkett, M.W.; Malyguine, A.M.; Young, H.A.

    2006-01-01

    The proinflammatory cytokine, interleukin-18 (IL-18), is a natural killer (NK) cell activator that induces NK cell cytotoxicity and interferon-?? (IFN-??) expression. In this report, we define a novel role for IL-18 as an NK cell protective agent. Specifically, IL-18 prevents NK cell death initiated by different and distinct stress mechanisms. IL-18 reduces NK cell self-destruction during NK-targeted cell killing, and in the presence of staurosporin, a potent apoptotic inducer, IL-18 reduces caspase-3 activity. The critical regulatory step in this process is downstream of the mitochondrion and involves reduced cleavage and activation of caspase-9 and caspase-3. The ability of IL-18 to regulate cell survival is not limited to a caspase death pathway in that IL-18 augments tumor necrosis factor (TNF) signaling, resulting in increased and prolonged mRNA expression of c-apoptosis inhibitor 2 (cIAP2), a prosurvival factor and caspase-3 inhibitor, and TNF receptor-associated factor 1 (TRAF1), a prosurvival protein. The cumulative effects of IL-18 define a novel role for this cytokine as a molecular survival switch that functions to both decrease cell death through inhibition of the mitochondrial apoptotic pathway and enhance TNF induction of prosurvival factors. ?? Mary Ann Liebert, Inc.

  14. Genistein alleviates lead-induced neurotoxicity in vitro and in vivo: Involvement of multiple signaling pathways.

    PubMed

    Su, Peng; Zhang, Jianbin; Wang, Siwang; Aschner, Michael; Cao, Zipeng; Zhao, Fang; Wang, Diya; Chen, Jiangyuan; Luo, Wenjing

    2016-03-01

    Lead (Pb) is a ubiquitous environmental and industrial pollutant. It induces neurotoxicity and cell death by disrupting the pro- and anti-oxidative balance; however, the mechanisms of its toxicity have yet to be fully understood. The soy-derived isoflavonoid, genistein (GEN), was reported to possess neuroprotective and antioxidative properties. The present study investigated the molecular mechanisms of Pb-induced neurotoxicity in vivo and in vitro, addressing the efficacy of GEN in protecting against Pb-induced toxicity. Pb exposure was associated with reduction of cell viability and cell apoptosis, concomitant with reactive oxygen species (ROS) generation in vitro, and pre-treatment with GEN markedly ameliorated the Pb-induced oxidative injury by increasing the expression of key antioxidant enzymes and the antioxidant transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2). Next, PKC-α activation was found after Pb exposure in vitro and pretreatment with GEN attenuated Pb-induced ROS generation by PKC-α inhibition. MAPK-NF-κB activation triggered by Pb was also inhibited by GEN. In summary, our study establishes that GEN alleviates Pb-induced impairment in spatial memory, and reduces cell apoptosis caused by Pb exposure and GEN protects neurons from Pb-induced neurotoxicity by downstream activation of antioxidant and anti-apoptotic pathways via regulation of Nrf2 and MAPK-NF-κB signaling. PMID:26797587

  15. Bias Characterization in Probabilistic Genotype Data and Improved Signal Detection with Multiple Imputation.

    PubMed

    Palmer, Cameron; Pe'er, Itsik

    2016-06-01

    Missing data are an unavoidable component of modern statistical genetics. Different array or sequencing technologies cover different single nucleotide polymorphisms (SNPs), leading to a complicated mosaic pattern of missingness where both individual genotypes and entire SNPs are sporadically absent. Such missing data patterns cannot be ignored without introducing bias, yet cannot be inferred exclusively from nonmissing data. In genome-wide association studies, the accepted solution to missingness is to impute missing data using external reference haplotypes. The resulting probabilistic genotypes may be analyzed in the place of genotype calls. A general-purpose paradigm, called Multiple Imputation (MI), is known to model uncertainty in many contexts, yet it is not widely used in association studies. Here, we undertake a systematic evaluation of existing imputed data analysis methods and MI. We characterize biases related to uncertainty in association studies, and find that bias is introduced both at the imputation level, when imputation algorithms generate inconsistent genotype probabilities, and at the association level, when analysis methods inadequately model genotype uncertainty. We find that MI performs at least as well as existing methods or in some cases much better, and provides a straightforward paradigm for adapting existing genotype association methods to uncertain data. PMID:27310603

  16. Bias Characterization in Probabilistic Genotype Data and Improved Signal Detection with Multiple Imputation

    PubMed Central

    Palmer, Cameron; Pe’er, Itsik

    2016-01-01

    Missing data are an unavoidable component of modern statistical genetics. Different array or sequencing technologies cover different single nucleotide polymorphisms (SNPs), leading to a complicated mosaic pattern of missingness where both individual genotypes and entire SNPs are sporadically absent. Such missing data patterns cannot be ignored without introducing bias, yet cannot be inferred exclusively from nonmissing data. In genome-wide association studies, the accepted solution to missingness is to impute missing data using external reference haplotypes. The resulting probabilistic genotypes may be analyzed in the place of genotype calls. A general-purpose paradigm, called Multiple Imputation (MI), is known to model uncertainty in many contexts, yet it is not widely used in association studies. Here, we undertake a systematic evaluation of existing imputed data analysis methods and MI. We characterize biases related to uncertainty in association studies, and find that bias is introduced both at the imputation level, when imputation algorithms generate inconsistent genotype probabilities, and at the association level, when analysis methods inadequately model genotype uncertainty. We find that MI performs at least as well as existing methods or in some cases much better, and provides a straightforward paradigm for adapting existing genotype association methods to uncertain data. PMID:27310603

  17. Multiple Frequency Audio Signal Communication as a Mechanism for Neurophysiology and Video Data Synchronization

    PubMed Central

    Topper, Nicholas C.; Burke, S.N.; Maurer, A.P.

    2014-01-01

    BACKGROUND Current methods for aligning neurophysiology and video data are either prepackaged, requiring the additional purchase of a software suite, or use a blinking LED with a stationary pulse-width and frequency. These methods lack significant user interface for adaptation, are expensive, or risk a misalignment of the two data streams. NEW METHOD A cost-effective means to obtain high-precision alignment of behavioral and neurophysiological data is obtained by generating an audio-pulse embedded with two domains of information, a low-frequency binary-counting signal and a high, randomly changing frequency. This enabled the derivation of temporal information while maintaining enough entropy in the system for algorithmic alignment. RESULTS The sample to frame index constructed using the audio input correlation method described in this paper enables video and data acquisition to be aligned at a sub-frame level of precision. COMPARISONS WITH EXISTING METHOD Traditionally, a synchrony pulse is recorded on-screen via a flashing diode. The higher sampling rate of the audio input of the camcorder enables the timing of an event to be detected with greater precision. CONCLUSIONS While On-line analysis and synchronization using specialized equipment may be the ideal situation in some cases, the method presented in the current paper presents a viable, low cost alternative, and gives the flexibility to interface with custom off-line analysis tools. Moreover, the ease of constructing and implements this set-up presented in the current paper makes it applicable to a wide variety of applications that require video recording. PMID:25256648

  18. Pollutants in particulate and gaseous fractions of ambient air interfere with multiple signaling pathways in vitro.

    PubMed

    Novák, Jirí; Jálová, Veronika; Giesy, John P; Hilscherová, Klára

    2009-01-01

    Traditionally, contamination of air has been evaluated primarily by chemical analyses of indicator contaminants and these studies have focused mainly on compounds associated with particulates. Some reports have shown that air contaminants can produce specific biological effects such as toxicity mediated by the aryl hydrocarbon receptor (AhR) or modulation of the endocrine system. This study assessed the dioxin-like toxicity, anti-/estrogenicity, anti-/androgenicity and anti-/retinoic activity of both the particulate and gas phase fractions of air in two regions with different types of pollution sources and a background locality situated in an agricultural area of Central Europe. The first region (A) is known to be significantly contaminated by organochlorine pesticides and chemical industry. The other region (B) has been polluted by historical releases of PCBs, but the major current sources of contamination are probably combustion sources from local traffic and heating. Samples of both particle and gas fractions produced dioxin-like (AhR-mediated) activity, anti-estrogenic and antiandrogenic effects, but none had any effect on retinoid signaling. AhR-mediated activities were observed in all samples and the TEQ values were comparable in both fractions in region A, but significantly greater in the particulate fraction in region B. The greater AhR-mediated activity corresponded to a greater coincident antiestrogenicity of both phases in region B. Our study is the first report of antiestrogenicity and antiandrogenicity in ambient air. Anti-androgenicity was observed in the gas phase of all regions, while in the particulate phase only in one region due to the specific type of pollution in that area. Even though based on concentrations of individual compounds, except for the OCPs, the level of contamination of the two regions was similar, there were strong differences in responses in the bioassays between the two regions. Moreover, AhR-mediated activity and

  19. Multiple effects of protein phosphatase 2A on nutrient-induced signalling in the yeast Saccharomyces cerevisiae.

    PubMed

    Sugajska, E; Swiatek, W; Zabrocki, P; Geyskens, I; Thevelein, J M; Zolnierowicz, S; Wera, S

    2001-05-01

    The trehalose-degrading enzyme trehalase is activated upon addition of glucose to derepressed cells or in response to nitrogen source addition to nitrogen-starved glucose-repressed yeast (Saccharomyces cerevisiae) cells. Trehalase activation is mediated by phosphorylation. Inactivation involves dephosphorylation, as trehalase protein levels do not change upon multiple activation/inactivation cycles. Purified trehalase can be inactivated by incubation with protein phosphatase 2A (PP2A) in vitro. To test whether PP2A was involved in trehalase inactivation in vivo, we overexpressed the yeast PP2A isoform Pph22. Unexpectedly, the moderate (approximately threefold) overexpression of Pph22 that we obtained increased basal trehalase activity and rendered this activity unresponsive to the addition of glucose or a nitrogen source. Concomitant with higher basal trehalase activity, cells overexpressing Pph22 did not store trehalose efficiently and were heat sensitive. After the addition of glucose or of a nitrogen source to starved cells, Pph22-overexpressing cells showed a delayed exit from stationary phase, a delayed induction of ribosomal gene expression and constitutive repression of stress-regulated element-controlled genes. Deletion of the SCH9 gene encoding a protein kinase involved in nutrient-induced signal transduction restored glucose-induced trehalase activation in Pph22-overexpressing cells. Taken together, our results indicate that yeast PP2A overexpression leads to the activation of nutrient-induced signal transduction pathways in the absence of nutrients. PMID:11401708

  20. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways

    PubMed Central

    Afsar, Tayyaba; Trembley, Janeen H.; Salomon, Christine E.; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

  1. A functional dissociation between language and multiple-demand systems revealed in patterns of BOLD signal fluctuations

    PubMed Central

    Kanwisher, Nancy; Fedorenko, Evelina

    2014-01-01

    What is the relationship between language and other high-level cognitive functions? Neuroimaging studies have begun to illuminate this question, revealing that some brain regions are quite selectively engaged during language processing, whereas other “multiple-demand” (MD) regions are broadly engaged by diverse cognitive tasks. Nonetheless, the functional dissociation between the language and MD systems remains controversial. Here, we tackle this question with a synergistic combination of functional MRI methods: we first define candidate language-specific and MD regions in each subject individually (using functional localizers) and then measure blood oxygen level-dependent signal fluctuations in these regions during two naturalistic conditions (“rest” and story-comprehension). In both conditions, signal fluctuations strongly correlate among language regions as well as among MD regions, but correlations across systems are weak or negative. Moreover, data-driven clustering analyses based on these inter-region correlations consistently recover two clusters corresponding to the language and MD systems. Thus although each system forms an internally integrated whole, the two systems dissociate sharply from each other. This independent recruitment of the language and MD systems during cognitive processing is consistent with the hypothesis that these two systems support distinct cognitive functions. PMID:24872535

  2. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways.

    PubMed

    Afsar, Tayyaba; Trembley, Janeen H; Salomon, Christine E; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

  3. A functional dissociation between language and multiple-demand systems revealed in patterns of BOLD signal fluctuations.

    PubMed

    Blank, Idan; Kanwisher, Nancy; Fedorenko, Evelina

    2014-09-01

    What is the relationship between language and other high-level cognitive functions? Neuroimaging studies have begun to illuminate this question, revealing that some brain regions are quite selectively engaged during language processing, whereas other "multiple-demand" (MD) regions are broadly engaged by diverse cognitive tasks. Nonetheless, the functional dissociation between the language and MD systems remains controversial. Here, we tackle this question with a synergistic combination of functional MRI methods: we first define candidate language-specific and MD regions in each subject individually (using functional localizers) and then measure blood oxygen level-dependent signal fluctuations in these regions during two naturalistic conditions ("rest" and story-comprehension). In both conditions, signal fluctuations strongly correlate among language regions as well as among MD regions, but correlations across systems are weak or negative. Moreover, data-driven clustering analyses based on these inter-region correlations consistently recover two clusters corresponding to the language and MD systems. Thus although each system forms an internally integrated whole, the two systems dissociate sharply from each other. This independent recruitment of the language and MD systems during cognitive processing is consistent with the hypothesis that these two systems support distinct cognitive functions. PMID:24872535

  4. Genes encoding isoforms of transcription elongation factor TFIIS in Xenopus and the use of multiple unusual RNA processing signals.

    PubMed Central

    Plant, K E; Hair, A; Morgan, G T

    1996-01-01

    We have identified cDNAs encoding three related forms of transcription elongation factor TFIIS (S-II) in Xenopus laevis ovary. Comparison of Xenopus and mammalian sequences identifies likely diagnostic amino acids that distinguish classes of vertebrate TFIIS. The diversity of TFIIS polypeptides in Xenopus is due partly to the presence of two diverged genes in this tetraploid genome. We isolated genomic clones containing one of the genes, xTFIIS.oA, and, unlike a previously described vertebrate TFIIS gene, found that it contains introns. Alternative splicing at a CAG/CAG motif containing the 3' splice site of intron 4 produces the third form of xTFIIS, which differs from one of the others simply in lacking Ser109. Intron 6 of xTFIIS.oA contains splice and branch site consensus sequences conforming to those of the minor class of AT-AC introns and this was confirmed for the homeologous xTFIIS.oB gene by genomic PCR. Other unusual but functional variants of RNA processing signals were found in xTFIIS genes at the 5' splice site of intron 8 and the polyadenylation hexanucleotides. Utilization of multiple unusual processing signals may make the generation of mature xTFIIS.o mRNAs inefficient and the possible regulatory consequences of this are discussed. PMID:8836176

  5. Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3

    PubMed Central

    Lv, Meng; Liang, Xiaodong; Dai, Hui; Qin, Xiaodan; Zhang, Yan; Hao, Jie; Sun, Xiuyuan; Yin, Yanhui; Huang, Xiaojun; Zhang, Jun; Lu, Jin; Ge, Qing

    2016-01-01

    Reelin is an extracellular matrix (ECM) protein that is essential for neuron migration and positioning. The expression of reelin in multiple myeloma (MM) cells and its association with cell adhesion and survival were investigated. Overexpression, siRNA knockdown, and the addition of recombinant protein of reelin were used to examine the function of reelin in MM cells. Clinically, high expression of reelin was negatively associated with progression-free survival and overall survival. Functionally, reelin promoted the adhesion of MM cells to fibronectin via activation of α5β1 integrin. The resulting phosphorylation of Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis. These findings indicate reelin's important role in the activation of integrin-β1 and STAT3/Akt pathways in multiple myeloma and highlight the therapeutic potential of targeting reelin/integrin/FAK axis. PMID:26848618

  6. Another kind of 'BOLD Response': answering multiple-choice questions via online decoded single-trial brain signals.

    PubMed

    Sorger, Bettina; Dahmen, Brigitte; Reithler, Joel; Gosseries, Olivia; Maudoux, Audrey; Laureys, Steven; Goebel, Rainer

    2009-01-01

    The term 'locked-in'syndrome (LIS) describes a medical condition in which persons concerned are severely paralyzed and at the same time fully conscious and awake. The resulting anarthria makes it impossible for these patients to naturally communicate, which results in diagnostic as well as serious practical and ethical problems. Therefore, developing alternative, muscle-independent communication means is of prime importance. Such communication means can be realized via brain-computer interfaces (BCIs) circumventing the muscular system by using brain signals associated with preserved cognitive, sensory, and emotional brain functions. Primarily, BCIs based on electrophysiological measures have been developed and applied with remarkable success. Recently, also blood flow-based neuroimaging methods, such as functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS), have been explored in this context. After reviewing recent literature on the development of especially hemodynamically based BCIs, we introduce a highly reliable and easy-to-apply communication procedure that enables untrained participants to motor-independently and relatively effortlessly answer multiple-choice questions based on intentionally generated single-trial fMRI signals that can be decoded online. Our technique takes advantage of the participants' capability to voluntarily influence certain spatio-temporal aspects of the blood oxygenation level-dependent (BOLD) signal: source location (by using different mental tasks), signal onset and offset. We show that healthy participants are capable of hemodynamically encoding at least four distinct information units on a single-trial level without extensive pretraining and with little effort. Moreover, real-time data analysis based on simple multi-filter correlations allows for automated answer decoding with a high accuracy (94.9%) demonstrating the robustness of the presented method. Following our 'proof of concept', the

  7. Multiple excitatory and inhibitory neural signals converge to fine-tune Caenorhabditis elegans feeding to food availability.

    PubMed

    Dallière, Nicolas; Bhatla, Nikhil; Luedtke, Zara; Ma, Dengke K; Woolman, Jonathan; Walker, Robert J; Holden-Dye, Lindy; O'Connor, Vincent

    2016-02-01

    How an animal matches feeding to food availability is a key question for energy homeostasis. We addressed this in the nematode Caenorhabditis elegans, which couples feeding to the presence of its food (bacteria) by regulating pharyngeal activity (pumping). We scored pumping in the presence of food and over an extended time course of food deprivation in wild-type and mutant worms to determine the neural substrates of adaptive behavior. Removal of food initially suppressed pumping but after 2 h this was accompanied by intermittent periods of high activity. We show pumping is fine-tuned by context-specific neural mechanisms and highlight a key role for inhibitory glutamatergic and excitatory cholinergic/peptidergic drives in the absence of food. Additionally, the synaptic protein UNC-31 [calcium-activated protein for secretion (CAPS)] acts through an inhibitory pathway not explained by previously identified contributions of UNC-31/CAPS to neuropeptide or glutamate transmission. Pumping was unaffected by laser ablation of connectivity between the pharyngeal and central nervous system indicating signals are either humoral or intrinsic to the enteric system. This framework in which control is mediated through finely tuned excitatory and inhibitory drives resonates with mammalian hypothalamic control of feeding and suggests that fundamental regulation of this basic animal behavior may be conserved through evolution from nematode to human. PMID:26514165

  8. Investigation of Pseudomonas aeruginosa quorum-sensing signaling system for identifying multiple inhibitors using molecular docking and structural analysis methodology.

    PubMed

    Soheili, Vahid; Bazzaz, Bibi Sedigheh Fazly; Abdollahpour, Nooshin; Hadizadeh, Farzin

    2015-12-01

    Pseudomonas aeruginosa is an opportunistic human pathogen and a common Gram-negative bacterium in hospital-acquired infections. It causes death in many burn victims, cystic-fibrosis and neutropenic-cancer patients. It is known that P. aeruginosa biofilm maturation and production of cell-associated and extracellular virulence factors such as pyocyanin, elastase and rhamnolipids are under the control of a quorum-sensing (QS) system. Among several proteins involved in the Pseudomonas QS mechanism, LasR and PqsE play an important role in its cascade signaling system. They can cause increases in QS factors, biofilm maturation, and the production of virulence factors. Therefore, inhibition of these proteins can reduce the pathogenicity of P. aeruginosa. According to the structure of corresponding auto-inducers bound to these proteins, in silico calculations were performed with some non-steroidal anti-inflammatory drugs (NSAIDs) to estimate possible interactions and find the co-inhibitors of LasR and PqsE. The results showed that oxicams (Piroxicam and Meloxicam) can interact well with active sites of both proteins with the Ki of 119.43 nM and 4.0 μM for Meloxicam and 201.39 nM and 4.88 μM against LasR and PqsE, respectively. These findings suggested that Piroxicam and Meloxicam can be used as potential inhibitors for control of the P. aeruginosa QS signaling system and biofilm formation, and may be used in the design of multiple inhibitors. PMID:26358567

  9. Klf5 Deletion Promotes Pten Deletion–Initiated Luminal-Type Mouse Prostate Tumors through Multiple Oncogenic Signaling Pathways12

    PubMed Central

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N.; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-01-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer—mutation/deletion of Pten and deletion of Klf5. PMID:25425963

  10. Signaling through three chemokine receptors triggers the migration of transplanted neural precursor cells in a model of multiple sclerosis.

    PubMed

    Cohen, Mikhal E; Fainstein, Nina; Lavon, Iris; Ben-Hur, Tamir

    2014-09-01

    Multiple sclerosis (MS) is a multifocal disease, and precursor cells need to migrate into the multiple lesions in order to exert their therapeutic effects. Therefore, cell migration is a crucial element in regenerative processes in MS, dictating the route of delivery, when cell transplantation is considered. We have previously shown that inflammation triggers migration of multi-potential neural precursor cells (NPCs) into the white matter of experimental autoimmune encephalomyelitis (EAE) rodents, a widely used model of MS. Here we investigated the molecular basis of this attraction. NPCs were grown from E13 embryonic mouse brains and transplanted into the lateral cerebral ventricles of EAE mice. Transplanted NPC migration was directed by three tissue-derived chemokines. Stromal cell-derived factor-1α, monocyte chemo-attractant protein-1 and hepatocyte growth factor were expressed in the EAE brain and specifically in microglia and astrocytes. Their cognate receptors, CXCR4, CCR2 or c-Met were constitutively expressed on NPCs. Selective blockage of CXCR4, CCR2 or c-Met partially inhibited NPC migration in EAE brains. Blocking all three receptors had an additive effect and resulted in profound inhibition of NPC migration, as compared to extensive migration of control NPCs. The inflammation-triggered NPC migration into white matter tracts was dependent on a motile NPC phenotype. Specifically, depriving NPCs from epidermal growth factor (EGF) prevented the induction of glial commitment and a motile phenotype (as indicated by an in vitro motility assay), hampering their response to neuroinflammation. In conclusion, signaling via three chemokine systems accounts for most of the inflammation-induced, tissue-derived attraction of transplanted NPCs into white matter tracts during EAE. PMID:25086214

  11. Demon voltammetry and analysis software: Analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures

    PubMed Central

    Yorgason, Jordan T.; España, Rodrigo A.; Jones, Sara R.

    2011-01-01

    The fast sampling rates of fast scan cyclic voltammetry make it a favorable method for measuring changes in brain monoamine release and uptake kinetics in slice, anesthetized, and freely moving preparations. The most common analysis technique for evaluating changes in dopamine signaling uses well-established Michaelis-Menten kinetic methods that can accurately model dopamine release and uptake parameters across multiple experimental conditions. Nevertheless, over the years, many researchers have turned to other measures to estimate changes in dopamine release and uptake, yet to our knowledge no systematic comparison amongst these measures has been conducted. To address this lack of uniformity in kinetic analyses, we have created the Demon Voltammetry and Analysis software suite, which is freely available to academic and non-profit institutions. Here we present an explanation of the Demon Acquisition and Analysis features, and demonstrate its utility for acquiring voltammetric data under in vitro, in vivo anesthetized, and freely moving conditions. Additionally, the software was used to compare the sensitivity of multiple kinetic measures of release and uptake to cocaine-induced changes in electrically evoked dopamine efflux in nucleus accumbens core slices. Specifically, we examined and compared tau, full width at half height, half-life, T20, T80, slope, peak height, calibrated peak dopamine concentration, and area under the curve to the well-characterized Michaelis-Menten parameters, dopamine per pulse, maximal uptake rate, and apparent affinity. Based on observed results we recommend tau for measuring dopamine uptake and calibrated peak dopamine concentration for measuring dopamine release. PMID:21392532

  12. Organized emergence of multiple-generations of teeth in snakes is dysregulated by activation of Wnt/beta-catenin signalling.

