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Sample records for extended multiplicative signal

  1. Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus.

    PubMed

    Demirci, F Yesim; Wang, Xingbin; Morris, David L; Feingold, Eleanor; Bernatsky, Sasha; Pineau, Christian; Clarke, Ann; Ramsey-Goldman, Rosalind; Manzi, Susan; Vyse, Timothy J; Kamboh, M I

    2017-06-01

    A major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 - 4.5  Mb) located at 8p23. Initially implicated genes included FAM167A-BLK and XKR6, of which BLK received major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported. In this case -control study, we further investigated the 'extended' 8p23 locus (~ 4  Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~ 1200  subjects) and a replication data set (> 10 000  subjects) comprising European-descent individuals. Meta-analysis of 8p23 SNPs, with p < 0.05 in both data sets, identified 51 genome-wide significant SNPs (p < 5.0 × 10(-8)). While most of these SNPs were related to previously implicated signals (XKR6-FAM167A-BLK subregion), our results also revealed two 'new' SLE signals, including SGK223-CLDN23-MFHAS1 (6.06 × 10(-9) ≤ meta p ≤ 4.88 × 10(-8)) and CTSB (meta p = 4.87 × 10(-8)) subregions that are located > 2 Mb upstream and ~ 0.3  Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putative cis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background. Our results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No

  2. Analyzing multiple nonlinear time series with extended Granger causality

    NASA Astrophysics Data System (ADS)

    Chen, Yonghong; Rangarajan, Govindan; Feng, Jianfeng; Ding, Mingzhou

    2004-04-01

    Identifying causal relations among simultaneously acquired signals is an important problem in multivariate time series analysis. For linear stochastic systems Granger proposed a simple procedure called the Granger causality to detect such relations. In this work we consider nonlinear extensions of Granger's idea and refer to the result as extended Granger causality. A simple approach implementing the extended Granger causality is presented and applied to multiple chaotic time series and other types of nonlinear signals. In addition, for situations with three or more time series we propose a conditional extended Granger causality measure that enables us to determine whether the causal relation between two signals is direct or mediated by another process.

  3. 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.

  4. 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…

  5. Extending a clinical repository to include multiple sites.

    PubMed Central

    Marrs, K. A.; Kahn, M. G.

    1995-01-01

    With the consolidation of health care organizations and services, a clinical repository comprising data from a single site is no longer sufficient. Individual patient data are now spread across multiple sites comprising a single enterprise. Users require an integrated view, or at least a common view, of these clinical data across multiple sites. Many issues arise when one tries to merge data from multiple, distinct organizations into an existing schema. We have addressed these issues while extending our clinical repository for Barnes Hospital with data from Jewish Hospital, both of which are members of the recently formed BJC Health System. We describe the architecture of our existing repository, approaches and issues in extending this repository to include multiple sites, and the specific issues we addressed in our system. PMID:8563308

  6. 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…

  7. Multiple emitter location and signal parameter estimation

    NASA Astrophysics Data System (ADS)

    Schmidt, R. O.

    1986-03-01

    Multiple signal classification (MUSIC) techniques involved in determining the parameters of multiple wavefronts arriving at an antenna array are discussed. A MUSIC algorithm is described, which provides asymptotically unbiased estimates of (1) the number of signals, (2) directions of arrival (or emitter locations), (3) strengths and cross correlations among the incident waveforms, and (4) the strength of noise/interference. The example of the use of the algorithm as a multiple frequency estimator operating on time series is examined. Comparisons of this method with methods based on maximum likelihood and maximum entropy, as well as conventional beamforming, are presented.

  8. 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.

  9. Random neural networks with multiple classes of signals.

    PubMed

    Gelenbe, E; Fourneau, J M

    1999-05-15

    By extending the pulsed recurrent random neural network (RNN) discussed in Gelenbe (1989, 1990, 1991), we propose a recurrent random neural network model in which each neuron processes several distinctly characterized streams of "signals" or data. The idea that neurons may be able to distinguish between the pulses they receive and use them in a distinct manner is biologically plausible. In engineering applications, the need to process different streams of information simultaneously is commonplace (e.g., in image processing, sensor fusion, or parallel processing systems). In the model we propose, each distinct stream is a class of signals in the form of spikes. Signals may arrive to a neuron from either the outside world (exogenous signals) or other neurons (endogenous signals). As a function of the signals it has received, a neuron can fire and then send signals of some class to another neuron or to the outside world. We show that the multiple signal class random model with exponential interfiring times, Poisson external signal arrivals, and Markovian signal movements between neurons has product form; this implies that the distribution of its state (i.e., the probability that each neuron of the network is excited) can be computed simply from the solution of a system of 2Cn simultaneous nonlinear equations where C is the number of signal classes and n is the number of neurons. Here we derive the stationary solution for the multiple class model and establish necessary and sufficient conditions for the existence of the stationary solution. The recurrent random neural network model with multiple classes has already been successfully applied to image texture generation (Atalay & Gelenbe, 1992), where multiple signal classes are used to model different colors in the image.

  10. 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. © 2015 John Wiley & Sons Ltd/CNRS.

  11. 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

  12. 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.

  13. Encoding olfactory signals via multiple chemosensory systems.

    PubMed

    Ma, Minghong

    2007-01-01

    Most animals have evolved multiple olfactory systems to detect general odors as well as social cues. The sophistication and interaction of these systems permit precise detection of food, danger, and mates, all crucial elements for survival. In most mammals, the nose contains two well described chemosensory apparatuses (the main olfactory epithelium and the vomeronasal organ), each of which comprises several subtypes of sensory neurons expressing distinct receptors and signal transduction machineries. In many species (e.g., rodents), the nasal cavity also includes two spatially segregated clusters of neurons forming the septal organ of Masera and the Grueneberg ganglion. Results of recent studies suggest that these chemosensory systems perceive diverse but overlapping olfactory cues and that some neurons may even detect the pressure changes carried by the airflow. This review provides an update on how chemosensory neurons transduce chemical (and possibly mechanical) stimuli into electrical signals, and what information each system brings into the brain. Future investigation will focus on the specific ligands that each system detects with a behavioral context and the processing networks that each system involves in the brain. Such studies will lead to a better understanding of how the multiple olfactory systems, acting in concert, offer a complete representation of the chemical world.

  14. A MUSIC (multiple signal classification) algorithm for specifying azimuth, elevation, and range of multiple sources

    NASA Astrophysics Data System (ADS)

    Zito, Richard R.

    2006-05-01

    The MUSIC (Multiple Signal Classification) algorithm uses the phase difference at different antenna elements of a receiving antenna array to determine the azimuth and elevation angles of a source. This algorithm can be extended to determine the range of multiple sources as well as their azimuth and elevation angles. In this report a generalized MUSIC algorithm is presented that accomplishes this task when the receiving antenna consists of a planar, rectangular, array of receiving elements. Greater range accuracies can be achieved by increasing the signal to noise ratio, increasing the number of PRIs per CPI, and searching for a solution over range space with a finer mesh. The mesh employed in this study had a range gate size that was 10% of the range space searched. An increase in range accuracy gained by the latter two methods comes at the price of increased processing time.

  15. 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.

  16. Extending Data Worth Analyses to Select Multiple Observations Targeting Multiple Forecasts.

    PubMed

    Vilhelmsen, Troels N; Ferré, Ty P A

    2017-09-15

    Hydrological models are often set up to provide specific forecasts of interest. Owing to the inherent uncertainty in data used to derive model structure and used to constrain parameter variations, the model forecasts will be uncertain. Additional data collection is often performed to minimize this forecast uncertainty. Given our common financial restrictions, it is critical that we identify data with maximal information content with respect to forecast of interest. In practice, this often devolves to qualitative decisions based on expert opinion. However, there is no assurance that this will lead to optimal design, especially for complex hydrogeological problems. Specifically, these complexities include considerations of multiple forecasts, shared information among potential observations, information content of existing data, and the assumptions and simplifications underlying model construction. In the present study, we extend previous data worth analyses to include: simultaneous selection of multiple new measurements and consideration of multiple forecasts of interest. We show how the suggested approach can be used to optimize data collection. This can be used in a manner that suggests specific measurement sets or that produces probability maps indicating areas likely to be informative for specific forecasts. Moreover, we provide examples documenting that sequential measurement election approaches often lead to suboptimal designs and that estimates of data covariance should be included when selecting future measurement sets. © 2017, National Ground Water Association.

  17. Angle-resolved photoemission extended fine structure: Multiple layers of emitters and multiple initial states

    SciTech Connect

    Huff, W.R.A.; Kellar, S.A.; Moler, E.J. |; Chen, Y.; Wu, H.; Shirley, D.A.; Hussain, Z.

    1995-08-01

    Recently, angle-resolved photoemission extended fine structure (ARPEFS) has been applied to experimental systems involving multiple layers of emitters and non-s core-level photoemission in an effort to broaden the utility of the technique. Most of the previous systems have been comprised of atomic or molecular overlayers adsorbed onto a single-crystal, metal surface and the photoemission data were taken from an s atomic core-level in the overlayer. For such a system, the acquired ARPEFS data is dominated by the p{sub o} final state wave backscattering from the substrate atoms and is well understood. In this study, we investigate ARPEFS as a surface-region structure determination technique when applied to experimental systems comprised of multiple layers of photoemitters and arbitrary initial state core-level photoemission. Understanding the data acquired from multiple layers of photoemitters is useful for studying multilayer interfaces, ''buried'' surfaces, and clean crystals in ultra- high vacuum. The ability to apply ARPEFS to arbitrary initial state core-level photoemission obviously opens up many systems to analysis. Efforts have been ongoing to understand such data in depth. We present clean Cu(111) 3s, 3p, and 3d core-level, normal photoemission data taken on a high resolution soft x-ray beamline 9.3.2 at the Advanced Light Source in Berkeley, California and clean Ni(111) 3p normal photoemission data taken at the National Synchrotron Light Source in Upton, New York, USA.

  18. 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.

  19. Teaching Math: Extending the Meaning of Multiplication and Division.

    ERIC Educational Resources Information Center

    May, Lola J.

    1994-01-01

    Describes three approaches teachers can use to help students understand multiplication and division: calculator explorations, problem solving, and discussion topics. Specific examples are provided for primary and upper grades. (MDM)

  20. Numerical simulation of radio signal from extended air showers

    NASA Astrophysics Data System (ADS)

    Liu, Wei; Chen, Xuelei

    2015-05-01

    The burst of radio emission by an extensive air shower provides a promising alternative for detecting ultra-high energy cosmic rays. We have developed an independent numerical program to simulate these radio signals. Our code is based on a microscopic treatment, with both the geosynchrotron radiation and charge included. Here we give the first presentation of our basic program and its results. When the time-domain signals for different polarizations are computed, we find that the pulses take on a bipolar pattern and the spectrum is suppressed towards the lower frequencies. We investigate how showers at different heights in the atmosphere contribute to the total signal, and examine the signal strength and distribution at sites with different elevations. We also study the signal from showers with different inclination angles and azimuth directions. In all these cases we find the charge excess effect is important. Supported by the National Natural Science Foundation of China.

  1. Signal processor having multiple distributed data buffers

    NASA Astrophysics Data System (ADS)

    Andersen, Victor A.

    1994-03-01

    A hydrophone analog signal data acquisition, A/D conversion and data transmission system includes a first-stage signal processing subsystem which provides digital representations of the hydrophone analog signal, which in turn are signal processed for transmission in the form of data packets by a second stage signal processing subsystem. Subsystem 40 includes a plurality of Data Multiplexer/FIFO units, including corresponding selectively acting data unit accumulators, each accumulator having a plurality of inputs coupled to output channels of the first-stage signal processing subsystem for receiving digital representations of hydrophone analog signals. Each data unit accumulator includes a first buffer for storing information that includes a digital representation of the analog hydrophone signal, an identification of a hydrophone that generated the acoustic information, and a time that the acoustic information is received from the hydrophone.

  2. Filtering skill for turbulent signals for a suite of nonlinear and linear extended Kalman filters

    NASA Astrophysics Data System (ADS)

    Branicki, M.; Gershgorin, B.; Majda, A. J.

    2012-02-01

    The filtering skill for turbulent signals from nature is often limited by errors due to utilizing an imperfect forecast model. In particular, real-time filtering and prediction when very limited or no a posteriori analysis is possible (e.g. spread of pollutants, storm surges, tsunami detection, etc.) introduces a number of additional challenges to the problem. Here, a suite of filters implementing stochastic parameter estimation for mitigating model error through additive and multiplicative bias correction is examined on a nonlinear, exactly solvable, stochastic test model mimicking turbulent signals in regimes ranging from configurations with strongly intermittent, transient instabilities associated with positive finite-time Lyapunov exponents to laminar behavior. Stochastic Parameterization Extended Kalman Filter (SPEKF), used as a benchmark here, involves exact formulas for propagating the mean and covariance of the augmented forecast model including the unresolved parameters. The remaining filters use the same nonlinear forecast model but they introduce model error through different moment closure approximations and/or linear tangent approximation used for computing the second-order statistics of the augmented stochastic forecast model. A comprehensive study of filter performance is carried out in the presence of various moment closure errors which are enhanced by additional model errors due to incorrect parameters inducing additive and multiplicative stochastic biases. The estimation skill of the unresolved stochastic parameters is also discussed and it is shown that the linear tangent filter, despite its popularity, is completely unreliable in many turbulent regimes for both parameter estimation and filtering; moreover, regimes of filter divergence for the linear tangent filter are identified. The results presented here provide useful guidelines for filtering turbulent, high-dimensional, spatially extended systems with more general model errors, as well as

  3. Extending the NegEx Lexicon for Multiple Languages

    PubMed Central

    Chapman, Wendy W.; Hilert, Dieter; Velupillai, Sumithra; Kvist, Maria; Skeppstedt, Maria; Chapman, Brian E.; Conway, Michael; Tharp, Melissa; Mowery, Danielle L.; Deleger, Louise

    2014-01-01

    We translated an existing English negation lexicon (NegEx) to Swedish, French, and German and compared the lexicon on corpora from each language. We observed Zipf’s law for all languages, i.e., a few phrases occur a large number of times, and a large number of phrases occur fewer times. Negation triggers “no” and “not” were common for all languages; however, other triggers varied considerably. The lexicon is available in OWL and RDF format and can be extended to other languages. We discuss the challenges in translating negation triggers to other languages and issues in representing multilingual lexical knowledge. PMID:23920642

  4. 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.

  5. 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.

  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.

  7. Multiple Source DF (Direction Finding) Signal Processing: An Experimental System,

    DTIC Science & Technology

    The MUltiple SIgnal Characterization ( MUSIC ) algorithm is an implementation of the Signal Subspace Approach to provide parameter estimates of...the signal subspace (obtained from the received data) and the array manifold (obtained via array calibration). The MUSIC algorithm has been

  8. 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.

  9. Adaptive Arrays for Multiple Simultaneous Desired Signals.

    DTIC Science & Technology

    1983-08-01

    weights [Equation (4)]. Using Equation (6), the inverse of the covariance matrix is given by 5 4 i *ŕm * T ". -1 1 I d Z dij (7) L -I + UT U* 4 di x di...Equations (11) and (12) p k = A k Ik d (14) dk aki*~~* ( ~ dk LJk Udk) and 1 t IjI II di l() 27 x = (1 + t UT U*) Thus, the output SNR of the kth desired...signals are assumed to be of the same frequency. There is no jammer 9 0 dB SIGNAL 10 dB SIGNAL 90 % 90 180 Fiur .dptdpatrnofalier rayo tn strpc lmet

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

    PubMed

    Davière, Jean-Michel; Achard, Patrick

    2016-01-04

    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.

  11. 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.

  12. Climate Signal Detection from Multiple Satellite Measurements

    NASA Astrophysics Data System (ADS)

    Jiang, Y.; Aumann, H.; Yung, Y. L.; Li, K.

    2009-12-01

    Clouds play an important role in the climate change. Many satellites have been observing the clouds over decades, but have not detected any trends in cloud cover (Wylie, DP, 2005). The Principle Component Analysis (PCA) provides a very sensitive tool to the analysis of the cloud signals from the enormous amount of data sets. In this study, we have analyzed measurements from the IRIS spectrometer (Prabhakara, 1988), AIRS (Chahine, 2006) and IASI infrared interferometer (Chalon, 2001). IRIS flew on Nimbus 4 satellite between April 1970 and January 1971, AIRS is on Aqua satellite since May 2, 2002, and IASI was launched on METOP-A satellite in 2006. The changes of the PCA eigenfunctions and eigenvalues from 1970 and 2008 may indicate the climate change due to the cloud variations.

  13. Multiple velocity encoding in the phase of an MRI signal

    NASA Astrophysics Data System (ADS)

    Benitez-Read, E. E.

    2017-01-01

    The measurement of fluid velocity by encoding it in the phase of a magnetic resonance imaging (MRI) signal could allow the discrimination of the stationary spins signals from those of moving spins. This results in a wide variety of applications i.e. in medicine, in order to obtain more than angiograms, blood velocity images of veins, arteries and other vessels without having static tissue perturbing the signal of fluid in motion. The work presented in this paper is a theoretical analysis of some novel methods for multiple fluid velocity encoding in the phase of an MRI signal. These methods are based on a tripolar gradient (TPG) and can be an alternative to the conventional methods based on a bipolar gradient (BPG) and could be more suitable for multiple velocity encoding in the phase of an MRI signal.

  14. 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

  15. Extended-release dalfampridine in the management of multiple-sclerosis-related walking impairment.

    PubMed

    Hersh, Carrie; Rae-Grant, Alex

    2012-07-01

    Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that causes neurological impairment in young adults. As part of the disease, ambulation remains one of the most disabling features of multiple sclerosis. Extended-release dalfampridine is a long-acting form of 4-aminopyridine that has been shown in two phase III trials to increase ambulation speed in a subset of patients with multiple sclerosis (timed walk responders). The primary endpoint of these studies was 'responder status', analyzing difference in the proportion of timed walk responders between extended-release dalfampridine and placebo groups. Extended-release dalfampridine exerts its effects by inhibiting voltage-activated K(+) channels and has been previously demonstrated to improve action potential propagation in demyelinated nerve fibers in vitro. Side effects of extended-release dalfampridine include increased urinary tract infections, insomnia, headache, asthenia, dizziness, back pain, and paresthesias. Rare seizure events are also reported on the approved dose of 10 mg every 12 h. In this review we will summarize the results of key phase II and phase III trials of extended-release dalfampridine, its safety, and potential use in patients with multiple sclerosis.

  16. Systematic quantitative characterization of cellular responses induced by multiple signals

    PubMed Central

    2011-01-01

    Background Cells constantly sense many internal and environmental signals and respond through their complex signaling network, leading to particular biological outcomes. However, a systematic characterization and optimization of multi-signal responses remains a pressing challenge to traditional experimental approaches due to the arising complexity associated with the increasing number of signals and their intensities. Results We established and validated a data-driven mathematical approach to systematically characterize signal-response relationships. Our results demonstrate how mathematical learning algorithms can enable systematic characterization of multi-signal induced biological activities. The proposed approach enables identification of input combinations that can result in desired biological responses. In retrospect, the results show that, unlike a single drug, a properly chosen combination of drugs can lead to a significant difference in the responses of different cell types, increasing the differential targeting of certain combinations. The successful validation of identified combinations demonstrates the power of this approach. Moreover, the approach enables examining the efficacy of all lower order mixtures of the tested signals. The approach also enables identification of system-level signaling interactions between the applied signals. Many of the signaling interactions identified were consistent with the literature, and other unknown interactions emerged. Conclusions This approach can facilitate development of systems biology and optimal drug combination therapies for cancer and other diseases and for understanding key interactions within the cellular network upon treatment with multiple signals. PMID:21624115

  17. Extraction of fetal ECG signal by an improved method using extended Kalman smoother framework from single channel abdominal ECG signal.