    PubMed

    Gaete, Marcia; Tucker, Abigail S

    2013-01-01

    In contrast to mammals, most reptiles constantly regenerate their teeth. In the snake, the epithelial dental lamina ends in a successional lamina, which proliferates and elongates forming multiple tooth generations, all linked by a permanent dental lamina. To investigate the mechanisms used to control the initiation of new tooth germs in an ordered sequential pattern we utilized the polyphodont (multiple-generation) corn snake (Pantherophis guttatus). We observed that the dental lamina expressed the transcription factor Sox2, a multipotent stem cell marker, whereas the successional lamina cells expressed the transcription factor Lef1, a Wnt/β-catenin pathway target gene. Activation of the Wnt/β-catenin pathway in culture increased the number of developing tooth germs, in comparison to control untreated cultures. These additional tooth germs budded off from ectopic positions along the dental lamina, rather than in an ordered sequence from the successional lamina. Wnt/β-catenin activation enhanced cell proliferation, particularly in normally non-odontogenic regions of the dental lamina, which widely expressed Lef1, restricting the Sox2 domain. This suggests an expansion of the successional lamina at the expense of the dental lamina. Activation of the Wnt/β-catenin pathway in cultured snake dental organs, therefore, led to changes in proliferation and to the molecular pattern of the dental lamina, resulting in loss of the organised emergence of tooth germs. These results suggest that epithelial compartments are critical for the arrangement of organs that develop in sequence, and highlight the role of Wnt/β-catenin signalling in such processes. PMID:24019968

  13. Organized Emergence of Multiple-Generations of Teeth in Snakes Is Dysregulated by Activation of Wnt/Beta-Catenin Signalling

    PubMed Central

    Gaete, Marcia; Tucker, Abigail S.

    2013-01-01

    In contrast to mammals, most reptiles constantly regenerate their teeth. In the snake, the epithelial dental lamina ends in a successional lamina, which proliferates and elongates forming multiple tooth generations, all linked by a permanent dental lamina. To investigate the mechanisms used to control the initiation of new tooth germs in an ordered sequential pattern we utilized the polyphodont (multiple-generation) corn snake (Pantherophis guttatus). We observed that the dental lamina expressed the transcription factor Sox2, a multipotent stem cell marker, whereas the successional lamina cells expressed the transcription factor Lef1, a Wnt/β-catenin pathway target gene. Activation of the Wnt/β-catenin pathway in culture increased the number of developing tooth germs, in comparison to control untreated cultures. These additional tooth germs budded off from ectopic positions along the dental lamina, rather than in an ordered sequence from the successional lamina. Wnt/β-catenin activation enhanced cell proliferation, particularly in normally non-odontogenic regions of the dental lamina, which widely expressed Lef1, restricting the Sox2 domain. This suggests an expansion of the successional lamina at the expense of the dental lamina. Activation of the Wnt/β-catenin pathway in cultured snake dental organs, therefore, led to changes in proliferation and to the molecular pattern of the dental lamina, resulting in loss of the organised emergence of tooth germs. These results suggest that epithelial compartments are critical for the arrangement of organs that develop in sequence, and highlight the role of Wnt/β-catenin signalling in such processes. PMID:24019968

  14. Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression.

    PubMed

    Frank, Valeska; Habbig, Sandra; Bartram, Malte P; Eisenberger, Tobias; Veenstra-Knol, Hermine E; Decker, Christian; Boorsma, Reinder A C; Göbel, Heike; Nürnberg, Gudrun; Griessmann, Anabel; Franke, Mareike; Borgal, Lori; Kohli, Priyanka; Völker, Linus A; Dötsch, Jörg; Nürnberg, Peter; Benzing, Thomas; Bolz, Hanno J; Johnson, Colin; Gerkes, Erica H; Schermer, Bernhard; Bergmann, Carsten

    2013-06-01

    Mutations affecting the integrity and function of cilia have been identified in various genes over the last decade accounting for a group of diseases called ciliopathies. Ciliopathies display a broad spectrum of phenotypes ranging from mild manifestations to lethal combinations of multiple severe symptoms and most of them share cystic kidneys as a common feature. Our starting point was a consanguineous pedigree with three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas and developmental heart disease. By genome-wide linkage analysis, we mapped the disease locus to chromosome 17q11 and identified a homozygous nonsense mutation in NEK8/NPHP9 that encodes a kinase involved in ciliary dynamics and cell cycle progression. Missense mutations in NEK8/NPHP9 have been identified in juvenile cystic kidney jck mice and in patients suffering from nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. This work confirmed a complete loss of NEK8 expression in the affected fetuses due to nonsense-mediated decay. In cultured fibroblasts derived from these fetuses, the expression of prominent polycystic kidney disease genes (PKD1 and PKD2) was decreased, whereas the oncogene c-MYC was upregulated, providing potential explanations for the observed renal phenotype. We furthermore linked NEK8 with NPHP3, another NPH protein known to cause a very similar phenotype in case of null mutations. Both proteins interact and activate the Hippo effector TAZ. Taken together, our study demonstrates that NEK8 is essential for organ development and that the complete loss of NEK8 perturbs multiple signalling pathways resulting in a severe early embryonic phenotype. PMID:23418306

  15. Nitric Oxide-cGMP Signaling Stimulates Erythropoiesis through Multiple Lineage-Specific Transcription Factors: Clinical Implications and a Novel Target for Erythropoiesis

    PubMed Central

    Ikuta, Tohru; Sellak, Hassan; Odo, Nadine; Adekile, Adekunle D.; Gaensler, Karin M. L.

    2016-01-01

    Much attention has been directed to the physiological effects of nitric oxide (NO)-cGMP signaling, but virtually nothing is known about its hematologic effects. We reported for the first time that cGMP signaling induces human γ-globin gene expression. Aiming at developing novel therapeutics for anemia, we examined here the hematologic effects of NO-cGMP signaling in vivo and in vitro. We treated wild-type mice with NO to activate soluble guanylate cyclase (sGC), a key enzyme of cGMP signaling. Compared to untreated mice, NO-treated mice had higher red blood cell counts and total hemoglobin but reduced leukocyte counts, demonstrating that when activated, NO-cGMP signaling exerts hematopoietic effects on multiple types of blood cells in vivo. We next generated mice which overexpressed rat sGC in erythroid and myeloid cells. The forced expression of sGCs activated cGMP signaling in both lineage cells. Compared with non-transgenic littermates, sGC mice exhibited hematologic changes similar to those of NO-treated mice. Consistently, a membrane-permeable cGMP enhanced the differentiation of hematopoietic progenitors toward erythroid-lineage cells but inhibited them toward myeloid-lineage cells by controlling multiple lineage-specific transcription factors. Human γ-globin gene expression was induced at low but appreciable levels in sGC mice carrying the human β-globin locus. Together, these results demonstrate that NO-cGMP signaling is capable of stimulating erythropoiesis in both in vitro and vivo settings by controlling the expression of multiple lineage-specific transcription factors, suggesting that cGMP signaling upregulates erythropoiesis at the level of gene transcription. The NO-cGMP signaling axis may constitute a novel target to stimulate erythropoiesis in vivo. PMID:26727002

  16. Butyrate induces profound changes in gene expression related to multiple signal pathways in bovine kidney epithelial cells

    PubMed Central

    Li, Robert W; Li, CongJun

    2006-01-01

    Background Global gene expression profiles of bovine kidney epithelial cells regulated by sodium butyrate were investigated with high-density oligonucleotide microarrays. The bovine microarray with 86,191 distinct 60mer oligonucleotides, each with 4 replicates, was designed and produced with Maskless Array Synthesizer technology. These oligonucleotides represent approximately 45,383 unique cattle sequences. Results 450 genes significantly regulated by butyrate with a median False Discovery Rate (FDR) = 0 % were identified. The majority of these genes were repressed by butyrate and associated with cell cycle control. The expression levels of 30 selected genes identified by the microarray were confirmed using real-time PCR. The results from real-time PCR positively correlated (R = 0.867) with the results from the microarray. Conclusion This study presented the genes related to multiple signal pathways such as cell cycle control and apoptosis. The profound changes in gene expression elucidate the molecular basis for the pleiotropic effects of butyrate on biological processes. These findings enable better recognition of the full range of beneficial roles butyrate may play during cattle energy metabolism, cell growth and proliferation, and possibly in fighting gastrointestinal pathogens. PMID:16972989

  17. Epigenetic identification of ZNF545 as a functional tumor suppressor in multiple myeloma via activation of p53 signaling pathway.

    PubMed

    Fan, Yu; Zhan, Qian; Xu, Hongying; Li, Lili; Li, Chen; Xiao, Qian; Xiang, Shili; Hui, Tianli; Xiang, Tingxiu; Ren, Guosheng

    2016-06-10

    The KRAB-zinc-finger protein ZNF545 was recently identified as a potential suppressor gene in several tumors. However, the regulatory mechanisms of ZNF545 in tumorigenesis remain unclear. In this study, we investigated the expression and roles of ZNF545 in multiple myeloma (MM). ZNF545 was frequently downregulated in MM tissues compared with non-tumor bone marrow tissues. ZNF545 expression was silenced by promoter methylation in MM cell lines, and could be restored by demethylation treatment. ZNF545 methylation was detected in 28.3% of MM tissues, compared with 4.3% of normal bone marrow tissues. ZNF545 transcriptionally activated the p53 signaling pathway but had no effect on Akt in MM, whereas ectopic expression of ZNF545 in silenced cells suppressed their proliferation and induced apoptosis. We therefore identified ZNF545 as a novel tumor suppressor inhibiting tumor growth through activation of the p53 pathway in MM. Moreover, tumor-specific methylation of ZNF545 may represent an epigenetic biomarker for MM diagnosis, and a potential target for specific therapy. PMID:27150632

  18. A novel nanosensor composed of aptamer bio-dots and gold nanoparticles for determination of thrombin with multiple signals.

    PubMed

    Kuang, Lan; Cao, Shu-Ping; Zhang, Li; Li, Qiu-Hong; Liu, Zhi-Chao; Liang, Ru-Ping; Qiu, Jian-Ding

    2016-11-15

    Thrombin is a crucial multifunctional enzyme involved in many physiological and pathological processes. Its detection is of great importance. In this work, a novel bio-dots nanosensor for detection of thrombin with colorimetric, fluorometric and light-scattering signals is developed. This nanosensor is composed of thrombin-binding aptamer bio-dots (TBA-dots) and gold nanoparticles (AuNPs), where TBA-dots serve as fluorometric reporter and AuNPs function as multiple roles as colorimetric reporter, light scattering reporter and fluorescence quencher. TBA-dots retain inherent structures of aptamer to specifically interact with thrombin and simultaneously induce the aggregation of AuNPs. The mechanism of the sensing system is based on distance-dependent aggregation of AuNPs and fluorescence resonance energy transfer (FRET). The nanosensor needs no further surface functionalization required for the as-prepared bio-dots and AuNPs, which provides a sensitive method for the selective detection of thrombin with a detection limit as low as 0.59nM. In addition, it provides a brand new perspective for bio-dots and its potential use in bioanalysis. PMID:27288712

  19. Adipocytes contribute to the growth and progression of multiple myeloma: Unraveling obesity related differences in adipocyte signaling.

    PubMed

    Bullwinkle, Erica M; Parker, Melissa D; Bonan, Nicole F; Falkenberg, Lauren G; Davison, Steven P; DeCicco-Skinner, Kathleen L

    2016-09-28

    The prevalence of obesity over the last several decades in the United States has tripled among children and doubled among adults. Obesity increases the incidence and progression of multiple myeloma (MM), yet the molecular mechanisms by which adipocytes contribute to cancer development and patient prognosis have yet to be fully elucidated. Here, we obtained human adipose-derived stem cells (ASCs) from twenty-nine normal (BMI = 20-25 kg/m(2)), overweight (25-30 kg/m(2)), obese (30-35 kg/m(2)), or super obese (35-40 kg/m(2)) patients undergoing elective liposuction. Upon differentiation, adipocytes were co-cultured with RPMI-8226 and NCI-H929 MM cell lines. Adipocytes from overweight, obese and super obese patients displayed increased PPAR-gamma, cytochrome C, interleukin-6, and leptin protein levels, and decreased fatty acid synthase protein. 8226 MM cells proliferated faster and displayed increased pSTAT-3/STAT-3 signaling when cultured in adipocyte conditioned media. Further, adipocyte conditioned media from obese and super obese patients significantly increased MM cell adhesion, and conditioned media from overweight, obese and super obese patients enhanced tube formation and expression of matrix metalloproteinase-2. In summary, our data suggest that adipocytes in the MM microenvironment contribute to MM growth and progression and should be further evaluated as a possible therapeutic target. PMID:27317873

  20. Signal degradation by multiple scattering in optical coherence tomography of dense tissue: a Monte Carlo study towards optical clearing of biotissues

    NASA Astrophysics Data System (ADS)

    Wang, Ruikang K.

    2002-07-01

    Multiple scattering is a major source that limits light penetration into biotissues, thereby preventing visualization of the deep microstructures for high-resolution optical imaging techniques. The optical clearing approach is a new adventure in biomedical optics for manipulating the optical properties of tissue; for example, the scattering coefficient and the degree of forward scattering of photons, by the use of the chemical administration method in order to improve the optical imaging depth, particularly for the recently developed optical coherence tomography (OCT). This paper investigates systematically how the multiple scattering affects signal attenuation and localization in general, and how the alterations of optical properties of tissue enhance the optical imaging depth and signal localization in particular, by the use of Monte Carlo simulations through the separate considerations of the least scattered photons (LSP) and multiple scattered photons (MSP). The LSP are those photons that contribute to the precise OCT signal, i.e. localization, and the MSP are those that degrade the OCT signal. It is shown that with either the reduction of the scattering coefficient or the increase of the degree of forward scattering, signal localization and imaging depth for OCT is enhanced. Whilst the increase of the anisotropic factor of the medium is more efficient in improving signal localization, it introduces more scattering events for the photons travelling within the tissue for both the LSP and MSP. It is also found that the OCT imaging resolution is almost reduced exponentially with the increase of the probing depth as opposed to the claimed system resolution. We demonstrate that optical clearing could be a useful tool to improve the imaging resolution when the light progressively penetrates the high scattering medium. Experimental results are also presented to show intuitively how multiple scattering affects OCT signal profiles by the use of intralipid solution and

  1. The β-catenin Axis Integrates Multiple Signals Downstream From RET/PTC and Leads to Cell Proliferation

    PubMed Central

    Castellone, Maria Domenica; De Falco, Valentina; Rao, Deva Magendra; Bellelli, Roberto; Muthu, Magesh; Basolo, Fulvio; Fusco, Alfredo; Gutkind, J. Silvio; Santoro, Massimo

    2009-01-01

    RET/PTC (RET/papillary thyroid carcinoma) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here we show that RET/PTC stimulates the β-catenin pathway. By stimulating PI3K/AKT and Ras/ERK, RET/PTC promotes GSK3β phosphorylation, thereby reducing GSK3β-mediated N-terminal β-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with β-catenin, and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)β-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3β complex and activates the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor. Moreover, through the ERK pathway, RET/PTC stimulates cAMP-responsive element binding protein (CREB) phosphorylation and promotes the formation of a β-catenin-CREB-CBP/p300 transcriptional complex. Transcriptional complexes containing β-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC expressing cells. Silencing of β-catenin by siRNA inhibits proliferation of RET/PTC transformed PC thyrocytes, whereas a constitutively active form of β-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on β-catenin to stimulate cell proliferation. PMID:19223551

  2. PSMB4 promotes multiple myeloma cell growth by activating NF-κB-miR-21 signaling

    SciTech Connect

    Zheng, Peihao; Guo, Honggang; Li, Guangchao; Han, Siqi; Luo, Fei; Liu, Yi

    2015-03-06

    Proteasomal subunit PSMB4, was recently identified as potential cancer driver genes in several tumors. However, the regulatory mechanism of PSMB4 on carcinogenesis process remains unclear. In this study, we investigated the expression and roles of PSMB4 in multiple myeloma (MM). We found a significant up-regulation of PSMB4 in MM plasma and cell lines. Ectopic overexpression of PSMB4 promoted cell growth and colony forming ability of MM cells, whereas inhibition of PSMB4 led to a decrease of such events. Furthermore, our results demonstrated the up-regulation of miR-21 and a positive correlation between the levels of miR-21 and PSMB4 in MM. Re-expression of miR-21 markedly rescued PSMB4 knockdown-mediated suppression of cell proliferation and clone-formation. Additionally, while enforced expression of PSMB4 profoundly increased NF-κB activity and the level of miR-21, PSMB4 knockdown or NF-κB inhibition suppressed miR-21 expression in MM cells. Taken together, our results demonstrated that PSMB4 regulated MM cell growth in part by activating NF-κB-miR-21 signaling, which may represent promising targets for novel specific therapies. - Highlights: • First reported upregulation of PSMB4 in MM plasma and cell lines. • PSMB4 promoted MM cell growth and colony forming ability. • Further found miR-21 was up-regulated by PSMB4 in MM plasma and cell lines. • PSMB4-induced miR-21 expression was modulated by NF-κB. • PSMB4-NF-κB-miR-21 axis may be potential therapeutic targets of MM.

  3. In-line phase-sensitive amplification of QPSK signal using multiple quasi-phase matched LiNbO₃ waveguide.

    PubMed

    Asobe, Masaki; Umeki, Takeshi; Takenouchi, Hirokazu; Miyamoto, Yutaka

    2014-11-01

    Phase-sensitive amplifiers (PSA) using periodically poled (PPLN) LiNbO₃ waveguides are promising as low-noise optical amplifiers. However, it is difficult to realize in-line operation for multi-level phase modulated signals using a PPLN based PSA with the conventional configuration. In this paper, we report a PPLN based in-line PSA that can regenerate quadrature phase shift keying (QPSK) signals. Multi-stage frequency mixing in a multiple quasi-phase matched LiNbO₃waveguide allows carrier phase recovery from a QPSK signal. Non-degenerate parametric amplification enables the phase-sensitive amplification of a QPSK signal. Amplitude and phase regeneration is examined utilizing gain saturation and phase squeezing capability. PMID:25401814

  4. Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy.

    PubMed Central

    Schwarz, J; Weis, S; Kraft, E; Tatsch, K; Bandmann, O; Mehraein, P; Vogl, T; Oertel, W H

    1996-01-01

    A correlation of clinical, MRI, and neuropathological data is reported in two patients with multiple system atrophy (MSA). On MRI, patient 1 showed striatal atrophy, reduction of T2 relaxation times within most of the putamen, and a band of hyperintense signal changes in the lateral putamen. In patient 2, MRI disclosed only shortening of the T2 signal in the putamen. Immunohistochemistry showed pronounced reactive microgliosis and astrogliosis in the affected brain regions. In patient 1, the area with the most pronounced microgliosis and astrogliosis most likely correlated with the area of hyperintense signal changes on MRI. This area also contained the highest amount of ferric iron, which was increased in the putamen of patient 1 but not patient 2. It is unlikely that the hypointense signal changes in the putamen are due to an increase of iron alone. Reactive microglial and astroglial cells may play a part in the pathogenesis of MSA. Images PMID:8558163

  5. Phospholipase C-delta extends intercellular signalling range and responses to injury-released growth factors in non-excitable cells

    PubMed Central

    Mi, L. Y.; Ettenson, D. S.; Edelman, E. R.

    2010-01-01

    Objectives Intercellular communication in non-excitable cells is restricted to a limited range close to the signal source. Here, we have examined whether modification of the intracellular microenvironment could prolong the spatial proposition of signal generation and could increase cell proliferation. Material and methods Mathematical models and experimental studies of endothelial repair after controlled mechanical injury were used. The models predict the diffusion range of injury-released growth factors and identify important parameters involved in a signalling regenerative mode. Transfected human umbilical vein endothelial cells (HUVECs) were used to validate model results, by examining intercellular calcium signalling range, cell proliferation and wound healing rate. Results The models predict that growth factors have a limited capacity of extracellular diffusion and that intercellular signals are specially sensitive to cell phospholipase C-delta (PLCδ) levels. As basal PLCδ levels are increased by transfection, a significantly increased intercellular calcium range, enhanced cell proliferation, and faster wound healing rate were observed. Conclusion Our in silico and in vitro studies demonstrated that non-excitable endothelial cells respond to stimuli in a complex manner, in which intercellular communication is controlled by physicochemical properties of the stimulus and by the cell microenvironment. Such findings may have profound implications for our understanding of the tight nature of autocrine cell growth control, compensation to stress states and response to altered microenvironment, under pathological conditions. PMID:18616695

  6. Signaling in multiple modalities in male rhesus macaques: sex skin coloration and barks in relation to androgen levels, social status, and mating behavior

    PubMed Central

    Higham, James P.; Pfefferle, Dana; Heistermann, Michael; Maestripieri, Dario; Stevens, Martin

    2014-01-01

    The past decade has seen an increasing shift in animal communication towards more studies that incorporate aspects of signaling in multiple modalities. Although nonhuman primates are an excellent group for studying the extent to which different aspects of condition may be signaled in different modalities, and how such information may be integrated during mate choice, very few studies of primate species have incorporated such analyses. Here, we present data from free-ranging male rhesus macaques on sex skin coloration (modeled to receiver perception), bark vocal signals, androgen levels, morphometric variables, dominance status, and female mate choice. We show that, consistent with data on females, most intra- and interindividual variation in sex skin appearance occurs in luminance rather than color. Sex skin luminance was significantly correlated across different skin regions. Sex skin luminance did not correlate with the majority of bark parameters, suggesting the potential for the two signals to convey different information. Sex skin appearance was not related to androgen levels although we found some evidence for links between androgen levels and bark parameters, several of which were also related to morphometric variables. We found no evidence that either signal was related to male dominance rank or used in female mate choice, though more direct measures of female proceptive behavior are needed. Overall, the function of male sex skin coloration in this species remains unclear. Our study is among the first nonhuman primate studies to incorporate measurements of multiple signals in multiple modalities, and we encourage other authors to incorporate such analyses into their work. PMID:25013266

  7. Quantitative genetics of female choice in an ultrasonic pyralid moth, Achroia grisella: variation and evolvability of preference along multiple dimensions of the male advertisement signal.

    PubMed

    Jang, Y; Greenfield, M D

    2000-01-01

    The mating system of Achroia grisella (Lepidoptera: Pyralidae) is characterized by male ultrasonic advertisement signalling to which females orientate. Although males provide no direct, somatic benefits to their mates, females prefer males whose signal characters are more exaggerated than the population means. Previous studies showed that the signal characters influencing mate attraction are highly repeatable and heritable. We measured the phenotypic and additive genetic variances (heritability) of female preference in A. grisella, as this additive genetic variance is one of the genetic assumptions of indirect models of sexual selection. We determined the preference index of female A. grisella by repeated phonotaxis trials in which a choice of simulated male signals was presented. These playback experiments showed that female preference indices varied but were repeatable within individuals. Specifically, females differ in the relative importance of the several signal characters during mate assessment. A subsequent half-sib breeding design revealed an amount of additive genetic variance for the female preference index (h(s)2 = 0.212, SE = 0.1347, P = 0.0611; CVA = 0.1826). Our study highlights the importance of careful preparation of test signals and experimental design for quantifying individual variation in (female) preference along multiple signal dimensions. PMID:10692013

  8. Analysis of low-frequency seismic signals generated during a multiple-iceberg calving event at Jakobshavn Isbræ, Greenland

    USGS Publications Warehouse

    Walter, Fabian; Amundson, Jason M.; O'Neel, Shad; Truffer, Martin; Fahnestock, Mark; Fricker, Helen A.

    2012-01-01

    We investigated seismic signals generated during a large-scale, multiple iceberg calving event that occurred at Jakobshavn Isbræ, Greenland, on 21 August 2009. The event was recorded by a high-rate time-lapse camera and five broadband seismic stations located within a few hundred kilometers of the terminus. During the event two full-glacier-thickness icebergs calved from the grounded (or nearly grounded) terminus and immediately capsized; the second iceberg to calve was two to three times smaller than the first. The individual calving and capsize events were well-correlated with the radiation of low-frequency seismic signals (<0.1 Hz) dominated by Love and Rayleigh waves. In agreement with regional records from previously published ‘glacial earthquakes’, these low-frequency seismic signals had maximum power and/or signal-to-noise ratios in the 0.05–0.1 Hz band. Similarly, full waveform inversions indicate that these signals were also generated by horizontal single forces acting at the glacier terminus. The signals therefore appear to be local manifestations of glacial earthquakes, although the magnitudes of the signals (twice-time integrated force histories) were considerably smaller than previously reported glacial earthquakes. We thus speculate that such earthquakes may be a common, if not pervasive, feature of all full-glacier-thickness calving events from grounded termini. Finally, a key result from our study is that waveform inversions performed on low-frequency, calving-generated seismic signals may have only limited ability to quantitatively estimate mass losses from calving. In particular, the choice of source time function has little impact on the inversion but dramatically changes the earthquake magnitude. Accordingly, in our analysis, it is unclear whether the smaller or larger of the two calving icebergs generated a larger seismic signal.

  9. Interaction between insulin-like growth factor-I receptor and alphaVbeta3 integrin linked signaling pathways: cellular responses to changes in multiple signaling inputs.

    PubMed

    Clemmons, D R; Maile, L A

    2005-01-01

    Integrins are heterodimeric transmembrane proteins that mediate cell attachment to extracellular matrix, migration, division, and inhibition of apoptosis. Because growth factors are also important for these processes, there has been interest in cooperative signaling between growth factor receptors and integrins. IGF-I is an important growth factor for vascular cells. One integrin, alphaVbeta3, that is expressed in smooth muscle cells modulates IGF-I actions. Ligand occupancy of alphaVbeta3 is required for IGF-I to stimulate cell migration and division. Src homology 2 containing tyrosine phosphatase (SHP-2) is a tyrosine phosphatase whose recruitment to signaling molecules is stimulated by growth factors including IGF-I. If alphaVbeta3 ligand occupancy is inhibited, there is no recruitment of SHP-2 to alphaVbeta3 and its transfer to downstream signaling molecules is blocked. Ligand occupancy of alphaVbeta3 stimulates tyrosine phosphorylation of the beta3-subunit, resulting in recruitment of SHP-2. This transfer is mediated by an insulin receptor substrate-1-related protein termed DOK-1. Subsequently, SHP-2 is transferred to another transmembrane protein, SHPS-1. This transfer requires IGF-I receptor-mediated tyrosine phosphorylation of SHPS-1, which contains two YXXL motifs that mediate SHP-2 binding. The transfer of SHP-2 to SHPS-1 is also required for recruitment of Shc to SHPS-1. Ligand occupancy of alphaVbeta3 results in sustained Shc phosphorylation and enhanced Shc recruitment. Shc activation results in induction of MAPK. Inhibition of the Shc/SHPS-1 complex formation results in failure to achieve sustained MAPK activation and an attenuated mitogenic response. Thus, within the vessel wall, a mechanism exists whereby ligand occupancy of the alphaVbeta3 integrin is required for assembly of a multicomponent membrane signaling complex that is necessary for cells to respond optimally to IGF-I. PMID:15528274

  10. Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models

    PubMed Central

    Choi, Catherine H.; Schoenfeld, Brian P.; Bell, Aaron J.; Hinchey, Joseph; Rosenfelt, Cory; Gertner, Michael J.; Campbell, Sean R.; Emerson, Danielle; Hinchey, Paul; Kollaros, Maria; Ferrick, Neal J.; Chambers, Daniel B.; Langer, Steven; Sust, Steven; Malik, Aatika; Terlizzi, Allison M.; Liebelt, David A.; Ferreiro, David; Sharma, Ali; Koenigsberg, Eric; Choi, Richard J.; Louneva, Natalia; Arnold, Steven E.; Featherstone, Robert E.; Siegel, Steven J.; Zukin, R. Suzanne; McDonald, Thomas V.; Bolduc, Francois V.; Jongens, Thomas A.; McBride, Sean M. J.

    2016-01-01

    Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model. PMID:27445731

  11. Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models.

    PubMed

    Choi, Catherine H; Schoenfeld, Brian P; Bell, Aaron J; Hinchey, Joseph; Rosenfelt, Cory; Gertner, Michael J; Campbell, Sean R; Emerson, Danielle; Hinchey, Paul; Kollaros, Maria; Ferrick, Neal J; Chambers, Daniel B; Langer, Steven; Sust, Steven; Malik, Aatika; Terlizzi, Allison M; Liebelt, David A; Ferreiro, David; Sharma, Ali; Koenigsberg, Eric; Choi, Richard J; Louneva, Natalia; Arnold, Steven E; Featherstone, Robert E; Siegel, Steven J; Zukin, R Suzanne; McDonald, Thomas V; Bolduc, Francois V; Jongens, Thomas A; McBride, Sean M J

    2016-01-01

    Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model. PMID:27445731

  12. IFNγR signaling in non-T cell targets regulates T cell-mediated intestinal inflammation through multiple mechanisms

    PubMed Central

    Do, Jeong-su; Asosingh, Kewal; Baldwin, William M.; Min, Booki

    2014-01-01

    Naïve CD4 T cells transferred into lymphopenic mice undergo spontaneous proliferation and induce chronic inflammation in the intestine. Cellular mechanisms regulating the proliferative and inflammatory processes are not fully understood. In this study, we report that IFNγ signaling in host cells plays a major role in limiting both T cell expansion and T cell-induced intestinal inflammation. However, the role for IFNγ appears to be distinct depending on the target cells. IFNγ signaling in DCs controls T cell expansion, while IFNγ signaling in neutrophils seems to regulate both T cell expansion and inflammation. IFNγ signaling in non-hematopoietic cells may control inflammation. Therefore, our results suggest novel immunoregulatory functions for IFNγ to orchestrate colitogenic T cell responses through its distinct action on different non-T cell target cells. PMID:24523506

  13. Enhanced in Vivo Efficacy of a Type I Interferon Superagonist with Extended Plasma Half-life in a Mouse Model of Multiple Sclerosis*

    PubMed Central

    Harari, Daniel; Kuhn, Nadine; Abramovich, Renne; Sasson, Keren; Zozulya, Alla L.; Smith, Paul; Schlapschy, Martin; Aharoni, Rina; Köster, Mario; Eilam, Raya; Skerra, Arne; Schreiber, Gideon

    2014-01-01

    IFNβ is a common therapeutic option to treat multiple sclerosis. It is unique among the family of type I IFNs in that it binds to the interferon receptors with high affinity, conferring exceptional biological properties. We have previously reported the generation of an interferon superagonist (dubbed YNSα8) that is built on the backbone of a low affinity IFNα but modified to exhibit higher receptor affinity than even for IFNβ. Here, YNSα8 was fused with a 600-residue hydrophilic, unstructured N-terminal polypeptide chain comprising proline, alanine, and serine (PAS) to prolong its plasma half-life via “PASylation.” PAS-YNSα8 exhibited a 10-fold increased half-life in both pharmacodynamic and pharmacokinetic assays in a transgenic mouse model harboring the human receptors, notably without any detectable loss in biological potency or bioavailability. This long-lived superagonist conferred significantly improved protection from MOG35–55-induced experimental autoimmune encephalomyelitis compared with IFNβ, despite being injected with a 4-fold less frequency and at an overall 16-fold lower dosage. These data were corroborated by FACS measurements showing a decrease of CD11b+/CD45hi myeloid lineage cells detectable in the CNS, as well as a decrease in IBA+ cells in spinal cord sections determined by immunohistochemistry for PAS-YNSα8-treated animals. Importantly, PAS-YNSα8 did not induce antibodies upon repeated administration, and its biological efficacy remained unchanged after 21 days of treatment. A striking correlation between increased levels of CD274 (PD-L1) transcripts from spleen-derived CD4+ cells and improved clinical response to autoimmune encephalomyelitis was observed, indicating that, at least in this mouse model of multiple sclerosis, CD274 may serve as a biomarker to predict the effectiveness of IFN therapy to treat this complex disease. PMID:25193661

  14. Spatially Extended fMRI Signal Response to Stimulus in Non-Functionally Relevant Regions of the Human Brain: Preliminary Results

    PubMed Central

    Kornak, John; Hall, Deborah A; Haggard, Mark P

    2011-01-01

    The blood-oxygenation level dependent (BOLD) haemodynamic response function (HDR) in functional magnetic resonance imaging (fMRI) is a delayed and indirect marker of brain activity. In this single case study a small BOLD response synchronised with the stimulus paradigm is found globally, i.e. in all areas outside those of expected activation in a single subject study. The nature of the global response has similar shape properties to the archetypal BOLD HDR, with an early positive signal and a late negative response typical of the negative overshoot. Fitting Poisson curves to these responses showed that voxels were potentially split into two sets: one with dominantly positive signal and the other predominantly negative. A description, quantification and mapping of the global BOLD response is provided along with a 2 × 2 classification table test to demonstrate existence with very high statistical confidence. Potential explanations of the global response are proposed in terms of 1) global HDR balancing; 2) resting state network modulation; and 3) biological systems synchronised with the stimulus cycle. Whilst these widespread and low-level patterns seem unlikely to provide additional information for determining activation in functional neuroimaging studies as conceived in the last 15 years, knowledge of their properties may assist more comprehensive accounts of brain connectivity in the future. PMID:21760873

  15. Extended structures and new infinite-dimensional hidden symmetries for the Einstein Maxwell-dilaton-axion theory with multiple vector fields

    NASA Astrophysics Data System (ADS)

    Gao, Ya-Jun

    2005-01-01

    A so-called extended elliptical-complex (EEC) function method is proposed and used to further study the Einstein Maxwell-dilaton-axion theory with p vector fields (EMDA-p theory, for brevity) for p = 1,2,ldots . An Ernst-like 2^{k+1}× 2^{k+1}(k = [(p+1)/2]) matrix EEC potential is introduced and the motion equations of the stationary axisymmetric EMDA-p theory are written as a so-called Hauser Ernst-like self-dual relation for the EEC matrix potential. In particular, for the EMDA-2 theory, two Hauser Ernst-type EEC linear systems are established and based on their solutions some new parametrized symmetry transformations are explicitly constructed. These hidden symmetries are verified to constitute an infinite-dimensional Lie algebra, which is the semidirect product of the Kac Moody algebra su(2,2)⊗ R(t,t^{-1}) and Virasoro algebra (without centre charges). These results show that the studied EMDA-p theories possess very rich symmetry structures and the EEC function method is necessary and effective.

  16. "Wave" signal-smoothing and mercury-removing device for laser ablation quadrupole and multiple collector ICPMS analysis: application to lead isotope analysis.

    PubMed

    Hu, Zhaochu; Zhang, Wen; Liu, Yongsheng; Gao, Shan; Li, Ming; Zong, Keqing; Chen, Haihong; Hu, Shenghong

    2015-01-20

    A novel "wave" signal-smoothing and mercury-removing device has been developed for laser ablation quadrupole and multiple collector ICPMS analysis. With the wave stabilizer that has been developed, the signal stability was improved by a factor of 6.6-10 and no oscillation of the signal intensity was observed at a repetition rate of 1 Hz. Another advantage of the wave stabilizer is that the signal decay time is similar to that without the signal-smoothing device (increased by only 1-2 s for a signal decay of approximately 4 orders of magnitude). Most of the normalized elemental signals (relative to those without the stabilizer) lie within the range of 0.95-1.0 with the wave stabilizer. Thus, the wave stabilizer device does not significantly affect the aerosol transport efficiency. These findings indicate that this device is well-suited for routine optimization of ICPMS, as well as low repetition rate laser ablation analysis, which provides smaller elemental fractionation and better spatial resolution. With the wave signal-smoothing and mercury-removing device, the mercury gas background is reduced by 1 order of magnitude. More importantly, the (202)Hg signal intensity produced in the sulfide standard MASS-1 by laser ablation is reduced from 256 to 0.7 mV by the use of the wave signal-smoothing and mercury-removing device. This result suggests that the mercury is almost completely removed from the sample aerosol particles produced by laser ablation with the operation of the wave mercury-removing device. The wave mercury-removing device that we have designed is very important for Pb isotope ratio and accessory mineral U-Pb dating analysis, where removal of the mercury from the background gas and sample aerosol particles is highly desired. The wave signal-smoothing and mercury-removing device was applied successfully to the determination of the (206)Pb/(204)Pb isotope ratio in samples with low Pb content and/or high Hg content. PMID:25511501

  17. Histamine H4 Receptor mediates interleukin-8 and TNF-α release in human mast cells via multiple signaling pathways.

    PubMed

    Chen, X-F; Zhang, Z; Dou, X; Li, J-J; Zhang, W; Yu, Y-Y; Yu, B; Yu, B

    2016-01-01

    Histamine, mainly produced by mast cells, is an important inflammatory mediator in immune response. Recently Histamine H4 Receptor (H4R) was also identified in mast cells, from which pro-inflammatory cytokines and chemokines are released. However, the mechanism of how H4R mediates these cytokines and chemokines release in mast cells was still unclear. To further explore the role of H4R in the immune inflammatory response in mast cells, we tested the release of inflammatory cytokine tumor necrosis factor-α (TNF-α), chemokine interleukin-8 (IL-8) and the relevant signaling pathways activated by H4R on LAD2 cells (a human mast cell line). We found that the release of IL-8 and TNF-α were blocked by inhibitors of PI3K, ERK and Ca2+-Calcineurin-NFAT signaling pathways, while the release of these cytokines and chemokines were enhanced by the inhibitor of P38 signaling pathway. However, inhibitors of the JNK and NF-κB signaling pathways had little effect on the expression of the pro-inflammatory mediators. Moreover, activation of the H4R could induce phosphorylation of ERK, p38 and AKT in mast cells. In conclusion, we found that H4R mediates the release of inflammatory cytokine TNF-α and chemokine IL-8 in human mast cells via PI3K, Ca2+-Calcineurin-NFAT and MAPKs signaling pathways. PMID:26828993

  18. Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9.

    PubMed

    Lindner, Maren; Thümmler, Katja; Arthur, Ariel; Brunner, Sarah; Elliott, Christina; McElroy, Daniel; Mohan, Hema; Williams, Anna; Edgar, Julia M; Schuh, Cornelia; Stadelmann, Christine; Barnett, Susan C; Lassmann, Hans; Mücklisch, Steve; Mudaliar, Manikhandan; Schaeren-Wiemers, Nicole; Meinl, Edgar; Linington, Christopher

    2015-07-01

    Remyelination failure plays an important role in the pathophysiology of multiple sclerosis, but the underlying cellular and molecular mechanisms remain poorly understood. We now report actively demyelinating lesions in patients with multiple sclerosis are associated with increased glial expression of fibroblast growth factor 9 (FGF9), which we demonstrate inhibits myelination and remyelination in vitro. This inhibitory activity is associated with the appearance of multi-branched 'pre-myelinating' MBP+ / PLP+ oligodendrocytes that interact with axons but fail to assemble myelin sheaths; an oligodendrocyte phenotype described previously in chronically demyelinated multiple sclerosis lesions. This inhibitory activity is not due to a direct effect of FGF9 on cells of the oligodendrocyte lineage but is mediated by factors secreted by astrocytes. Transcriptional profiling and functional validation studies demonstrate that these include effects dependent on increased expression of tissue inhibitor of metalloproteinase-sensitive proteases, enzymes more commonly associated with extracellular matrix remodelling. Further, we found that FGF9 induces expression of Ccl2 and Ccl7, two pro-inflammatory chemokines that contribute to recruitment of microglia and macrophages into multiple sclerosis lesions. These data indicate glial expression of FGF9 can initiate a complex astrocyte-dependent response that contributes to two distinct pathogenic pathways involved in the development of multiple sclerosis lesions. Namely, induction of a pro-inflammatory environment and failure of remyelination; a combination of effects predicted to exacerbate axonal injury and loss in patients. PMID:25907862

  19. Characteristics of CTX-M Extended-Spectrum β-Lactamase-Producing Escherichia coli Strains Isolated from Multiple Rivers in Southern Taiwan.

    PubMed

    Chen, Po-An; Hung, Chih-Hsin; Huang, Ping-Chih; Chen, Jung-Ren; Huang, I-Fei; Chen, Wan-Ling; Chiou, Yee-Hsuan; Hung, Wan-Yu; Wang, Jiun-Ling; Cheng, Ming-Fang

    2016-03-01

    Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli sequence type ST131 has emerged as the leading cause of community-acquired urinary tract infections and bacteremia worldwide. Whether environmental water is a potential reservoir of these strains remains unclear. River water samples were collected from 40 stations in southern Taiwan from February to August 2014. PCR assay and multilocus sequence typing (MLST) analysis were conducted to determine the CTX-M group and sequence type, respectively. In addition, we identified the seasonal frequency of ESBL-producing E. coli strains and their geographical relationship with runoffs from livestock and poultry farms between February and August 2014. ESBL-producing E. coli accounted for 30% of the 621 E. coli strains isolated from river water in southern Taiwan. ESBL-producing E. coli ST131 was not detected among the isolates. The most commonly detected strain was E. coli CTX-M group 9. Among the 92 isolates selected for MLST analysis, the most common ESBL-producing clonal complexes were ST10 and ST58. The proportion of ESBL-producing E. coli was significantly higher in areas with a lower river pollution index (P = 0.025) and regions with a large number of chickens being raised (P = 0.013). ESBL-producing E. coli strains were commonly isolated from river waters in southern Taiwan. The most commonly isolated ESBL-producing clonal complexes were ST10 and ST58, which were geographically related to chicken farms. ESBL-producing E. coli ST131, the major clone causing community-acquired infections in Taiwan and worldwide, was not detected in river waters. PMID:26773082

  20. Fosfomycin, interesting alternative drug for treatment of urinary tract infections created by multiple drug resistant and extended spectrum β-lactamase producing strains

    PubMed Central

    Yeganeh-Sefidan, Fatemeh; Ghotaslou, Reza; Akhi, Mohammad Taghi; Sadeghi, Mohammad Reza; Mohammadzadeh-Asl, Yalda; Bannazadeh Baghi, Hussein

    2016-01-01

    Background and Objectives: The emergence and spread of multidrug resistant (MDR) and extended spectrum β-lactamase (ESBL) producing strains reduces the number of effective drugs that can be used for treatment. The aim of this study was to evaluate the susceptibility profile of Enterobacteriaceae isolated from UTIs, specifically MDR and ESBL producing strains, to fosfomycin and other antibiotics. Materials and Methods: The study was performed during a 6 month period (February 2014 to August 2015). A total of 219 non-duplicate urinary isolates of Enterobacteriaceae were collected. Identification and susceptibility testing was done according to standard microbiological procedures and the Kirby-Bauer test, respectively. Based on the results obtained from susceptibility testing, MDR bacteria were recovered and identification of ESBL production was done according to CLSI recommendation. Results: Isolates of E. coli and Klebsiella spp. were responsible for 80.8% and 12.8% of patients with UTIs respectively. The rates of resistance to ampicillin, cefazolin, nalidixic acid, trimethoprim-sulfamethoxazole were 86.3%, 79.4%, 68.5% and 63.9% respectively. In contrast, high sensitivity rates were detected to fosfomycin, amikacin and amoxicillin-clavulanic acid with 97.3%, 91.8% and 80.8%, respectively. Of all isolates, 167 (76.3%) were detected as MDR and 75 (34.2%) as ESBL producing strains. Conclusion: The rate of antibiotic resistance among uropathogens Enterobacteriaceae is remarkably high. The most effective antibiotic was fosfomycin. Moreover, susceptibility to fosfomycin is over 90% for MDR and ESBL producer isolates. Therefore, fosfomycin can be a good option for treating UTIs. PMID:27307978

  1. The root hair assay facilitates the use of genetic and pharmacological tools in order to dissect multiple signalling pathways that lead to programmed cell death.

    PubMed

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  2. The Root Hair Assay Facilitates the Use of Genetic and Pharmacological Tools in Order to Dissect Multiple Signalling Pathways That Lead to Programmed Cell Death

    PubMed Central

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F.

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  3. The multiple signals assessed by female satin bowerbirds: could they be used to narrow down females' choices of mates?

    PubMed Central

    Robson, Timothy E; Goldizen, Anne W; Green, David J

    2005-01-01

    Female choice based on multiple male traits has been documented in many species but the functions of such multiple traits are still under debate. The satin bowerbird has a polygynous mating system in which males attract females to bowers for mating; females choose mates based on multiple aspects of males and their bowers. In this paper, we demonstrate that females use some cues to decide which males to examine closely and other cues to decide which males to mate with. Female visitation rates to bowers were significantly related to male size and the males' ‘solitary’ display rates, and, to a lesser extent, to the numbers of bower decorations. After controlling for female visitation rates, it was found that a male's mating success was significantly related to his size and the rate at which he ‘painted’ his bower with saliva and chewed up plant material. PMID:17148183

  4. Spatially Extended Modelocking

    NASA Technical Reports Server (NTRS)

    Fork, Richard L.; Diffey, William M.; Gamble, Lisa; Keys, Andrew S.

    1999-01-01

    We examine the properties of optical fields that are extended in space over transverse dimensions of several meters or more in terms of both multiple spatial modes and also multiple temporal modes. We focus attention on the task of producing and maintaining well defined phase relationships for the set of spatial and temporal modes. In particular, we address operating regimes where the optical fields are not confined within an optical resonator, but still have well defined phase relations through the use of optical field sensing and correction techniques. Special applications of interest occur in safe beaming of optical power and in approaching optical intensities capable of producing nonlinear phenomena in the vacuum.

  5. Assigning Quantitative Function to Post-Translational Modifications Reveals Multiple Sites of Phosphorylation That Tune Yeast Pheromone Signaling Output

    PubMed Central

    Pincus, David; Ryan, Christopher J.; Smith, Richard D.

    2013-01-01

    Cell signaling systems transmit information by post-translationally modifying signaling proteins, often via phosphorylation. While thousands of sites of phosphorylation have been identified in proteomic studies, the vast majority of sites have no known function. Assigning functional roles to the catalog of uncharacterized phosphorylation sites is a key research challenge. Here we present a general approach to address this challenge and apply it to a prototypical signaling pathway, the pheromone response pathway in Saccharomyces cerevisiae. The pheromone pathway includes a mitogen activated protein kinase (MAPK) cascade activated by a G-protein coupled receptor (GPCR). We used published mass spectrometry-based proteomics data to identify putative sites of phosphorylation on pheromone pathway components, and we used evolutionary conservation to assign priority to a list of candidate MAPK regulatory sites. We made targeted alterations in those sites, and measured the effects of the mutations on pheromone pathway output in single cells. Our work identified six new sites that quantitatively tuned system output. We developed simple computational models to find system architectures that recapitulated the quantitative phenotypes of the mutants. Our results identify a number of putative phosphorylation events that contribute to adjust the input-output relationship of this model eukaryotic signaling system. We believe this combined approach constitutes a general means not only to reveal modification sites required to turn a pathway on and off, but also those required for more subtle quantitative effects that tune pathway output. Our results suggest that relatively small quantitative influences from individual phosphorylation events endow signaling systems with plasticity that evolution may exploit to quantitatively tailor signaling outcomes. PMID:23554854

  6. Assigning Quantitative Function to Post-Translational Modifications Reveals Multiple Sites of Phosphorylation That Tune Yeast Pheromone Signaling Output

    SciTech Connect

    Pincus, David; Ryan, Christopher J.; Smith, Richard D.; Brent, Roger; Resnekov, Orna; Hakimi, Mohamed Ali

    2013-03-12

    Cell signaling systems transmit information by post-­translationally modifying signaling proteins, often via phosphorylation. While thousands of sites of phosphorylation have been identified in proteomic studies, the vast majority of sites have no known function. Assigning functional roles to the catalog of uncharacterized phosphorylation sites is a key research challenge. Here we present a general approach to address this challenge and apply it to a prototypical signaling pathway, the pheromone response pathway in Saccharomyces cerevisiae. The pheromone pathway includes a mitogen activated protein kinase (MAPK) cascade activated by a G-­protein coupled receptor (GPCR). We used mass spectrometry-based proteomics to identify sites whose phosphorylation changed when the system was active, and evolutionary conservation to assign priority to a list of candidate MAPK regulatory sites. We made targeted alterations in those sites, and measured the effects of the mutations on pheromone pathway output in single cells. Our work identified six new sites that quantitatively tuned system output. We developed simple computational models to find system architectures that recapitulated the quantitative phenotypes of the mutants. Our results identify a number of regulated phosphorylation events that contribute to adjust the input-­output relationship of this model eukaryotic signaling system. We believe this combined approach constitutes a general means not only to reveal modification sites required to turn a pathway on and off, but also those required for more subtle quantitative effects that tune pathway output. Our results further suggest that relatively small quantitative influences from individual regulatory phosphorylation events endow signaling systems with plasticity that evolution may exploit to quantitatively tailor signaling outcomes.

  7. Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of Drosophila melanogaster

    PubMed Central

    Mockett, Robin J.; Sohal, Barbara H.; Sohal, Rajindar S.