    PubMed

    Panigrahy, D; Sahu, P K

    2017-02-16

    This paper proposes a five-stage based methodology to extract the fetal electrocardiogram (FECG) from the single channel abdominal ECG using differential evolution (DE) algorithm, extended Kalman smoother (EKS) and adaptive neuro fuzzy inference system (ANFIS) framework. The heart rate of the fetus can easily be detected after estimation of the fetal ECG signal. The abdominal ECG signal contains fetal ECG signal, maternal ECG component, and noise. To estimate the fetal ECG signal from the abdominal ECG signal, removal of the noise and the maternal ECG component presented in it is necessary. The pre-processing stage is used to remove the noise from the abdominal ECG signal. The EKS framework is used to estimate the maternal ECG signal from the abdominal ECG signal. The optimized parameters of the maternal ECG components are required to develop the state and measurement equation of the EKS framework. These optimized maternal ECG parameters are selected by the differential evolution algorithm. The relationship between the maternal ECG signal and the available maternal ECG component in the abdominal ECG signal is nonlinear. To estimate the actual maternal ECG component present in the abdominal ECG signal and also to recognize this nonlinear relationship the ANFIS is used. Inputs to the ANFIS framework are the output of EKS and the pre-processed abdominal ECG signal. The fetal ECG signal is computed by subtracting the output of ANFIS from the pre-processed abdominal ECG signal. Non-invasive fetal ECG database and set A of 2013 physionet/computing in cardiology challenge database (PCDB) are used for validation of the proposed methodology. The proposed methodology shows a sensitivity of 94.21%, accuracy of 90.66%, and positive predictive value of 96.05% from the non-invasive fetal ECG database. The proposed methodology also shows a sensitivity of 91.47%, accuracy of 84.89%, and positive predictive value of 92.18% from the set A of PCDB.

  18. Automatic Modulation Recognition of Mixed Multiple Source Signals

    NASA Astrophysics Data System (ADS)

    Tan, Xiaobo; Zhang, Hang; Lu, Wei

    2011-03-01

    In this paper, automatic modulation recognition of mixed multiple source signals is discussed. At first, the algorithm of equivariant adaptive source separation (EASI) is employed to separate signals from their mixed waveforms. Four features of five modulated signals are extracted and then two classifiers, decision tree and neutral network are used to complete modulation classification. The effects of symbol shaping on features extraction and validation of source separation are also investigated. Simulations show that the average probability of correct recognition of the classifiers is very depended on the performance of source separation. When SNR (Signal to Noise Ratio) is larger than 15 dB and the number of mixed source signals is less than 4, the average probability of correct recognition is above 0.6 for decision tree classifier and 0.63 for neutral network classifier. Simulations and discussions about automatic modulation recognition for source signals surfed Rayleigh flat fading are also presented.

  19. Impact and point prediction using a neural extended Kalman filter with multiple sensors

    NASA Astrophysics Data System (ADS)

    Stubberud, Stephen C.; Kramer, Kathleen A.

    2007-04-01

    The neural extended Kalman filter is an adaptive estimation technique that has been shown to learn on-line the maneuver model of the trajectory of a target. This improved motion model can be used to better predict the location of a target at given point in time, especially when the target, such as a mortar shell, has limited maneuvering capabilities. In this paper, the neural extended Kalman filter is used to predict, with multiple-sensor-systems provided measurement reports, impact point and impact time of a ballistic-like projectile when the drag on the shell was not accurately modeled in the motion model. In previous work, the neural extended Kalman filter was shown to work well with a single sensor with a uniform sample rate. Multiple sensors can incorporate two major differences into the problem. The first difference is that of the multiple aspect angles and uncertainty that are used in the model adaptation. The second difference is that of a non-uniform update rate of the measurements to the tracking system. While most tracking systems can easily handle this difference, the adaptation of the neural network training parameters can be deleteriously affected by these variations. The first of these two differences, potential concerns to the neural extended Kalman filter's implementation, is investigated in this effort. In this effort, performance of this adaptive and predictive scheme with multiple sensors in a three dimensional space is shown to provide a quality impact estimate.

  20. Extended H2 synthesis for multiple degree-of-freedom controllers

    NASA Astrophysics Data System (ADS)

    Hampton, R. David; Knospe, Carl R.

    1992-05-01

    H2 synthesis techniques are developed for a general multiple-input-multiple-output (MIMO) system subject to both stochastic and deterministic disturbances. The H2 synthesis is extended by incorporation of anticipated disturbances power-spectral-density information into the controller-design process, as well as by frequency weightings of generalized coordinates and control inputs. The methodology is applied to a simple single-input-multiple-output (SIMO) problem, analogous to the type of vibration isolation problem anticipated in microgravity research experiments.

  1. Extended H2 synthesis for multiple degree-of-freedom controllers

    NASA Technical Reports Server (NTRS)

    Hampton, R. David; Knospe, Carl R.

    1992-01-01

    H2 synthesis techniques are developed for a general multiple-input-multiple-output (MIMO) system subject to both stochastic and deterministic disturbances. The H2 synthesis is extended by incorporation of anticipated disturbances power-spectral-density information into the controller-design process, as well as by frequency weightings of generalized coordinates and control inputs. The methodology is applied to a simple single-input-multiple-output (SIMO) problem, analogous to the type of vibration isolation problem anticipated in microgravity research experiments.

  2. Extended Kalman smoother with differential evolution technique for denoising of ECG signal.

    PubMed

    Panigrahy, D; Sahu, P K

    2016-09-01

    Electrocardiogram (ECG) signal gives a lot of information on the physiology of heart. In reality, noise from various sources interfere with the ECG signal. To get the correct information on physiology of the heart, noise cancellation of the ECG signal is required. In this paper, the effectiveness of extended Kalman smoother (EKS) with the differential evolution (DE) technique for noise cancellation of the ECG signal is investigated. DE is used as an automatic parameter selection method for the selection of ten optimized components of the ECG signal, and those are used to create the ECG signal according to the real ECG signal. These parameters are used by the EKS for the development of the state equation and also for initialization of the parameters of EKS. EKS framework is used for denoising the ECG signal from the single channel. The effectiveness of proposed noise cancellation technique has been evaluated by adding white, colored Gaussian noise and real muscle artifact noise at different SNR to some visually clean ECG signals from the MIT-BIH arrhythmia database. The proposed noise cancellation technique of ECG signal shows better signal to noise ratio (SNR) improvement, lesser mean square error (MSE) and percent of distortion (PRD) compared to other well-known methods.

  3. Thermoelastic analysis of multiple defects with the extended finite element method

    NASA Astrophysics Data System (ADS)

    Jia, Honggang; Nie, Yufeng

    2016-12-01

    In this paper, the extended finite element method (XFEM) is adopted to analyze the interaction between a single macroscopic inclusion and a single macroscopic crack as well as that between multiple macroscopic or microscopic defects under thermal/mechanical load. The effects of different shapes of multiple inclusions on the material thermomechanical response are investigated, and the level set method is coupled with XFEM to analyze the interaction of multiple defects. Further, the discretized extended finite element approximations in relation to thermoelastic problems of multiple defects under displacement or temperature field are given. Also, the interfaces of cracks or materials are represented by level set functions, which allow the mesh assignment not to conform to crack or material interfaces. Moreover, stress intensity factors of cracks are obtained by the interaction integral method or the M-integral method, and the stress/strain/stiffness fields are simulated in the case of multiple cracks or multiple inclusions. Finally, some numerical examples are provided to demonstrate the accuracy of our proposed method.

  4. Multiple Signal Classification for Gravitational Wave Burst Search

    NASA Astrophysics Data System (ADS)

    Cao, Junwei; He, Zhengqi

    2013-01-01

    This work is mainly focused on the application of the multiple signal classification (MUSIC) algorithm for gravitational wave burst search. This algorithm extracts important gravitational wave characteristics from signals coming from detectors with arbitrary position, orientation and noise covariance. In this paper, the MUSIC algorithm is described in detail along with the necessary adjustments required for gravitational wave burst search. The algorithm's performance is measured using simulated signals and noise. MUSIC is compared with the Q-transform for signal triggering and with Bayesian analysis for direction of arrival (DOA) estimation, using the Ω-pipeline. Experimental results show that MUSIC has a lower resolution but is faster. MUSIC is a promising tool for real-time gravitational wave search for multi-messenger astronomy.

  5. Multiple Routes of Light Signaling during Root Photomorphogenesis.

    PubMed

    Lee, Hyo-Jun; Park, Young-Joon; Ha, Jun-Ho; Baldwin, Ian T; Park, Chung-Mo

    2017-09-01

    Plants dynamically adjust their architecture to optimize growth and performance under fluctuating light environments, a process termed photomorphogenesis. A variety of photomorphogenic responses have been studied extensively in the shoots, where diverse photoreceptors and signaling molecules have been functionally characterized. Notably, accumulating evidence demonstrates that the underground roots also undergo photomorphogenesis, raising the question of how roots perceive and respond to aboveground light. Recent findings indicate that root photomorphogenesis is mediated by multiple signaling routes, including shoot-to-root transmission of mobile signaling molecules, direct sensing of light by the roots, and light channeling through the plant body. In this review we discuss recent advances in how light signals are transmitted to the roots to trigger photomorphogenic responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Progressive alignment of genomic signals by multiple dynamic time warping.

    PubMed

    Skutkova, Helena; Vitek, Martin; Sedlar, Karel; Provaznik, Ivo

    2015-11-21

    This paper presents the utilization of progressive alignment principle for positional adjustment of a set of genomic signals with different lengths. The new method of multiple alignment of signals based on dynamic time warping is tested for the purpose of evaluating the similarity of different length genes in phylogenetic studies. Two sets of phylogenetic markers were used to demonstrate the effectiveness of the evaluation of intraspecies and interspecies genetic variability. The part of the proposed method is modification of pairwise alignment of two signals by dynamic time warping with using correlation in a sliding window. The correlation based dynamic time warping allows more accurate alignment dependent on local homologies in sequences without the need of scoring matrix or evolutionary models, because mutual similarities of residues are included in the numerical code of signals.

  7. 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.

  8. 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

  9. Biophysical mechanisms of MRI signal frequency contrast in multiple sclerosis

    PubMed Central

    Yablonskiy, Dmitriy A.; Luo, Jie; Sukstanskii, Alexander L.; Iyer, Aditi; Cross, Anne H.

    2012-01-01

    Phase images obtained with gradient echo MRI provide image contrast distinct from T1- and T2-weighted images. It is commonly assumed that the local contribution to MRI signal phase directly relates to local bulk tissue magnetic susceptibility. Here, we use Maxwell’s equations and Monte Carlo simulations to provide theoretical background to the hypothesis that the local contribution to MRI signal phase does not depend on tissue bulk magnetic susceptibility but tissue magnetic architecture—distribution of magnetic susceptibility inclusions (lipids, proteins, iron, etc.) at the cellular and subcellular levels. Specifically, we show that the regular longitudinal structures forming cylindrical axons (myelin sheaths and neurofilaments) can be locally invisible in phase images. Contrary to an expectation that the phase contrast in multiple sclerosis lesions should always increase in degree along with worsening of lesion severity (which happens for all known MR magnitude-based contrast mechanisms), we show that phase contrast can actually disappear with extreme tissue destruction. We also show that the phase contrast in multiple sclerosis lesions could be altered without loss of nervous system tissue, which happens in mild injury to the myelin sheaths or axonal neurofilaments. Moreover, we predict that the sign of phase contrast in multiple sclerosis lesions indicates the predominant type of tissue injury—myelin damage (positive sign) vs. axonal neurofilament damage (negative sign). Therefore, our theoretical and experimental results shed light on understanding the relationship between gradient echo MRI signal phase and multiple sclerosis pathology. PMID:22891307

  10. 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

  11. 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.

  12. Passive detection, characterization, and localization of multiple LFMCW LPI signals

    NASA Astrophysics Data System (ADS)

    Hamschin, Brandon; Clancy, John; Grabbe, Mike; Fortier, Matthew; Novak, John

    2014-06-01

    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. In contrast to other detection and characterization approaches, such as those based on the Wigner-Ville Transform (WVT) 1or the Wigner-Ville Hough Transform (WVHT) ,2 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 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. Using this model of the signal, which we refer to as the Short-Time Harmonic Model (STHM), we implement a detection statistic based on Thompson's Method for harmonic analysis,3 which leads to a detection threshold that is a function of False Alarm Probability PFA and not a function of the noise properties. By doing so 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 variances for a subset of these parameters, and produce Time-of-Arrival (TOA) estimates that can be used to estimate the geographical location of (i.e., localize) each LFMCW source. Finally, by using the entire time-series we refine these parameter estimates by using them as initial conditions to the Maximum Likelihood Estimator (MLE), which was originally given in1 and later found in2 to be too computationally expensive for multiple LFMCW signals if accurate initial conditions were not available to limit the search space. We demonstrate the performance of our approach via simulation.

  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. Activation of multiple angiogenic signaling pathways in hemangiopericytoma.

    PubMed

    Pierscianek, Daniela; Michel, Anna; Hindy, Nicolai El; Keyvani, Kathy; Dammann, Philipp; Oezkan, Neriman; Mueller, Oliver; Sure, Ulrich; Zhu, Yuan

    2016-07-01

    Hemangiopericytoma (HPC) is a highly vascularized mesenchymal tumor. Local recurrence and distant metastasis are common features of HPC. Considering the remarkable hyper-vasculature phenotype of HPC, we assumed that dysregulated angiogenic signaling pathways were involved in HPC. The key components of angiogenic signaling pathways including VEGF-VEGF-R2, EphrinB2-EphB4 and DLL4-Notch were examined by real-time RT-PCR, Western blotting and immunostaining in 17 surgical specimens of HPC patients and in 6 controls. A significant upregulation of VEGF and VEGF-R2 associated with elevated levels of p-Akt and proliferating cell nuclear antigen (PCNA) was detected in HPC. Moreover, a dramatic increase in the mRNA and protein expression of EphB4 and its downstream factor p-Erk1/2 was found in HPC. A massive activation of core-components of DLL4-Notch signaling was detected in HPC. Double-immunofluorescent staining confirmed the expression of these upregulated key factors in the endothelial cells of tumor vessels. The present study identified the activation of multiple and crucial angiogenic signaling pathways, which could function individually and/or synergistically to stimulate angiogenesis in HPC and eventually contribute to tumor growth and progression. Our findings emphasize the importance to target multiple angiogenic signaling pathways when an anti-angiogenic therapy is considered for this highly vascularized tumor.

  15. Chaos control using small-amplitude damping signals of the extended Duffing equation

    NASA Astrophysics Data System (ADS)

    Lazzouni, Sihem A.; Bowong, Samuel; Kakmeni, F. M. Moukam; Cherki, Brahim; Ghouali, Noureddine

    2007-08-01

    This paper examines the application of a simple feedback controller to eliminate the chaotic behavior in a controlled extended Duffing system. The main idea is to regulate the chaotic motion of an extended Duffing system around less complex attractors, such as equilibrium points and periodic orbits. The proposed feedback controller is composed by a high-pass filter and a saturator, so its implementation is quite simple and can be made on the basis of measured signals. The affectivity of the proposed feedback control strategy is illustrated by means of numerical simulations.

  16. Multiplicity counting from fission chamber signals in the current mode

    NASA Astrophysics Data System (ADS)

    Pázsit, I.; Pál, L.; Nagy, L.

    2016-12-01

    In nuclear safeguards, estimation of sample parameters using neutron-based non-destructive assay methods is traditionally based on multiplicity counting with thermal neutron detectors in the pulse mode. These methods in general require multi-channel analysers and various dead time correction methods. This paper proposes and elaborates on an alternative method, which is based on fast neutron measurements with fission chambers in the current mode. A theory of "multiplicity counting" with fission chambers is developed by incorporating Böhnel's concept of superfission [1] into a master equation formalism, developed recently by the present authors for the statistical theory of fission chamber signals [2,3]. Explicit expressions are derived for the first three central auto- and cross moments (cumulants) of the signals of up to three detectors. These constitute the generalisation of the traditional Campbell relationships for the case when the incoming events represent a compound Poisson distribution. Because now the expressions contain the factorial moments of the compound source, they contain the same information as the singles, doubles and triples rates of traditional multiplicity counting. The results show that in addition to the detector efficiency, the detector pulse shape also enters the formulas; hence, the method requires a more involved calibration than the traditional method of multiplicity counting. However, the method has some advantages by not needing dead time corrections, as well as having a simpler and more efficient data processing procedure, in particular for cross-correlations between different detectors, than the traditional multiplicity counting methods.

  17. Remote Entanglement by Coherent Multiplication of Concurrent Quantum Signals.

    PubMed

    Roy, Ananda; Jiang, Liang; Stone, A Douglas; Devoret, Michel

    2015-10-09

    Concurrent remote entanglement of distant, noninteracting quantum entities is a crucial function for quantum information processing. In contrast with the existing protocols which employ the addition of signals to generate entanglement between two remote qubits, the continuous variable protocol we present is based on the multiplication of signals. This protocol can be straightforwardly implemented by a novel Josephson junction mixing circuit. Our scheme would be able to generate provable entanglement even in the presence of practical imperfections: finite quantum efficiency of detectors and undesired photon loss in current state-of-the-art devices.

  18. Discriminating spurious signals in radar data using multiple channels

    NASA Astrophysics Data System (ADS)

    Doerry, A. W.; Bickel, D. L.

    2017-05-01

    Spurious energy in received radar data is unanticipated and undesired signal relevant to radar target signatures, usually a consequence of nonideal component and circuit behavior, perhaps due to I/Q imbalance, nonlinear component behavior, additive interference (e.g. cross-talk, etc.), or other sources. The manifestation of the spurious energy in a range-Doppler map or image can often be influenced by appropriate pulse-to-pulse phase modulation. Comparing multiple images having been processed with the same data but different signal paths and modulations allows identifying undesired spurs and then cropping or apodizing them.

  19. Multiple Scale and Hamilton-Jacobi Analysis of Extended Mathieu Equation

    NASA Astrophysics Data System (ADS)

    Yešiltaš, Özlem; Šimšek, Mehmet

    2005-05-01

    In this study, we use perturbation approximations and semiclassical methods to investigate the boundary solutions of non-linear vibrating systems. The extended Mathieu Equation, related to the perturbed Van der Pol oscillator with periodic coefficients, is solved using multiple time scales. Then, using the Von Zeipel Method, which is based on the Hamilton-Jacobi theory, stability conditions are presented. It is shown that the stability boundaries are the same with those obtained by both methods.

  20. Single- and Multiple-dose Pharmacokinetics of a Lorcaserin Extended-release Tablet.

    PubMed

    Christopher, Ronald; Morgan, Mike; Ferry, Jim; Rege, Bhaskar; Tang, Yong; Kristensen, Allan; Shanahan, William

    2016-10-01

    Lorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration-approved, extended-release, 20-mg once-daily formulation. We performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions. Compared with lorcaserin IR, the Tmax after a single dose of lorcaserin extended-release was greater (median, 12 vs 3 hours), and the Cmax was 26% lower (38.8 vs 52.3 ng/mL). AUC data were bioequivalent for the 2 formulations in both single- and multiple-dose regimens, confirming no formulation effect on lorcaserin bioavailability. In fasted and fed conditions, Tmax after a single dose was identical (median, 12 hours), but Cmax was approximately 45% higher in the fed state (mean, 38.5 ng/mL fasted vs 56.1 ng/mL fed). However, at steady state, Cmax and AUC were determined to be bioequivalent between the fasted and fed states, indicating no clinically relevant food effect on the pharmacokinetic properties of lorcaserin extended-release. The safety profile was consistent between the 2 formulations. Overall, the results indicate that lorcaserin extended-release is a suitable once-daily alternative to the approved IR BID formulation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Multiple signal pathways in obesity-associated cancer.

    PubMed

    Chen, J

    2011-12-01

    Obesity is increasing worldwide and reaches to a large proportion of the population in developed countries. Thus, obesity-associated cancer has become a major health problem. Multiple cancer risk factors in obesity have been identified including insulin/insulin-like growth factor axis, adipokines and cytokines; and multiple intracellular signal pathways have been studied. However, the role of each signal pathway in obesity-associated cancer is controversial. In this review, the recent studies on signal pathways in obesity-associated cancer are summarized and a unified explanation is provided. Multiple risk factors could initially activate phosphoinositide 3-kinase (PI3K/Akt), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) pathways. With increased severity of obesity, mammalian target of rapamycin (mTOR), which is down-stream of both PI3K/Akt and MAPK, is highly activated. Activated mTOR in turn inhibits the PI3K/Akt pathway and further activates the STAT3 pathway. This may explain the activation of the PI3K/Akt pathway at the early stage of obesity and its inhibition at the later stage. mTOR inhibition may be used for cancer therapy, but it may be necessary to be combined with the PI3K/Akt inhibitor as decreased mTOR activity will release its feedback inhibition on the PI3K/Akt pathway, which is under the influence of multiple cancer risk factors in obesity. Thus, dual inhibitors of PI3K and mTOR may provide a novel approach. © 2011 The Author. obesity reviews © 2011 International Association for the Study of Obesity.