    2010-01-01

    The simultaneous overexpression of multiple copies of Mn superoxide dismutase (SOD) and ectopic catalase (mtCat) transgenes in the mitochondria of the fruit fly, Drosophila melanogaster, was shown previously to diminish the life span. The hypothesis tested in the present study was that this effect was due primarily to the presence of one or the other transgene. An alternative hypothesis was that both transgenes have additive, negative effects. Crosses were performed between five pairs of transgenic lines containing single-copy insertions of either mtCat, Mn SOD, or P element vector control transgenes at unique loci, and the life spans of progeny containing two mtCat, Mn SOD or vector insertions were determined. Increasing amounts of mitochondrial catalase activity tended to be associated with decreases in mean life span. Overexpression of two copies of the genomic Mn SOD transgene had no effect on life span. The results do not support the hypothesis that enhanced mitochondrial SOD or catalase activity promotes longevity in flies. PMID:20923705

  8. Microbiological, physico-chemical, nutritional and sensory characterization of traditional Matsoni: selection and use of autochthonous multiple strain cultures to extend its shelf-life.

    PubMed

    Quero, Grazia Marina; Fusco, Vincenzina; Cocconcelli, Pier Sandro; Owczarek, Lubomila; Borcakli, Mehlika; Fontana, Cecilia; Skapska, Sylwia; Jasinska, Urszula T; Ozturk, Tarik; Morea, Maria

    2014-04-01

    Matsoni, a traditional Georgian fermented milk, has variable quality and stability besides a short shelf-life (72-120 h at 6 °C) due to inadequate production and storage conditions. To individuate its typical traits as well as select and exploit autochthonous starter cultures to standardize its overall quality without altering its typicality, we carried out a thorough physico-chemical, sensorial and microbial characterization of traditional Matsoni. A polyphasic approach, including a culture-independent (PCR-DGGE) and two PCR culture-dependent methods, was employed to study the ecology of Matsoni. Overall, the microbial ecosystem of Matsoni resulted largely dominated by Streptococcus (S.) thermophilus and Lactobacillus (Lb.) delbrueckii subsp. bulgaricus. High loads of other lactic acid bacteria species, including Lb. helveticus, Lb. paracasei and Leuconostoc (Leuc.) lactis were found to occur as well. A selected autochthonous multiple strain culture (AMSC) composed of one Lb. bulgaricus, one Lb. paracasei and one S. thermophilus strain, applied for the pilot-scale production of traditional Matsoni, resulted the best in terms of enhanced shelf-life (one month), sensorial and nutritional quality without altering its overall typical quality. This AMSC is at disposal of SMEs who need to exploit and standardize the overall quality of this traditional fermented milk, preserving its typicality. PMID:24290642

  9. Investigation of in-band transmission of both spectral amplitude coding/optical code division multiple-access and wavelength division multiplexing signals

    NASA Astrophysics Data System (ADS)

    Ashour, Isaac A. M.; Shaari, Sahbudin; Shalaby, Hossam M. H.; Menon, P. Susthitha

    2011-06-01

    The transmission of both optical code division multiple-access (OCDMA) and wavelength division multiplexing (WDM) users on the same band is investigated. Code pulses of spectral amplitude coding (SAC)/optical code division multiple-access (CDMA) are overlaid onto a multichannel WDM system. Notch filters are utilized in order to suppress the WDM interference signals for detection of optical broadband CDMA signals. Modified quadratic congruence (MQC) codes are used as the signature codes for the SAC/OCDMA system. The proposed system is simulated and its performance in terms of both the bit-error rate and Q-factor are determined. In addition, eavesdropper probability of error-free code detection is evaluated. Our results are compared to traditional nonhybrid systems. It is concluded that the proposed hybrid scheme still achieves acceptable performance. In addition, it provides enhanced data confidentiality as compared to the scheme with SAC/OCDMA only. It is also shown that the performance of the proposed system is limited by the interference of the WDM signals. Furthermore, the simulation illustrates the tradeoff between the performance and confidentiality for authorized users.

  10. Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells

    PubMed Central

    2012-01-01

    Background Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells. Results Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control. Conclusion These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells. PMID:22260501

  11. Comparison of single-dose and multiple-dose pharmacokinetics between two formulations of hydrocodone bitartrate/acetaminophen: immediate-release versus biphasic immediate-release/extended release

    PubMed Central

    Devarakonda, Krishna; Kostenbader, Kenneth; Giuliani, Michael J; Young, Jim L

    2015-01-01

    Objective This study aimed to compare the single-dose and steady-state pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) hydrocodone bitartrate (HB)/acetaminophen (APAP) and IR HB/APAP. Setting The study was conducted in a contract research center. Participants The study included healthy adults. Interventions In a three-way crossover study, Study 1, participants received the following treatments: (A1) a single dose of IR/ER HB/APAP 7.5/325 mg one tablet, followed by one tablet every 12 hours (q12h); (B1) a single dose of IR/ER HB/APAP 7.5/325 mg two tablets, followed by two tablets q12h; (C1) a single dose of IR HB/APAP 7.5/325 mg two tablets (one tablet at hours 0 and 6), followed by one tablet q6h. In a two-way crossover study, Study 2, participants received the following treatments: (A2) an initial dose of IR/ER HB/APAP 7.5/325 mg three tablets, followed by two tablets q12h; (B2) three doses of IR HB/APAP 7.5/325 mg one tablet q4h, followed by one tablet q6h. Main outcome measures PK values were compared, and adverse events were assessed. Results Single-dose and steady-state area under the concentration–time curves for hydrocodone and APAP were similar for IR/ER and IR HB/APAP; the steady-state peak plasma concentrations (Cmax) at steady state were also similar, but single-dose Cmax for hydrocodone was lower for IR/ER HB/APAP. For most PK parameters, 90% confidence intervals for geometric least squares mean ratios were not meaningfully different (80%–125%). Steady state was achieved in 2−3 days for IR/ER HB/APAP and in 2 days for IR HB/APAP. Median time to Cmax was longer for IR/ER HB/APAP versus IR HB/APAP (P,0.05). Adverse events were similar across treatments. Conclusion PK outcomes and tolerability were similar for IR/ER HB/APAP and IR HB/APAP. PMID:26392786

  12. Rap1 promotes multiple pancreatic islet cell functions and signals through mammalian target of rapamycin complex 1 to enhance proliferation.

    PubMed

    Kelly, Patrick; Bailey, Candice L; Fueger, Patrick T; Newgard, Christopher B; Casey, Patrick J; Kimple, Michelle E

    2010-05-21

    Recent studies have implicated Epac2, a guanine-nucleotide exchange factor for the Rap subfamily of monomeric G proteins, as an important regulator of insulin secretion from pancreatic beta-cells. Although the Epac proteins were originally identified as cAMP-responsive activators of Rap1 GTPases, the role of Rap1 in beta-cell biology has not yet been defined. In this study, we examined the direct effects of Rap1 signaling on beta-cell biology. Using the Ins-1 rat insulinoma line, we demonstrate that activated Rap1A, but not related monomeric G proteins, promotes ribosomal protein S6 phosphorylation. Using isolated rat islets, we show that this signaling event is rapamycin-sensitive, indicating that it is mediated by the mammalian target of rapamycin complex 1-p70 S6 kinase pathway, a known growth regulatory pathway. This newly defined beta-cell signaling pathway acts downstream of cAMP, in parallel with the stimulation of cAMP-dependent protein kinase, to drive ribosomal protein S6 phosphorylation. Activated Rap1A promotes glucose-stimulated insulin secretion, islet cell hypertrophy, and islet cell proliferation, the latter exclusively through mammalian target of rapamycin complex 1, suggesting that Rap1 is an important regulator of beta-cell function. This newly defined signaling pathway may yield unique targets for the treatment of beta-cell dysfunction in diabetes. PMID:20339002

  13. Robust frequency diversity based algorithm for clutter noise reduction of ultrasonic signals using multiple sub-spectrum phase coherence

    SciTech Connect

    Gongzhang, R.; Xiao, B.; Lardner, T.; Gachagan, A.; Li, M.

    2014-02-18

    This paper presents a robust frequency diversity based algorithm for clutter reduction in ultrasonic A-scan waveforms. The performance of conventional spectral-temporal techniques like Split Spectrum Processing (SSP) is highly dependent on the parameter selection, especially when the signal to noise ratio (SNR) is low. Although spatial beamforming offers noise reduction with less sensitivity to parameter variation, phased array techniques are not always available. The proposed algorithm first selects an ascending series of frequency bands. A signal is reconstructed for each selected band in which a defect is present when all frequency components are in uniform sign. Combining all reconstructed signals through averaging gives a probability profile of potential defect position. To facilitate data collection and validate the proposed algorithm, Full Matrix Capture is applied on the austenitic steel and high nickel alloy (HNA) samples with 5MHz transducer arrays. When processing A-scan signals with unrefined parameters, the proposed algorithm enhances SNR by 20dB for both samples and consequently, defects are more visible in B-scan images created from the large amount of A-scan traces. Importantly, the proposed algorithm is considered robust, while SSP is shown to fail on the austenitic steel data and achieves less SNR enhancement on the HNA data.

  14. MADS-box transcription factor AGL21 regulates lateral root development and responds to multiple external and physiological signals.

    PubMed

    Yu, Lin-Hui; Miao, Zi-Qing; Qi, Guo-Feng; Wu, Jie; Cai, Xiao-Teng; Mao, Jie-Li; Xiang, Cheng-Bin

    2014-11-01

    Plant root system morphology is dramatically influenced by various environmental cues. The adaptation of root system architecture to environmental constraints, which mostly depends on the formation and growth of lateral roots, is an important agronomic trait. Lateral root development is regulated by the external signals coordinating closely with intrinsic signaling pathways. MADS-box transcription factors are known key regulators of the transition to flowering and flower development. However, their functions in root development are still poorly understood. Here we report that AGL21, an AGL17-clade MADS-box gene, plays a crucial role in lateral root development. AGL21 was highly expressed in root, particularly in the root central cylinder and lateral root primordia. AGL21 overexpression plants produced more and longer lateral roots while agl21 mutants showed impaired lateral root development, especially under nitrogen-deficient conditions. AGL21 was induced by many plant hormones and environmental stresses, suggesting a function of this gene in root system plasticity in response to various signals. Furthermore, AGL21 was found positively regulating auxin accumulation in lateral root primordia and lateral roots by enhancing local auxin biosynthesis, thus stimulating lateral root initiation and growth. We propose that AGL21 may be involved in various environmental and physiological signals-mediated lateral root development and growth. PMID:25122697

  15. MADS-Box Transcription Factor AGL21 Regulates Lateral Root Development and Responds to Multiple External and Physiological Signals

    PubMed Central

    Yu, Lin-Hui; Miao, Zi-Qing; Qi, Guo-Feng; Wu, Jie; Cai, Xiao-Teng; Mao, Jie-Li; Xiang, Cheng-Bin

    2014-01-01

    Plant root system morphology is dramatically influenced by various environmental cues. The adaptation of root system architecture to environmental constraints, which mostly depends on the formation and growth of lateral roots, is an important agronomic trait. Lateral root development is regulated by the external signals coordinating closely with intrinsic signaling pathways. MADS-box transcription factors are known key regulators of the transition to flowering and flower development. However, their functions in root development are still poorly understood. Here we report that AGL21, an AGL17-clade MADS-box gene, plays a crucial role in lateral root development. AGL21 was highly expressed in root, particularly in the root central cylinder and lateral root primordia. AGL21 overexpression plants produced more and longer lateral roots while agl21 mutants showed impaired lateral root development, especially under nitrogen-deficient conditions. AGL21 was induced by many plant hormones and environmental stresses, suggesting a function of this gene in root system plasticity in response to various signals. Furthermore, AGL21 was found positively regulating auxin accumulation in lateral root primordia and lateral roots by enhancing local auxin biosynthesis, thus stimulating lateral root initiation and growth. We propose that AGL21 may be involved in various environmental and physiological signals-mediated lateral root development and growth. PMID:25122697

  16. EXTENDED CYTOPROTECTIVE EFFECT OF AUTOPHAGY IN THE LATE STAGES OF SEPSIS AND FLUCTUATIONS IN SIGNAL TRANSDUCTION PATHWAYS IN A RAT EXPERIMENTAL MODEL OF KIDNEY INJURY

    PubMed Central

    Karagiannidis, Ioannis; Kataki, Agapi; Glustianou, Georgia; Memos, Nikolaos; Papalois, Apostolos; Alexakis, Nikolaos; Zografos, George C.; Konstadoulakis, Manoussos M.

    2016-01-01

    ABSTRACT The impact of a potential autophagy (LC3a/b) deregulation in hyper and in hypo stages during sepsis-induced kidney injury and the temporal profile of phosphorylated extracellular signal-related kinase, P38 (pP38), Akt (pAKT), and 13-3-3β protein were investigated in the current study, using a rat cecal ligation and puncture (CLP) model, by means of flow cytometry and immunohistochemistry. Cell viability was assessed by protein C zymogen concentrate (PC), 7-aminoactinomycin D (7-AAD) staining and inflammation by S100 protein immunostaining. The impact of reduced kidney inflammation in autophagy was assessed by PC administration, an anti-inflammatory and cytoprotective substance. Sepsis induction increased LC3a/b expression, which presented two peaks at 6 and 36 h after CLP, both in the percentage of positive cells (P = 0.024, P = 0.025, respectively) and in fluorescence intensity. At 6 h when inflammation was already apparent, LC3a/b increase was escorted by phosphorylated extracellular signal-related kinase stimulation and high cell viability (65%), designating autophagy as a cytoprotective mechanism against microbial infection. The phosphorylation of P38 was delayed to 12 h after CLP, when autophagy was reduced. pAkt and 14-3-3β expression was stimulated between 6 and 36 h after CLP, although a slight inhibition of pAkt within each cell was detected (lower MnIX value). During the second peak, inflammation was intensified, necrosis was significantly increased with LC3a/b+/7-AAD + cells to present a 1.5-fold increase. Protein C zymogen concentrate administration declined autophagy at 6 and 36 h after CLP and reduced necrosis, whereas double positive LC3a/b and 7-AAD cells were increased by 1.68 and 2.78-fold, respectively. These data open new prospectives in sepsis treatment, since they further support that autophagy represents a cytoprotective mechanism triggered by stress conditions, rather than an alternative cell death pathway. PMID

  17. Sorting out the Signal: Do Multiple Measures of Teachers' Effectiveness Provide Consistent Information to Teachers and Principals?

    ERIC Educational Resources Information Center

    Strunk, Katharine O.; Weinstein, Tracey L.; Makkonen, Reino

    2014-01-01

    There is increasing policy interest in the use of standards-based multiple measure teacher evaluation systems that include both observational and value-added measures of teacher effectiveness. The growing literature that assesses the relationships between these measures does so mainly in academic settings using a validity lens. While valuable in…

  18. Systemic Inhibition of Canonical Notch Signaling Results in Sustained Callus Inflammation and Alters Multiple Phases of Fracture Healing

    PubMed Central

    Dishowitz, Michael I.; Mutyaba, Patricia L.; Takacs, Joel D.; Barr, Andrew M.; Engiles, Julie B.; Ahn, Jaimo; Hankenson, Kurt D.

    2013-01-01

    The Notch signaling pathway is an important regulator of embryological bone development, and many aspects of development are recapitulated during bone repair. We have previously reported that Notch signaling components are upregulated during bone fracture healing. However, the significance of the Notch pathway in bone regeneration has not been described. Therefore, the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model (Mx1-Cre;dnMAMLf/-) to impair RBPjκ-mediated canonical Notch signaling. The Mx1 promoter was synthetically activated resulting in temporally regulated systemic dnMAML expression just prior to creation of bilateral tibial fractures. This allowed for mice to undergo unaltered embryological and post-natal skeletal development. Results showed that systemic Notch inhibition prolonged expression of inflammatory cytokines and neutrophil cell inflammation, and reduced the proportion of cartilage formation within the callus at 10 days-post-fracture (dpf) Notch inhibition did not affect early bone formation at 10dpf, but significantly altered bone maturation and remodeling at 20dpf. Increased bone volume fraction in dnMAML fractures, which was due to a moderate decrease in callus size with no change in bone mass, coincided with increased trabecular thickness but decreased connectivity density, indicating that patterning of bone was altered. Notch inhibition decreased total osteogenic cell density, which was comprised of more osteocytes rather than osteoblasts. dnMAML also decreased osteoclast density, suggesting that osteoclast activity may also be important for altered fracture healing. It is likely that systemic Notch inhibition had both direct effects within cell types as well as indirect effects initiated by temporally upstream events in the fracture healing cascade. Surprisingly, Notch inhibition did not alter cell proliferation

  19. A non-contact method based on multiple signal classification algorithm to reduce the measurement time for accurately heart rate detection.

    PubMed

    Bechet, P; Mitran, R; Munteanu, M

    2013-08-01

    Non-contact methods for the assessment of vital signs are of great interest for specialists due to the benefits obtained in both medical and special applications, such as those for surveillance, monitoring, and search and rescue. This paper investigates the possibility of implementing a digital processing algorithm based on the MUSIC (Multiple Signal Classification) parametric spectral estimation in order to reduce the observation time needed to accurately measure the heart rate. It demonstrates that, by proper dimensioning the signal subspace, the MUSIC algorithm can be optimized in order to accurately assess the heart rate during an 8-28 s time interval. The validation of the processing algorithm performance was achieved by minimizing the mean error of the heart rate after performing simultaneous comparative measurements on several subjects. In order to calculate the error the reference value of heart rate was measured using a classic measurement system through direct contact. PMID:24007088

  20. A non-contact method based on multiple signal classification algorithm to reduce the measurement time for accurately heart rate detection

    NASA Astrophysics Data System (ADS)

    Bechet, P.; Mitran, R.; Munteanu, M.

    2013-08-01

    Non-contact methods for the assessment of vital signs are of great interest for specialists due to the benefits obtained in both medical and special applications, such as those for surveillance, monitoring, and search and rescue. This paper investigates the possibility of implementing a digital processing algorithm based on the MUSIC (Multiple Signal Classification) parametric spectral estimation in order to reduce the observation time needed to accurately measure the heart rate. It demonstrates that, by proper dimensioning the signal subspace, the MUSIC algorithm can be optimized in order to accurately assess the heart rate during an 8-28 s time interval. The validation of the processing algorithm performance was achieved by minimizing the mean error of the heart rate after performing simultaneous comparative measurements on several subjects. In order to calculate the error the reference value of heart rate was measured using a classic measurement system through direct contact.

  1. Multiple quantum filtered 23Na NMR in the Langendorff perfused mouse heart: Ratio of triple/double quantum filtered signals correlates with [Na]i

    PubMed Central

    Eykyn, Thomas R.; Aksentijević, Dunja; Aughton, Karen L.; Southworth, Richard; Fuller, William; Shattock, Michael J.

    2015-01-01

    We investigate the potential of multiple quantum filtered (MQF) 23Na NMR to probe intracellular [Na]i in the Langendorff perfused mouse heart. In the presence of Tm(DOTP) shift reagent the triple quantum filtered (TQF) signal originated largely from the intracellular sodium pool with a 32 ± 6% contribution of the total TQF signal arising from extracellular sodium, whilst the rank 2 double-quantum filtered signal (DQF), acquired with a 54.7° flip-angle pulse, originated exclusively from the extracellular sodium pool. Given the different cellular origins of the 23Na MQF signals we propose that the TQF/DQF ratio can be used as a semi-quantitative measure of [Na]i in the mouse heart. We demonstrate a good correlation of this ratio with [Na]i measured with shift reagent at baseline and under conditions of elevated [Na]i. We compare the measurements of [Na]i using both shift reagent and TQF/DQF ratio in a cohort of wild type mouse hearts and in a transgenic PLM3SA mouse expressing a non-phosphorylatable form of phospholemman, showing a modest but measurable elevation of baseline [Na]i. MQF filtered 23Na NMR is a potentially useful tool for studying normal and pathophysiological changes in [Na]i, particularly in transgenic mouse models with altered Na regulation. PMID:26196304

  2. Signal-Amplified Near-Infrared Ratiometric Electrochemiluminescence Aptasensor Based on Multiple Quenching and Enhancement Effect of Graphene/Gold Nanorods/G-Quadruplex.

    PubMed

    Shao, Kang; Wang, Biru; Ye, Shiyi; Zuo, Yunpeng; Wu, Long; Li, Qin; Lu, Zhicheng; Tan, XueCai; Han, Heyou

    2016-08-16

    Dual-signaling ratiometric electrochemiluminescence (ECL) technology has attracted particular attention in analytical science due to its precise measurement to normalize variation in environmental changes. Creating new mated ECL report units with two emitting states and improving the detection sensitivity are major challenges for ratiometric ECL measurement. Here, we fabricate an ultrasensitive near-infrared ratiometric ECL aptasensor based on a dual-potential signal amplification strategy triggered by the quencher/enhancer [graphene/hemin/gold nanorods/G-quadruplex-hemin (rGO-H-AuNRs-G4H) composite]. The composite was initially prepared through three consecutive steps: the π-π stacking interaction between hemin and graphene, in-site growth of AuNRs, and surface ligand exchange. Dual ECL quenching of quantum dots (QDs) and multiple signal enhancement of luminol can be achieved simultaneously by the fabrication of the sandwich "thrombin aptamer I (TBA1)-TB-TBA2 (rGO-H-AuNRs-G4H)" mode: (i) the formation of three-dimensional G-quadruplex between aptamer and thrombin not only shortens the distance between the donor (QDs) and receptor (rGO-H and AuNRs) to trigger electrochemiluminescence energy transfer but also provides the place for intercalating hemin; (ii) the hemin intercalated into G4 structure and hemin connected onto rGO together with AuNRs/rGO nanomaterials can achieve the multiple peroxidase-like catalysis of H2O2 to greatly enhance the ECL of luminol. The ratiometric ECL aptasensor self-calibrated by the internal reference (luminol or QDs) exhibits ultrasensitive and accurate analytical performance toward thrombin (TB) with a linear detection range from 100 ng/mL to 0.5 pg/mL and a detection limit of 4.2 fg/mL [defined as signal-to-noise ratio (S/N) = 3]. PMID:27435830

  3. Cadmium Activates Multiple Signaling Pathways That Coordinately Stimulate Akt Activity to Enhance c-Myc mRNA Stability

    PubMed Central

    Tsai, Jia-Shiuan; Chao, Cheng-Han; Lin, Lih-Yuan

    2016-01-01

    Cadmium is a known environmental carcinogen. Exposure of Cd leads to the activation of several proto-oncogenes in cells. We investigated here the mechanism of c-Myc expression in hepatic cells under Cd treatment. The c-Myc protein and mRNA levels increased in dose- and time-dependent manners in HepG2 cells with Cd treatment. This increase was due to an increase in c-Myc mRNA stability. To explore the mechanism involved in enhancing the mRNA stability, several cellular signaling factors that evoked by Cd treatment were analyzed. PI3K, p38, ERK and JNK were activated by Cd. However, ERK did not participate in the Cd-induced c-Myc expression. Further analysis revealed that mTORC2 was a downstream factor of p38. PI3K, JNK and mTORC2 coordinately activated Akt. Akt was phosphorylated at Thr450 in the untreated cells. Cd treatment led to additional phosphorylation at Thr308 and Ser473. Blocking any of the three signaling factors resulted in the reduction of phosphorylation level at all three Akt sites. The activated Akt phosphorylated Foxo1 and allowed the modified protein to translocate into the cytoplasm. We conclude that Cd-induced accumulation of c-Myc requires the activation of several signaling pathways. The signals act coordinately for Akt activation and drive the Foxo1 from the nucleus to the cytoplasm. Reduction of Foxo1 in the nucleus reduces the transcription of its target genes that may affect c-Myc mRNA stability, resulting in a higher accumulation of the c-Myc proteins. PMID:26751215

  4. LRP-6 is a coreceptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1

    PubMed Central

    Ren, Shuyu; Johnson, Bryce G.; Kida, Yujiro; Ip, Colin; Davidson, Kathryn C.; Lin, Shuei-Liong; Kobayashi, Akio; Lang, Richard A.; Hadjantonakis, Anna-Katerina; Moon, Randall T.; Duffield, Jeremy S.