  2. Bacillus subtilis biofilm extends Caenorhabditis elegans longevity through downregulation of the insulin-like signalling pathway

    PubMed Central

    Donato, Verónica; Ayala, Facundo Rodríguez; Cogliati, Sebastián; Bauman, Carlos; Costa, Juan Gabriel; Leñini, Cecilia; Grau, Roberto

    2017-01-01

    Beneficial bacteria have been shown to affect host longevity, but the molecular mechanisms mediating such effects remain largely unclear. Here we show that formation of Bacillus subtilis biofilms increases Caenorhabditis elegans lifespan. Biofilm-proficient B. subtilis colonizes the C. elegans gut and extends worm lifespan more than biofilm-deficient isogenic strains. Two molecules produced by B. subtilis — the quorum-sensing pentapeptide CSF and nitric oxide (NO) — are sufficient to extend C. elegans longevity. When B. subtilis is cultured under biofilm-supporting conditions, the synthesis of NO and CSF is increased in comparison with their production under planktonic growth conditions. We further show that the prolongevity effect of B. subtilis biofilms depends on the DAF-2/DAF-16/HSF-1 signalling axis and the downregulation of the insulin-like signalling (ILS) pathway. PMID:28134244

  3. 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

  4. On using the Multiple Signal Classification algorithm to study microbaroms

    NASA Astrophysics Data System (ADS)

    Marcillo, O. E.; Blom, P. S.; Euler, G. G.

    2016-12-01

    Multiple Signal Classification (MUSIC) (Schmidt, 1986) is a well-known high-resolution algorithm used in array processing for parameter estimation. We report on the application of MUSIC to infrasonic array data in a study of the structure of microbaroms. Microbaroms can be globally observed and display energy centered around 0.2 Hz. Microbaroms are an infrasonic signal generated by the non-linear interaction of ocean surface waves that radiate into the ocean and atmosphere as well as the solid earth in the form of microseisms. Microbaroms sources are dynamic and, in many cases, distributed in space and moving in time. We assume that the microbarom energy detected by an infrasonic array is the result of multiple sources (with different back-azimuths) in the same bandwidth and apply the MUSIC algorithm accordingly to recover the back-azimuth and trace velocity of the individual components. Preliminary results show that the multiple component assumption in MUSIC allows one to resolve the fine structure in the microbarom band that can be related to multiple ocean surface phenomena.

  5. Time-reversal imaging with multiple signal classification considering multiple scattering between the targets

    NASA Astrophysics Data System (ADS)

    Gruber, Fred K.; Marengo, Edwin A.; Devaney, Anthony J.

    2004-06-01

    The time-reversal imaging with multiple signal classification method for the location of point targets developed within the framework of the Born approximation in Lehman and Devaney [``Transmission mode time-reversal super-resolution imaging,'' J. Acoust. Soc. Am. 113, 2742-2753 (2003)] is generalized to incorporate multiple scattering between the targets. It is shown how the same method can be used in the location of point targets even if there is multiple scattering between them. On the other hand, both the conventional images and the calculated values of the target scattering amplitudes are scattering model-dependent.

  6. Multiple-gain-ranging readout method to extend the dynamic range of amorphous silicon flat-panel imagers

    NASA Astrophysics Data System (ADS)

    Roos, Pieter G.; Colbeth, Richard E.; Mollov, Ivan; Munro, Peter; Pavkovich, John; Seppi, Edward J.; Shapiro, Edward G.; Tognina, Carlo A.; Virshup, Gary F.; Yu, J. Micheal; Zentai, George; Kaissl, Wolfgang; Matsinos, Evangelos; Richters, Jeroen; Riem, Heinrich

    2004-05-01

    The dynamic range of many flat panel imaging systems are fundamentally limited by the dynamic range of the charge amplifier and readout signal processing. We developed two new flat panel readout methods that achieve extended dynamic range by changing the read out charge amplifier feedback capacitance dynamically and on a real-time basis. In one method, the feedback capacitor is selected automatically by a level sensing circuit, pixel-by-pixel, based on its exposure level. Alternatively, capacitor selection is driven externally, such that each pixel is read out two (or more) times, each time with increased feedback capacitance. Both methods allow the acquisition of X-ray image data with a dynamic range approaching the fundamental limits of flat panel pixels. Data with an equivalent bit depth of better than 16 bits are made available for further image processing. Successful implementation of these methods requires careful matching of selectable capacitor values and switching thresholds, with the imager noise and sensitivity characteristics, to insure X-ray quantum limited operation over the whole extended dynamic range. Successful implementation also depends on the use of new calibration methods and image reconstruction algorithms, to insure artifact free rebuilding of linear image data by the downstream image processing systems. The multiple gain ranging flat panel readout method extends the utility of flat panel imagers and paves the way to new flat panel applications, such as cone beam CT. We believe that this method will provide a valuable extension to the clinical application of flat panel imagers.

  7. 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.

  8. 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.

    2016-10-01

    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.

  9. A plant virus evolved by acquiring multiple nonconserved genes to extend its host range

    PubMed Central

    Tatineni, Satyanarayana; Robertson, Cecile J.; Garnsey, Stephen M.; Dawson, William O.

    2011-01-01

    Viruses have evolved as combinations of genes whose products interact with cellular components to produce progeny virus throughout the plants. Some viral genes, particularly those that are involved in replication and assembly, tend to be relatively conserved, whereas other genes that have evolved for interactions with the specific host for movement and to counter host–defense systems tend to be less conserved. Closteroviridae encode 1–5 nonconserved ORFs. Citrus tristeza virus (CTV), a Closterovirus, possesses nonconserved p33, p18, and p13 genes that are expendable for systemic infection of the two laboratory hosts, Citrus macrophylla and Mexican lime. In this study, we show that the extended host range of CTV requires these nonconserved genes. The p33 gene was required to systemically infect sour orange and lemon trees, whereas either the p33 or the p18 gene was sufficient for systemic infection of grapefruit trees and the p33 or the p13 gene was sufficient for systemic infection of calamondin plants. Thus, these three genes are required for systemic infection of the full host range of CTV, but different genes were specific for different hosts. Remarkably, either of two genes was sufficient for infection of some citrus hybrids. These findings suggest that CTV acquired multiple nonconserved genes (p33, p18, and p13) and, as a result, gained the ability to interact with multiple hosts, thus extending its host range during the course of evolution. These results greatly extend the complexity of known virus–plant interactions. PMID:21987809

  10. Diagnosis of multiple sclerosis from EEG signals using nonlinear methods.

    PubMed

    Torabi, Ali; Daliri, Mohammad Reza; Sabzposhan, Seyyed Hojjat

    2017-09-08

    EEG signals have essential and important information about the brain and neural diseases. The main purpose of this study is classifying two groups of healthy volunteers and Multiple Sclerosis (MS) patients using nonlinear features of EEG signals while performing cognitive tasks. EEG signals were recorded when users were doing two different attentional tasks. One of the tasks was based on detecting a desired change in color luminance and the other task was based on detecting a desired change in direction of motion. EEG signals were analyzed in two ways: EEG signals analysis without rhythms decomposition and EEG sub-bands analysis. After recording and preprocessing, time delay embedding method was used for state space reconstruction; embedding parameters were determined for original signals and their sub-bands. Afterwards nonlinear methods were used in feature extraction phase. To reduce the feature dimension, scalar feature selections were done by using T-test and Bhattacharyya criteria. Then, the data were classified using linear support vector machines (SVM) and k-nearest neighbor (KNN) method. The best combination of the criteria and classifiers was determined for each task by comparing performances. For both tasks, the best results were achieved by using T-test criterion and SVM classifier. For the direction-based and the color-luminance-based tasks, maximum classification performances were 93.08 and 79.79% respectively which were reached by using optimal set of features. Our results show that the nonlinear dynamic features of EEG signals seem to be useful and effective in MS diseases diagnosis.

  11. Extraretinal signal metrics in multiple-saccade sequences.

    PubMed

    Collins, Thérèse

    2010-12-06

    Executing sequences of memory-guided movements requires combining sensory information with information about previously made movements. In the oculomotor system, extraretinal information must be combined with stored visual information about target location. The use of extraretinal signals in oculomotor planning can be probed in the double-step task. Using this task and a multiple-step version, the present study examined whether an extraretinal signal was used on every trial, whether its metrics represented desired or actual eye displacement, and whether it was best characterized as a direct estimate of orbital eye position or a vector representation of eye displacement. The results show that accurate information, including saccadic adaptation, about the first saccade is used to plan the second saccade. Furthermore, with multiple saccades, endpoint variability increases with the number of saccades. Controls ruled out that this was due to the perceptual or memory requirements of storing several target locations. Instead, each memory-guided movement depends on an internal copy of an executed movement, which may present a small discrepancy with the actual movement. Increasing the number of estimates increases the variability because this small discrepancy accumulates over several saccades. Such accumulation is compatible with a corollary discharge signal carrying metric information about saccade vectors.

  12. Solar axion search technique with correlated signals from multiple detectors

    DOE PAGES

    Xu, Wenqin; Elliott, Steven R.

    2017-01-25

    The coherent Bragg scattering of photons converted from solar axions inside crystals would boost the signal for axion-photon coupling enhancing experimental sensitivity for these hypothetical particles. Knowledge of the scattering angle of solar axions with respect to the crystal lattice is required to make theoretical predications of signal strength. Hence, both the lattice axis angle within a crystal and the absolute angle between the crystal and the Sun must be known. In this paper, we examine how the experimental sensitivity changes with respect to various experimental parameters. We also demonstrate that, in a multiple-crystal setup, knowledge of the relative axismore » orientation between multiple crystals can improve the experimental sensitivity, or equivalently, relax the precision on the absolute solar angle measurement. However, if absolute angles of all crystal axes are measured, we find that a precision of 2°–4° will suffice for an energy resolution of σE = 0.04E and a flat background. Lastly, we also show that, given a minimum number of detectors, a signal model averaged over angles can substitute for precise crystal angular measurements, with some loss of sensitivity.« less

  13. Solar axion search technique with correlated signals from multiple detectors

    NASA Astrophysics Data System (ADS)

    Xu, Wenqin; Elliott, Steven R.

    2017-03-01

    The coherent Bragg scattering of photons converted from solar axions inside crystals would boost the signal for axion-photon coupling enhancing experimental sensitivity for these hypothetical particles. Knowledge of the scattering angle of solar axions with respect to the crystal lattice is required to make theoretical predications of signal strength. Hence, both the lattice axis angle within a crystal and the absolute angle between the crystal and the Sun must be known. In this paper, we examine how the experimental sensitivity changes with respect to various experimental parameters. We also demonstrate that, in a multiple-crystal setup, knowledge of the relative axis orientation between multiple crystals can improve the experimental sensitivity, or equivalently, relax the precision on the absolute solar angle measurement. However, if absolute angles of all crystal axes are measured, we find that a precision of 2∘ -4∘ will suffice for an energy resolution of σE = 0.04 E and a flat background. Finally, we also show that, given a minimum number of detectors, a signal model averaged over angles can substitute for precise crystal angular measurements, with some loss of sensitivity.

  14. Chlorogenic Acid Extends the Lifespan of Caenorhabditis elegans via Insulin/IGF-1 Signaling Pathway.

    PubMed

    Zheng, Shan-Qing; Huang, Xiao-Bing; Xing, Ti-Kun; Ding, Ai-Jun; Wu, Gui-Sheng; Luo, Huai-Rong

    2017-04-01

    Coffee and tea, two of the most popular drinks around the world, share many in common from chemical components to beneficial effects on human health. One of their shared components, the polyphenols, most notably chlorogenic acid (CGA), was supposed to account for many of the beneficial effects on ameliorating diseases occurred accompanying people aging, such as the antioxidant effect and against diabetes and cardiovascular disease. CGA is also present in many traditional Chinese medicines. However, the mechanism of these effects was vague. The aging signaling pathways were conservative from yeast and worms to mammals. So, we tested if CGA had an effect on aging in Caenorhabditis elegans. We found that CGA could extend the lifespan of C. elegans by up to 20.1%, delay the age-related decline of body movement, and improve stress resistance. We conducted genetic analysis with a series of worm mutants and found that CGA could extend the lifespan of the mutants of eat-2, glp-1, and isp-1, but not of daf-2, pdk-1, akt-1, akt-2, sgk-1, and clk-1. CGA could activate the FOXO transcription factors DAF-16, HSF-1, SKN-1, and HIF-1, but not SIR-2.1. Taken together, CGA might extend the lifespan of C. elegans mainly via DAF-16 in insulin/IGF-1 signaling pathway. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. 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.

  16. 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.

  17. 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.

  18. Constraints on plant signals and rewards to multiple mutualists?

    PubMed

    Whitney, Kenneth D; Rudgers, Jennifer A

    2009-09-01

    Many plants invest substantial resources in signaling to and rewarding two kinds of 'interguild' mutualists, pollinators and seed dispersers. The signals and rewards are expressed via traits of flowers and fruits. Pollinators and seed dispersers could act in synergistic or antagonistic ways to influence selection on these traits. Here, we address the issue of whether plant species might be constrained in signaling to and rewarding multiple mutualists that provide different types of benefits to plants. Specifically, does investment in one type of mutualist limit investment in another? We examined the correlation between flower size and fruit size for 472 plant species spanning three regional floras. Our analyses made the assumption that structure size is related to plant investment in signals and/or rewards. We expect that a constraint due to interguild mutualisms would be evidenced by a negative correlation between flower and fruit size. Instead, we found significantly positive relationships between flower size and fruit size in all three regional floras. These relationships remained robust after correcting for plant evolutionary history using phylogenetically independent contrasts. These patterns may reflect synergies in selection by pollinators and seed dispersers, genetically-based or resource-based constraints on investment in reproductive tissues, and/or an underlying trade-off in structure size versus number.

  19. Constraints on plant signals and rewards to multiple mutualists?

    PubMed Central

    Rudgers, Jennifer A

    2009-01-01

    Many plants invest substantial resources in signaling to and rewarding two kinds of ‘interguild’ mutualists, pollinators and seed dispersers. The signals and rewards are expressed via traits of flowers and fruits. Pollinators and seed dispersers could act in synergistic or antagonistic ways to influence selection on these traits. Here, we address the issue of whether plant species might be constrained in signaling to and rewarding multiple mutualists that provide different types of benefits to plants. Specifically, does investment in one type of mutualist limit investment in another? We examined the correlation between flower size and fruit size for 472 plant species spanning three regional floras. Our analyses made the assumption that structure size is related to plant investment in signals and/or rewards. We expect that a constraint due to interguild mutualisms would be evidenced by a negative correlation between flower and fruit size. Instead, we found significantly positive relationships between flower size and fruit size in all three regional floras. These relationships remained robust after correcting for plant evolutionary history using phylogenetically independent contrasts. These patterns may reflect synergies in selection by pollinators and seed dispersers, genetically-based or resource-based constraints on investment in reproductive tissues, and/or an underlying trade-off in structure size versus number. PMID:19847123

  20. Extended motion adaptive signal integration technique for real-time image enhancement

    NASA Astrophysics Data System (ADS)

    Zhang, David C.; Piacentino, Michael; Chai, Sek

    2012-06-01

    Fast moving cameras often generate distorted and blurred images characterized by reduced sharpness (due to motion blur) and insufficient dynamic range. Reducing sensor integration times to minimize blur are often used but the light intensity and image Signal-to-Noise-Ratio (SNR) would be reduced as well. We propose a Motion Adaptive Signal Integration (MASI) algorithm that operates the sensor at a high frame rate, with real time alignment of individual image frames to form an enhanced quality video output. This technique enables signal integration in the digital domain, allowing both high SNR performance and low motion blur induced by the camera motion. We also show, in an Extended MASI (EMASI) algorithm, that high dynamic range can be achieved by combining high frame rate images of varying exposures. EMASI broadens the dynamic range of the sensor and extends the sensitivity to work in low light and noisy conditions. In a moving platform, it also reduces static noise in the sensor. This technology can be used in aerial surveillance, satellite imaging, border securities, wearable sensing, video conferencing and camera phone imaging applications.

  1. Method for acquiring extended real-time kinetic signals in nanosecond laser flash photolysis experiments

    NASA Astrophysics Data System (ADS)

    Banderini, Andrea; Sottini, Silvia; Viappiani, Cristiano

    2004-07-01

    We report a data acquisition method for detecting transient absorbance signals extended in time which require nanosecond resolution and need to span several decades in time up to the hundreds of milliseconds. A microprocessor is used to generate a sequence of up to 100, 2.120 μs wide radio frequency signals at 500 MHz which are used to trigger the analog-to-digital conversion on a digital oscilloscope, operating in the external clock mode. During these radio frequency bursts the data are sampled at a sampling rate of 500 Ms/s. The delay of each sampling burst can be set at arbitrary values with respect to the first signal, with a minimum delay of 0.96 μs for the second pulse, and 1.2 μs for all other pulses. The microprocessor provides accessory synchronization outputs for laser triggering and for shutter opening and closing. This data acquisition system allows measuring the complete time course of extended kinetics after each laser shot, thus reducing acquisition times and data size. We prove the complete equivalence of the proposed acquisition method with standard methods, where several time bases are acquired to cover the complete kinetic trace for the ligand rebinding to myoglobin after photolysis of a gel embedded myoglobin-CO complex.

  2. Impairment of insulin signalling in peripheral tissue fails to extend murine lifespan.

    PubMed

    Merry, Troy L; Kuhlow, Doreen; Laube, Beate; Pöhlmann, Doris; Pfeiffer, Andreas F H; Kahn, C Ronald; Ristow, Michael; Zarse, Kim

    2017-08-01

    Impaired insulin/IGF1 signalling has been shown to extend lifespan in model organisms ranging from yeast to mammals. Here we sought to determine the effect of targeted disruption of the insulin receptor (IR) in non-neuronal tissues of adult mice on the lifespan. We induced hemizygous (PerIRKO(+/-) ) or homozygous (PerIRKO(-/-) ) disruption of the IR in peripheral tissue of 15-weeks-old mice using a tamoxifen-inducible Cre transgenic mouse with only peripheral tissue expression, and subsequently monitored glucose metabolism, insulin signalling and spontaneous death rates over 4 years. Complete peripheral IR disruption resulted in a diabetic phenotype with increased blood glucose and plasma insulin levels in young mice. Although blood glucose levels returned to normal, and fat mass was reduced in aged PerIRKO(-/-) mice, their lifespan was reduced. By contrast, heterozygous disruption had no effect on lifespan. This was despite young male PerIRKO(+/-) mice showing reduced fat mass and mild increase in hepatic insulin sensitivity. In conflict with findings in metazoans like Caenorhabditis elegans and Drosophila melanogaster, our results suggest that heterozygous impairment of the insulin signalling limited to peripheral tissues of adult mice fails to extend lifespan despite increased systemic insulin sensitivity, while homozygous impairment shortens lifespan. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  3. Tuning Cell and Tissue Development by Combining Multiple Mechanical Signals.

    PubMed

    Sinha, Ravi; Verdonschot, Nico; Koopman, Bart; Rouwkema, Jeroen

    2017-05-03

    Mechanical signals offer a promising way to control cell and tissue development. It has been established that cells constantly probe their mechanical microenvironment and employ force feedback mechanisms to modify themselves and when possible, their environment, to reach a homeostatic state. Thus, a correct mechanical microenvironment (external forces and mechanical properties and shapes of cellular surroundings) is necessary for the proper functioning of cells. In vitro or in the case of nonbiological implants in vivo, where cells are in an artificial environment, addition of the adequate mechanical signals can, therefore, enable the cells to function normally as in vivo. Hence, a wide variety of approaches have been developed to apply mechanical stimuli (such as substrate stretch, flow-induced shear stress, substrate stiffness, topography, and modulation of attachment area) to cells in vitro. These approaches have not just revealed the effects of the mechanical signals on cells but also provided ways for probing cellular molecules and structures that can provide a mechanistic understanding of the effects. However, they remain lower in complexity compared with the in vivo conditions, where the cellular mechanical microenvironment is the result of a combination of multiple mechanical signals. Therefore, combinations of mechanical stimuli have also been applied to cells in vitro. These studies have had varying focus-developing novel platforms to apply complex combinations of mechanical stimuli, observing the co-operation/competition between stimuli, combining benefits of multiple stimuli toward an application, or uncovering the underlying mechanisms of their action. In general, they provided new insights that could not have been predicted from previous knowledge. We present here a review of several such studies and the insights gained from them, thereby making a case for such studies to be continued and further developed.

  4. Aspirin increases metabolism through germline signalling to extend the lifespan of Caenorhabditis elegans

    PubMed Central

    Huang, Xiao-Bing; Mu, Xiao-Hui; Wan, Qin-Li; He, Xiao-Ming; Wu, Gui-Sheng

    2017-01-01

    Aspirin is a prototypic cyclooxygenase inhibitor with a variety of beneficial effects on human health. It prevents age-related diseases and delays the aging process. Previous research has shown that aspirin might act through a dietary restriction-like mechanism to extend lifespan. To explore the mechanism of action of aspirin on aging, we determined the whole-genome expression profile of Caenorhabditis elegans treated with aspirin. Transcriptome analysis revealed the RNA levels of genes involved in metabolism were primarily increased. Reproduction has been reported to be associated with metabolism. We found that aspirin did not extend the lifespan or improve the heat stress resistance of germline mutants of glp-1. Furthermore, Oil Red O staining showed that aspirin treatment decreased lipid deposition and increased expression of lipid hydrolysis and fatty acid β-oxidation-related genes. The effect of germline ablation on lifespan was mainly mediated by DAF-12 and DAF-16. Next, we performed genetic analysis with a series of worm mutants and found that aspirin did not further extend the lifespans of daf-12 and daf-16 single mutants, glp-1;daf-12 and glp-1;daf-16 double mutants, or glp-1;daf-12;daf-16 triple mutants. The results suggest that aspirin increase metabolism and regulate germline signalling to activate downstream DAF-12 and DAF-16 to extend lifespan. PMID:28910305

  5. Aspirin increases metabolism through germline signalling to extend the lifespan of Caenorhabditis elegans.

    PubMed

    Huang, Xiao-Bing; Mu, Xiao-Hui; Wan, Qin-Li; He, Xiao-Ming; Wu, Gui-Sheng; Luo, Huai-Rong

    2017-01-01

    Aspirin is a prototypic cyclooxygenase inhibitor with a variety of beneficial effects on human health. It prevents age-related diseases and delays the aging process. Previous research has shown that aspirin might act through a dietary restriction-like mechanism to extend lifespan. To explore the mechanism of action of aspirin on aging, we determined the whole-genome expression profile of Caenorhabditis elegans treated with aspirin. Transcriptome analysis revealed the RNA levels of genes involved in metabolism were primarily increased. Reproduction has been reported to be associated with metabolism. We found that aspirin did not extend the lifespan or improve the heat stress resistance of germline mutants of glp-1. Furthermore, Oil Red O staining showed that aspirin treatment decreased lipid deposition and increased expression of lipid hydrolysis and fatty acid β-oxidation-related genes. The effect of germline ablation on lifespan was mainly mediated by DAF-12 and DAF-16. Next, we performed genetic analysis with a series of worm mutants and found that aspirin did not further extend the lifespans of daf-12 and daf-16 single mutants, glp-1;daf-12 and glp-1;daf-16 double mutants, or glp-1;daf-12;daf-16 triple mutants. The results suggest that aspirin increase metabolism and regulate germline signalling to activate downstream DAF-12 and DAF-16 to extend lifespan.

  6. 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. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. Noise removal in extended depth of field microscope images through nonlinear signal processing.

    PubMed

    Zahreddine, Ramzi N; Cormack, Robert H; Cogswell, Carol J

    2013-04-01

    Extended depth of field (EDF) microscopy, achieved through computational optics, allows for real-time 3D imaging of live cell dynamics. EDF is achieved through a combination of point spread function engineering and digital image processing. A linear Wiener filter has been conventionally used to deconvolve the image, but it suffers from high frequency noise amplification and processing artifacts. A nonlinear processing scheme is proposed which extends the depth of field while minimizing background noise. The nonlinear filter is generated via a training algorithm and an iterative optimizer. Biological microscope images processed with the nonlinear filter show a significant improvement in image quality and signal-to-noise ratio over the conventional linear filter.

  8. Synergism between soluble guanylate cyclase signaling and neuropeptides extends lifespan in the nematode Caenorhabditis elegans.

    PubMed

    Abergel, Rachel; Livshits, Leonid; Shaked, Maayan; Chatterjee, Arijit Kumar; Gross, Einav

    2017-04-01

    Oxygen (O2 ) homeostasis is important for all aerobic animals. However, the manner by which O2 sensing and homeostasis contribute to lifespan regulation is poorly understood. Here, we use the nematode Caenorhabditis elegans to address this question. We demonstrate that a loss-of-function mutation in the neuropeptide receptor gene npr-1 and a deletion mutation in the atypical soluble guanylate cyclase gcy-35 O2 sensor interact synergistically to extend worm lifespan. The function of npr-1 and gcy-35 in the O2 -sensing neurons AQR, PQR, and URX shortens the lifespan of the worm. By contrast, the activity of the atypical soluble guanylate cyclase O2 sensor gcy-33 in these neurons is crucial for lifespan extension. In addition to AQR, PQR, and URX, we show that the O2 -sensing neuron BAG and the interneuron RIA are also important for the lifespan lengthening. Neuropeptide processing by the proprotein convertase EGL-3 is essential for lifespan extension, suggesting that the synergistic effect of joint loss of function of gcy-35 and npr-1 is mediated through neuropeptide signal transduction. The extended lifespan is regulated by hypoxia and insulin signaling pathways, mediated by the transcription factors HIF-1 and DAF-16. Moreover, reactive oxygen species (ROS) appear to play an important function in lifespan lengthening. As HIF-1 and DAF-16 activities are modulated by ROS, we speculate that joint loss of function of gcy-35 and npr-1 extends lifespan through ROS signaling. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  9. 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.

  10. Multiple signal classification algorithm for super-resolution fluorescence microscopy

    PubMed Central

    Agarwal, Krishna; Macháň, Radek

    2016-01-01

    Single-molecule localization techniques are restricted by long acquisition and computational times, or the need of special fluorophores or biologically toxic photochemical environments. Here we propose a statistical super-resolution technique of wide-field fluorescence microscopy we call the multiple signal classification algorithm which has several advantages. It provides resolution down to at least 50 nm, requires fewer frames and lower excitation power and works even at high fluorophore concentrations. Further, it works with any fluorophore that exhibits blinking on the timescale of the recording. The multiple signal classification algorithm shows comparable or better performance in comparison with single-molecule localization techniques and four contemporary statistical super-resolution methods for experiments of in vitro actin filaments and other independently acquired experimental data sets. We also demonstrate super-resolution at timescales of 245 ms (using 49 frames acquired at 200 frames per second) in samples of live-cell microtubules and live-cell actin filaments imaged without imaging buffers. PMID:27934858

  11. Multiple signal classification algorithm for super-resolution fluorescence microscopy

    NASA Astrophysics Data System (ADS)

    Agarwal, Krishna; Macháň, Radek

    2016-12-01

    Single-molecule localization techniques are restricted by long acquisition and computational times, or the need of special fluorophores or biologically toxic photochemical environments. Here we propose a statistical super-resolution technique of wide-field fluorescence microscopy we call the multiple signal classification algorithm which has several advantages. It provides resolution down to at least 50 nm, requires fewer frames and lower excitation power and works even at high fluorophore concentrations. Further, it works with any fluorophore that exhibits blinking on the timescale of the recording. The multiple signal classification algorithm shows comparable or better performance in comparison with single-molecule localization techniques and four contemporary statistical super-resolution methods for experiments of in vitro actin filaments and other independently acquired experimental data sets. We also demonstrate super-resolution at timescales of 245 ms (using 49 frames acquired at 200 frames per second) in samples of live-cell microtubules and live-cell actin filaments imaged without imaging buffers.

  12. Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

    PubMed

    Guan, S-M; Fu, S-M; He, J-J; Zhang, M

    2011-01-01

    Prostaglandin E(2) (PGE(2)) plays important roles in the bone resorption of inflammatory diseases such as rheumatoid arthritis and periodontitis via specific prostaglandin receptors (i.e., EP1-EP4). In this study, the authors examined whether Prevotella intermedia regulates PGE(2) production and EP expression in human periodontal ligament fibroblasts (hPDLs); they also explored the potential signaling pathways involved in PGE(2) production. P. intermedia induced PGE(2) production and cyclooxygenase-2 (COX-2) expression in a dose- and time-dependent manner. Indomethacin and NS-398 completely abrogated the P. intermedia-induced PGE(2) production without modulating COX-2 expression. Specific inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, phosphatidylinositol 3-kinase, and protein kinase C--but not c-AMP and protein kinase A--significantly attenuated the P. intermedia-induced COX-2 and PGE(2) expression. P. intermedia reduced EP1 expression in a concentration- and time-dependent manner. The results indicate that the COX-2-dependent induction of PGE(2) by P. intermedia in hPDLs is mediated by multiple signaling pathways.

  13. Multiple telencephalic and extratelencephalic embryonic domains contribute neurons to the medial extended amygdala.

    PubMed

    Bupesh, Munisamy; Legaz, Isabel; Abellán, Antonio; Medina, Loreta

    2011-06-01

    Dysfunctions in emotional control and social behavior are behind human neuropsychiatric disorders, some of which are associated with an alteration of amygdalar development. The medial extended amygdala is a key telencephalic center for control of social behavior, but very little is known about its development. We used in vitro migration assays for analyzing the origin of the neurons of the medial extended amygdala in mouse embryos (E13.5-E16.5). We compared the migration assays with immunofluorescence/immunohistochemistry for calbindin and radial glial fibers and with mRNA expression of several genetic markers of distinct forebrain subdivisions. We provide experimental evidence for multiple embryonic origins of the principal neurons of the medial extended amygdala. In particular, we provide novel evidence indicating that a major part of the neurons derives from a caudoventral pallidal subdivision (previously called or included as part of the anterior peduncular area), forming a cell corridor with similar molecular features (expression of Lhx6 and calbindin), connectivity, and function, which relates to reproductive behavior. We also provide novel experimental evidence indicating that the ventral pallium produces some neurons for the medial amygdala, which correlates with data from Lhx9 expression. Our results also confirm that some neurons of the medial extended amygdala originate in the preoptic area (our results indicate that these cells specifically originate in its commissural subdivision) and the supraoptoparaventricular domain of the hypothalamus. Our study helps to set up the foundations for a better understanding of medial amygdalar control of behavior in normal and abnormal conditions.

  14. Experimental evaluation of the extended Dytlewski-style dead time correction formalism for neutron multiplicity counting

    DOE PAGES

    Lockhart, M.; Henzlova, D.; Croft, S.; ...

    2017-09-20

    Over the past few decades, neutron multiplicity counting has played an integral role in Special Nuclear Material (SNM) characterization pertaining to nuclear safeguards. Current neutron multiplicity analysis techniques use singles, doubles, and triples count rates because a methodology to extract and dead time correct higher order count rates (i.e. quads and pents) was not fully developed. This limitation is overcome by the recent extension of a popular dead time correction method developed by Dytlewski. This extended dead time correction algorithm, named Dytlewski-Croft-Favalli (DCF), is detailed in reference Croft and Favalli (2017), which gives an extensive explanation of the theory andmore » implications of this new development. Dead time corrected results can then be used to assay SNM by inverting a set of extended point model equations which as well have only recently been formulated. Here, we discuss and present the experimental evaluation of practical feasibility of the DCF dead time correction algorithm to demonstrate its performance and applicability in nuclear safeguards applications. In order to test the validity and effectiveness of the dead time correction for quads and pents, 252Cf and SNM sources were measured in high efficiency neutron multiplicity counters at the Los Alamos National Laboratory (LANL) and the count rates were extracted up to the fifth order and corrected for dead time. To assess the DCF dead time correction, the corrected data is compared to traditional dead time correction treatment within INCC. The DCF dead time correction is found to provide adequate dead time treatment for broad range of count rates available in practical applications.« less

  15. An Extended Mission to Multiple Asteroid Flybys after Lunar Exploration: Design and analysis

    NASA Astrophysics Data System (ADS)

    Dong, Qiao; Pingyuan, Cui; Hutao, Cui

    Asteroids are key objects for the research of the origin and evolution of the solar system, because they relatively well conserve their past, as they are often said to be the fossil from the early phase of the solar system. Human have carried out many small celestial body missions (such as DS-I, NEAR, Stardust, Deep impact, etc) and gained a plenty of valuable experience. With many new asteroid or comet missions in various stages of development (Dawn, ROSETTA, Hayabusa-II), the situation regarding our understanding of these bodies can improve in the future. With the success of "Chang-Er" program for lunar exploration and the development of "Ying-Huo" program for Mars exploration, it will provide the great opportunity for Chinese development of the deep space exploration. Following up the "Chang-Er" and "Ying-Huo" program, two promising scenarios have been discussed. One of them is a multiple asteroid rendezvous and sample return mission aiming at several spectral known Near-Earth asteroids. The other is a multiple asteroid flyby mission which is an extended "Chang-Er" mission for lunar exploration. Here, an extended mission to multiple asteroid flybys after lunar exploration is proposed and discussed. We investigated feasible mission scenarios. According to the constraints of the mission, we search and present the optimal rendezvous and flyby opportunities for potential asteroids. The preliminary design results of the proposed missions will be reported. Finally, we analyze the trajectory characteristics and gave some key parameters, which would have a direct impact on communication system, power system, thermal control system of spacecraft and the optical instrument for science mission etc.

  16. Serotonergic neurons signal reward and punishment on multiple timescales.

    PubMed

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

    2015-02-25

    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.

  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. An extended macro traffic flow model accounting for multiple optimal velocity functions with different probabilities

    NASA Astrophysics Data System (ADS)

    Cheng, Rongjun; Ge, Hongxia; Wang, Jufeng

    2017-08-01

    Due to the maximum velocity and safe headway distance of the different vehicles are not exactly the same, an extended macro model of traffic flow with the consideration of multiple optimal velocity functions with probabilities is proposed in this paper. By means of linear stability theory, the new model's linear stability condition considering multiple probabilities optimal velocity is obtained. The KdV-Burgers equation is derived to describe the propagating behavior of traffic density wave near the neutral stability line through nonlinear analysis. The numerical simulations of influences of multiple maximum velocities and multiple safety distances on model's stability and traffic capacity are carried out. The cases of two different kinds of maximum speeds with same safe headway distance, two different types of safe headway distances with same maximum speed and two different max velocities and two different time-gaps are all explored by numerical simulations. First cases demonstrate that when the proportion of vehicles with a larger vmax increase, the traffic tends to unstable, which also means that jerk and brakes is not conducive to traffic stability and easier to result in stop and go phenomenon. Second cases show that when the proportion of vehicles with greater safety spacing increases, the traffic tends to be unstable, which also means that too cautious assumptions or weak driving skill is not conducive to traffic stability. Last cases indicate that increase of maximum speed is not conducive to traffic stability, while reduction of the safe headway distance is conducive to traffic stability. Numerical simulation manifests that the mixed driving and traffic diversion does not have effect on the traffic capacity when traffic density is low or heavy. Numerical results also show that mixed driving should be chosen to increase the traffic capacity when the traffic density is lower, while the traffic diversion should be chosen to increase the traffic capacity when

  19. Extended storage of multiple excitons in trap states of semiconductor nanocrystals

    SciTech Connect

    Xu, Qinfeng; Huang, Xiangnan; Hua, Zheng; Zhang, Chunfeng; Wang, Xiaoyong; Hu, Lian; Du, Lingxiao; Wu, Huizhen; Xiao, Min

    2016-02-29

    Owing to the Auger recombination effect, multiple excitons (MEs) in semiconductor nanocrystals (NCs) are dissipated nonradiatively at the sub-nanosecond time scale, which sets a stringent limit on the time window within which one can operate with them. Here, we show that this issue can be resolved by utilizing an intrinsic energy transfer system in CdSe NCs, where MEs created in the donor quantized states can be effectively extracted to the acceptor trap states. This was evidenced by the step-like increase in the intensity and the apparent decrease in the rise time of the trap-state photoluminescence with the elevated laser excitation power. With the radiative lifetime being tens of nanoseconds for the trap states, extended storage of MEs has been achieved and marks a crucial step towards flexible manipulations of their optoelectronic properties.

  20. Real-Time Clustered Multiple Signal Classification (RTC-MUSIC).

    PubMed

    Dinh, Christoph; Esch, Lorenz; Rühle, Johannes; Bollmann, Steffen; Güllmar, Daniel; Baumgarten, Daniel; Hämäläinen, Matti S; Haueisen, Jens

    2017-09-06

    Magnetoencephalography (MEG) and electroencephalography provide a high temporal resolution, which allows estimation of the detailed time courses of neuronal activity. However, in real-time analysis of these data two major challenges must be handled: the low signal-to-noise ratio (SNR) and the limited time available for computations. In this work, we present real-time clustered multiple signal classification (RTC-MUSIC) a real-time source localization algorithm, which can handle low SNRs and can reduce the computational effort. It provides correlation information together with sparse source estimation results, which can, e.g., be used to identify evoked responses with high sensitivity. RTC-MUSIC clusters the forward solution based on an anatomical brain atlas and optimizes the scanning process inherent to MUSIC approaches. We evaluated RTC-MUSIC by analyzing MEG auditory and somatosensory data. The results demonstrate that the proposed method localizes sources reliably. For the auditory experiment the most dominant correlated source pair was located bilaterally in the superior temporal gyri. The highest activation in the somatosensory experiment was found in the contra-lateral primary somatosensory cortex.

  1. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

    PubMed

    Kunnumakkara, Ajaikumar B; Bordoloi, Devivasha; Harsha, Choudhary; Banik, Kishore; Gupta, Subash C; Aggarwal, Bharat B

    2017-08-01

    Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  2. NF-κB Signaling: Multiple angles to target OA

    PubMed Central

    Marcu, Kenneth B.; Otero, Miguel; Olivotto, Eleonora; Borzi, Rosa Maria; Goldring, Mary B.

    2011-01-01

    In the context of OA disease, NF-κB transcription factors can be triggered by a host of stress-related stimuli including pro-inflammatory cytokines, excessive mechanical stress and ECM degradation products. Activated NF-κB regulates the expression of many cytokines and chemokines, adhesion molecules, inflammatory mediators, and several matrix degrading enzymes. NF-κB also influences the regulated accumulation and remodeling of ECM proteins and has indirect positive effects on downstream regulators of terminal chondrocyte differentiation (including β-catenin and Runx2). Although driven partly by pro-inflammatory and stress-related factors, OA pathogenesis also involves a “loss of maturational arrest” that inappropriately pushes chondrocytes towards a more differentiated, hypertrophic-like state. Growing evidence points to NF-κB signaling as not only playing a central role in the pro-inflammatory stress-related responses of chondrocytes to extra- and intra-cellular insults, but also in the control of their differentiation program. Thus unlike other signaling pathways the NF-κB activating kinases are potential therapeutic OA targets for multiple reasons. Targeted strategies to prevent unwanted NF-κB activation in this context, which do not cause side effects on other proteins or signaling pathways, need to be focused on the use of highly specific drug modalities, siRNAs or other biological inhibitors that are targeted to the activating NF-κB kinases IKKα or IKKβ or specific activating canonical NF-κB subunits. However, work remains in its infancy to evaluate the effects of efficacious, targeted NF-κB inhibitors in animal models of OA disease in vivo and to also target these strategies only to affected cartilage and joints to avoid other undesirable systemic effects. PMID:20199390

  3. 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

  4. Global Registration of Kinect Point Clouds using Augmented Extended Information Filter and Multiple Features

    NASA Astrophysics Data System (ADS)

    Kang, Z.; Chang, M.

    2016-10-01

    Because the Infra-Red (IR) Kinect sensor only provides accurate depths up to 5 m for a limited field of view (60°), the problem of registration error accumulation becomes inevitable in indoor mapping. Therefore, in this paper, a global registration method is proposed based on augmented extended Information Filter (AEIF). The point cloud registration is regarded as a stochastic system so that AEIF is used to produces the accurate estimates of rigid transformation parameters through eliminating the error accumulation suffered by the pair-wise registration. Moreover, because the indoor scene normally contains planar primitives, they can be employed to control the registration of multiple scans. Therefore, the planar primitives are first fitted based on optimized BaySAC algorithm and simplification algorithm preserving the feature points. Besides the constraint of corresponding points, we then derive the plane normal vector constraint as an additional observation model of AEIF to optimize the registration parameters between each pair of adjacent scans. The proposed approach is tested on point clouds acquired by a Kinect camera from an indoor environment. The experimental results show that our proposed algorithm is proven to be capable of improving the accuracy of multiple scans aligning by 90%.