    2013-01-01

    Fibrosis of vital organs is a major public health problem with limited therapeutic options. Mesenchymal cells including microvascular mural cells (pericytes) are major progenitors of scar-forming myofibroblasts in kidney and other organs. Here we show pericytes in healthy kidneys have active WNT/β-catenin signaling responses that are markedly up-regulated following kidney injury. Dickkopf-related protein 1 (DKK-1), a ligand for the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP-5 and LRP-6) and an inhibitor of WNT/β-catenin signaling, effectively inhibits pericyte activation, detachment, and transition to myofibroblasts in vivo in response to kidney injury, resulting in attenuated fibrogenesis, capillary rarefaction, and inflammation. DKK-1 blocks activation and proliferation of established myofibroblasts in vitro and blocks pericyte proliferation to PDGF, pericyte migration, gene activation, and cytoskeletal reorganization to TGF-β or connective tissue growth factor. These effects are largely independent of inhibition of downstream β-catenin signaling. DKK-1 acts predominantly by inhibiting PDGF-, TGF-β–, and connective tissue growth factor-activated MAPK and JNK signaling cascades, acting via LRP-6 with associated WNT ligand. Biochemically, LRP-6 interacts closely with PDGF receptor β and TGF-β receptor 1 at the cell membrane, suggesting that it may have roles in pathways other than WNT/β-catenin. In summary, DKK-1 blocks many of the changes in pericytes required for myofibroblast transition and attenuates established myofibroblast proliferation/activation by mechanisms dependent on LRP-6 and WNT ligands but not the downstream β-catenin pathway. PMID:23302695

  5. A SPR biosensor based on signal amplification using antibody-QD conjugates for quantitative determination of multiple tumor markers.

    PubMed

    Wang, Huan; Wang, Xiaomei; Wang, Jue; Fu, Weiling; Yao, Chunyan

    2016-01-01

    The detection of tumor markers is very important in early cancer diagnosis; however, tumor markers are usually present at very low concentrations, especially in the early stages of tumor development. Surface plasmon resonance (SPR) is widely used to detect biomolecular interactions; it has inherent advantages of being high-throughput, real-time, and label-free technique. However, its sensitivity needs essential improvement for practical applications. In this study, we developed a signal amplification strategy using antibody-quantum dot (QD) conjugates for the sensitive and quantitative detection of α-fetoprotein (AFP), carcinoembryonic antigen (CEA) and cytokeratin fragment 21-1 (CYFRA 21-1) in clinical samples. The use of a dual signal amplification strategy using AuNP-antibody and antibody-QD conjugates increased the signal amplification by 50-folds. The constructed SPR biosensor showed a detection limit as low as 0.1 ng/mL for AFP, CEA, and CYFRA 21-1. Moreover, the results obtained using this SPR biosensor were consistent with those obtained using the electrochemiluminescence method. Thus, the constructed SPR biosensor provides a highly sensitive and specific approach for the detection of tumor markers. This SPR biosensor can be expected to be readily applied for the detection of other tumor markers and can offer a potentially powerful solution for tumor screening. PMID:27615417

  6. Sub-femtomolar DNA detection based on layered molybdenum disulfide/multi-walled carbon nanotube composites, Au nanoparticle and enzyme multiple signal amplification.

    PubMed

    Huang, Ke-Jing; Liu, Yu-Jie; Wang, Hai-Bo; Wang, Ya-Ya; Liu, Yan-Ming

    2014-05-15

    A novel 2-dimensional graphene analog molybdenum disulfide/multi-walled carbon nanotube (MoS2/MWCNT) was synthesized by a simple hydrothermal method to achieve excellent electrochemical properties. An ultrasensitive electrochemical DNA biosensor was subsequently constructed by assembling a thiol-tagged DNA probe on a MoS2/MWCNT and gold nanoparticle (AuNP)-modified electrode that has already been coupled with glucose oxidase (GOD). In this work, GOD was used as a redox marker. The heteronanostructure formed on the biosensor surface appeared relatively good conductor for accelerating the electron transfer, while the modification of GOD and AuNPs provided multiple signal amplification for electrochemical biosensing. The multiple signal amplification strategy produced an ultrasensitive electrochemical detection of DNA down to 0.79 fM with a linear range from 10 fM to 10(7)fM, and appeared high selectivity to differentiate three-base mismatched DNA and one-base mismatched DNA. The developed approach provided a simple and reliable method for DNA detection with high sensitivity and specificity, and would open new opportunities for sensitive detection of other biorecognition events. PMID:24384259

  7. An autonomous battery-less sensor module powered by piezoelectric energy harvesting with RF transmission of multiple measurement signals

    NASA Astrophysics Data System (ADS)

    Ferrari, Marco; Ferrari, Vittorio; Guizzetti, Michele; Marioli, Daniele

    2009-08-01

    An energy-autonomous battery-less sensor module is presented, entirely powered by a piezoelectric energy converter driven by mechanical vibrations from the environment. The module manages and stores the converted energy, interfaces to one or more passive sensors and periodically sends the corresponding measurement signals over a radio-frequency (RF) link. As an additional variant, the module can send a programmable identification (ID) code on the RF carrier, in order to enable module tagging and tracking by the external receiver unit. The module's general architecture is presented and the strategy used for sensor signal conditioning and transmission is illustrated. The architecture and principle have been experimentally validated on a fabricated prototype including a piezoelectric bimorph converter, two passive sensors made by a resistive-capacitive sensor pair and purposely designed electronic circuitry based on low-power off-the-shelf components. In the tested experimental conditions, the prototype features a typical time interval between measurement-and-transmission events of a few tens of seconds, with event durations of the order of tens of milliseconds, corresponding to an operation duty cycle of the order of 0.1%. Peak power consumption during transmission is of the order of 20 mW and operative range is of the order of meters in a laboratory environment. The obtained results show that the proposed approach has attractive characteristics because of the total absence of batteries and, despite the inherent intermittent operation, provides significant measurement performances in terms of achievable sensitivity and resolution.

  8. FUS3 phosphorylates multiple components of the mating signal transduction cascade: evidence for STE12 and FAR1.

    PubMed Central

    Elion, E A; Satterberg, B; Kranz, J E

    1993-01-01

    The mitogen-activated protein (MAP) kinase homologue FUS3 mediates both transcription and G1 arrest in a pheromone-induced signal transduction cascade in Saccharomyces cerevisiae. We report an in vitro kinase assay for FUS3 and its use in identifying candidate substrates. The assay requires catalytically active FUS3 and pheromone induction. STE7, a MAP kinase kinase homologue, is needed for maximal activity. At least seven proteins that specifically associate with FUS3 are phosphorylated in the assay. Many of these substrates are physiologically relevant and are affected by in vivo levels of numerous signal transduction components. One substrate is likely to be the transcription factor STE12. A second is likely to be FAR1, a protein required for G1 arrest. FAR1 was isolated as a multicopy suppressor of a nonarresting fus3 mutant and interacts with FUS3 in a two hybrid system. Consistent with this FAR1 is a good substrate in vitro and generates a FUS3-associated substrate of expected size. These data support a model in which FUS3 mediates transcription and G1 arrest by direct activation of STE12 and FAR1 and phosphorylates many other proteins involved in the response to pheromone. Images PMID:8334305

  9. Knockdown of Human TCF4 Affects Multiple Signaling Pathways Involved in Cell Survival, Epithelial to Mesenchymal Transition and Neuronal Differentiation

    PubMed Central

    Forrest, Marc P.; Waite, Adrian J.; Martin-Rendon, Enca; Blake, Derek J.

    2013-01-01

    Haploinsufficiency of TCF4 causes Pitt-Hopkins syndrome (PTHS): a severe form of mental retardation with phenotypic similarities to Angelman, Mowat-Wilson and Rett syndromes. Genome-wide association studies have also found that common variants in TCF4 are associated with an increased risk of schizophrenia. Although TCF4 is transcription factor, little is known about TCF4-regulated processes in the brain. In this study we used genome-wide expression profiling to determine the effects of acute TCF4 knockdown on gene expression in SH-SY5Y neuroblastoma cells. We identified 1204 gene expression changes (494 upregulated, 710 downregulated) in TCF4 knockdown cells. Pathway and enrichment analysis on the differentially expressed genes in TCF4-knockdown cells identified an over-representation of genes involved in TGF-β signaling, epithelial to mesenchymal transition (EMT) and apoptosis. Among the most significantly differentially expressed genes were the EMT regulators, SNAI2 and DEC1 and the proneural genes, NEUROG2 and ASCL1. Altered expression of several mental retardation genes such as UBE3A (Angelman Syndrome), ZEB2 (Mowat-Wilson Syndrome) and MEF2C was also found in TCF4-depleted cells. These data suggest that TCF4 regulates a number of convergent signaling pathways involved in cell differentiation and survival in addition to a subset of clinically important mental retardation genes. PMID:24058414

  10. Modeling the effects of AADT on predicting multiple-vehicle crashes at urban and suburban signalized intersections.

    PubMed

    Chen, Chen; Xie, Yuanchang

    2016-06-01

    Annual Average Daily Traffic (AADT) is often considered as a main covariate for predicting crash frequencies at urban and suburban intersections. A linear functional form is typically assumed for the Safety Performance Function (SPF) to describe the relationship between the natural logarithm of expected crash frequency and covariates derived from AADTs. Such a linearity assumption has been questioned by many researchers. This study applies Generalized Additive Models (GAMs) and Piecewise Linear Negative Binomial (PLNB) regression models to fit intersection crash data. Various covariates derived from minor-and major-approach AADTs are considered. Three different dependent variables are modeled, which are total multiple-vehicle crashes, rear-end crashes, and angle crashes. The modeling results suggest that a nonlinear functional form may be more appropriate. Also, the results show that it is important to take into consideration the joint safety effects of multiple covariates. Additionally, it is found that the ratio of minor to major-approach AADT has a varying impact on intersection safety and deserves further investigations. PMID:26974024

  11. OAM multiple transmission using uniform circular arrays: Numerical modeling and experimental verification with two digital television signals

    NASA Astrophysics Data System (ADS)

    Gaffoglio, Rossella; Cagliero, Andrea; Vita, Assunta De; Sacco, Bruno

    2016-06-01

    In this work we present the outcomes of a radio frequency orbital angular momentum (OAM) transmission between two antenna arrays performed in a real-world context. The analysis is supplemented by deep simulative investigations able to provide both a preliminary overview of the experimental scenario and a posteriori validation of the achieved results. As a first step, the far-field OAM communication link is tested at various frequencies and the corresponding link budget is studied by means of an angular scan generated by the rotation of the receiving system. Then, on the same site, two digital television signals encoded as OAM modes (ℓ = 1 and ℓ =- 1) are simultaneously transmitted at a common frequency of 198.5 MHz with good mode insulation.

  12. MEG (Magnetoencephalography) multipolar modeling of distributed sources using RAP-MUSIC (Recursively Applied and Projected Multiple Signal Characterization)

    SciTech Connect

    Mosher, J. C.; Baillet, S.; Jerbi, K.; Leahy, R. M.

    2001-01-01

    We describe the use of truncated multipolar expansions for producing dynamic images of cortical neural activation from measurements of the magnetoencephalogram. We use a signal-subspace method to find the locations of a set of multipolar sources, each of which represents a region of activity in the cerebral cortex. Our method builds up an estimate of the sources in a recursive manner, i.e. we first search for point current dipoles, then magnetic dipoles, and finally first order multipoles. The dynamic behavior of these sources is then computed using a linear fit to the spatiotemporal data. The final step in the procedure is to map each of the multipolar sources into an equivalent distributed source on the cortical surface. The method is illustrated through an application to epileptic interictal MEG data.

  13. RIP4 is a target of multiple signal transduction pathways in keratinocytes: Implications for epidermal differentiation and cutaneous wound repair

    SciTech Connect

    Adams, Stephanie; Munz, Barbara

    2010-01-01

    Receptor interacting protein 4 (RIP4) is an important regulator of epidermal morphogenesis during embryonic development. We could previously show that expression of the rip4 gene is strongly downregulated in cutaneous wound repair, which might be initiated by a broad variety of growth factors and cytokines. Here, we demonstrate that in keratinocytes, rip4 expression is controlled by a multitude of different signal transduction pathways, such as the p38 mitogen-activated protein kinase (MAPK) and the nuclear factor kappa B (NF-{kappa}B) cascade, in a unique and specific manner. Furthermore, we show that the steroid dexamethasone abolishes the physiological rip4 downregulation after injury and might thus contribute to the phenotype of reduced and delayed wound reepithelialization seen in glucocorticoid-treated patients. As a whole, our data indicate that rip4 expression is regulated in a complex manner, which might have therapeutic implications.

  14. SC06, a novel small molecule compound, displays preclinical activity against multiple myeloma by disrupting the mTOR signaling pathway

    PubMed Central

    Han, Kunkun; Xu, Xin; Xu, Zhuan; Chen, Guodong; Zeng, Yuanying; Zhang, Zubin; Cao, Biyin; Kong, Yan; Tang, Xiaowen; Mao, Xinliang

    2015-01-01

    The mammalian target of rapamycin (mTOR) is extensively involved in multiple myeloma (MM) pathophysiology. In the present study, we reported a novel small molecule SC06 that induced MM cell apoptosis and delayed MM xenograft growth in vivo. Oral administration of SC06 to mice bearing human MM xenografts resulted in significant inhibition of tumor growth at doses that were well tolerated. Mechanistic studies revealed that SC06 selectively inhibited the mTOR signaling pathway but had no effects on other associated kinases, such as AKT, ERK, p38, c-Src and JNK. Further studies showed that SC06-decreased mTOR activation was associated with the downregulation of Raptor, a key component of the mTORC1 complex. SC06 also suppressed the phosphorylation of 4E-BP1 and P70S6K, two typical substrates in the mTORC1 signaling pathway. Notably, expression of Raptor, phosphorylation of mTOR and phosphorylated 4E-BP1 was also decreased in the tumor tissues from SC06-treated mice, which was consistent with the cellular studies. Therefore, given the potency and low toxicity, SC06 could be developed as a potential anti-MM drug candidate by disrupting the mTOR signaling. PMID:26329846

  15. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation.

    PubMed Central

    Brockman, J A; Scherer, D C; McKinsey, T A; Hall, S M; Qi, X; Lee, W Y; Ballard, D W

    1995-01-01

    The eukaryotic transcription factor NF-kappa B plays a central role in the induced expression of human immunodeficiency virus type 1 and in many aspects of the genetic program mediating normal T-cell activation and growth. The nuclear activity of NF-kappa B is tightly regulated from the cytoplasmic compartment by an inhibitory subunit called I kappa B alpha. This cytoplasmic inhibitor is rapidly phosphorylated and degraded in response to a diverse set of NF-kappa B-inducing agents, including T-cell mitogens, proinflammatory cytokines, and viral transactivators such as the Tax protein of human T-cell leukemia virus type 1. To explore these I kappa B alpha-dependent mechanisms for NF-kappa B induction, we identified novel mutants of I kappa B alpha that uncouple its inhibitory and signal-transducing functions in human T lymphocytes. Specifically, removal of the N-terminal 36 amino acids of I kappa B alpha failed to disrupt its ability to form latent complexes with NF-kappa B in the cytoplasm. However, this deletion mutation prevented the induced phosphorylation, degradative loss, and functional release of I kappa B alpha from NF-kappa B in Tax-expressing cells. Alanine substitutions introduced at two serine residues positioned within this N-terminal regulatory region of I kappa B alpha also yielded constitutive repressors that escaped from Tax-induced turnover and that potently inhibited immune activation pathways for NF-kappa B induction, including those initiated from antigen and cytokine receptors. In contrast, introduction of a phosphoserine mimetic at these sites rectified this functional defect, a finding consistent with a causal linkage between the phosphorylation status and proteolytic stability of this cytoplasmic inhibitor. Together, these in vivo studies define a critical signal response domain in I kappa B alpha that coordinately controls the biologic activities of I kappa B alpha and NF-kappa B in response to viral and immune stimuli. PMID:7739562

  16. Multiple cis-acting signals for export of pre-U1 snRNA from the nucleus.

    PubMed

    Terns, M P; Dahlberg, J E; Lund, E

    1993-10-01

    We have identified cis-acting sequences that promote nuclear export of pre-U1 RNA injected into Xenopus oocyte nuclei. At least three elements, the 5' m7G cap, the 3'-terminal stem-loop structure, and sequences in the 5'-terminal 124 nucleotides, contribute to efficient export of this RNA. Both the 5' and 3' export signals can function separately and do so independently of the cap structure. Experiments using hybrid RNAs indicate that the 5' and 3' export sequences of U1 RNA are sufficient to direct export of the heterologous, otherwise nonexportable, U6 RNA. The absence of comparable export signals in U6 RNA appears to be responsible for its retention in the nucleus. Stability of the pre-snRNAs in the nucleus depends on the presence of both a 5' cap structure and a 3' base-paired stem. The 5' m7G cap is neither sufficient nor necessary for nuclear export. The m7G cap by itself did not promote export of U6 RNA or nonspecific small RNAs. Moreover, substitution of this cap with either an AppG cap or gamma-mppG cap did not eliminate export of either full-length or a "minimal" U1 RNA (lacking most of the internal U1 RNA sequences), but it reduced the rate of export by about two to threefold. However, in the absence of the 3' stem-loop, substitution of the m7G cap led to a greater decrease in export rate, underscoring the cooperative action of the three different export elements of pre-U1 RNA. The m7G cap analog, m7GpppG, selectively destabilized pre-U1 RNA within the nucleus. Thus, nuclear components that recognize the 5' m7G cap may be important for both the stability and the export of pre-U1 RNA. PMID:8405997

  17. Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells.

    PubMed

    Rios, Carmen; D'Ippolito, Gianluca; Curtis, Kevin M; Delcroix, Gaëtan J-R; Gomez, Lourdes A; El Hokayem, Jimmy; Rieger, Megan; Parrondo, Ricardo; de Las Pozas, Alicia; Perez-Stable, Carlos; Howard, Guy A; Schiller, Paul C

    2016-06-01

    Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and β-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells. PMID:27059084

  18. The floor plate: multiple cells, multiple signals.

    PubMed

    Placzek, Marysia; Briscoe, James

    2005-03-01

    One of the key organizers in the CNS is the floor plate - a group of cells that is responsible for instructing neural cells to acquire distinctive fates, and that has an important role in establishing the elaborate neuronal networks that underlie the function of the brain and spinal cord. In recent years, considerable controversy has arisen over the mechanism by which floor plate cells form. Here, we describe recent evidence that indicates that discrete populations of floor plate cells, with characteristic molecular properties, form in different regions of the neuraxis, and we discuss data that imply that the mode of floor plate induction varies along the anteroposterior axis. PMID:15738958

  19. Stanniocalcin-1 Protects a Mouse Model from Renal Ischemia-Reperfusion Injury by Affecting ROS-Mediated Multiple Signaling Pathways

    PubMed Central

    Liu, Dajun; Shang, Huiping; Liu, Ying

    2016-01-01

    Stanniocalcin-1 (STC-1) protects against renal ischemia-reperfusion injury (RIRI). However, the molecular mechanisms remain widely unknown. STC-1 inhibits reactive oxygen species (ROS), whereas most ROS-mediated pathways are associated with ischemic injury. Therefore, to explore the mechanism, the effects of STC-1 on ROS-medicated pathways were studied. Non-traumatic vascular clamps were used to establish RIRI mouse models. The serum levels of STC-1, interleukin-6 (IL-6), interferon (IFN) γ, P53, and capase-3 were measured by ELISA kits. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by fluorescence spectrofluorometer. All these molecules changed significantly in a RIRI model mouse when compared with those in a sham control. Kidney cells were isolated from sham and model mice. STC-1 was overexpressed or knockout in these kidney cells. The molecules in ROS-medicated pathways were measured by real-time quantitative PCR and Western blot. The results showed that STC-1 is an effective ROS scavenger. The serum levels of STC-1, MDA and SOD activity were increased while the serum levels of IL-6, iIFN-γ, P53, and capase-3 were decreased in a model group when compared with a sham control (p < 0.05). Furthermore, the levels of STC-1,p53, phosphorylated mitogen-activated protein kinase kinase (p-MEKK-1), c-Jun N-terminal kinase (p-JNK), extracellular signal-regulated kinase (p-ERK), IkB kinase (p-IKK), nuclear factor (NF) κB, apoptosis signal-regulating kinase 1 (ASK-1) and caspase-3 changed significantly in kidney cells isolated from a RIRI model when compared to those isolated from a sham control (p < 0.05). Meanwhile, STC-1 overexpression or silence caused significant changes of the levels of these ROS-mediated molecules. Therefore, STC-1 maybe improve anti-inflammation, anti-oxidant and anti-apoptosis activities by affecting ROS-mediated pathways, especially the phospho-modifications of the respective proteins, resulting in the increase of SOD and

  20. Molecular mechanism of anticancer effect of Sclerotium rolfsii lectin in HT29 cells involves differential expression of genes associated with multiple signaling pathways: A microarray analysis.

    PubMed

    Barkeer, Srikanth; Guha, Nilanjan; Hothpet, Vishwanathreddy; Saligrama Adavigowda, Deepak; Hegde, Prajna; Padmanaban, Arunkumar; Yu, Lu-Gang; Swamy, Bale M; Inamdar, Shashikala R

    2015-12-01

    Sclerotium rolfsii lectin (SRL) is a lectin isolated from fungus S. rolfsii and has high binding specificity toward the oncofetal Thomsen-Friedenreich carbohydrate antigen (Galβ1-3GalNAc-α-O-Ser/Thr, T or TF), which is expressed in more than 90% of human cancers. Our previous studies have shown that binding of SRL to human colon, breast and ovarian cancer cells induces cell apoptosis in vitro and suppresses tumor growth in vivo. This study investigated the SRL-mediated cell signaling in human colon cancer HT29 cells by mRNA and miRNA microarrays. It was found that SRL treatment results in altered expression of several hundred molecules including mitogen-activated protein kinase (MAPK) and c-JUN-associated, apoptosis-associated and cell cycle and DNA replication-associated signaling molecules. Pathway analysis using GeneSpring 12.6.1 revealed that SRL treatment induces changes of MAPK and c-JUN-associated signaling pathways as early as 2 h while changes of cell cycle, DNA replication and apoptosis pathways were significantly affected only after 24 h. A significant change of cell miRNA expression was also observed after 12 h treatment of the cells with SRL. These changes were further validated by quantitative real time polymerase chain reaction and immunoblotting. This study thus suggests that the presence of SRL affects multiple signaling pathways in cancer cells with early effects on cell proliferation pathways associated with MAPK and c-JUN, followed by miRNA-associated cell activity and apoptosis. This provides insight information into the molecular mechanism of the anticancer activity of this fungal lectin. PMID:26347523

  1. Systems Biological Approaches Reveal Non-additive Responses and Multiple Crosstalk Mechanisms between TLR and GPCR Signaling

    PubMed Central

    Krishnan, Jayalakshmi

    2012-01-01

    A variety of ligands differ in their capacity to bind the receptor, elicit gene expression, and modulate physiological responses. Such receptors include Toll-like receptors (TLRs), which recognize various patterns of pathogens and lead to primary innate immune activation against invaders, and G-protein coupled receptors (GPCRs), whose interaction with their cognate ligands activates heterotrimeric G proteins and regulates specific downstream effectors, including immuno-stimulating molecules. Once TLRs are activated, they lead to the expression of hundreds of genes together and bridge the arm of innate and adaptive immune responses. We characterized the gene expression profile of Toll-like receptor 4 (TLR4) in RAW 264.7 cells when it bound with its ligand, 2-keto-3-deoxyoctonate (KDO), the active part of lipopolysaccharide. In addition, to determine the network communications among the TLR, Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and GPCR, we tested RAW 264.7 cells with KDO, interferon-β, or cAMP analog 8-Br. The ligands were also administered as a pair of double and triple combinations. PMID:23166526

  2. Novel signal-dependent filter bank method for identification of multiple basal ganglia nuclei in Parkinsonian patients

    NASA Astrophysics Data System (ADS)

    Pinzon-Morales, R. D.; Orozco-Gutierrez, A. A.; Castellanos-Dominguez, G.

    2011-06-01

    Microelectrode recordings are a valuable tool for assisting localization targets during deep brain stimulation procedures in Parkinson's disease neurosurgery. Attempts to automate and standardize this process have been limited by variability in patient neurophysiology and strong dynamics of microelectrode recordings. In this paper, a methodology for the identification of basal ganglia nuclei is presented that is based on a signal-dependent filter bank method using microelectrode recordings. The method is a customized realization of the discrete wavelet transform via the lifting scheme that is optimally tuned by genetic algorithms. Using this method, unique mother wavelet functions that exhibit an adaptable spectrum to the microelectrode recording dynamic are generated. Additionally, by extracting morphological features from the space-transformed microelectrode recording, it is possible to integrate them into three-dimensional (3D) feature spaces with maximum class separability. Finally, high discriminant feature spaces are fed into basic classifiers to recognize up to four basal nuclei. Comparison with several existing wavelets highlights the characteristics of new mother wavelets. Additionally, classification results show that identification of addressed nuclei in the basal ganglia can be performed with 95% confidence.

  3. Multiple sequence signals direct recognition and degradation of protein substrates by the AAA+ protease HslUV.

    PubMed

    Sundar, Shankar; McGinness, Kathleen E; Baker, Tania A; Sauer, Robert T

    2010-10-29

    Proteolysis is important for protein quality control and for the proper regulation of many intracellular processes in prokaryotes and eukaryotes. Discerning substrates from other cellular proteins is a key aspect of proteolytic function. The Escherichia coli HslUV protease is a member of a major family of ATP-dependent AAA+ degradation machines. HslU hexamers recognize and unfold native protein substrates and then translocate the polypeptide into the degradation chamber of the HslV peptidase. Although a wealth of structural information is available for this system, relatively little is known about mechanisms of substrate recognition. Here, we demonstrate that mutations in the unstructured N-terminal and C-terminal sequences of two model substrates alter HslUV recognition and degradation kinetics, including changes in V(max). By introducing N- or C-terminal sequences that serve as recognition sites for specific peptide-binding proteins, we show that blocking either terminus of the substrate interferes with HslUV degradation, with synergistic effects when both termini are obstructed. These results support a model in which one terminus of the substrate is tethered to the protease and the other terminus is engaged by the translocation/unfolding machinery in the HslU pore. Thus, degradation appears to consist of discrete steps, which involve the interaction of different terminal sequence signals in the substrate with different receptor sites in the HslUV protease. PMID:20837023

  4. Gravitational waves and red shifts - A space experiment for testing relativistic gravity using multiple time-correlated radio signals

    NASA Technical Reports Server (NTRS)

    Smarr, L. L.; Vessot, R. F. C.; Lundquist, C. A.; Decher, R.; Piran, T.

    1983-01-01

    A two-step satellite mission for improving the accuracy of gravitational wave detection and for observing actual gravity waveforms is proposed. The spacecraft would carry both a highly stable hydrogen maser, which would control a transmitter sending signals to earth, and a Doppler transponder operating in the two-way mode. The use of simultaneous one- and two-way Doppler transmissions offers four time records of frequency pulsations, which can reveal gravitational radiation at 1-10 MHz with an amplitude accuracy of a factor of six. The first mission phase would consist of a Shuttle launch into a highly eccentric orbit to obtain measurements of the gravitational redshift using gravitational potentials of different earth regions to establish that gravity is describable by a metric theory. Then, after a boost into a heliocentric orbit at 6 AU, the earth-satellite system could detect gravitational waves in the solar system, as well as bursts emitted by the collisions of supermassive black holes.

  5. Sensory versus motor loci for integration of multiple motion signals in smooth pursuit eye movements and human motion perception.

    PubMed

    Niu, Yu-Qiong; Lisberger, Stephen G

    2011-08-01

    We have investigated how visual motion signals are integrated for smooth pursuit eye movements by measuring the initiation of pursuit in monkeys for pairs of moving stimuli of the same or differing luminance. The initiation of pursuit for pairs of stimuli of the same luminance could be accounted for as a vector average of the responses to the two stimuli singly. When stimuli comprised two superimposed patches of moving dot textures, the brighter stimulus suppressed the inputs from the dimmer stimulus, so that the initiation of pursuit became winner-take-all when the luminance ratio of the two stimuli was 8 or greater. The dominance of the brighter stimulus could be not attributed to either the latency difference or the ratio of the eye accelerations for the bright and dim stimuli presented singly. When stimuli comprised either spot targets or two patches of dots moving across separate locations in the visual field, the brighter stimulus had a much weaker suppressive influence; the initiation of pursuit could be accounted for by nearly equal vector averaging of the responses to the two stimuli singly. The suppressive effects of the brighter stimulus also appeared in human perceptual judgments, but again only for superimposed stimuli. We conclude that one locus of the interaction of two moving visual stimuli is shared by perception and action and resides in local inhibitory connections in the visual cortex. A second locus resides deeper in sensory-motor processing and may be more closely related to action selection than to stimulus selection. PMID:21593392

  6. Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations.

    PubMed

    Nakatsu, Yusuke; Matsunaga, Yasuka; Yamamotoya, Takeshi; Ueda, Koji; Inoue, Yuki; Mori, Keiichi; Sakoda, Hideyuki; Fujishiro, Midori; Ono, Hiraku; Kushiyama, Akifumi; Asano, Tomoichiro

    2016-01-01

    Prolyl isomerases are divided into three groups, the FKBP family, Cyclophilin and the Parvulin family (Pin1 and Par14). Among these isomerases, Pin1 is a unique prolyl isomerase binding to the motif including pSer/pThr-Pro that is phosphorylated by kinases. Once bound, Pin1 modulates the enzymatic activity, protein stability or subcellular localization of target proteins by changing the cis- and trans-formations of proline. Several studies have examined the roles of Pin1 in the pathogenesis of cancers and Alzheimer's disease. On the other hand, recent studies have newly demonstrated Pin1 to be involved in regulating glucose and lipid metabolism. Interestingly, while Pin1 expression is markedly increased by high-fat diet feeding, Pin1 KO mice are resistant to diet-induced obesity, non-alcoholic steatohepatitis and diabetic vascular dysfunction. These phenomena result from the binding of Pin1 to several key factors regulating metabolic functions, which include insulin receptor substrate-1, AMPK, Crtc2 and NF-κB p65. In this review, we focus on recent advances in elucidating the physiological roles of Pin1 as well as the pathogenesis of disorders involving this isomerase, from the viewpoint of the relationships between signal transductions and metabolic functions. PMID:27618008

  7. Identification of multiple open and fatigue cracks in beam-like structures using wavelets on deflection signals

    NASA Astrophysics Data System (ADS)

    Andreaus, Ugo; Casini, Paolo

    2016-03-01

    A novel method for damage detection of multi-cracked beam-like structures by analyzing the static deflection is presented. The damage incurred produces a change in the stiffness of the beam. This causes a localized singularity which can be identified by a wavelet analysis of the displacement response. The existence and location of the cracks can be revealed by positions of the peaks in the continuous wavelet transform (CWT). To achieve this, the static profile of beams is analyzed with Gauss2 wavelet to identify the cracks. Beams under some ideal boundary and prescribed load conditions are considered. The deflected shape of the beam with open and fatigue cracks has been simulated under static loading using lumped crack models adopted from fracture mechanics and involving various degrees of complexity. The deflection of cracked beam in closed form for several cases of loads, crack sizes, and crack locations is calculated, and an explicit expression for the damage index (DI), based on CWT, is developed; it is demonstrated that the proposed damage index does not depend on mechanical properties of a homogeneous beam, and that the DI of one crack does not depend on the size and location of other cracks in a multiple cracked beam. Hence, the obtained expression for the DI can be used to find the size of each crack independently. Numerical results show that the method can detect cracks of small depth and is also applicable under the presence of measurement noise.

  8. DeltaA/DeltaD regulate multiple and temporally distinct phases of notch signaling during dopaminergic neurogenesis in zebrafish.

    PubMed

    Mahler, Julia; Filippi, Alida; Driever, Wolfgang

    2010-12-01

    Dopaminergic neurons develop at distinct anatomical sites to form some of the major neuromodulatory systems in the vertebrate brain. Despite their relevance in neurodegenerative diseases and the interests in reconstitutive therapies from stem cells, mechanisms of the neurogenic switch from precursor populations to dopaminergic neurons are not well understood. Here, we investigated neurogenesis of different dopaminergic and noradrenergic neuron populations in the zebrafish embryo. Birth-dating analysis by EdU (5-ethynyl-2'-deoxyuridine) incorporation revealed temporal dynamics of catecholaminergic neurogenesis. Analysis of Notch signaling mutants and stage-specific pharmacological inhibition of Notch processing revealed that dopaminergic neurons form by temporally distinct mechanisms: dopaminergic neurons of the posterior tuberculum derive directly from neural plate cells during primary neurogenesis, whereas other dopaminergic groups form in continuous or wavelike neurogenesis phases from proliferating precursor pools. Systematic analysis of Notch ligands revealed that the two zebrafish co-orthologs of mammalian Delta1, DeltaA and DeltaD, control the neurogenic switch of all early developing dopaminergic neurons in a partially redundant manner. DeltaA/D may also be involved in maintenance of dopaminergic precursor pools, as olig2 expression in ventral diencephalic dopaminergic precursors is affected in dla/dld mutants. DeltaA/D act upstream of sim1a and otpa during dopaminergic specification. However, despite the fact that both dopaminergic and corticotropin-releasing hormone neurons derive from sim1a- and otpa-expressing precursors, DeltaA/D does not act as a lineage switch between these two neuronal types. Rather, DeltaA/D limits the size of the sim1a- and otpa-expressing precursor pool from which dopaminergic neurons differentiate. PMID:21148001

  9. Retinol induces morphological alterations and proliferative focus formation through free radical-mediated activation of multiple signaling pathways

    PubMed Central

    Gelain, Daniel Pens; Pasquali, Matheus Augusto de Bittencourt; Caregnato, Fernanda Freitas; Castro, Mauro Antonio Alves; Moreira, José Claudio Fonseca

    2012-01-01

    Aim: Toxicity of retinol (vitamin A) has been previously associated with apoptosis and/or cell malignant transformation. Thus, we investigated the pathways involved in the induction of proliferation, deformation and proliferative focus formation by retinol in cultured Sertoli cells of rats. Methods: Sertoli cells were isolated from immature rats and cultured. The cells were subjected to a 24-h treatment with different concentrations of retinol. Parameters of oxidative stress and cytotoxicity were analyzed. The effects of the p38 inhibitor SB203580 (10 μmol/L), the JNK inhibitor SP600125 (10 μmol/L), the Akt inhibitor LY294002 (10 μmol/L), the ERK inhibitor U0126 (10 μmol/L) the pan-PKC inhibitor Gö6983 (10 μmol/L) and the PKA inhibitor H89 (1 μmol/L) on morphological and proliferative/transformation-associated modifications were studied. Results: Retinol (7 and 14 μmol/L) significantly increases the reactive species production in Sertoli cells. Inhibition of p38, JNK, ERK1/2, Akt, and PKA suppressed retinol-induced [3H]dT incorporation into the cells, while PKC inhibition had no effect. ERK1/2 and p38 inhibition also blocked retinol-induced proliferative focus formation in the cells, while Akt and JNK inhibition partially decreased focus formation. ERK1/2 and p38 inhibition hindered transformation-associated deformation in retinol-treated cells, while other treatments had no effect. Conclusion: Our results suggest that activation of multiple kinases is responsible for morphological and proliferative changes associated to malignancy development in Sertoli cells by retinol at the concentrations higher than physiological level. PMID:22426700

  10. Very simple combination of TROSY, CRINEPT and multiple quantum coherence for signal enhancement in an HN(CO)CA experiment for large proteins

    NASA Astrophysics Data System (ADS)

    Bayrhuber, Monika; Riek, Roland

    2011-04-01

    Sensitivity enhancement in liquid state nuclear magnetic resonance (NMR) triple resonance experiments for the sequential assignment of proteins is important for the investigation of large proteins or protein complexes. We present here the 3D TROSY-MQ/CRINEPT-HN(CO)CA which makes use of a 15N- 1H-TROSY element and a 13C'- 13CA CRINEPT step combined with a multiple quantum coherence during the 13CA evolution period. Because of the introduction of these relaxation-optimized elements and 10 less pulses required, when compared with the conventional TROSY-HN(CO)CA experiment an average signal enhancement of a factor of 1.8 was observed for the membrane protein-detergent complex KcsA with a rotational correlation time τ c of around 60 ns.

  11. Removal of multiple arginine-framed trafficking signals overcomes misprocessing of delta F508 CFTR present in most patients with cystic fibrosis.

    PubMed

    Chang, X B; Cui, L; Hou, Y X; Jensen, T J; Aleksandrov, A A; Mengos, A; Riordan, J R

    1999-07-01

    Many cystic fibrosis transmembrane conductance regulator (CFTR) mutants are recognized as aberrant by the quality control apparatus at the endoplasmic reticulum (ER) and are targeted for degradation. The mechanism whereby nascent chains are distinguished as either competent or incompetent for ER export has not been elucidated. Here we show that export-incompetent chains display multiple arginine-framed tripeptide sequences like the one recently identified in ATP-sensitive K+ channels. Replacement of arginine residues at positions R29, R516, R555, and R766 with lysine residues to inactivate four of these motifs simultaneously causes delta F508 CFTR, present in approximately 90% of CF patients, to escape ER quality control and function at the cell surface. Interference with recognition of these signals may be helpful in the management of CF. PMID:10445036

  12. Multiple tree-ring chronologies (ring width, δ13C and δ18O) reveal dry and rainy season signals of rainfall in Indonesia

    NASA Astrophysics Data System (ADS)

    Schollaen, Karina; Heinrich, Ingo; Neuwirth, Burkhard; Krusic, Paul J.; D'Arrigo, Rosanne D.; Karyanto, Oka; Helle, Gerhard

    2013-08-01

    Climatic hazards, such as severe droughts and floods, affect extensive areas across monsoon Asia and can have profound impacts on the populations of that region. The area surrounding Indonesia, including large portions of the eastern Indian Ocean and Java Sea, plays a key role in the global climate system because of the enormous heat and moisture exchange that occurs between the ocean and atmosphere there. Here, we evaluate the influence of rainfall variability on multiple tree-ring parameters of teak (Tectona grandis) trees growing in a lowland rain forest in Central Java (Indonesia). We assess the potential of, annually resolved, tree-ring width, stable carbon (δ13C) and oxygen (δ18O) isotope records to improve our understanding of the Asian monsoon variability. Climate response analysis with regional, monthly rainfall data reveals that all three tree-ring parameters are significantly correlated to rainfall, albeit during different monsoon seasons. Precipitation in the beginning of the rainy season (Sep-Nov) is important for tree-ring width, confirming previous studies. Compared to ring width, the stable isotope records possess a higher degree of common signal, especially during portions of the peak rainy season (δ13C: Dec-May; δ18O: Nov-Feb) and are negatively correlated to rainfall. In addition, tree-ring δ18O also responds positively to peak dry season rainfall, although the δ18O rainy season signal is stronger and more time-stable. The correlations of opposite sign reflect the distinct seasonal contrast of the δ18O signatures in rainfall (18OPre) during the dry (18O-enriched rain) and rainy (18O-depleted rain) seasons. This difference in 18OPre signal reflects the combination of two signals in the annual tree-ring δ18O record. Highly resolved intra-annual δ18O isotope analyses suggest that the signals of dry and rainy season can be distinguished clearly. Thereby reconstructions can improve our understanding of variations and trends of the

  13. Fast and Broadband Signal Integrity Analysis of Multiple Vias in Heterogeneous 3D IC and Die-Level Packaging by Using Generalized Foldy-Lax Scattering Method

    NASA Astrophysics Data System (ADS)

    Chang, Xin

    This dissertation proposal is concerned with the use of fast and broadband full-wave electromagnetic methods for modeling high speed interconnects (e.g, vertical vias and horizontal traces) and passive components (e.g, decoupling capacitors) for structures of PCB and packages, in 3D IC, Die-level packaging and SIW based devices, to effectively modeling the designs signal integrity (SI) and power integrity (PI) aspects. The main contributions finished in this thesis is to create a novel methodology, which hybridizes the Foldy-Lax multiple scattering equations based fast full wave method, method of moment (MoM) based 1D technology, modes decoupling based geometry decomposition and cavity modes expansions, to model and simulate the electromagnetic scattering effects for the irregular power/ground planes, multiple vias and traces, for fast and accurate analysis of link level simulation on multilayer electronic structures. For the modeling details, the interior massively-coupled multiple vias problem is modeled most-analytically by using the Foldy-Lax multiple scattering equations. The dyadic Green's functions of the magnetic field are expressed in terms of waveguide modes in the vertical direction and vector cylindrical wave expansions or cavity modes expansions in the horizontal direction, combined with 2D MoM realized by 1D technology. For the incident field of the case of vias in the arbitrarily shaped antipad in finite large cavity/waveguide, the exciting and scattering field coefficients are calculated based on the transformation which converts surface integration of magnetic surface currents in antipad into 1D line integration of surface charges on the vias and on the ground plane. Geometry decomposition method is applied to model and integrate both the vertical and horizontal interconnects/traces in arbitrarily shaped power/ground planes. Moreover, a new form of multiple scattering equations is derived for solving coupling effects among mixed metallic

  14. MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma

    PubMed Central

    He, Jie; Liu, Xi; Qu, Ying; Yan, Wenqing; Fan, Jianling; Li, Rong; Xi, Hao; Fu, Weijun; Zhang, Chunyang; Yang, Jing; Hou, Jian

    2015-01-01

    Side population (SP) cells are an enriched source of cancer-initiating cells with stemness characteristics, generated by increased ABC transporter activity, which has served as a unique hallmark for multiple myeloma (MM) stem cell studies. Here we isolated and identified MM SP cells via Hoechst 33342 staining. Furthermore, we demonstrate that SP cells possess abnormal cell cycle, clonogenicity, and high drug efflux characteristics-all of which are features commonly seen in stem cells. Interestingly, we found that bortezomib, As2O3, and melphalan all affected apoptosis and clonogenicity in SP cells. We followed by characterizing the miRNA signature of MM SP cells and validated the specific miR-451 target tuberous sclerosis 1 (TSC1) gene to reveal that it activates the PI3K/Akt/mTOR signaling in MM SP cells. Inhibition of miR-451 enhanced anti-myeloma novel agents' effectiveness, through increasing cells apoptosis, decreasing clonogenicity, and reducing MDR1 mRNA expression. Moreover, the novel specific PI3K/Akt/mTOR signaling inhibitor S14161 displayed its prowess as a potential therapeutic agent by targeting MM SP cells. Our findings offer insights into the mechanisms regulating MM SP cells and provide a novel strategy to overcome resistance to existing therapies against myeloma. PMID:25915427

  15. The role of the PI3K-Akt signal transduction pathway in Autographa californica multiple nucleopolyhedrovirus infection of Spodoptera frugiperda cells

    SciTech Connect

    Xiao Wei; Yang Yi; Weng Qingbei; Lin Tiehao; Yuan Meijin; Yang Kai; Pang Yi

    2009-08-15

    Many viruses activate the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, thereby modulating diverse downstream signaling pathways associated with antiapoptosis, proliferation, cell cycling, protein synthesis and glucose metabolism, in order to augment their replication. To date, the role of the PI3K-Akt pathway in Baculovirus replication has not been defined. In the present study, we demonstrate that infection of Sf9 cells with Autographa californica multiple nucleopolyhedrovirus (AcMNPV) elevated cellular Akt phosphorylation at 1 h post-infection. The maximum Akt phosphorylation occurred at 6 h post-infection and remained unchanged until 18 h post-infection. The PI3K-specific inhibitor, LY294002, suppressed Akt phosphorylation in a dose-dependent manner, suggesting that AcMNPV-induced Akt phosphorylation is PI3K-dependent. The inhibition of PI3K-Akt activation by LY294002 significantly reduced the viral yield, including a reduction in budded viruses and occlusion bodies. The virus production was reduced only when the inhibitor was added within 24 h of infection, implying that activation of PI3K occurred early in infection. Correspondingly, both viral DNA replication and late (VP39) and very late (POLH) viral protein expression were impaired by LY294002 treatment; LY294002 had no effect on immediate-early (IE1) and early-late (GP64) protein expression. These results demonstrate that the PI3K-Akt pathway is required for efficient Baculovirus replication.

  16. Deletion of atbf1/zfhx3 in mouse prostate causes neoplastic lesions, likely by attenuation of membrane and secretory proteins and multiple signaling pathways.

    PubMed

    Sun, Xiaodong; Fu, Xiaoying; Li, Jie; Xing, Changsheng; Frierson, Henry F; Wu, Hao; Ding, Xiaokun; Ju, Tongzhong; Cummings, Richard D; Dong, Jin-Tang

    2014-05-01

    The ATBF1/ZFHX3 gene at 16q22 is the second most frequently mutated gene in human prostate cancer and has reduced expression or mislocalization in several types of human tumors. Nonetheless, the hypothesis that ATBF1 has a tumor suppressor function in prostate cancer has not been tested. In this study, we examined the role of ATBF1 in prostatic carcinogenesis by specifically deleting Atbf1 in mouse prostatic epithelial cells. We also examined the effect of Atbf1 deletion on gene expression and signaling pathways in mouse prostates. Histopathologic analyses showed that Atbf1 deficiency caused hyperplasia and mouse prostatic intraepithelial neoplasia (mPIN) primarily in the dorsal prostate but also in other lobes. Hemizygous deletion of Atbf1 also increased the development of hyperplasia and mPIN, indicating a haploinsufficiency of Atbf1. The mPIN lesions expressed luminal cell markers and harbored molecular changes similar to those in human PIN and prostate cancer, including weaker expression of basal cell marker cytokeratin 5 (Ck5), cell adhesion protein E-cadherin, and the smooth muscle layer marker Sma; elevated expression of the oncoproteins phospho-Erk1/2, phospho-Akt and Muc1; and aberrant protein glycosylation. Gene expression profiling revealed a large number of genes that were dysregulated by Atbf1 deletion, particularly those that encode for secretory and cell membrane proteins. The four signaling networks that were most affected by Atbf1 deletion included those centered on Erk1/2 and IGF1, Akt and FSH, NF-κB and progesterone and β-estradiol. These findings provide in vivo evidence that ATBF1 is a tumor suppressor in the prostate, suggest that loss of Atbf1 contributes to tumorigenesis by dysregulating membrane and secretory proteins and multiple signaling pathways, and provide a new animal model for prostate cancer. PMID:24934715

  17. Deletion of Atbf1/Zfhx3 In Mouse Prostate Causes Neoplastic Lesions, Likely by Attenuation of Membrane and Secretory Proteins and Multiple Signaling Pathways

    PubMed Central

    Sun, Xiaodong; Fu, Xiaoying; Li, Jie; Xing, Changsheng; Frierson, Henry F.; Wu, Hao; Ding, Xiaokun; Ju, Tongzhong; Cummings, Richard D.; Dong, Jin-Tang

    2014-01-01

    The ATBF1/ZFHX3 gene at 16q22 is the second most frequently mutated gene in human prostate cancer and has reduced expression or mislocalization in several types of human tumors. Nonetheless, the hypothesis that ATBF1 has a tumor suppressor function in prostate cancer has not been tested. In this study, we examined the role of ATBF1 in prostatic carcinogenesis by specifically deleting Atbf1 in mouse prostatic epithelial cells. We also examined the effect of Atbf1 deletion on gene expression and signaling pathways in mouse prostates. Histopathologic analyses showed that Atbf1 deficiency caused hyperplasia and mouse prostatic intraepithelial neoplasia (mPIN) primarily in the dorsal prostate but also in other lobes. Hemizygous deletion of Atbf1 also increased the development of hyperplasia and mPIN, indicating a haploinsufficiency of Atbf1. The mPIN lesions expressed luminal cell markers and harbored molecular changes similar to those in human PIN and prostate cancer, including weaker expression of basal cell marker cytokeratin 5 (Ck5), cell adhesion protein E-cadherin, and the smooth muscle layer marker Sma; elevated expression of the oncoproteins phospho-Erk1/2, phospho-Akt and Muc1; and aberrant protein glycosylation. Gene expression profiling revealed a large number of genes that were dysregulated by Atbf1 deletion, particularly those that encode for secretory and cell membrane proteins. The four signaling networks that were most affected by Atbf1 deletion included those centered on Erk1/2 and IGF1, Akt and FSH, NF-κB and progesterone and β-estradiol. These findings provide in vivo evidence that ATBF1 is a tumor suppressor in the prostate, suggest that loss of Atbf1 contributes to tumorigenesis by dysregulating membrane and secretory proteins and multiple signaling pathways, and provide a new animal model for prostate cancer. PMID:24934715

  18. Modulation of TLR3/TLR4 inflammatory signaling by the GABAB receptor agonist baclofen in glia and immune cells: relevance to therapeutic effects in multiple sclerosis

    PubMed Central

    Crowley, Tadhg; Fitzpatrick, John-Mark; Kuijper, Teun; Cryan, John F.; O’Toole, Orna; O’Leary, Olivia F.; Downer, Eric J.