  5. Multiple Antibiotic-Resistant, Extended Spectrum-β-Lactamase (ESBL)-Producing Enterobacteria in Fresh Seafood.

    PubMed

    Sanjit Singh, Asem; Lekshmi, Manjusha; Prakasan, Sreepriya; Nayak, Binaya Bhusan; Kumar, Sanath

    2017-08-30

    Members of the family Enterobacteriaceae include several human pathogens that can be acquired through contaminated food and water. In this study, the incidence of extended spectrum β-lactamase (ESBL)-producing enterobacteria was investigated in fresh seafood sold in retail markets. The ESBL-positive phenotype was detected in 169 (78.60%) isolates, with Escherichia coli being the predominant species (53), followed by Klebsiella oxytoca (27), and K. pneumoniae (23). More than 90% of the isolates were resistant to third generation cephalosporins, cefotaxime, ceftazidime, and cefpodoxime. Sixty-five percent of the isolates were resistant to the monobactam drug aztreonam, 40.82% to ertapenem, and 31.36% to meropenem. Resistance to at least five antibiotics was observed in 38.46% of the isolates. Polymerase Chain Reaction (PCR) analysis of ESBL-encoding genes detected blaCTX, blaSHV, and blaTEM genes in 76.92%, 63.3%, and 44.37% of the isolates, respectively. Multiple ESBL genes were detected in majority of the isolates. The recently discovered New Delhi metallo-β-lactamase gene (blaNDM-1) was detected in two ESBL⁺ isolates. Our study shows that secondary contamination of fresh seafood with enteric bacteria resistant to multiple antibiotics may implicate seafood as a potential carrier of antibiotic resistant bacteria and emphasizes an urgent need to prevent environmental contamination and dissemination of such bacteria.

  6. Depression alters maternal extended amygdala response and functional connectivity during distress signals in attachment relationship.

    PubMed

    Ho, S Shaun; Swain, James E

    2017-05-15

    Maternal attachment-related parenting behaviors require mothers to regulate self-related and child-related distress. Emotion regulation is, in turn, influenced by maternal mood and personal developmental history. In the current study we examined how depressive mood may alter maternal limbic system function and functional connectivity underlying defensive and hedonic motivations. Twenty nine mothers were recruited to undergo a baby-cry task during a functional magnetic resonance imaging (fMRI) scan. Based on self-reported depression symptoms and clinical interview, the participants were grouped as healthy controls (n=15) and currently depressed (n=14). In the baby-cry task, 30s-long auditory stimuli of baby-cry sounds were presented to simulate four conditions: generic baby-cry (Just-Listen), baby-cry as if it were their own child's cry (Your-Baby), baby-cry as if it were themselves (Self), and matched control sounds (Noise). Depressed mothers, as compared to healthy controls, showed greater Self versus Just-Listen responses in left extended amygdala and decreased functional coupling between this left extended amygdala as the seed and nucleus accumbens (NAc) in self-oriented (Self versus Just-Listen) and child-oriented (Your-Baby versus Just-Listen) distress signals. Moreover, the extended amygdala's differential functional connectivity with dorsomedial prefrontal cortex (dmPFC) during the Your-Baby versus Self was increased for depressed mothers and decreased for healthy controls. Thus, depression may affect mothers by increasing baby-cry threat responses and dysregulating associations between threat and heathy child-oriented parenting motivations. These results are discussed in the context of attachment and self-psychology. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    PubMed Central

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

    2015-01-01

    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

  8. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.

    PubMed

    Goodman, Andrew D; Brown, Theodore R; Edwards, Keith R; Krupp, Lauren B; Schapiro, Randall T; Cohen, Ron; Marinucci, Lawrence N; Blight, Andrew R

    2010-10-01

    A previous phase 3 study showed significant improvement in walking ability in multiple sclerosis (MS) patients treated with oral, extended-release dalfampridine (4-aminopyridine) 10mg twice daily. The current study was designed to confirm efficacy and further define safety and pharmacodynamics. This was a 39-center, double-blind trial in patients with definite MS of any course type. Participants were randomized to 9 weeks of treatment with dalfampridine (10mg twice daily; n = 120) or placebo (n = 119). Response was defined as consistent improvement on the Timed 25-Foot Walk, with percentage of timed walk responders (TWRs) in each treatment group as the primary outcome. The last on-treatment visit provided data from 8 to 12 hours postdose, to examine maintenance of effect. One patient from each group was excluded from the modified Intention to Treat population. The proportion of TWRs was higher in the dalfampridine group (51/119 or 42.9%) compared to the placebo group (11/118 or 9.3%, p < 0.0001). The average improvement in walking speed among dalfampridine-treated TWRs during the 8-week efficacy evaluation period was 24.7% from baseline (95% confidence interval, 21.0-28.4%); the mean improvement at the last on-treatment visit was 25.7%, showing maintenance of effect over the interdosing period. There were no new safety findings. This interventional study provides class 1 evidence that dalfampridine extended-release tablets produce clinically meaningful improvement in walking ability in a subset of people with MS, with the effect maintained between doses.

  9. Advanced UXO discrimination: resolving multiple targets and overlapping EMI signals

    NASA Astrophysics Data System (ADS)

    Shubitidze, Fridon; Barrowes, Benjamin E.; Shamatava, Irma; Fernandez, Juan Pablo; Bijamov, Alex; O'Neill, Kevin

    2011-06-01

    In this paper we employ advanced electromagnetic induction models to resolve multiple targets with overlapping EMI signals-i.e. to discriminate objects of interest, such as unexploded ordnance (UXO), from innocuous items. The models include a) a joint diagonalization (JD) technique that takes data from next-generation EMI sensors and uses the eigenvalues of the multistatic response matrix to estimate the number of potential targets, and b) the orthonormalized volume magnetic source (ONVMS) model, a physically complete, fast, and accurate forward model whose representation of a target's intrinsic EMI response is used to extract classification parameters. In the given approach the overall EMI inversion and classification problem proceeds as follows: first, the JD is applied to the data and the number of targets is estimated; once this is known, the ONVMS is combined with an optimization technique to yield the location and orientation of each buried object, as well as the amplitude of its ONVMS. Finally, a total ONVMS is calculated for each object and used as a discriminant to distinguish between UXO and non-UXO items and between different kinds of UXO. We illustrate the applicability of our multi-target analysis technique by using it on several teststand and live-site datasets collected with the TEMTADS sensor array. We end by demonstrating the superior performance of the ONVMS by applying it to multi-target blind-test data compiled at the Aberdeen Proving Ground test-stand facility.

  10. 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

  11. Instance influence estimation for hyperspectral target signature characterization using extended functions of multiple instances

    NASA Astrophysics Data System (ADS)

    Zou, Sheng; Zare, Alina

    2016-05-01

    The Extended Functions of Multiple Instances (eFUMI) algorithm1 is a generalization of Multiple Instance Learning (MIL). In eFUMI, only bag level (i.e. set level) labels are needed to estimate target signatures from mixed data. The training bags in eFUMI are labeled positive if any data point in a bag contains or represents any proportion of the target signature and are labeled as a negative bag if all data points in the bag do not represent any target. From these imprecise labels, eFUMI has been shown to be effective at estimating target signatures in hyperspectral subpixel target detection problems. One motivating scenario for the use of eFUMI is where an analyst circles objects/regions of interest in a hyperspectral scene such that the target signatures of these objects can be estimated and be used to determine whether other instances of the object appear elsewhere in the image collection. The regions highlighted by the analyst serve as the imprecise labels for eFUMI. Often, an analyst may want to iteratively refine their imprecise labels. In this paper, we present an approach for estimating the influence on the estimated target signature if the label for a particular input data point is modified. This instance influence estimation guides an analyst to focus on (re-)labeling the data points that provide the largest change in the resulting estimated target signature and, thus, reduce the amount of time an analyst needs to spend refining the labels for a hyperspectral scene. Results are shown on real hyperspectral sub-pixel target detection data sets.

  12. Multiple sclerosis and alcohol use disorders: In-hospital mortality, extended hospital stays, and overexpenditures.

    PubMed

    Gili-Miner, M; López-Méndez, J; Vilches-Arenas, A; Ramírez-Ramírez, G; Franco-Fernández, D; Sala-Turrens, J; Béjar-Prado, L

    2016-10-22

    The objective of this study was to analyse the impact of alcohol use disorders (AUD) in patients with multiple sclerosis (MS) in terms of in-hospital mortality, extended hospital stays, and overexpenditures. We conducted a retrospective observational study in a sample of MS patients obtained from minimal basic data sets from 87 Spanish hospitals recorded between 2008 and 2010. Mortality, length of hospital stays, and overexpenditures attributable to AUD were calculated. We used a multivariate analysis of covariance to control for such variables as age and sex, type of hospital, type of admission, other addictions, and comorbidities. The 10,249 patients admitted for MS and aged 18-74 years included 215 patients with AUD. Patients with both MS and AUD were predominantly male, with more emergency admissions, a higher prevalence of tobacco or substance use disorders, and higher scores on the Charlson comorbidity index. Patients with MS and AUD had a very high in-hospital mortality rate (94.1%) and unusually lengthy stays (2.4 days), and they generated overexpenditures (1,116.9euros per patient). According to the results of this study, AUD in patients with MS results in significant increases in-hospital mortality and the length of the hospital stay and results in overexpenditures. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  13. hTERT Extends the Life of Human Fibroblasts without Compromising Type I Interferon Signaling

    PubMed Central

    Perusina Lanfranca, Mirna; Davido, David J.

    2013-01-01

    Primary cells are often used to study viral replication and host-virus interactions as their antiviral pathways have not been altered or inactivated; however, their use is restricted by their short lifespan. Conventional methods to extend the life of primary cultures typically utilize viral oncogenes. Many of these oncogenes, however, perturb or inactivate cellular antiviral pathways, including the interferon (IFN) response. It has been previously shown that expression of the telomerase reverse transcriptase (TERT) gene extends the life of certain cell types. The effect that TERT expression has on the innate antiviral response to RNA- and DNA-containing viruses has not been examined. In the current study, we introduced the human TERT (hTERT) gene into a primary human embryonic lung (HEL-299) cell strain, which is known to respond to the type I IFN, IFN-β. We show that the resulting HEL-TERT cell line is capable of replicating beyond 100 population doublings without exhibiting signs of senescence. Treatment with IFN-β resulted in the upregulation of four model IFN stimulated genes (ISGs) in HEL-299 and HEL-TERT cells. Both cell lines supported the replication of herpes simplex virus type 1 (HSV-1) and vesicular stomatitis virus (VSV) and impaired the replication of both viruses upon IFN-β pretreatment. Introduction of the viral oncoprotein, simian virus 40 (SV40) large T-antigen, which is frequently used to immortalize cells, largely negated this effect. Taken together, our data indicate that expression of hTERT does not alter type 1 IFN signaling and/or the growth of two viruses, making this cell line a useful reagent for studying viral replication and virus-cell interactions. PMID:23472163

  14. 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.

  15. 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.

  16. Single-channel mixed signal blind source separation algorithm based on multiple ICA processing

    NASA Astrophysics Data System (ADS)

    Cheng, Xiefeng; Li, Ji

    2017-01-01

    Take separating the fetal heart sound signal from the mixed signal that get from the electronic stethoscope as the research background, the paper puts forward a single-channel mixed signal blind source separation algorithm based on multiple ICA processing. Firstly, according to the empirical mode decomposition (EMD), the single-channel mixed signal get multiple orthogonal signal components which are processed by ICA. The multiple independent signal components are called independent sub component of the mixed signal. Then by combining with the multiple independent sub component into single-channel mixed signal, the single-channel signal is expanded to multipath signals, which turns the under-determined blind source separation problem into a well-posed blind source separation problem. Further, the estimate signal of source signal is get by doing the ICA processing. Finally, if the separation effect is not very ideal, combined with the last time's separation effect to the single-channel mixed signal, and keep doing the ICA processing for more times until the desired estimated signal of source signal is get. The simulation results show that the algorithm has good separation effect for the single-channel mixed physiological signals.

  17. Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways.

    PubMed

    Lunghi, Paolo; Giuliani, Nicola; Mazzera, Laura; Lombardi, Guerino; Ricca, Micaela; Corradi, Attilio; Cantoni, Anna Maria; Salvatore, Luigi; Riccioni, Roberta; Costanzo, Antonio; Testa, Ugo; Levrero, Massimo; Rizzoli, Vittorio; Bonati, Antonio

    2008-09-15

    We demonstrate that blockade of the MEK/ERK signaling module, using the small-molecule inhibitors PD184352 or PD325901 (PD), strikingly enhances arsenic trioxide (ATO)-induced cytotoxicity in human myeloma cell lines (HMCLs) and in tumor cells from patients with multiple myeloma (MM) through a caspase-dependent mechanism. In HMCLs retaining a functional p53, PD treatment greatly enhances the ATO-induced p53 accumulation and p73, a p53 paralog, cooperates with p53 in caspase activation and apoptosis induction. In HMCLs carrying a nonfunctional p53, cotreatment with PD strikingly elevates the (DR4 + DR5)/(DcR1 + DcR2) tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors ratio and caspase-8 activation of ATO-treated cells. In MM cells, irrespective of p53 status, the combined PD/ATO treatment increases the level of the proapoptotic protein Bim (PD-mediated) and decreases antiapoptotic protein Mcl-1 (ATO-mediated). Moreover, Bim physically interacts with both DR4 and DR5 TRAIL receptors in PD/ATO-treated cells, and loss of Bim interferes with the activation of both extrinsic and intrinsic apoptotic pathways in response to PD/ATO. Finally, PD/ATO treatment induces tumor regression, prolongs survival, and is well tolerated in vivo in a human plasmacytoma xenograft model. These preclinical studies provide the framework for testing PD325901 and ATO combination therapy in clinical trials aimed to improve patient outcome in MM.

  18. Targeting Multiple Key Signaling Pathways in Melanoma using Leelamine

    PubMed Central

    Gowda, Raghavendra; Madhunapantula, SubbaRao V.; Kuzu, Omer F.; Sharma, Arati; Robertson, Gavin P.

    2015-01-01

    Melanoma is a highly drug resistant cancer with resistance developing to agents targeting single proteins. To circumvent this problem, a new class of agent inhibiting multiple key pathways important in this disease is being developed to reduce the likelihood of developing resistant disease. The PI3 kinase (PI3K), MAP kinase (MAPK) and STAT3 pathways are constitutively activated in 50–70% of melanomas promoting disease development. To identify a drug simultaneously targeting the PI3K, MAPK and STAT3 cascades, a natural product library was screened to identifying leelamine as a potential inhibitor. Leelamine was 4.5-fold more effective at inhibiting cultured melanoma cell survival than normal cells, with average IC50 values of 2 and 9.3 µmol/L, respectively. It inhibited cellular proliferation at a concentration of 2.5 µmol/L by 40–80% and longer exposure increased apoptosis 600% through a mechanism detailed in the article in the current issue of this journal by Kuzu OF et al. Leelamine inhibited the growth of preexisting xenografted melanoma tumors by an average of 60% by targeting the PI3K, MAPK and STAT3 pathways without affecting animal body weight or blood markers of major organ function. The mechanism of action of leelamine is mediated by disruption of cholesterol transport, causing decreased cellular proliferation and, consequently leading to increased tumor cell apoptosis as well as decreased tumor vascularization. Thus, a unique agent and novel mechanism of action has been identified for the treatment of melanoma that acts by inhibiting the activity of three major signaling pathways regulating the development of this disease. PMID:24688050

  19. The Cbln family of proteins interact with multiple signaling pathways.

    PubMed

    Wei, Peng; Pattarini, Roberto; Rong, Yongqi; Guo, Hong; Bansal, Parmil K; Kusnoor, Sheila V; Deutch, Ariel Y; Parris, Jennifer; Morgan, James I

    2012-06-01

    Cerebellin precursor protein (Cbln1) is essential for synapse integrity in cerebellum through assembly into complexes that bridge pre-synaptic β-neurexins (Nrxn) to post-synaptic GluRδ2. However, GluRδ2 is largely cerebellum-specific, yet Cbln1 and its little studied family members, Cbln2 and Cbln4, are expressed throughout brain. Therefore, we investigated whether additional proteins mediate Cbln family actions. Whereas Cbln1 and Cbln2 bound to GluRδ2 and Nrxns1-3, Cbln4 bound weakly or not at all, suggesting it has distinct binding partners. In a candidate receptor-screening assay, Cbln4 (but not Cbln1 or Cbln2) bound selectively to the netrin receptor, (deleted in colorectal cancer (DCC) in a netrin-displaceable fashion. To determine whether Cbln4 had a netrin-like function, Cbln4-null mice were generated. Cbln4-null mice did not phenocopy netrin-null mice. Cbln1 and Cbln4 were likely co-localized in neurons thought to be responsible for synaptic changes in striatum of Cbln1-null mice. Furthermore, complexes containing Cbln1 and Cbln4 had greatly reduced affinity to DCC but increased affinity to Nrxns, suggesting a functional interaction. However, Cbln4-null mice lacked the striatal synaptic changes seen in Cbln null mice. Thus, Cbln family members interact with multiple receptors/signaling pathways in a subunit composition-dependent manner and have independent functions with Cbln4 potentially involved in the less well-characterized role of netrin/DCC in adult brain.

  20. 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.

  1. Target of rapamycin signalling mediates the lifespan-extending effects of dietary restriction by essential amino acid alteration.

    PubMed

    Emran, Sahar; Yang, Mingyao; He, Xiaoli; Zandveld, Jelle; Piper, Matthew D W

    2014-05-01

    Dietary restriction (DR), defined as a moderate reduction in food intake short of malnutrition, has been shown to extend healthy lifespan in a diverse range of organisms, from yeast to primates. Reduced signalling through the insulin/IGF-like (IIS) and Target of Rapamycin (TOR) signalling pathways also extend lifespan. InDrosophila melanogaster the lifespan benefits of DR can be reproduced by modulating only the essential amino acids in yeast based food. Here, we show that pharmacological downregulation of TOR signalling, but not reduced IIS, modulates the lifespan response to DR by amino acid alteration. Of the physiological responses flies exhibit upon DR, only increased body fat and decreased heat stress resistance phenotypes correlated with longevity via reduced TOR signalling. These data indicate that lowered dietary amino acids promote longevity via TOR, not by enhanced resistance to molecular damage, but through modified physiological conditions that favour fat accumulation.

  2. Target of rapamycin signalling mediates the lifespan-extending effects of dietary restriction by essential amino acid alteration

    PubMed Central

    Emran, Sahar; Yang, Mingyao; He, Xiaoli; Zandveld, Jelle; Piper, Matthew D. W.

    2014-01-01

    Dietary restriction (DR), defined as a moderate reduction in food intake short of malnutrition, has been shown to extend healthy lifespan in a diverse range of organisms, from yeast to primates. Reduced signalling through the insulin/IGF-like (IIS) and Target of Rapamycin (TOR) signalling pathways also extend lifespan. In Drosophila melanogaster the lifespan benefits of DR can be reproduced by modulating only the essential amino acids in yeast based food. Here, we show that pharmacological downregulation of TOR signalling, but not reduced IIS, modulates the lifespan response to DR by amino acid alteration. Of the physiological responses flies exhibit upon DR, only increased body fat and decreased heat stress resistance phenotypes correlated with longevity via reduced TOR signalling. These data indicate that lowered dietary amino acids promote longevity via TOR, not by enhanced resistance to molecular damage, but through modified physiological conditions that favour fat accumulation. PMID:24861087

  3. Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine.

    PubMed

    Olsson, B; Szamosi, J

    2001-01-01

    To determine the multiple dose pharmacokinetics of a new extended release (ER) capsule formulation of tolterodine, compared with the existing immediate release (IR) tablet, in healthy volunteers. Nonblind, randomised, 2-way crossover trial. 19 healthy volunteers (7 females, 12 males), mean age 33 years (range 18 to 55 years). Prior to the study, all volunteers were classified as either extensive or poor metabolisers by cytochrome P450 2D6 genotyping. Volunteers received tolterodine ER 4mg once daily or tolterodine IR 2mg twice daily for 6 days (all doses given as the L-tartrate salt). A washout period of 7 days separated the 2 treatments. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (extensive metabolisers: sum of unbound tolterodine + 5-HM; poor metabolisers: unbound tolterodine) were measured for up to 48 hours post-dose on day 6 (steady state). Tolerability was also determined. 17 volunteers (13 extensive metabolisers, 4 poor metabolisers) completed the study and were evaluable for both treatment periods. The 90% confidence interval for the geometric mean ratio of area under the serum concentration-time curve to 24 hours (AUC24) of the active moiety, for all volunteers combined, indicated equivalence for the 2 formulations. Pooled analysis also demonstrated that the peak serum concentration (Cmax) of the active moiety following administration of tolterodine ER was around 75% of that observed for the IR tablet, whereas the trough concentration was around 1.5-fold higher. Overall, the pharmacokinetics of tolterodine (irrespective of genotype) and 5-HM (extensive metabolisers only) were consistent with sustained drug release over 24 hours. Tolterodine ER was well tolerated. The new once daily ER formulation of tolterodine 4mg shows pharmacokinetic equivalence (AUC24) to the existing IR tablet given at a dose of 2mg twice daily. Findings of lower Cmax for tolterodine ER may explain the significantly lower

  4. Waveform inversion of volcano-seismic signals for an extended source

    USGS Publications Warehouse

    Nakano, M.; Kumagai, H.; Chouet, B.; Dawson, P.