    2015-01-01

    The GABAB receptor agonist, baclofen, is used to treat muscle tightness and cramping caused by spasticity in a number of disorders including multiple sclerosis (MS), but its precise mechanism of action is unknown. Neuroinflammation drives the central pathology in MS and is mediated by both immunoreactive glial cells and invading lymphocytes. Furthermore, a body of data indicates that the Toll-like receptor (TLR) family of innate immune receptors is implicated in MS progression. In the present study we investigated whether modulation of GABAB receptors using baclofen can exert anti-inflammatory effects by targeting TLR3 and(or) TLR4-induced inflammatory signaling in murine glial cells and human peripheral blood mononuclear cells (PBMCs) isolated from healthy control individuals and patients with the relapse-remitting (RR) form of MS. TLR3 and TLR4 stimulation promoted the nuclear sequestration of NF-κB and pro-inflammatory cytokine expression in murine glia, while TLR4, but not TLR3, promoted pro-inflammatory cytokine expression in PBMCs isolated from both healthy donors and RR-MS patients. Importantly, this effect was exacerbated in RR-MS patient immune cells. We present further evidence that baclofen dose-dependently attenuated TLR3- and TLR4-induced inflammatory signaling in primary glial cells. Pre-exposure of PBMCs isolated from healthy donors to baclofen attenuated TLR4-induced TNF-α expression, but did not affect TLR4-induced TNF-α expression in RR-MS patient PBMCs. Interestingly, mRNA expression of the GABAB receptor was reduced in PBMCs from RR-MS donors when compared to healthy controls, an effect that might contribute to the differential sensitivity to baclofen seen in healthy and RR-MS patient cells. Overall these findings indicate that baclofen differentially regulates TLR3 and TLR4 signaling in glia and immune cells, and offers insight on the role of baclofen in the treatment of neuroinflammatory disease states including MS. PMID:26283920

  19. Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway

    PubMed Central

    Li, Feng; Rajendran, Peramaiyan; Sethi, Gautam

    2010-01-01

    BACKGROUND AND PURPOSE Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) pathway is frequently encountered in several human cancers including multiple myeloma (MM). Thus, agents that suppress STAT3 phosphorylation have a potential for treatment of MM. In the present report, we investigated whether thymoquinone (TQ), the main component isolated from the medicinal plant Nigella sativa, modulated the STAT3 signalling pathway in MM cells. EXPERIMENTAL APPROACH The effect of TQ on both constitutive and IL-6-induced STAT3 activation, associated protein kinases, STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation and apoptosis in MM cells, was investigated. KEY RESULTS We found that TQ inhibited both constitutive and IL-6-inducible STAT3 phosphorylation which correlated with the inhibition of c-Src and JAK2 activation. Vanadate reversed the TQ-induced down-regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that TQ can induce the expression of Src homology-2 phosphatase 2 that correlated with suppression of STAT3 activation. TQ also down-regulated the expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, TQ induced the accumulation of cells in sub-G1 phase, inhibited proliferation and induced apoptosis, as indicated by poly ADP ribose polymerase cleavage. TQ also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells. CONCLUSIONS AND IMPLICATIONS Our study has identified STAT3 signalling as a target of TQ and has thus raised its potential application in the prevention and treatment of MM and other cancers. PMID:20880395

  20. Extended Active Disturbance Rejection Controller

    NASA Technical Reports Server (NTRS)

    Gao, Zhiqiang (Inventor); Tian, Gang (Inventor)

    2016-01-01

    Multiple designs, systems, methods and processes for controlling a system or plant using an extended active disturbance rejection control (ADRC) based controller are presented. The extended ADRC controller accepts sensor information from the plant. The sensor information is used in conjunction with an extended state observer in combination with a predictor that estimates and predicts the current state of the plant and a co-joined estimate of the system disturbances and system dynamics. The extended state observer estimates and predictions are used in conjunction with a control law that generates an input to the system based in part on the extended state observer estimates and predictions as well as a desired trajectory for the plant to follow.

  1. Extended Active Disturbance Rejection Controller

    NASA Technical Reports Server (NTRS)

    Gao, Zhiqiang (Inventor); Tian, Gang (Inventor)

    2014-01-01

    Multiple designs, systems, methods and processes for controlling a system or plant using an extended active disturbance rejection control (ADRC) based controller are presented. The extended ADRC controller accepts sensor information from the plant. The sensor information is used in conjunction with an extended state observer in combination with a predictor that estimates and predicts the current state of the plant and a co-joined estimate of the system disturbances and system dynamics. The extended state observer estimates and predictions are used in conjunction with a control law that generates an input to the system based in part on the extended state observer estimates and predictions as well as a desired trajectory for the plant to follow.

  2. Extended active disturbance rejection controller

    NASA Technical Reports Server (NTRS)

    Gao, Zhiqiang (Inventor); Tian, Gang (Inventor)

    2012-01-01

    Multiple designs, systems, methods and processes for controlling a system or plant using an extended active disturbance rejection control (ADRC) based controller are presented. The extended ADRC controller accepts sensor information from the plant. The sensor information is used in conjunction with an extended state observer in combination with a predictor that estimates and predicts the current state of the plant and a co-joined estimate of the system disturbances and system dynamics. The extended state observer estimates and predictions are used in conjunction with a control law that generates an input to the system based in part on the extended state observer estimates and predictions as well as a desired trajectory for the plant to follow.

  3. Pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sIAHP in CA1 pyramidal neurons by activating multiple signaling pathways

    PubMed Central

    Taylor, Ruth DT; Madsen, Marita Grønning; Krause, Michael; Sampedro-Castañeda, Marisol; Stocker, Martin; Pedarzani, Paola

    2014-01-01

    The slow afterhyperpolarizing current (sIAHP) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sIAHP is a well-known target of modulation by several neurotransmitters acting via the cyclic AMP (cAMP) and protein kinase A (PKA)-dependent pathway. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its receptors are present in the hippocampal formation. In this study we have investigated the effect of PACAP on the sIAHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sIAHP, resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sIAHP by PACAP is mediated by PAC1 and VPAC1 receptors. Inhibition of PKA reduced the effect of PACAP on sIAHP, suggesting that PACAP exerts part of its inhibitory effect on sIAHP by increasing cAMP and activating PKA. The suppression of sIAHP by PACAP was also strongly hindered by the inhibition of p38 MAP kinase (p38 MAPK). Concomitant inhibition of PKA and p38 MAPK indicates that these two kinases act in a sequential manner in the same pathway leading to the suppression of sIAHP. Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sIAHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sIAHP through the activation of multiple signaling pathways, most prominently cAMP/PKA and p38 MAPK. Our findings disclose a novel modulatory action of p38 MAPK on intrinsic excitability and the sIAHP, underscoring the role of this current as a neuromodulatory hub regulated by multiple protein kinases in cortical neurons. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc. PMID:23996525

  4. Multiple tree-ring chronologies (ring width, δ13C and δ18O) reveal dry and rainy season signals in Indonesia

    NASA Astrophysics Data System (ADS)

    Schollaen, Karina; Heinrich, Ingo; Neuwirth, Burkhard; Krusic, Paul; D`Arrigo, Rosanne; Karyanto, Oka; Helle, Gerhard

    2013-04-01

    The tropical Indonesian region plays a key role in the global climate system because of the enormous heat and moisture exchange between ocean and atmosphere in that area. Here, we evaluate the influence of rainfall variability on multiple tree-ring parameters of Teak (Tectona grandis) trees growing in a lowland rain forest in Central Java (Indonesia). Three, annually resolved, chronologies of tree-ring width, stable carbon (δ13C) and oxygen (δ18O) isotopes were developed for the twentieth century (1900-2007). Climate response analysis with regional rainfall data has revealed that all three tree-ring parameters are significantly sensitive to rainfall during different intervals of the seasonal monsoon pattern. The amount of rainfall at the beginning of the rainy season (Sep-Nov) is important for tree-ring width, confirming previous studies. The stable isotope records best represent slightly different sub-periods of the prime rainy season (δ13C: Dec-May; δ18O: Nov-Feb) with negative correlations. Tree-ring δ18O additionally responds well to peak dry season rainfall with positive correlation. The correlations of opposite sign reflect the distinct seasonal contrast of the δ18O signatures of rainfall during the dry (18O-enriched rain) and rainy (18O-depleted rain) seasons in conjunction with changing rainfall amount. Dry season periods with rainfall amounts above average have an exceptionally strong influence on tree-ring δ18O in years with below average rainy season rainfall. In such cases, the dry season signal reduces the signal strength of the prime rainy season in tree-ring δ18O. However, the rainy season signal is still strong and stable over the 20th century. Further, the δ18O record correlates with several ENSO events, supported by spectral analysis which reveals significant peaks on the 2-4 year band. Highly resolved intra-annual δ18O isotope analyses suggest that the signals of dry and rainy season can be distinguished clearly and demonstrate a new

  5. Extending quantum mechanics entails extending special relativity

    NASA Astrophysics Data System (ADS)

    Aravinda, S.; Srikanth, R.

    2016-05-01

    The complementarity between signaling and randomness in any communicated resource that can simulate singlet statistics is generalized by relaxing the assumption of free will in the choice of measurement settings. We show how to construct an ontological extension for quantum mechanics (QMs) through the oblivious embedding of a sound simulation protocol in a Newtonian spacetime. Minkowski or other intermediate spacetimes are ruled out as the locus of the embedding by virtue of hidden influence inequalities. The complementarity transferred from a simulation to the extension unifies a number of results about quantum non-locality, and implies that special relativity has a different significance for the ontological model and for the operational theory it reproduces. Only the latter, being experimentally accessible, is required to be Lorentz covariant. There may be certain Lorentz non-covariant elements at the ontological level, but they will be inaccessible at the operational level in a valid extension. Certain arguments against the extendability of QM, due to Conway and Kochen (2009) and Colbeck and Renner (2012), are attributed to their assumption that the spacetime at the ontological level has Minkowski causal structure.

  6. Hedgehog signalling.

    PubMed

    Lee, Raymond Teck Ho; Zhao, Zhonghua; Ingham, Philip W

    2016-02-01

    The Hedgehog (Hh) signalling pathway is one of the key regulators of metazoan development. Hh proteins have been shown to play roles in many developmental processes and have become paradigms for classical morphogens. Dysfunction of the Hh pathway underlies a number of human developmental abnormalities and diseases, making it an important therapeutic target. Interest in Hh signalling thus extends across many fields, from evo-devo to cancer research and regenerative medicine. Here, and in the accompanying poster, we provide an outline of the current understanding of Hh signalling mechanisms, highlighting the similarities and differences between species. PMID:26839340

  7. Multiple single-point imaging (mSPI) as a tool for capturing and characterizing MR signals and repetitive signal disturbances with high temporal resolution: the MRI scanner as a high-speed camera.

    PubMed

    Bakker, Chris J G; van Gorp, Jetse S; Verwoerd, Jan L; Westra, Albert H; Bouwman, Job G; Zijlstra, Frank; Seevinck, Peter R

    2013-09-01

    In this paper we aim to lay down and demonstrate the use of multiple single-point imaging (mSPI) as a tool for capturing and characterizing steady-state MR signals and repetitive disturbances thereof with high temporal resolution. To achieve this goal, various 2D mSPI sequences were derived from the nearest standard 3D imaging sequences by (i) replacing the excitation of a 3D slab by the excitation of a 2D slice orthogonal to the read axis, (ii) setting the readout gradient to zero, and (iii) leaving out the inverse Fourier transform in the read direction. The thus created mSPI sequences, albeit slow with regard to the spatial encoding part, were shown to result into a series of densely spaced 2D single-point images in the time domain enabling monitoring of the evolution of the magnetization with a high temporal resolution and without interference from any encoding gradients. The high-speed capabilities of mSPI were demonstrated by capturing and characterizing the free induction decays and spin echoes of substances with long T2s (>30 ms) and long and short T2*s (4 - >30 ms) and by monitoring the perturbation of the transverse magnetization by, respectively, a titanium cylinder, representing a static disturbance; a pulsed magnetic field gradient, representing a stimulus inherent to a conventional MRI experiment; and a pulsed electric current, representing an external stimulus. The results of the study indicate the potential of mSPI for assessing the evolution of the magnetization and, when properly synchronized with the acquisition, repeatable disturbances thereof with a temporal resolution that is ultimately limited by the bandwidth of the receiver, but in practice governed by the SNR of the experiment and the magnitude of the disturbance. Potential applications of mSPI can be envisaged in research areas that are concerned with MR signal behavior, MR system performance and MR evaluation of magnetically evoked responses. PMID:23759651

  8. Farnesol inhibits tumor growth and enhances the anticancer effects of bortezomib in multiple myeloma xenograft mouse model through the modulation of STAT3 signaling pathway.

    PubMed

    Lee, Jong Hyun; Kim, Chulwon; Kim, Sung-Hoon; Sethi, Gautam; Ahn, Kwang Seok

    2015-05-01

    Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is frequently observed in multiple myeloma (MM) cancer and can upregulate the expression of several genes involved in proliferation, survival, metastasis, and angiogenesis. The effect of farnesol (FOH) on STAT3 activation, associated protein kinases, its regulated gene products, cellular proliferation, and apoptosis was examined. The in vivo effect of FOH on the growth of human MM xenograft tumors alone and in combination with bortezomib (Bor) in athymic nu/nu female mice was also investigated. We found that FOH suppressed both constitutive and inducible STAT3 activation at Tyr705 in MM cells. The suppression of STAT3 was mediated through the inhibition of activation of upstream JAK1, JAK2, and c-Src kinases. Also, treatment with the protein tyrosine phosphatase (PTP) inhibitor, pervanadate treatment reversed the FOH-induced down-regulation of STAT3, possibly indicating the involvement of a PTP. Indeed, we found that FOH treatment induces the increased expression of SHP-2 protein and knockdown of the SHP-2 gene by small interfering RNA suppressed the ability of FOH to inhibit STAT3 activation. FOH inhibited proliferation and significantly potentiated the apoptotic effects of bortezomib (Bor) in U266 cells. When administered intraperitoneally, FOH enhanced Bor-induced growth suppression of human MM xenograft tumors in athymic nu/nu female mice. Our results suggest that FOH is a novel blocker of STAT3 signaling pathway and exerts both anti-proliferative and apoptotic activities in MM in vitro and in vivo. PMID:25697480

  9. Proteomic and Phosphoproteomic Insights into a Signaling Hub Role for Cdc14 in Asexual Development and Multiple Stress Responses in Beauveria bassiana

    PubMed Central

    Wang, Zhi-Kang; Wang, Jie; Liu, Jing; Ying, Sheng-Hua; Peng, Xiao-Jun; Feng, Ming-Guang

    2016-01-01

    Cdc14 is a dual-specificity phosphatase that regulates nuclear behavior by dephosphorylating phosphotyrosine and phosphoserine/phosphothreonine in fungi. Previously, Cdc14 was shown to act as a positive regulator of cytokinesis, asexual development and multiple stress responses in Beauveria bassiana, a fungal insect pathogen. This study seeks to gain deep insight into a pivotal role of Cdc14 in the signaling network of B. bassiana by analyzing the Cdc14-specific proteome and phosphoproteome generated by the 8-plex iTRAQ labeling and MS/MS analysis of peptides and phosphopeptides. Under normal conditions, 154 proteins and 86 phosphorylation sites in 67 phosphoproteins were upregulated in Δcdc14 versus wild-type, whereas 117 proteins and 85 phosphorylation sites in 58 phosphoproteins were significantly downregulated. Co-cultivation of Δcdc14 with NaCl (1 M), H2O2 (3 mM) and Congo red (0.15 mg/ml) resulted in the upregulation / downregulation of 23/63, 41/39 and 79/79 proteins and of 127/112, 52/47 and 105/226 phosphorylation sites in 85/92, 45/36 and 79/146 phosphoproteins, respectively. Bioinformatic analyses revealed that Cdc14 could participate in many biological and cellular processes, such as carbohydrate metabolism, glycerophospholipid metabolism, the MAP Kinase signaling pathway, and DNA conformation, by regulating protein expression and key kinase phosphorylation in response to different environmental cues. These indicate that in B. bassiana, Cdc14 is a vital regulator of not only protein expression but also many phosphorylation events involved in developmental and stress-responsive pathways. Fourteen conserved and novel motifs were identified in the fungal phosphorylation events. PMID:27055109

  10. The collagen triple helix repeat containing 1 facilitates hepatitis B virus-associated hepatocellular carcinoma progression by regulating multiple cellular factors and signal cascades.

    PubMed

    Zhang, Rui; Cao, Yanhua; Bai, Lan; Zhu, Chengliang; Li, Rui; He, Hui; Liu, Yingle; Wu, Kailang; Liu, Fang; Wu, Jianguo

    2015-12-01

    Hepatitis B virus (HBV) infection is one of the major causes of acute and chronic liver diseases, fulminant hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). HCC accounts for more than 85% of primary liver cancers and is the seventh most common cancer and the third leading cause of cancer-related deaths. However, the mechanism by which HBV induces HCC is largely unknown. Collagen triple helixes repeat containing 1 (CTHRC1) is a secreted protein and has characteristics of a circulating hormone with potentially broad implications for cell metabolism and physiology. CTHRC1 is associated with human cancers, but its effect on HCC is unknown. Here, we revealed that CTHRC1 expression is highly correlated with HCC progression in HBV-infected patients, and demonstrated that HBV stimulates CTHRC1 expression by activating nuclear factor-kappa B (NF-κB) and cAMP response element binding protein (CREB), through extracellular signal-regulated kinase/c-Jun N-terminal kinase (ERK/c-JNK) pathway. In addition, CTHRC1 activates hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) through regulating phosphoinosmde-3-kinase/protein kinase B/mammalian target of rapamycin (PI-3K/AKT/mTOR) pathway. More interestingly, CTHRC1 enhances colony formation, migration, and invasion of hepatoma cells by regulating p53 and stimulating matrix metalloproteinase-9 (MMP-9) expression. In addition, knock-down of CTHRC1 results in the repression of HBV-associated carcinogenesis in nude mice. Thus, we revealed a novel mechanism by which HBV facilitates HCC development through activating the oncoprotein CTHRC1, which in turn enhances HBV-related HCC progression by stimulates colony formation, migration, and invasion of hepatoma cells through regulating multiple cellular factors and signal cascades. PMID:25263696

  11. Hemodynamic Signal Changes Accompanying Execution and Imagery of Swallowing in Patients with Dysphagia: A Multiple Single-Case Near-Infrared Spectroscopy Study

    PubMed Central

    Kober, Silvia Erika; Bauernfeind, Günther; Woller, Carina; Sampl, Magdalena; Grieshofer, Peter; Neuper, Christa; Wood, Guilherme

    2015-01-01

    In the present multiple case study, we examined hemodynamic changes in the brain in response to motor execution (ME) and motor imagery (MI) of swallowing in dysphagia patients compared to healthy matched controls using near-infrared spectroscopy (NIRS). Two stroke patients with cerebral lesions in the right hemisphere, two stroke patients with lesions in the brainstem, and two neurologically healthy control subjects actively swallowed saliva (ME) and mentally imagined to swallow saliva (MI) in a randomized order while changes in concentration of oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) were assessed. In line with recent findings in healthy young adults, MI and ME of swallowing led to the strongest NIRS signal change in the inferior frontal gyrus in stroke patients as well as in healthy elderly. We found differences in the topographical distribution and time course of the hemodynamic response in dependence on lesion location. Dysphagia patients with lesions in the brainstem showed bilateral hemodynamic signal changes in the inferior frontal gyrus during active swallowing comparable to healthy controls. In contrast, dysphagia patients with cerebral lesions in the right hemisphere showed more unilateral activation patterns during swallowing. Furthermore, patients with cerebral lesions showed a prolonged time course of the hemodynamic response during MI and ME of swallowing compared to healthy controls and patients with brainstem lesions. Brain activation patterns associated with ME and MI of swallowing were largely comparable, especially for changes in deoxy-Hb. Hence, the present results provide new evidence regarding timing and topographical distribution of the hemodynamic response during ME and MI of swallowing in dysphagia patients and may have practical impact on future dysphagia treatment. PMID:26217298

  12. Proteomic and Phosphoproteomic Insights into a Signaling Hub Role for Cdc14 in Asexual Development and Multiple Stress Responses in Beauveria bassiana.

    PubMed

    Wang, Zhi-Kang; Wang, Jie; Liu, Jing; Ying, Sheng-Hua; Peng, Xiao-Jun; Feng, Ming-Guang

    2016-01-01

    Cdc14 is a dual-specificity phosphatase that regulates nuclear behavior by dephosphorylating phosphotyrosine and phosphoserine/phosphothreonine in fungi. Previously, Cdc14 was shown to act as a positive regulator of cytokinesis, asexual development and multiple stress responses in Beauveria bassiana, a fungal insect pathogen. This study seeks to gain deep insight into a pivotal role of Cdc14 in the signaling network of B. bassiana by analyzing the Cdc14-specific proteome and phosphoproteome generated by the 8-plex iTRAQ labeling and MS/MS analysis of peptides and phosphopeptides. Under normal conditions, 154 proteins and 86 phosphorylation sites in 67 phosphoproteins were upregulated in Δcdc14 versus wild-type, whereas 117 proteins and 85 phosphorylation sites in 58 phosphoproteins were significantly downregulated. Co-cultivation of Δcdc14 with NaCl (1 M), H2O2 (3 mM) and Congo red (0.15 mg/ml) resulted in the upregulation / downregulation of 23/63, 41/39 and 79/79 proteins and of 127/112, 52/47 and 105/226 phosphorylation sites in 85/92, 45/36 and 79/146 phosphoproteins, respectively. Bioinformatic analyses revealed that Cdc14 could participate in many biological and cellular processes, such as carbohydrate metabolism, glycerophospholipid metabolism, the MAP Kinase signaling pathway, and DNA conformation, by regulating protein expression and key kinase phosphorylation in response to different environmental cues. These indicate that in B. bassiana, Cdc14 is a vital regulator of not only protein expression but also many phosphorylation events involved in developmental and stress-responsive pathways. Fourteen conserved and novel motifs were identified in the fungal phosphorylation events. PMID:27055109

  13. Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer.

    PubMed

    Su, Yen-Hao; Tang, Wan-Chun; Cheng, Ya-Wen; Sia, Peik; Huang, Chi-Chen; Lee, Yi-Chao; Jiang, Hsin-Yi; Wu, Ming-Heng; Lai, I-Lu; Lee, Jun-Wei; Lee, Kuen-Haur

    2015-10-01

    There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-β-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC. PMID:25982393

  14. Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptor α and β.

    PubMed

    Rossi, V; Bellastella, G; De Rosa, C; Abbondanza, C; Visconti, D; Maione, L; Chieffi, P; Della Ragione, F; Prezioso, D; De Bellis, A; Bellastella, A; Sinisi, A A

    2011-05-01

    Raloxifene (RAL), a selective estrogen receptor (ER) modulator (SERM) seems to induce apoptosis in both androgen-dependent and -independent prostate cell (PC) lines via activation of ERβ and an antagonistic effect on ERα. In this study, we evaluated the effects of RAL on epithelial PC growth using the two following in vitro models: the androgen-dependent cell line EPN which expressed both ERs; and a stabilized epithelial cell line derived from a prostate cancer specimen (CPEC), which expressed low levels of ERβ and lacked ERα. In EPN cells, there was an increase in the pre-G1 apoptotic peak and a reduction in the S phase of the cell cycle with G0/G1 arrest after E2 or RAL treatment; bcl-2 mRNA and Bcl-2 protein levels were significantly reduced, while activated caspase-3 and Par-4 levels increased significantly after either E2 or RAL treatment; in addition, c-myc transcript was inhibited after 10(-6)  M RAL treatment. A dose-dependent increase of metallothionein II gene RNA level was also induced by RAL in EPN. In CPEC, there was only a weak apoptotic peak associated with caspase-3 activation and Par-4 increase after either E2 or RAL treatment; while c-myc transcript level increased. RAL induced a rapid but transient phosphorylation of ERK 1/2 in EPN cells but generated a sustained effect in CPEC. These findings suggest that RAL effects on PC growth control in vitro are cell-specific, depending on ERβ or ERβ/ERα relative expression levels. Moreover, this study demonstrated that RAL affected both transcriptional regulation and non-genomic signals, which resulted in the modulation of multiple signaling pathways of apoptosis and of cell cycle progression. PMID:20945400

  15. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    PubMed Central

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

    2015-01-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. PMID:25448439

  16. Applying Ligands Profiling Using Multiple Extended Electron Distribution Based Field Templates and Feature Trees Similarity Searching in the Discovery of New Generation of Urea-Based Antineoplastic Kinase Inhibitors

    PubMed Central

    Dokla, Eman M.; Mahmoud, Amr H.; Elsayed, Mohamed S. A.; El-Khatib, Ahmed H.; Linscheid, Michael W.; Abouzid, Khaled A.