    2007-01-01

    We propose a method to investigate the dimensions and oscillation characteristics of the source of volcano-seismic signals based on waveform inversion for an extended source. An extended source is realized by a set of point sources distributed on a grid surrounding the centroid of the source in accordance with the source geometry and orientation. The source-time functions for all point sources are estimated simultaneously by waveform inversion carried out in the frequency domain. We apply a smoothing constraint to suppress short-scale noisy fluctuations of source-time functions between adjacent sources. The strength of the smoothing constraint we select is that which minimizes the Akaike Bayesian Information Criterion (ABIC). We perform a series of numerical tests to investigate the capability of our method to recover the dimensions of the source and reconstruct its oscillation characteristics. First, we use synthesized waveforms radiated by a kinematic source model that mimics the radiation from an oscillating crack. Our results demonstrate almost complete recovery of the input source dimensions and source-time function of each point source, but also point to a weaker resolution of the higher modes of crack oscillation. Second, we use synthetic waveforms generated by the acoustic resonance of a fluid-filled crack, and consider two sets of waveforms dominated by the modes with wavelengths 2L/3 and 2W/3, or L and 2L/5, where W and L are the crack width and length, respectively. Results from these tests indicate that the oscillating signature of the 2L/3 and 2W/3 modes are successfully reconstructed. The oscillating signature of the L mode is also well recovered, in contrast to results obtained for a point source for which the moment tensor description is inadequate. However, the oscillating signature of the 2L/5 mode is poorly recovered owing to weaker resolution of short-scale crack wall motions. The triggering excitations of the oscillating cracks are successfully

  5. 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…

  6. [Multiple Dopamine Signals and Their Contributions to Reinforcement Learning].

    PubMed

    Matsumoto, Masayuki

    2016-10-01

    Midbrain dopamine neurons are activated by reward and sensory cue that predicts reward. Their responses resemble reward prediction error that indicates the discrepancy between obtained and expected reward values, which has been thought to play an important role as a teaching signal in reinforcement learning. Indeed, pharmacological blockade of dopamine transmission interferes with reinforcement learning. Recent studies reported, however, that not all dopamine neurons transmit the reward-related signal. They found that a subset of dopamine neurons transmits signals related to non-rewarding, salient experiences such as aversive stimulations and cognitively demanding events. How these signals contribute to animal behavior is not yet well understood. This article reviews recent findings on dopamine signals related to rewarding and non-rewarding experiences, and discusses their contributions to reinforcement learning.

  7. Enhanced method with superposed signal-based visible light communication system using multiple-input signal-output beamforming

    NASA Astrophysics Data System (ADS)

    Qiao, Liang; Liang, Shangyu; Lu, Xingyu; Zhou, Yingjun; Jiang, Yi; Chi, Nan

    2017-08-01

    As a promising candidate technology for the next generation communication systems, visible light communication (VLC), combined with high modulation and coding schemes, can be used to achieve throughput much higher than the traditional RF wireless ones. We propose adopting multiple light-emitting diodes (LEDs) on the transmit side to form a multiple-input signal-output (MISO) VLC system. Through the maximum ratio transmit beamforming, the signals from the multiple LEDs can be added coherently at the receiver side, and, therefore, the signal-to-noise ratio of the system can be improved slightly. Meanwhile, a method of channel estimation with superposed signal is employed for better channel estimation. Extensive lab experiments demonstrate that a two-LED MISO-VLC system can achieve a data rate of 1.0 Gbit/s over a free-space link of 1.2 m.

  8. Extended Salecker-Wigner formula for optimal accuracy in reading a clock via a massive signal particle

    SciTech Connect

    Kudaka, Shoju; Matsumoto, Shuichi

    2007-07-15

    In order to acquire an extended Salecker-Wigner formula from which to derive the optimal accuracy in reading a clock with a massive particle as the signal, von Neumann's classical measurement is employed, by which simultaneously both position and momentum of the signal particle can be measured approximately. By an appropriate selection of wave function for the initial state of the composite system (a clock and a signal particle), the formula is derived accurately. Valid ranges of the running time of a clock with a given optimal accuracy are also given. The extended formula means that contrary to the Salecker-Wigner formula there exists the possibility of a higher accuracy of time measurement, even if the mass of the clock is very small.

  9. 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.

  10. Seismic Signals from Multiple Near-Simultaneous Nuclear Explosions

    NASA Astrophysics Data System (ADS)

    Stevens, J. L.; O'Brien, M.

    2016-12-01

    An important open nuclear monitoring question is whether multiple nuclear explosions conducted either simultaneously or very close together in time generate seismic waves that are sufficiently different from a tamped single explosion to cause errors in yield estimation or discrimination. In particular, Novaya Zemlya tests with multiple explosions were observed to have low mb, leading to possible underestimation of the total explosion yield. The Soviet Union conducted many "salvo explosions" which is defined to mean two or more separate explosions where the period of time between successive individual explosions does not exceed 5 seconds for each event. Most of these were performed at the Novaya Zemlya test site, and as many as eight near-simultaneous explosions were conducted in a single test. The United States also did some multiple explosion tests. For example, Rio Blanco, a natural gas reservoir stimulation test in Colorado, consisted of three 33 kiloton explosions vertically spaced approximately 100 meters apart. To address this question, we are performing nonlinear calculations of multiple explosions, and modeling a number of known multiple explosions. For each test, we also perform a calculation of a single explosion with the same total yield. We propagate the results of the calculation to distant stations using the representation theorem and compare the results of the single and multiple explosion calculations. An initial calculation of Rio Blanco shows that far-field P-waves from the multiple explosions vary as a function of take-off angle, and are more complex than the single explosion, particularly at higher frequencies. However the P-waves from the single and multiple explosions are identical at frequencies less than about 5 Hz.

  11. 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

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

    PubMed Central

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

    2008-01-01

    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

  13. Multiple Choices after School: Findings from the Extended-Service Schools Initiative.

    ERIC Educational Resources Information Center

    Grossman, Jean Baldwin; Price, Marilyn L.; Fellerath, Veronica; Jucovy, Linda Z.; Kotloff, Lauren J.; Raley, Rebecca; Walker, Karen E.

    This study evaluated the effectiveness of the Extended-Service Schools (ESS) Initiative, which supported the creation of 60 after school programs in 20 low-income communities nationwide. Each community adapted one of four nationally recognized models that had been successfully developed and implemented in other cities. The models all promoted…

  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. 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…

  16. Are Luxury Brand Labels and "Green" Labels Costly Signals of Social Status? An Extended Replication.

    PubMed

    Berger, Joël

    2017-01-01

    Costly signaling theory provides an explanation for why humans are willing to a pay a premium for conspicuous products such as luxury brand-labeled clothing or conspicuous environmentally friendly cars. According to the theory, the extra cost of such products is a signal of social status and wealth and leads to advantages in social interactions for the signaler. A previous study found positive evidence for the case of luxury brand labels. However, an issue of this study was that some of the experiments were not conducted in a perfectly double-blind manner. I resolved this by replicating variations of the original design in a double-blind procedure. Additionally, besides the luxury label condition, I introduced a "green" label condition. Thus, the hypothesis that signaling theory is able to explain pro-environmental behavior was tested for the first time in a natural field setting. Further, I conducted experiments in both average and below-average socioeconomic neighborhoods, where, according to signaling theory, the effects of luxury signals should be even stronger. In contrast to the original study, I did not find positive effects of the luxury brand label in any of the five experiments. Nor did I find evidence for a green-signaling effect. Moreover, in poor neighborhoods a negative tendency of the luxury label actually became evident. This suggests that a signaling theory explanation of costly labels must take into account the characteristics of the observers, e.g. their social status.

  17. Reconstruction of Multidimensional Signals from Multiple Level Threshold Crossings.

    DTIC Science & Technology

    1988-01-01

    New York: Springer-Verlag, 1978. [38] A. Mostowski and M. Stark. Introducion to Higher Algebra . New York: Mac-Millan Co., 1964. 139] A. Zakhor and D...thresholds. I- orde-’ to circumvent this difficulty, we-pepeeea second approach which is implicit, ~aauses algebraic geometric concepts to find conditions...approach which is implicit, and uses algebraic geometric con- cepts to find conditions under which a signal is almost always reconstructible from its

  18. RNAi Induces Innate Immunity through Multiple Cellular Signaling Pathways

    PubMed Central

    Wu, Jun; Pei, Rongjuan; Xu, Yang; Yang, Dongliang; Roggendorf, Michael; Lu, Mengji

    2013-01-01

    Background & Aims Our previous results showed that the knockdown of woodchuck hepatitis virus (WHV) by RNA interference (RNAi) led to upregulation of interferon stimulated genes (ISGs) in primary hepatocytes. In the present study, we tested the hypothesis that the cellular signaling pathways recognizing RNA molecules may be involved the ISG stimulation by RNAi. Methods Primary murine hepatocytes (PMHs) from wild type mice and WHV transgenic (Tg) mice were prepared and treated with defined siRNAs. The mRNA levels of target genes and ISGs were detected by real-time RT-PCR. The involvement of the signaling pathways including RIG-I/MDA5, PKR, and TLR3/7/8/9 was examined by specific inhibition and the analysis of their activation by Western blotting. Results In PMHs from WHV Tg mice, specific siRNAs targeting WHV, mouse β-actin, and GAPDH reduced the levels of targeted mRNAs and increased the mRNA expression of IFN-β, MxA, and IP-10. The enhanced ISG expression by siRNA transfection were abolished by siRNA-specific 2′-O-methyl antisense RNA and the inhibitors 2-AP and chloroquine blocking PKR and other TLR-mediated signaling pathways. Furthermore, Western blotting revealed that RNAi results in an increase in PKR phosphorylation and nuclear translocation of IRF3 and NF-êB, indicating the possible role of IRF3 in the RNAi-directed induction of ISGs. In contrast, silencing of RIG-I and MDA5 failed to block RNAi-mediated MxA induction. Conclusions RNAi is capable of enhancing innate immune responses through the PKR- and TLR-dependent signaling pathways in primary hepatocytes. The immune stimulation by RNAi may contribute to the antiviral activity of siRNAs in vivo. PMID:23700487

  19. Multiple Distinct Targeting Signals in Integral Peroxisomal Membrane Proteins

    PubMed Central

    Jones, Jacob M.; Morrell, James C.; Gould, Stephen J.

    2001-01-01

    Peroxisomal proteins are synthesized on free polysomes and then transported from the cytoplasm to peroxisomes. This process is mediated by two short well-defined targeting signals in peroxisomal matrix proteins, but a well-defined targeting signal has not yet been described for peroxisomal membrane proteins (PMPs). One assumption in virtually all prior studies of PMP targeting is that a given protein contains one, and only one, distinct targeting signal. Here, we show that the metabolite transporter PMP34, an integral PMP, contains at least two nonoverlapping sets of targeting information, either of which is sufficient for insertion into the peroxisome membrane. We also show that another integral PMP, the peroxin PEX13, also contains two independent sets of peroxisomal targeting information. These results challenge a major assumption of most PMP targeting studies. In addition, we demonstrate that PEX19, a factor required for peroxisomal membrane biogenesis, interacts with the two minimal targeting regions of PMP34. Together, these results raise the interesting possibility that PMP import may require novel mechanisms to ensure the solubility of integral PMPs before their insertion in the peroxisome membrane, and that PEX19 may play a central role in this process. PMID:11402059

  20. 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

  1. An ion-transporting ATPase encodes multiple apical localization signals

    PubMed Central

    1993-01-01

    Epithelial cells accumulate distinct populations of membrane proteins at their two plasmalemmal domains. We have examined the molecular signals which specify the differential subcellular distributions of two closely related ion pumps. The Na,K-ATPase is normally restricted to the basolateral membranes of numerous epithelial cell types, whereas the H,K-ATPase is a component of the apical surfaces of the parietal cells of the gastric epithelium. We have expressed full length and chimeric H,K-ATPase/Na,K-ATPase cDNAs in polarized renal proximal tubular epithelial cells (LLC-PK1). We find that both the alpha and beta subunits of the H,K-ATPase encode independent signals that specify apical localization. Furthermore, the H,K-ATPase beta-subunit possesses a sequence which mediates its participation in the endocytic pathway. The interrelationship between epithelial sorting and endocytosis signals suggested by these studies supports the redefinition of apical and basolateral as functional, rather than simply topographic domains. PMID:8385670

  2. Multiple roles and therapeutic implications of Akt signaling in cancer

    PubMed Central

    Calvo, Emiliano; Bolós, Victoria; Grande, Enrique

    2009-01-01

    The prominence of the PI3K-Akt signaling pathway in several tumors indicates a relationship with tumor grade and proliferation. Critical cellular processes are driven through this pathway. More detailed knowledge of the pathogenesis of tumors would enable us to design targeted drugs to block both membrane tyrosine kinase receptors and the intracellular kinases involved in the transmission of the signal. The newly approved molecular inhibitors sunitinib (an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and other tyrosine kinase receptors), sorafenib (a serine–threonine kinase inhibitor that acts against B-Raf) and temsirolimus (an mTOR inhibitor) shown clinical activity in advanced kidney cancer. Chronic myeloid leukemia has changed its natural history thanks to imatinib and dasatinib, both of which inhibit the intracellular bcr/abl protein derived from the alteration in the Philadelphia chromosome. Intracellular pathways are still important in cancer development and their blockade directly affects outcome. Cross-talk has been observed but is not well understood. Vertical and horizontal pathway blockade are promising anticancer strategies. Indeed, preclinical and early clinical data suggest that combining superficial and intracellular blocking agents can synergize and leverage single-agent activity. The implication of the Akt signaling pathway in cancer is well established and has led to the development of new anticancer agents that block its activation. PMID:20616901

  3. Code division multiple access signaling for modulated reflector technology

    DOEpatents

    Briles, Scott D [Los Alamos, NM

    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.

  4. IL-17RC is required for immune signaling via an extended SEF/IL-17R signaling domain in the cytoplasmic tail.

    PubMed

    Ho, Allen W; Shen, Fang; Conti, Heather R; Patel, Nayan; Childs, Erin E; Peterson, Alanna C; Hernández-Santos, Nydiaris; Kolls, Jay K; Kane, Lawrence P; Ouyang, Wenjun; Gaffen, Sarah L

    2010-07-15

    IL-17 mediates essential inflammatory responses in host defense and autoimmunity. The IL-17A-IL-17F signaling complex is composed of IL-17RA and IL-17RC, both of which are necessary for signal transduction. To date, the specific contribution of IL-17RC to downstream signaling remains poorly understood. To define the regions within the IL-17RC cytoplasmic tail required for signal transduction, we assayed signaling by a panel of IL-17RC deletion mutants. These findings reveal that IL-17RC inducibly associates with a specific glycosylated IL-17RA isoform, in a manner independent of the IL-17RC cytoplasmic tail. Using expression of the IL-17 target genes IL-6 and 24p3/lipocalin-2 as a readout, functional reconstitution of signaling in IL-17RC(-/-) fibroblasts required the SEF/IL-17R signaling domain (SEFIR), a conserved motif common to IL-17R family members. Unexpectedly, the IL-17RC SEFIR alone was not sufficient to reconstitute IL-17-dependent signaling. Rather, an additional sequence downstream of the SEFIR was also necessary. We further found that IL-17RC interacts directly with the adaptor/E3 ubiquitin ligase Act1, and that the functional IL-17RC isoforms containing the extended SEFIR region interact specifically with a phosphorylated isoform of Act1. Finally, we show that IL-17RC is required for in vivo IL-17-dependent responses during oral mucosal infections caused by the human commensal fungus Candida albicans. These results indicate that IL-17RC is vital for IL-17-dependent signaling both in vitro and in vivo. Insight into the mechanisms by which IL-17RC signals helps shed light on IL-17-dependent inflammatory responses and may ultimately provide an avenue for therapeutic intervention in IL-17-mediated diseases.

  5. Osteochondroma of the cervical spine extending multiple segments with cord compression.

    PubMed

    Moon, Kyung-Sub; Lee, Jung-Kil; Kim, Yeon-Seong; Kwak, Hyung-Jun; Joo, Sung-Pil; Kim, In-Young; Kim, Jae-Hyoo; Kim, Soo-Han

    2006-01-01

    Involvement of the cervical spinal cord by a solitary osteochondroma is rare. We describe a case of cervical osteochondroma extending from C5 to C7 in a 16-year-old male. The tumor, arising from the inner aspect of the C6 spinous process, projected longitudinally into the spinal canal and compressed the spinal cord; this caused clinical symptoms associated with myelopathy and radiculopathy. Total excision of the tumor by C5-C7 hemilaminectomy resulted in a good functional recovery.

  6. A combination assay for simultaneous assessment of multiple signaling pathways.

    PubMed

    Goetz, A S; Liacos, J; Yingling, J; Ignar, D M

    1999-12-01

    We have developed an assay in which modulation of two or more signaling pathways can be assessed concurrently by combining reporter gene systems with fluorescent probe technology. The validation of this method was achieved by indirect analysis of adenylyl cyclase activation with the use of a cyclic AMP response element (CRE)-luciferase reporter system in combination with the measurement of calcium mobilization by Calcium Green-1 AM fluorescence on a fluorescent imaging plate reader. To demonstrate the utility of the method in studying the pharmacology of receptors that couple to more than one G protein, Chinese hamster ovary (CHO) cells, which stably expressed both the CRE-luciferase reporter gene and the human pituitary adenylyl cyclase-activating peptide (PACAP) receptor, were treated with PACAP 1-27 and 1-38. Calcium mobilization and the induction of adenylyl cyclase activity in response to each concentration of peptide were assessed in individuals wells. This assay may also be used to screen for ligands of two or more unrelated receptors simultaneously without compromising the assessment of either signaling pathway. To illustrate this point, Rat-1 fibroblasts, which expressed human alpha1A receptors, were cocultured with CRE-luciferase CHO cells, which expressed human GLP-1 receptors. Calcium mobilization elicited by phenylephrine agonism of the alpha1A receptor was assessed in the same assay as GLP-1-induced activation of adenylyl cyclase. The pEC(50) for each agonist was similar to that observed when the cell lines were not cocultured. The number of different receptors that can be screened per well is limited only by the ability to distinguish different reporter gene signals and fluorescent indicators.

  7. 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.

  8. Signal Detection and Frame Synchronization of Multiple Wireless Networking Waveforms

    DTIC Science & Technology

    2007-09-01

    dividing the spectrum into subchannels . The OFDM transmitter divides its high data rate stream into smaller parallel substreams with symbol periods...greater than the channel delay spread. From Table 1, an IEEE 802.11a signal has a bandwidth of 20 MHz and divides the spectrum into 64 subchannels so...that each subchannel has a bandwidth of 312.5 kHz. The maximum allowed rms delay spread for a coherent bandwidth of 20 MHz is 10 ns. The maximum

  9. Multiple stress signals activate mutant p53 in vivo

    PubMed Central

    Suh, Young-Ah; Post, Sean M.; Elizondo-Fraire, Ana C.; Maccio, Danela R.; Jackson, James G.; El-Naggar, Adel K.; Van Pelt, Carolyn; Terzian, Tamara; Lozano, Guillermina

    2012-01-01

    p53 levels are tightly regulated in normal cells, and thus the wild-type p53 protein is nearly undetectable until stimulated through a variety of stresses. In response to stress, p53 is released from its negative regulators, mainly Mdm2, allowing p53 to be stabilized to activate cell cycle arrest, senescence, and apoptosis programs. Many of the upstream signals that regulate wild type p53 are known; however, limited information for the regulation of mutant p53 exists. Previously, we demonstrated that wild-type and mutant p53R172H are regulated in a similar manner in the absence of Mdm2 or p16. Additionally, this stabilization of mutant p53 is responsible for the gain-of-function metastatic phenotype observed in the mouse. In this report, we examined the role of oncogenes, DNA damage, and reactive oxygen species, signals that stabilize wild type p53, on the stabilization of mutant p53 in vivo and the consequences of this expression on tumor formation and survival. These factors stabilized mutant p53 protein which often times contributed to exacerbated tumor phenotypes. These findings, coupled with the fact that patients carry p53 mutations without stabilization of p53, suggest that personalized therapeutic schemes may be needed for individual patients depending on their p53 status. PMID:21983037

  10. An Extended Literature Review: The Effect of Multiple Intelligences on Elementary Student Performance

    ERIC Educational Resources Information Center

    Johnson, Marisa

    2007-01-01

    Multiple Intelligences (MI) curriculum has demonstrated increased student achievement including improved engagement and performance on standardized tests. MI-based instruction also improves student achievement in science. Many educators focus solely on delivering content standards instead of infusing their curriculum with pedagogy that engages…

  11. Extended slow-roll conditions and primordial fluctuations: multiple scalar fields and generalized gravity

    SciTech Connect

    Chiba, Takeshi; Yamaguchi, Masahide E-mail: gucci@phys.aoyama.ac.jp

    2009-01-15

    As an extension of our previous study, we derive slow-roll conditions for multiple scalar fields which are non-minimally coupled with gravity and for generalized gravity theories of the form f({phi}, R). We provide simple formulae of the spectral indices of scalar/tensor perturbations in terms of the slow-roll parameters.

  12. 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…

  13. 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…

  14. 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.

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

    PubMed Central

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

    2015-01-01

    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

  16. Experimental evaluation of a radio-on-FSO communication system for multiple RF signal transmission

    NASA Astrophysics Data System (ADS)

    Kazaura, Kamugisha; Dat, Pham; Bekkali, Abdelmoula; Shah, Alam; Suzuki, Toshiji; Wakamori, Kazuhiko; Matsumoto, Mitsuji; Nakamura, Takuya; Takahashi, Koichi; Higashino, Takeshi; Aburakawa, Yuji; Tsukamoto, Katsutoshi; Komaki, Shozo

    2009-02-01

    In this paper we present the design concept plus experimental results and evaluation of a newly developed advanced DWDM Radio-on-Free-Space Optical (RoFSO) communication system capable of simultaneous transmission of multiple RF signals. The RoFSO system is evaluated based on the performance metric parameters defined for the various RF signals comprising of different wireless services including terrestrial digital broadcasting signals, cellular 3GPP W-CDMA signals, IEEE 802.11 WLAN based signals etc being transmitted over the RoFSO link. The performance metric parameters being considered include standard optical received power, CNR and BER characteristics, W-CDMA signal transmission metric parameters like Adjacent Channel Leakage Ratio (ACLR) and Error Vector Magnitude (EVM), modulation error ratio (MER) for digital terrestrial television broadcasting signals as well as spectrum mask and EVM for IEEE 802.11 Wireless LAN signal transmission.

  17. TGF-β signaling is required for multiple processes during Xenopus tail regeneration

    PubMed Central

    Ho, Diana M.; Whitman, Malcolm

    2008-01-01

    Xenopus tadpoles can fully regenerate all major tissue types following tail amputation. TGF-β signaling plays essential roles in growth, repair, specification, and differentiation of tissues throughout development and adulthood. We examined the localization of key components of the TGF-β signaling pathway during regeneration and characterized the effects of loss of TGF-β signaling on multiple regenerative events. Phosphorylated Smad2 (p-Smad2) is initially restricted to the p63+ basal layer of the regenerative epithelium shortly after amputation, and is later found in multiple tissue types in the regeneration bud. TGF-β ligands are also upregulated throughout regeneration. Treatment of amputated tails with SB-431542, a specific and reversible inhibitor of TGF-β signaling, blocks tail regeneration at multiple points. Inhibition of TGF-β signaling immediately following tail amputation reversibly prevents formation of a wound epithelium over the future regeneration bud. Even brief inhibition immediately following amputation is sufficient, however, to irreversibly block the establishment of structures and cell types that characterize regenerating tissue and to prevent the proper activation of BMP and ERK signaling pathways. Inhibition of TGF-β signaling after regeneration has already commenced blocks cell proliferation in the regeneration bud. These data reveal several spatially and temporally distinct roles for TGF-β signaling during regeneration: 1) wound epithelium formation, 2) establishment of regeneration bud structures and signaling cascades, and 3) regulation of cell proliferation. PMID:18234181

  18. 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.

  19. 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.

  20. Multiple Signal Classification for Determining Direction of Arrival of Frequency Hopping Spread Spectrum Signals

    DTIC Science & Technology

    2014-03-27

    specific frequency band [16]. In many military applications , FHSS modulation is used to mitigate possible jamming threats. The goal is to extend the...amplitude modulation ( QAM ). Therefore, a pre-step was taken to build BPSK, QPSK and 16- QAM modulators in MATLAB®. At first, single user is transmitting using...Review . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1 Communication Modulation : . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.1

  1. Efficient and extendible class scheme for the combined reaction-diffusion of multiple molecular species

    NASA Astrophysics Data System (ADS)

    Stella, Sabrina; Chignola, Roberto; Milotti, Edoardo

    2014-03-01

    When dealing with large numbers of cells in biophysical simulations, it is important to properly manage the different substances that diffuse and react in and around cells. Although in an object-oriented programming environment it seems more natural to define cells as the basic objects, it turns out that individual substances are better suited to take this role. Here we describe the biophysical problem and our computational solution, and display the results obtained with a toy model. We find that the new implementation does not decrease performance and yet it leads to a much better structured and modular code. This will make more realistic programs with many molecular pathways much more modular and readily extendible.

  2. Extended spectrum of HIV-1 reverse transcriptase mutations in patients receiving multiple nucleoside analog inhibitors

    PubMed Central

    Gonzales, Matthew J.; Wu, Thomas D.; Taylor, Jonathan; Belitskaya, Ilana; Kantor, Rami; Israelski, Dennis; Chou, Sunwen; Zolopa, Andrew R.; Fessel, W. Jeffrey; Shafer, Robert W.

    2008-01-01

    Objective To characterize reverse transcriptase (RT) mutations by their association with extent of nucleoside RT inhibitor (NRTI) therapy. To identify mutational clusters in RT sequences from persons receiving multiple NRTI. Design A total of 1210 RT sequences from persons with known antiretroviral therapy were analyzed: 641 new sequences were performed at Stanford University Hospital; 569 were previously published. Methods Chi-square tests and logistic regression were done to identify associations between mutations and NRTI therapy. Correlation studies were done to identify mutational clusters. The Benjamini-Hochberg procedure was used to correct for multiple comparisons. Results Mutations at 26 positions were significantly associated with NRTI including 17 known resistance mutations (positions 41, 44, 62, 65, 67, 69, 70, 74, 75, 77, 116, 118, 151, 184, 210, 215, 219) and nine previously unreported mutations (positions 20, 39, 43, 203, 208, 218, 221, 223, 228). The nine new mutations correlated linearly with number of NRTI; 777 out of 817 (95%) instances occurred with known drug resistance mutations. Positions 203, 208, 218, 221, 223, and 228 were conserved in untreated persons; positions 20, 39, and 43 were polymorphic. Most NRTI-associated mutations clustered into three groups: (i) 62, 65, 75, 77, 115, 116, 151; (ii) 41, 43, 44, 118, 208, 210, 215, 223; (iii) 67, 69, 70, 218, 219, 228. Conclusions Mutations at nine previously unreported positions are associated with NRTI therapy. These mutations are probably accessory because they occur almost exclusively with known drug resistance mutations. Most NRTI mutations group into one of three clusters, although several (e.g., M184V) occur in multiple mutational contexts. PMID:12660525

  3. 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.

  4. Multiplexed FRET to image multiple signaling events in live cells.

    PubMed

    Grant, David M; Zhang, Wei; McGhee, Ewan J; Bunney, Tom D; Talbot, Clifford B; Kumar, Sunil; Munro, Ian; Dunsby, Christopher; Neil, Mark A A; Katan, Matilda; French, Paul M W

    2008-11-15

    We report what to our knowledge is a novel approach for simultaneous imaging of two different Förster resonance energy transfer (FRET) sensors in the same cell with minimal spectral cross talk. Previous methods based on spectral ratiometric imaging of the two FRET sensors have been limited by the availability of suitably bright acceptors for the second FRET pair and the spectral cross talk incurred when measuring in four spectral windows. In contrast to spectral ratiometric imaging, fluorescence lifetime imaging (FLIM) requires measurement of the donor fluorescence only and is independent of emission from the acceptor. By combining FLIM-FRET of the novel red-shifted TagRFP/mPlum FRET pair with spectral ratiometric imaging of an ECFP/Venus pair we were thus able to maximize the spectral separation between our chosen fluorophores while at the same time overcoming the low quantum yield of the far red acceptor mPlum. Using this technique, we could read out a TagRFP/mPlum intermolecular FRET sensor for reporting on small Ras GTP-ase activation in live cells after epidermal growth factor stimulation and an ECFP/Venus Cameleon FRET sensor for monitoring calcium transients within the same cells. The combination of spectral ratiometric imaging of ECFP/Venus and high-speed FLIM-FRET of TagRFP/mPlum can thus increase the spectral bandwidth available and provide robust imaging of multiple FRET sensors within the same cell. Furthermore, since FLIM does not require equal stoichiometries of donor and acceptor, this approach can be used to report on both unimolecular FRET biosensors and protein-protein interactions with the same cell.

  5. Testosterone and dihydrotestosterone inhibit gallbladder motility through multiple signalling pathways.

    PubMed

    Kline, Loren W; Karpinski, Edward

    2008-10-01

    Testosterone (T) has been shown to cause vasodilation in rabbit coronary arteries through a nongenomic pathway. Part of this T-induced relaxation was shown to be mediated by opening voltage dependent K(+) channels. T infusion also reduces peripheral resistance in human males with heart failure. The effects of T or its active metabolite 5-alpha dihydrotestosterone (DHT) are not well studied. This study investigates the effect of T and DHT on contraction in guinea pig gallbladder strips. T or DHT induced a concentration-dependent relaxation of cholecystokinin octapeptide (CCK)-induced tension. Pretreatment of the strips with PKA inhibitor 14-22 amide myristolated had no significant effect on the relaxation induced by either T or DHT. Pretreatment of strips with 2-APB, an inhibitor of IP(3) induced Ca(2+) release, produced a significant (p<0.001) reduction in the T- or DHT-induced relaxation. Bisindolymaleimide IV and chelerythrine Cl(-) when used in combination had no significant effect on the amount of CCK-induced tension, but significantly (p<0.01) decreased the amount of T- or DHT-induced relaxation. The flavone chrysin, an aromatase inhibitor, and genistein, an isoflavone, each produced a significant (p<0.01) reduction in CCK-induced tension. Chrysin significantly (p<0.05) increased T-induced relaxation; however, genistein had no effect on T-induced relaxation. It is concluded that T and DHT inhibits gallbladder motility rapidly by nongenomic actions of the hormones. Multiple pathways that include inhibition of intracellular Ca(2+) release, inhibition of extracellular Ca(2+) entry, and the actions of PKC may mediate this effect.

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

    PubMed

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

    2015-01-01

    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.

  7. 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.

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

    PubMed

    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

    2014-08-01

    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.

  9. 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

  10. Extended Y chromosome haplotypes resolve multiple and unique lineages of the Jewish priesthood.

    PubMed

    Hammer, Michael F; Behar, Doron M; Karafet, Tatiana M; Mendez, Fernando L; Hallmark, Brian; Erez, Tamar; Zhivotovsky, Lev A; Rosset, Saharon; Skorecki, Karl

    2009-11-01

    It has been known for over a decade that a majority of men who self report as members of the Jewish priesthood (Cohanim) carry a characteristic Y chromosome haplotype termed the Cohen Modal Haplotype (CMH). The CMH has since been used to trace putative Jewish ancestral origins of various populations. However, the limited number of binary and STR Y chromosome markers used previously did not provide the phylogenetic resolution needed to infer the number of independent paternal lineages that are encompassed within the Cohanim or their coalescence times. Accordingly, we have genotyped 75 binary markers and 12 Y-STRs in a sample of 215 Cohanim from diverse Jewish communities, 1,575 Jewish men from across the range of the Jewish Diaspora, and 2,099 non-Jewish men from the Near East, Europe, Central Asia, and India. While Cohanim from diverse backgrounds carry a total of 21 Y chromosome haplogroups, 5 haplogroups account for 79.5% of Cohanim Y chromosomes. The most frequent Cohanim lineage (46.1%) is marked by the recently reported P58 T->C mutation, which is prevalent in the Near East. Based on genotypes at 12 Y-STRs, we identify an extended CMH on the J-P58* background that predominates in both Ashkenazi and non-Ashkenazi Cohanim and is remarkably absent in non-Jews. The estimated divergence time of this lineage based on 17 STRs is 3,190 +/- 1,090 years. Notably, the second most frequent Cohanim lineage (J-M410*, 14.4%) contains an extended modal haplotype that is also limited to Ashkenazi and non-Ashkenazi Cohanim and is estimated to be 4.2 +/- 1.3 ky old. These results support the hypothesis of a common origin of the CMH in the Near East well before the dispersion of the Jewish people into separate communities, and indicate that the majority of contemporary Jewish priests descend from a limited number of paternal lineages.

  11. 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.

  12. 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.

  13. 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.

  14. Multiple functional ECG signal is processing for wearable applications of long-term cardiac monitoring.

    PubMed

    Liu, Xin; Zheng, Yuanjin; Phyu, Myint Wai; Zhao, Bin; Je, Minkyu; Yuan, Xiaojun

    2011-02-01

    In this paper, an integrated electrocardiogram (ECG) signal-processing scheme is proposed. Using a systematic wavelet transform algorithm, this signal-processing scheme can realize multiple functions in real time, including baseline-drift removal, noise suppression, QRS detection, heart beat rate prediction and classification, and clean ECG reconstruction. Utilizing the novel low-cost hardware architecture, the proposed ECG signal-processing scheme is implemented in application-specific integrated circuits with 0.18 μ m CMOS technology. This ECG signal-processor chip achieves low area and power consumptions, and is highly suitable for wearable applications of long-term cardiac monitoring.

  15. 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

  16. 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.

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

    PubMed

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

    2003-03-22

    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.

  18. 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.

  19. Association Analysis of the Extended MHC Region in Celiac Disease Implicates Multiple Independent Susceptibility Loci

    PubMed Central

    Ahn, Richard; Ding, Yuan Chun; Murray, Joseph; Fasano, Alessio; Green, Peter H. R.; Neuhausen, Susan L.; Garner, Chad

    2012-01-01

    Celiac disease is a common autoimmune disease caused by sensitivity to the dietary protein gluten. Forty loci have been implicated in the disease. All disease loci have been characterized as low-penetrance, with the exception of the high-risk genotypes in the HLA-DQA1 and HLA-DQB1 genes, which are necessary but not sufficient to cause the disease. The very strong effects from the known HLA loci and the genetically complex nature of the major histocompatibility complex (MHC) have precluded a thorough investigation of the region. The purpose of this study was to test the hypothesis that additional celiac disease loci exist within the extended MHC (xMHC). A set of 1898 SNPs was analyzed for association across the 7.6 Mb xMHC region in 1668 confirmed celiac disease cases and 517 unaffected controls. Conditional recursive partitioning was used to create an informative indicator of the known HLA-DQA1 and HLA-DQB1 high-risk genotypes that was included in the association analysis to account for their effects. A linkage disequilibrium-based grouping procedure was utilized to estimate the number of independent celiac disease loci present in the xMHC after accounting for the known effects. There was significant statistical evidence for four new independent celiac disease loci within the classic MHC region. This study is the first comprehensive association analysis of the xMHC in celiac disease that specifically accounts for the known HLA disease genotypes and the genetic complexity of the region. PMID:22615847

  20. 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.

  1. 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.

  2. 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. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. 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.

  4. 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).

  5. Control of Kaposi's Sarcoma-Associated Herpesvirus Reactivation Induced by Multiple Signals

    PubMed Central

    Feng, Jiaying; Li, Xudong; Liao, Chia Wei; Ho, Chih-Ming; Shamma, Jeff S.; Sun, Ren

    2011-01-01

    The ability to control cellular functions can bring about many developments in basic biological research and its applications. The presence of multiple signals, internal as well as externally imposed, introduces several challenges for controlling cellular functions. Additionally the lack of clear understanding of the cellular signaling network limits our ability to infer the responses to a number of signals. This work investigates the control of Kaposi's sarcoma-associated herpesvirus reactivation upon treatment with a combination of multiple signals. We utilize mathematical model-based as well as experiment-based approaches to achieve the desired goals of maximizing virus reactivation. The results show that appropriately selected control signals can induce virus lytic gene expression about ten folds higher than a single drug; these results were validated by comparing the results of the two approaches, and experimentally using multiple assays. Additionally, we have quantitatively analyzed potential interactions between the used combinations of drugs. Some of these interactions were consistent with existing literature, and new interactions emerged and warrant further studies. The work presents a general method that can be used to quantitatively and systematically study multi-signal induced responses. It enables optimization of combinations to achieve desired responses. It also allows identifying critical nodes mediating the multi-signal induced responses. The concept and the approach used in this work will be directly applicable to other diseases such as AIDS and cancer. PMID:21904595

  6. Multiple intermolecular bend vibrational excitation of a hydrogen bond: An extended infrared study of OCOHF

    NASA Astrophysics Data System (ADS)

    Nesbitt, David J.; Lovejoy, Christopher M.

    1990-12-01

    We report the use of near infrared tunable difference frequency laser absorption methods to investigate low-frequency bending of the intermolecular hydrogen bond in OCOHF complexes. By deliberate thermal warming of the slit jet expansion to 16 K, we observe bending ``hot band'' transitions built on the fundamental vHF=1←0 HF stretch from the lowest five internally excited bending states (i.e., vlbend=00←00, 11←11, 20←20, 22←22, and 31←31) which correspond to low-frequency, skeletal bending of the intermolecular hydrogen bond. In addition, much weaker parallel (Δl=0) combination band transitions (vlbend=20←00 and 31←11 ) are observed at ≲5% of the 00←00 intensity. Furthermore, measurements of the extremely weak 11←00 perpendicular (Δl=1) band are obtained at ≲1% of the 00←00 intensity. The fundamental, hot band, and combination band data permit quantitative measurement of the absolute vibrational energies of all vibrational levels for the l=0 and 1 manifolds in both HF excited (vHF=1) and ground-state (vHF=0) complexes. The bending frequencies are surprisingly low (˜10 cm-1 ) and exhibit positive anharmonicity (i.e., the energy level spacings increase with vlbend ). The results suggest nearly unrestricted bending of the hydrogen bond in a very flat, highly anharmonic angular potential. In contrast with many other weakly bound complexes, the lowest bending frequency decreases dramatically upon HF excitation, which signals a vHF vibrationally induced shift from a linear to a nonlinear equilibrium geometry for the vHF=1 excited OCOHF potential surface. Excess Lorentzian line widths are observed in all OCOHF transitions, attributable to vibrational predissociation lifetimes that vary smoothly from 1.2 ns (vlbend=00) to 650 ps (vlbend=31) as a function of intermolecular bending excitation.

  7. Integrated QSAR study for inhibitors of hedgehog signal pathway against multiple cell lines:a collaborative filtering method

    PubMed Central

    2012-01-01

    proposed several possible chemical modifications to improve the inhibitor affinity towards multiple targets in the Hedgehog Signaling Pathway. Conclusions Our model with the feature selection strategy presented here is efficient, robust, and flexible, and can be easily extended to model large-scale multiple cell line/QSAR data. The data and scripts for collaborative QSAR modeling are available in the Additional file 1. PMID:22849868

  8. Genes that integrate multiple adipogenic signaling pathways in human mesenchymal stem cells.

    PubMed

    Ito, Tomoya; Tsuruta, So; Tomita, Koki; Kikuchi, Kunio; Yokoi, Takahide; Aizawa, Yasunori

    2011-06-17

    Adipogenesis is a well-characterized cell differentiation process. A large body of evidence has revealed the core transcription factors and signaling pathways that govern adipogenesis, but cross-talks between these cellular signals and its functional consequences have not been thoroughly investigated. We, therefore, sought to identify genes that are regulated by multiple signaling pathways during adipogenesis of human mesenchymal stem cells. Focusing on the early stage of adipogenesis, microarray analysis and quantitative RT-PCR identified 12 genes whose transcription levels were dramatically affected by the complete adipogenic induction cocktail but not by the cocktail's individual components. Expression kinetics of these genes indicate diverse mechanisms of transcriptional regulation during adipogenesis. Functional relationships between these genes and adipogenic differentiation were frequently unknown. This study thus provided novel adipogenic gene candidates that likely mediate communications among multiple signaling pathways within human mesenchymal stem cells.