    2012-01-01

    This study provides a comprehensive computational procedure for the discovery of novel urea-based antineoplastic kinase inhibitors while focusing on diversification of both chemotype and selectivity pattern. It presents a systematic structural analysis of the different binding motifs of urea-based kinase inhibitors and the corresponding configurations of the kinase enzymes. The computational model depends on simultaneous application of two protocols. The first protocol applies multiple consecutive validated virtual screening filters including SMARTS, support vector-machine model (ROC = 0.98), Bayesian model (ROC = 0.86) and structure-based pharmacophore filters based on urea-based kinase inhibitors complexes retrieved from literature. This is followed by hits profiling against different extended electron distribution (XED) based field templates representing different kinase targets. The second protocol enables cancericidal activity verification by using the algorithm of feature trees (Ftrees) similarity searching against NCI database. Being a proof-of-concept study, this combined procedure was experimentally validated by its utilization in developing a novel series of urea-based derivatives of strong anticancer activity. This new series is based on 3-benzylbenzo[d]thiazol-2(3H)-one scaffold which has interesting chemical feasibility and wide diversification capability. Antineoplastic activity of this series was assayed in vitro against NCI 60 tumor-cell lines showing very strong inhibition of GI50 as low as 0.9 uM. Additionally, its mechanism was unleashed using KINEX™ protein kinase microarray-based small molecule inhibitor profiling platform and cell cycle analysis showing a peculiar selectivity pattern against Zap70, c-src, Mink1, csk and MeKK2 kinases. Interestingly, it showed activity on syk kinase confirming the recent studies finding of the high activity of diphenyl urea containing compounds against this kinase. Allover, the new series, which is

  17. Maize ABP9 enhances tolerance to multiple stresses in transgenic Arabidopsis by modulating ABA signaling and cellular levels of reactive oxygen species.

    PubMed

    Zhang, Xia; Wang, Lei; Meng, Hui; Wen, Hongtao; Fan, Yunliu; Zhao, Jun

    2011-03-01

    The phytohormone abscisic acid (ABA) and reactive oxygen species (ROS) play critical roles in mediating abiotic stress responses in plants. It is well known that ABA is involved in the modulation of ROS levels by regulating ROS-producing and ROS-scavenging genes, but the molecular mechanisms underlying this regulation are poorly understood. Here we show that the expression of maize ABP9 gene, which encodes a bZIP transcription factor capable of binding to the ABRE2 motif in the maize Cat1 promoter, is induced by ABA, H(2)O(2), drought and salt. Constitutive expression of ABP9 in transgenic Arabidopsis leads to remarkably enhanced tolerance to multiple stresses including drought, high salt, freezing temperature and oxidative stresses. ABP9 expressing Arabidopsis plants also exhibit increased sensitivity to exogenously applied ABA during seed germination, root growth and stomatal closure and improved water-conserving capacity. Moreover, constitutive expression of ABP9 causes reduced cellular levels of ROS, alleviated oxidative damage and reduced cell death, accompanied by elevated expression of many stress/ABA responsive genes including those for scavenging and regulating ROS. Taken together, these results suggest that ABP9 may play a pivotal role in plant tolerance to abiotic stresses by fine tuning ABA signaling and control of ROS accumulation. PMID:21327835

  18. Targeting of the Plant Vacuolar Sorting Receptor BP80 Is Dependent on Multiple Sorting Signals in the Cytosolic Tail[W

    PubMed Central

    daSilva, Luis L.P.; Foresti, Ombretta; Denecke, Jurgen

    2006-01-01

    Although signals for vacuolar sorting of soluble proteins are well described, we have yet to learn how the plant vacuolar sorting receptor BP80 reaches its correct destination and recycles. To shed light on receptor targeting, we used an in vivo competition assay in which a truncated receptor (green fluorescent protein-BP80) specifically competes with sorting machinery and causes hypersecretion of BP80-ligands from tobacco (Nicotiana tabacum) leaf protoplasts. We show that both the transmembrane domain and the cytosolic tail of BP80 contain information necessary for efficient progress to the prevacuolar compartment (PVC). Furthermore, the tail must be exposed on the correct membrane surface to compete with sorting machinery. Mutational analysis of conserved residues revealed that multiple sequence motifs are necessary for competition, one of which is a typical Tyr-based motif (YXXΦ). Substitution of Tyr-612 for Ala causes partial retention in the Golgi apparatus, mistargeting to the plasma membrane (PM), and slower progress to the PVC. A role in Golgi-to-PVC transport was confirmed by generating the corresponding mutation on full-length BP80. The mutant receptor was partially mistargeted to the PM and induced the secretion of a coexpressed BP80-ligand. Further mutants indicate that the cytosolic tail is likely to contain other information besides the YXXΦ motif, possibly for endoplasmic reticulum export, endocytosis from the PM, and PVC-to-Golgi recycling. PMID:16714388

  19. 3-Formylchromone inhibits proliferation and induces apoptosis of multiple myeloma cells by abrogating STAT3 signaling through the induction of PIAS3.

    PubMed

    Ko, Jeong-Hyeon; Ho Baek, Seung; Nam, Dongwoo; Chung, Won-Seok; Lee, Seok-Geun; Lee, Junhee; Mo Yang, Woong; Um, Jae-Young; Seok Ahn, Kwang

    2016-10-01

    Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently observed and closely linked with proliferation, survival, metastasis and angiogenesis of various cancer cells, and thus its inhibition can be considered a potential therapeutic strategy. We found that 3-formylchromone (3FC) inhibited both constitutive and inducible STAT3 activation in multiple myeloma (MM) cells. Besides the inhibition of STAT3 phosphorylation, 3FC also abrogated constitutive activity and nuclear translocation of STAT3. This suppression was mediated through the inhibition of phosphorylation of Janus-activated kinase (JAK) 1/2 and Src. Furthermore, 3FC induced the expression of the protein inhibitors of activated STAT3 (PIAS3), and gene silencing of the PIAS3 by small interfering RNA abolished the ability of 3FC to inhibit STAT3 activation, suggesting a critical role for PIAS3 in the action of 3FC. 3FC also downregulated the expression of STAT3-regulated gene products such as Bcl-2, Bcl-xl, Mcl-1, Survivin, inhibitor of apoptosis protein-1 (IAP-1), Cyclin D1, cyclooxygenase-2 (COX-2), and matrix metalloproteinases-9 (MMP-9) in MM cells. This correlated with induction of substantial apoptosis as indicated by an increase in the sub-G1 cell population and caspase-3 induced poly ADP ribose polymerase (PARP) cleavage. Overall, these results suggest that 3FC is a novel blocker of STAT3 activation pathway thus may have a potential in therapy of MM and other cancers. PMID:27324722

  20. Role of IL-33 and ST2 signalling pathway in multiple sclerosis: expression by oligodendrocytes and inhibition of myelination in central nervous system.

    PubMed

    Allan, Debbie; Fairlie-Clarke, Karen J; Elliott, Christina; Schuh, Cornelia; Barnett, Susan C; Lassmann, Hans; Linnington, Christopher; Jiang, Hui-Rong

    2016-01-01

    Recent research findings have provided convincing evidence indicating a role for Interleukin-33 (IL-33) signalling pathway in a number of central nervous system (CNS) diseases including multiple sclerosis (MS) and Alzheimer's disease. However, the exact function of IL-33 molecule within the CNS under normal and pathological conditions is currently unknown. In this study, we have mapped cellular expression of IL-33 and its receptor ST2 by immunohistochemistry in the brain tissues of MS patients and appropriate controls; and investigated the functional significance of these findings in vitro using a myelinating culture system. Our results demonstrate that IL-33 is expressed by neurons, astrocytes and microglia as well as oligodendrocytes, while ST2 is expressed in the lesions by oligodendrocytes and within and around axons. Furthermore, the expression levels and patterns of IL-33 and ST2 in the lesions of acute and chronic MS patient brain samples are enhanced compared with the healthy brain tissues. Finally, our data using rat myelinating co-cultures suggest that IL-33 may play an important role in MS development by inhibiting CNS myelination. PMID:27455844

  1. Real-time extended dynamic range imaging in shearography

    SciTech Connect

    Groves, Roger M.; Pedrini, Giancarlo; Osten, Wolfgang

    2008-10-20

    Extended dynamic range (EDR) imaging is a postprocessing technique commonly associated with photography. Multiple images of a scene are recorded by the camera using different shutter settings and are merged into a single higher dynamic range image. Speckle interferometry and holography techniques require a well-modulated intensity signal to extract the phase information, and of these techniques shearography is most sensitive to different object surface reflectivities as it uses self-referencing from a sheared image. In this paper the authors demonstrate real-time EDR imaging in shearography and present experimental results from a difficult surface reflectivity sample: a wooden panel painting containing gold and dark earth color paint.

  2. Real-time extended dynamic range imaging in shearography.

    PubMed

    Groves, Roger M; Pedrini, Giancarlo; Osten, Wolfgang

    2008-10-20

    Extended dynamic range (EDR) imaging is a postprocessing technique commonly associated with photography. Multiple images of a scene are recorded by the camera using different shutter settings and are merged into a single higher dynamic range image. Speckle interferometry and holography techniques require a well-modulated intensity signal to extract the phase information, and of these techniques shearography is most sensitive to different object surface reflectivities as it uses self-referencing from a sheared image. In this paper the authors demonstrate real-time EDR imaging in shearography and present experimental results from a difficult surface reflectivity sample: a wooden panel painting containing gold and dark earth color paint. PMID:18936802

  3. Acquisition signal transmitter

    NASA Technical Reports Server (NTRS)

    Friedman, Morton L. (Inventor)

    1989-01-01

    An encoded information transmitter which transmits a radio frequency carrier that is amplitude modulated by a constant frequency waveform and thereafter amplitude modulated by a predetermined encoded waveform, the constant frequency waveform modulated carrier constituting an acquisition signal and the encoded waveform modulated carrier constituting an information bearing signal, the acquisition signal providing enhanced signal acquisition and interference rejection favoring the information bearing signal. One specific application for this transmitter is as a distress transmitter where a conventional, legislated audio tone modulated signal is transmitted followed first by the acquisition signal and then the information bearing signal, the information bearing signal being encoded with, among other things, vehicle identification data. The acquistion signal enables a receiver to acquire the information bearing signal where the received signal is low and/or where the received signal has a low signal-to-noise ratio in an environment where there are multiple signals in the same frequency band as the information bearing signal.

  4. Development of a robust flow cytometry-based pharmacodynamic assay to detect phospho-protein signals for phosphatidylinositol 3-kinase inhibitors in multiple myeloma

    PubMed Central

    2013-01-01

    Background The phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in multiple myeloma (MM), a blood cancer associated with uncontrolled proliferation of bone marrow plasma cells. This study aimed to develop a robust clinical pharmacodynamic (PD) assay to measure the on-target PD effects of the selective PI3K inhibitor GDC-0941 in MM patients. Methods We conducted an in vitro drug wash-out study to evaluate the feasibility of biochemical approaches in measuring the phosphorylation of S6 ribosomal protein (S6), one of the commonly used PD markers for PI3K pathway inhibition. We then developed a 7-color phospho-specific flow cytometry assay, or phospho flow assay, to measure the phosphorylation state of intracellular S6 in bone marrow aspirate (BMA) and peripheral blood (PB). Integrated mean fluorescence intensity (iMFI) was used to calculate fold changes of phosphorylation. Assay sensitivity was evaluated by comparing phospho flow with Meso Scale Discovery (MSD) and immunohistochemistry (IHC) assays. Finally, a sample handling method was developed to maintain the integrity of phospho signal during sample shipping and storage to ensure clinical application. Results The phospho flow assay provided single-cell PD monitoring of S6 phosphorylation in tumor and surrogate cells using fixed BMA and PB, assessing pathway modulation in response to GDC-0941 with sensitivity similar to that of MSD assay. The one-shot sample fixation and handling protocol herein demonstrated exceptional preservation of protein phosphorylation. In contrast, the IHC assay was less sensitive in terms of signal quantification while the biochemical approach (MSD) was less suitable to assess PD activities due to the undesirable impact associated with cell isolation on the protein phosphorylation in tumor cells. Conclusions We developed a robust PD biomarker assay for the clinical evaluation of PI3K inhibitors in MM, allowing one to decipher the PD response in a relevant cell

  5. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    SciTech Connect

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

    2014-12-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  6. Methylation and mRNA expression levels of P15, death-associated protein kinase, and suppressor of cytokine signaling-1 genes in multiple myeloma

    PubMed Central

    Liu, Lin; Tan, Lin; He, Zhenxin

    2016-01-01

    Objective(s): The aim of this study was to investigate the methylation status and mRNA expression levels of P15, death-associated protein kinase (DAPK), and suppressor of cytokine signaling-1 (SOCS1) genes in multiple myeloma (MM). Materials and Methods: The bone marrow samples of 54 MM patients were collected and the methylation status of the P15, DAPK, and SOCS1 gene promoter regions was determined by methylation-specific polymerase chain reaction. Automated sequencing technology was used to sequence the amplified products in order to analyze the base methylation sites. mRNA expression levels were determined using real-time fluorescent quantitative polymerase chain reaction. Results: Among the 54 MM patients, the positive methylation rates of the P15, DAPK, and SOCS1 genes were 27.78%, 18.52%, and 16.67%, respectively. The methylation results were confirmed by sequencing. The positive methylation rates of the P15, DAPK, and SOCS1 genes showed no correlation with patient gender, age, typing, staging, and grouping (P>0.05). There was no significant difference in the mRNA expression levels of the P15, DAPK, and SOCS1 genes between the MM patient group and the control group (P>0.05). Conclusions: Aberrant methylation of the P15, DAPK, and SOCS1 genes exists in MM, and these genes may play certain roles in pathogenesis of MM. There was no significant difference in mRNA expression levels between the methylated group and the non-methylated group, suggesting that these genes are regulated by other mechanisms during their transcription.

  7. Secretome Analysis Identifies Novel Signal Peptide Peptidase-Like 3 (SPPL3) Substrates and Reveals a Role of SPPL3 in Multiple Golgi Glycosylation Pathways*

    PubMed Central

    Kuhn, Peer-Hendrik; Voss, Matthias; Haug-Kröper, Martina; Schröder, Bernd; Schepers, Ute; Bräse, Stefan; Haass, Christian; Lichtenthaler, Stefan F.; Fluhrer, Regina

    2015-01-01

    Signal peptide peptidase-like 3 (SPPL3) is a Golgi-resident intramembrane-cleaving protease that is highly conserved among multicellular eukaryotes pointing to pivotal physiological functions in the Golgi network which are only beginning to emerge. Recently, SPPL3 was shown to control protein N-glycosylation, when the key branching enzyme N-acetylglucosaminyltransferase V (GnT-V) and other medial/trans Golgi glycosyltransferases were identified as first physiological SPPL3 substrates. SPPL3-mediated endoproteolysis releases the catalytic ectodomains of these enzymes from their type II membrane anchors. Protein glycosylation is a multistep process involving numerous type II membrane-bound enzymes, but it remains unclear whether only few of them are SPPL3 substrates or whether SPPL3 cleaves many of them and thereby controls protein glycosylation at multiple levels. Therefore, to systematically identify SPPL3 substrates we used Sppl3-deficient and SPPL3-overexpression cell culture models and analyzed them for changes in secreted membrane protein ectodomains using the proteomics “secretome protein enrichment with click sugars (SPECS)” method. SPECS analysis identified numerous additional new SPPL3 candidate glycoprotein substrates, several of which were biochemically validated as SPPL3 substrates. All novel SPPL3 substrates adopt a type II topology. The majority localizes to the Golgi network and is implicated in Golgi functions. Importantly, most of the novel SPPL3 substrates catalyze the modification of N-linked glycans. Others contribute to O-glycan and in particular glycosaminoglycan biosynthesis, suggesting that SPPL3 function is not restricted to N-glycosylation, but also functions in other forms of protein glycosylation. Hence, SPPL3 emerges as a crucial player of Golgi function and the newly identified SPPL3 substrates will be instrumental to investigate the molecular mechanisms underlying the physiological function of SPPL3 in the Golgi network and in vivo

  8. ERK and β-arrestin interaction: a converging-point of signaling pathways for multiple types of cell-surface receptors

    PubMed Central

    Eishingdrelo, Haifeng; Sun, Wei; Li, Hua; Wang, Li; Eishingdrelo, Alex; Dai, Sheng; McKew, John C.; Zheng, Wei

    2016-01-01

    β-arrestin, a signal adaptor protein, mediates intracellular signal transductions through protein-protein interactions by bringing two or more proteins in proximity. Extracellular signal-regulated kinase (ERK), a protein kinase in the family of mitogen-activated protein kinases (MAPKs), is involved in various receptor signal pathways. Interaction of ERK with β-arrestin or formation of ERK/β-arrestin signal complex occurs in response to activation of a variety of cell-surface receptors. The ERK/β-arrestin signal complex may be a common transducer to converge a variety of extracellular stimuli to similar downstream intracellular signaling pathways. By using a cell based protein-protein interaction LinkLight assay technology, we demonstrate a direct interaction between ERK and β-arrestin in respond to extracellular stimuli, which can be sensitively and quantitatively monitored. Activations of G-protein coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and cytokine receptors promote formation of the ERK/β-arrestin signal complex. Our data indicate that the ERK/β-arrestin signal complex is a common transducer participated in a variety of receptor signaling pathways. Furthermore, we demonstrate that receptor antagonists or kinase inhibitors can block the agonist induced ERK and β-arrestin interaction. Thus, the ERK/β-arrestin interaction assay is useful for screening of new receptor modulators. PMID:25361946

  9. A chaos secure communication scheme based on multiplication modulation

    NASA Astrophysics Data System (ADS)

    Fallahi, Kia; Leung, Henry

    2010-02-01

    A secure spread spectrum communication scheme using multiplication modulation is proposed. The proposed system multiplies the message by chaotic signal. The scheme does not need to know the initial condition of the chaotic signals and the receiver is based on an extended Kalman filter (EKF). This signal encryption scheme lends itself to cheap implementation and can therefore be used effectively for ensuring security and privacy in commercial consumer electronics products. To illustrate the effectiveness of the proposed scheme, a numerical example based on Genesio-Tesi system and also Chen dynamical system is presented and the results are compared.

  10. Combined inadequacies of multiple B-vitamins amplify colonic Wnt-signaling and promote intestinal tumorigenesis in BAT-LacZxApc1368N mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Wnt pathway is a pivotal signaling cascade in colorectal carcinogenesis. The purpose of this work is to determine whether depletion of folate and other metabolically-related one-carbon vitamins induces in vivo activation of intestinal Wnt signaling, and whether this occurs in parallel with incre...

  11. Combined inadequacies of multiple B-vitamins amplify colonic Wnt-signaling and promote intestinal tumorigenesis in BAT-LacZ X Apc1638N mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Wnt pathway is a pivotal signaling cascade in colorectal carcinogenesis. The purpose of this work is to determine whether depletion of folate and other metabolically-related one-carbon vitamins induces in vivo activation of intestinal Wnt signaling, and whether this occurs in parallel with incre...

  12. The X-33 Extended Flight Test Range

    NASA Technical Reports Server (NTRS)

    Mackall, Dale A.; Sakahara, Robert; Kremer, Steven E.

    1998-01-01

    Development of an extended test range, with range instrumentation providing continuous vehicle communications, is required to flight-test the X-33, a scaled version of a reusable launch vehicle. The extended test range provides vehicle communications coverage from California to landing at Montana or Utah. This paper provides an overview of the approaches used to meet X-33 program requirements, including using multiple ground stations, and methods to reduce problems caused by reentry plasma radio frequency blackout. The advances used to develop the extended test range show other hypersonic and access-to-space programs can benefit from the development of the extended test range.

  13. The Multiple DSF-family QS Signals are Synthesized from Carbohydrate and Branched-chain Amino Acids via the FAS Elongation Cycle

    PubMed Central

    Zhou, Lian; Yu, Yonghong; Chen, Xiping; Diab, Abdelgader Abdeen; Ruan, Lifang; He, Jin; Wang, Haihong; He, Ya-Wen

    2015-01-01

    Members of the diffusible signal factor (DSF) family are a novel class of quorum sensing (QS) signals in diverse Gram-negative bacteria. Although previous studies have identified RpfF as a key enzyme for the biosynthesis of DSF family signals, many questions in their biosynthesis remain to be addressed. In this study with the phytopathogen Xanthomonas campestris pv. campestris (Xcc), we show that Xcc produces four DSF-family signals (DSF, BDSF, CDSF and IDSF) during cell culture, and that IDSF is a new functional signal characterized as cis-10-methyl-2-dodecenoic acid. Using a range of defined media, we further demonstrate that Xcc mainly produces BDSF in the presence of carbohydrates; leucine and valine are the primary precursor for DSF biosynthesis; isoleucine is the primary precursor for IDSF biosynthesis. Furthermore, our biochemical analyses show that the key DSF synthase RpfF has both thioesterase and dehydratase activities, and uses 3-hydroxydedecanoyl-ACP as a substrate to produce BDSF. Finally, our results show that the classic fatty acid synthesis elongation cycle is required for the biosynthesis of DSF-family signals. Taken all together, these findings establish a general biosynthetic pathway for the DSF-family quorum sensing signals. PMID:26289160

  14. Extended-Synaptotagmins (E-Syts); the extended story.

    PubMed

    Herdman, Chelsea; Moss, Tom

    2016-05-01

    The Extended-Synaptotagmin (E-Syt) membrane proteins were only recently discovered, but have already been implicated in a range of interrelated cellular functions, including calcium and receptor signaling, and membrane lipid transport. However, despite their evolutionary conservation and detailed studies of their molecular actions, we still have little idea of how and when these proteins are required in cellular and organism physiology. Here we review our present understanding of the E-Syts and discuss the molecular functions and in vivo requirements for these proteins. PMID:26926095

  15. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells.

    PubMed

    Sutherland, Claire L; Chalupny, N Jan; Schooley, Kenneth; VandenBos, Tim; Kubin, Marek; Cosman, David

    2002-01-15

    The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules that were identified as targets of the human CMV glycoprotein, UL16. We have previously shown that ULBP expression renders a relatively resistant target cell sensitive to NK cytotoxicity, presumably by engaging NKG2D, an activating receptor expressed by NK and other immune effector cells. In this study we show that NKG2D is the ULBP counterstructure on primary NK cells and that its expression is up-regulated by IL-15 stimulation. Soluble forms of ULBPs induce marked protein tyrosine phosphorylation, and activation of the Janus kinase 2, STAT5, extracellular signal-regulated kinase, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signal transduction pathways. ULBP-induced activation of Akt and extracellular signal-regulated kinase and ULBP-induced IFN-gamma production are blocked by inhibitors of PI 3-kinase, consistent with the known binding of PI 3-kinase to DAP10, the membrane-bound signal-transducing subunit of the NKG2D receptor. While all three ULBPs activate the same signaling pathways, ULBP3 was found to bind weakly and to induce the weakest signal. In summary, we have shown that NKG2D is the ULBP counterstructure on primary NK cells and for the first time have identified signaling pathways that are activated by NKG2D ligands. These results increase our understanding of the mechanisms by which NKG2D activates immune effector cells and may have implications for immune surveillance against pathogens and tumors. PMID:11777960

  16. Using an Extended Dynamic Drag-and-Drop Assistive Program to Assist People with Multiple Disabilities and Minimal Motor Control to Improve Computer Drag-and-Drop Ability through a Mouse Wheel

    ERIC Educational Resources Information Center

    Shih, Ching-Hsiang

    2012-01-01

    Software technology is adopted by the current research to improve the Drag-and-Drop abilities of two people with multiple disabilities and minimal motor control. This goal was realized through a Dynamic Drag-and-Drop Assistive Program (DDnDAP) in which the complex dragging process is replaced by simply poking the mouse wheel and clicking. However,…

  17. Signal-to-noise ratio requirements for detection of multiple pulses subject to partially correlated fading with chi-squared statistics of various degrees of freedom

    NASA Astrophysics Data System (ADS)

    Nuttall, Albert H.; Eby, Edward S.

    1986-06-01

    The transmitted signal in a fading medium is composed of several pulses separated in time so as to achieve diversity and thereby combat deep fades and loss of signal. Receiver processing consists of matched filtering of each of the pulses, followed by summation of the squared envelopes of all the filter outputs. In addition to additive Gaussian background noise, the signal is subject to slow medium fading which has