  9. 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.

  10. STRUCTURE OF THE EGF RECEPTOR TRANSACTIVATION CIRCUIT INTEGRATES MULTIPLE SIGNALS WITH CELL CONTEXT

    PubMed Central

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

    2012-01-01

    Summary Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ligands or by modification of the activity of the EGFR. As a first step towards building a predictive model of the EGFR transactivation circuit, we quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR to regulate extracellular signal regulated kinase (ERK) activity in human mammary epithelial cells. By using a “non-binding” reporter of ligand shedding, we found that transactivation triggers a positive feedback loop from ERK back to the EGFR such that ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. Importantly, activated Ras and ERK levels were nearly linear functions of ligand shedding and the effect of multiple, sub-saturating inputs was additive. Simulations showed that ERK-mediated feedback through ligand shedding resulted in a stable steady-state level of activated ERK, but also showed that the extracellular environment can modulate the level of feedback. Our results suggest that the transactivation circuit acts as a context-dependent integrator and amplifier of multiple extracellular signals and that signal integration can effectively occur at multiple points in the EGFR pathway. PMID:20458382

  11. Control packet signaling mechanism using electronic code division multiple access for packet-based networks

    NASA Astrophysics Data System (ADS)

    Nadarajah, Nishaanthan

    2008-10-01

    We propose and experimentally demonstrate the feasibility of a control packet signaling technique using electronic code division multiple access for a wavelength division multiplexing packet-based network, whereby each wavelength channel is assigned a unique electronic code based label on a radio frequency subcarrier. Such a technique allows each wavelength channel to be electronically identified without requiring the use of a WDM demultiplexer. We experimentally demonstrate this technique with two wavelength channels each with 1.25 Gb/s baseband payload data and 10 Mb/s header coded onto an electronic code at 160 Mb/s. A performance study of the electronic code division multiple access based control signaling scheme in a wavelength division multiplexed packet-based access network is also performed in terms of the required power budget to monitor the electronic code division multiple access control signals in the presence of several sources of noise for error-free transmission of both payload data and electronic code division multiple access based control signals. It is shown that the modulation depth of each signal impacts the amount of required optical tap power. As the modulation depth of the electronic code division multiple access based control signal is increased, the required optical tap power is reduced. However, this increases the bit-error-rate for the payload data. Therefore, there lies a maximum and a minimum of the required tap optical power for the successful recovery of both signals. The lower bound of this range is usually determined by the successful recovery of electronic code division multiple access based control signal while the upper bound is determined by the successful recovery of payload data. The required optical tap power is analyzed for different transmission bit rates of the payload data for various receiver architecture scenarios without an optical amplifier at the receiver. The scalability analyses were repeated with an optical

  12. 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

  13. Stress and radiation-induced activation of multiple intracellular signaling pathways.

    PubMed

    Dent, Paul; Yacoub, Adly; Contessa, Joseph; Caron, Ruben; Amorino, George; Valerie, Kristoffer; Hagan, Michael P; Grant, Steven; Schmidt-Ullrich, Rupert

    2003-03-01

    Exposure of cells to a variety of stresses induces compensatory activations of multiple intracellular signaling pathways. These activations can play critical roles in controlling cell survival and repopulation effects in a stress-specific and cell type-dependent manner. Some stress-induced signaling pathways are those normally activated by mitogens such as the EGFR/RAS/PI3K-MAPK pathway. Other pathways activated by stresses such as ionizing radiation include those downstream of death receptors, including pro-caspases and the transcription factor NFKB. This review will attempt to describe some of the complex network of signals induced by ionizing radiation and other cellular stresses in animal cells, with particular attention to signaling by growth factor and death receptors. This includes radiation-induced signaling via the EGFR and IGFI-R to the PI3K, MAPK, JNK, and p38 pathways as well as FAS-R and TNF-R signaling to pro-caspases and NFKB. The roles of autocrine ligands in the responses of cells and bystander cells to radiation and cellular stresses will also be discussed. Based on the data currently available, it appears that radiation can simultaneously activate multiple signaling pathways in cells. Reactive oxygen and nitrogen species may play an important role in this process by inhibiting protein tyrosine phosphatase activity. The ability of radiation to activate signaling pathways may depend on the expression of growth factor receptors, autocrine factors, RAS mutation, and PTEN expression. In other words, just because pathway X is activated by radiation in one cell type does not mean that pathway X will be activated in a different cell type. Radiation-induced signaling through growth factor receptors such as the EGFR may provide radioprotective signals through multiple downstream pathways. In some cell types, enhanced basal signaling by proto-oncogenes such as RAS may provide a radioprotective signal. In many cell types, this may be through PI3K, in others

  14. 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

  15. 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

  16. Caloric Restriction Extends Yeast Chronological Life Span by Optimizing the Snf1 (AMPK) Signaling Pathway.

    PubMed

    Wierman, Margaret B; Maqani, Nazif; Strickler, Erika; Li, Mingguang; Smith, Jeffrey S

    2017-07-01

    AMP-activated protein kinase (AMPK) and the homologous yeast SNF1 complex are key regulators of energy metabolism that counteract nutrient deficiency and ATP depletion by phosphorylating multiple enzymes and transcription factors that maintain energetic homeostasis. AMPK/SNF1 also promotes longevity in several model organisms, including yeast. Here we investigate the role of yeast SNF1 in mediating the extension of chronological life span (CLS) by caloric restriction (CR). We find that SNF1 activity is required throughout the transition of log phase to stationary phase (diauxic shift) for effective CLS extension. CR expands the period of maximal SNF1 activation beyond the diauxic shift, as indicated by Sak1-dependent T210 phosphorylation of the Snf1 catalytic α-subunit. A concomitant increase in ADP is consistent with SNF1 activation by ADP in vivo Downstream of SNF1, the Cat8 and Adr1 transcription factors are required for full CR-induced CLS extension, implicating an alternative carbon source utilization for acetyl coenzyme A (acetyl-CoA) production and gluconeogenesis. Indeed, CR increased acetyl-CoA levels during the diauxic shift, along with expression of both acetyl-CoA synthetase genes ACS1 and ACS2 We conclude that CR maximizes Snf1 activity throughout and beyond the diauxic shift, thus optimizing the coordination of nucleocytosolic acetyl-CoA production with massive reorganization of the transcriptome and respiratory metabolism. Copyright © 2017 American Society for Microbiology.

  17. Fiber-optic signal processor with applications to matrix-vector multiplication and lattice filtering.

    PubMed

    Tur, M; Goodman, J W; Moslehi, B; Bowers, J E; Shaw, H J

    1982-09-01

    A new fiber-optic signal processor is proposed to implement systolic matrix-vector multipliers and lattice filters. 10(9) multiplications/sec can be achieved with currently available components for matrix-vector multiplications that involve Toeplitz matrices. A 2 x 2 (Toeplitz) matrix-vector multiplier has been experimentally demonstrated using single-mode fibers and directional couplers. The filtering characteristics of the device are also discussed.

  18. Effect of signaling reinforcement on resistance to change in a multiple schedule.

    PubMed

    Bell, Matthew C; Seip, Katharine M; Fitzsimmons, Kathleen S

    2007-01-10

    This study evaluated the effect of a signal on resistance to change using a multiple schedule of reinforcement. Experiment 1 presented pigeons with three schedules: a signaled delay to reinforcement schedule (a two-link chain schedule with a variable-interval 120-s initial link followed by a 5-s fixed-time schedule), an unsignaled delay schedule (a comparable two-link tandem schedule), and an immediate, zero-delay variable-interval 125-s schedule. Two separate disruption procedures assessed resistance to change: extinction and adding a variable-time 20-s schedule of reinforcement to the inter-component interval. Resistance to change tests were conducted twice, once with the signal stimulus (the terminal link of the chain schedule) present and once with it absent. Results from both disruption procedures showed that signal absence reduced resistance to change for the pre-signal stimulus. In probe choice tests subjects strongly preferred the signal stimulus over the unsignaled stimulus and exhibited no reliable preference when given a choice between the signal stimulus and immediate stimulus. Experiment 2 presented two equal signaled schedules where, during resistance to change tests, the signal remained for one schedule and was removed for the second. Resistance to change was consistently lower when the signal was absent.

  19. Signals, resistance to change, and conditioned reinforcement in a multiple schedule.

    PubMed

    Bell, Matthew C; Gomez, Belen E; Kessler, Kira

    2008-06-01

    The effect of signals on resistance to change was evaluated using pigeons responding on a three-component multiple schedule. Each component contained a variable-interval initial link followed by a fixed-time terminal link. One component was an unsignaled-delay schedule, and two were equivalent signaled-delay schedules. After baseline training, resistance to change was assessed through (a) extinction and (b) adding free food to the intercomponent interval. During these tests, the signal stimulus from one of the signaled-delay components (SIG-T) was replaced with the initial-link stimulus from that component, converting it to an unsignaled-delay schedule. That signal stimulus was added to the delay period of the unsignaled-delay component (UNS), converting it to a signaled-delay schedule. The remaining signaled component remained unchanged (SIG-C). Resistance-to-change tests showed removing the signal had a minimal effect on resistance to change in the SIG-T component compared to the unchanged SIG-C component except for one block during free-food testing. Adding the signal to the UNS component significantly increased response rates suggesting that component had low response strength. Interestingly, the direction of the effect was in the opposite direction from what is typically observed. Results are consistent with the conclusion that the signal functioned as a conditioned reinforcer and inconsistent with a generalization-decrement explanation.

  20. The Role of +4U as an Extended Translation Termination Signal in Bacteria

    PubMed Central

    Wei, Yulong; Xia, Xuhua

    2017-01-01

    Termination efficiency of stop codons depends on the first 3′ flanking (+4) base in bacteria and eukaryotes. In both Escherichia coli and Saccharomyces cerevisiae, termination read-through is reduced in the presence of +4U; however, the molecular mechanism underlying +4U function is poorly understood. Here, we perform comparative genomics analysis on 25 bacterial species (covering Actinobacteria, Bacteriodetes, Cyanobacteria, Deinococcus-Thermus, Firmicutes, Proteobacteria, and Spirochaetae) with bioinformatics approaches to examine the influence of +4U in bacterial translation termination by contrasting highly- and lowly-expressed genes (HEGs and LEGs, respectively). We estimated gene expression using the recently formulated Index of Translation Elongation, ITE, and identified stop codon near-cognate transfer RNAs (tRNAs) from well-annotated genomes. We show that +4U was consistently overrepresented in UAA-ending HEGs relative to LEGs. The result is consistent with the interpretation that +4U enhances termination mainly for UAA. Usage of +4U decreases in GC-rich species where most stop codons are UGA and UAG, with few UAA-ending genes, which is expected if UAA usage in HEGs drives up +4U usage. In HEGs, +4U usage increases significantly with abundance of UAA nc_tRNAs (near-cognate tRNAs that decode codons differing from UAA by a single nucleotide), particularly those with a mismatch at the first stop codon site. UAA is always the preferred stop codon in HEGs, and our results suggest that UAAU is the most efficient translation termination signal in bacteria. PMID:27903612

  1. Presenting multiple auditory signals using multiple sound cards in Visual Basic 6.0.

    PubMed

    Chan, Jason S; Spence, Charles

    2003-02-01

    In auditory research, it is often desirable to present more than two auditory stimuli at any one time. Although the technology has been available for some time, the majority of researchers have not utilized it. This article provides a simple means of presenting multiple, concurrent, independent auditory events, using two or more different sound cards installed within a single computer. By enabling the presentation of more auditory events, we can hope to gain a better understanding of the cognitive and attentional processes operating under more complex and realistic scenes, such as that embodied by the cocktail party effect. The software requirements are Windows 98SR2/Me/NT4/2000/XP, Visual Basic 6.0, and DirectX 7.0 or above. The hardware requirements are a Pentium II, 128 MB RAM, and two or more different sound cards.

  2. 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.

  3. Bmi-1 extends the lifespan of normal human oral keratinocytes by inhibiting the TGF-β signaling

    PubMed Central

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

    2010-01-01

    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-β signaling pathway. Serial subculture of NHOK resulted in replicative senescence and terminal differentiation, and activation of TGF-β signaling pathway. This was accompanied with enhanced intracellular and secreted TGF-β1 levels, phosphorylation of Smad2/3, and increased expression of p15INK4B and p57KIP2. An ectopic expression of Bmi-1 in NHOK (HOK/Bmi-1) decreased intracellular and secreted TGF-β1 level, induced dephosphorylation of Smad2/3, and diminished the level of p15INK4B and p57KIP2. Moreover, Bmi-1 expression led to inhibition of TGF-β-responsive promoter activity in dose-specific manner. Knockdown of Bmi-1 in rapidly proliferating HOK/Bmi-1 and cancer cells increased the level of phosphorylated Smad2/3, p15INK4B and p57KIP2. In addition, an exposure of senescent NHOK to TGF-β receptor I kinase inhibitor or anti-TGF-β antibody resulted in enhanced replicative potential of cells. Taken together, these data suggest that Bmi-1 suppresses senescence of cells by inhibiting the TGF-β signaling pathway in NHOK. PMID:20630502

  4. Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala

    PubMed Central

    De Bundel, Dimitri; Zussy, Charleine; Espallergues, Julie; Gerfen, Charles R; Girault, Jean-Antoine; Valjent, Emmanuel

    2016-01-01

    Overgeneralization of conditioned threat responses is a robust clinical marker of anxiety disorders. In overgeneralization, responses that are appropriate to threat-predicting cues are evoked by perceptually similar safety-predicting cues. Inappropriate learning of conditioned threat responses may thus form an etiological basis for anxiety disorders. The role of dopamine (DA) in memory encoding is well established. Indeed by signaling salience and valence, DA is thought to facilitate discriminative learning between stimuli representing safety or threat. However, the neuroanatomical and biochemical substrates through which DA modulates overgeneralization of threat responses remain poorly understood. Here we report that the modulation of DA D2 receptor (D2R) signaling bidirectionally regulates the consolidation of fear responses. While the blockade of D2R induces generalized fear responses, its stimulation facilitates discriminative learning between stimuli representing safety or threat. Moreover, we show that controlled fear generalization requires the coordinated activation of D2R in the bed nucleus of the stria terminalis (BNST) and the central amygdala (CEA). Finally, we identify the mTORC1 cascade activation as an important molecular event by which D2R mediates its effects. These data reveal that D2R signaling in the extended amygdala constitutes an important checkpoint through which DA participates in the control of threat processing and the emergence of overgeneralized fear responses. PMID:26782052

  5. 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.

  6. 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.

  7. Extended defects in InGaAs/InGaAs strain-balanced multiple quantum wells for photovoltaic applications

    NASA Astrophysics Data System (ADS)

    Nasi, Lucia; Ferrari, Claudio; Lazzarini, Laura; Salviati, Giancarlo; Tundo, Stefania; Mazzer, Massimo; Clarke, Graham; Rohr, Carsten

    2002-12-01

    Different strain-balanced InGaAs/InGaAs multiple quantum wells (MQWs) were grown on (001) InP changing the In composition in the wells/barriers in order to extend the absorption edge beyond 2 μm for thermophotovoltaic applications. The strain increase in the structures results in the formation of isolated highly defected regions taking their origin from lateral layer thickness modulations. Experimental results are consistent with the existence of a critical elastic energy density for the development of MQW waviness. An empirical model for predicting the maximum number of layers that can be grown without modulations as a function of the strain energy stored in the MQW period is presented.

  8. 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.

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

    NASA Astrophysics Data System (ADS)

    McGuffin, Bruce F.

    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.

  10. 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.

  11. Extending technology-aided leisure and communication programs to persons with spinal cord injury and post-coma multiple disabilities.

    PubMed

    Lancioni, Giulio E; Singh, Nirbhay N; O'Reilly, Mark F; Sigafoos, Jeff; Ricciuti, Riccardo A; Trignani, Roberto; Oliva, Doretta; Signorino, Mario; D'Amico, Fiora; Sasanelli, Giovanni

    2015-01-01

    These two studies extended technology-aided programs to promote leisure and communication opportunities to a man with cervical spinal cord injury and a post-coma man with multiple disabilities. The studies involved the use of ABAB designs, in which A and B represented baseline and intervention phases, respectively. The programs focused on enabling the participants to activate songs, videos, requests, text messages, and telephone calls. These options were presented on a computer screen and activated through a small pressure microswitch by the man with spinal cord injury and a special touch screen by the post-coma man. To help the latter participant, who had no verbal skills, with requests and telephone calls, series of words and phrases were made available that he could activate in those situations. Data showed that both participants were successful in managing the programs arranged for them. The man with spinal cord injury activated mean frequencies of above five options per 10-min session. The post-coma man activated mean frequencies of about 12 options per 20-min session. Technology-aided programs for promoting leisure and communication opportunities might be successfully tailored to persons with spinal cord injury and persons with post-coma multiple disabilities. Implications for Rehabilitation Technology-aided programs may be critical to enable persons with pervasive motor impairment to engage in leisure activities and communication events independently. Persons with spinal cord injury, post-coma extended brain damage, and forms of neurodegenerative disease, such as amyotrophic lateral sclerosis, may benefit from those programs. The programs could be adapted to the participants' characteristics, both in terms of technology and contents, so as to improve their overall impact on the participants' functioning and general mood.

  12. Luminous Infrared Galaxies. III. Multiple Merger, Extended Massive Star Formation, Galactic Wind, and Nuclear Inflow in NGC 3256

    NASA Astrophysics Data System (ADS)

    Lípari, S.; Díaz, R.; Taniguchi, Y.; Terlevich, R.; Dottori, H.; Carranza, G.

    2000-08-01

    We report detailed evidence for multiple merger, extended massive star formation, galactic wind, and circular/noncircular motions in the luminous infrared galaxy NGC 3256, based on observations of high-resolution imaging (Hubble Space Telescope, ESO NTT), and extensive spectroscopic data (more than 1000 spectra, collected at Estación Astrofísica de Bosque Alegre, Complejo Astronómico el Leoncito, Cerro Tololo InterAmerican Observatory, and IUE observatories). We find in a detailed morphological study (resolution ~15 pc) that the extended massive star formation process detected previously in NGC 3256 shows extended triple asymmetrical spiral arms (r~5 kpc), emanating from three different nuclei. The main optical nucleus shows a small spiral disk (r~500 pc), which is a continuation of the external one and reaches the very nucleus. The core shows blue elongated structure (50 pc×25 pc) and harbors a blue stellar cluster candidate (r~8 pc). We discuss this complex morphology in the framework of an extended massive star formation driven by a multiple merger process (models of Hernquist et al. and Taniguchi et al.). We study the kinematics of this system and present a detailed Hα velocity field for the central region (40''×40'' rmax~30''~5 kpc), with a spatial resolution of 1" and errors of +/-15 km s-1. The color and isovelocity maps show mainly (1) a kinematic center of circular motion with ``spider'' shape, located between the main optical nucleus and the close (5") mid-IR nucleus and (2) noncircular motions in the external parts. We obtained three ``sinusoidal rotation curves'' (from the Hα velocity field) around position angle (P.A.) ~55°, ~90°, and ~130°. In the main optical nucleus we found a clear ``outflow component'' associated with galactic winds plus an ``inflow radial motion.'' The outflow component was also detected in the central and external regions (r<=5-6 kpc). The main axis of the inflow region (P.A.~80deg) is practically perpendicular to the

  13. Extended culture up to the blastocyst stage: a strategy to avoid multiple pregnancies in assisted reproductive technologies.

    PubMed

    Sepúlveda, Soledad J; Portella, Jimmy R; Noriega, Luis P; Escudero, Ernesto L; Noriega, Luis H

    2011-01-01

    The aim of this study was to review the experience and outcomes of assisted reproduction cycles with embryos grown up to day 5 of development, comparing different parameters according to the ages of the patients. We retrospectively studied 1,874 assisted reproduction cycles where embryo culture was extended up to the fifth or sixth day of development. All IVF and ICSI cycles were included, comparing, according to patient age, the following rates: blastocyst formation, pregnancy, implantation and abortion. As control, we analyzed cycles with donated oocytes from young donors (OD). The number of embryos reaching the blastocyst stage is similar in all groups of patients. Only the OD group was different in terms of blastocyst formation, pregnancy and implantation rates. Patients over 39 years of age had an abortion rate of 59.1 %, which is significantly higher than the other groups. Extended embryo culture up to the blastocyst stage can be implemented in programs of assisted reproduction in order to increase the pregnancy rate. The potential of blastocyst implantation is high, allowing us to transfer fewer embryos and reduce the probability of multiple pregnancies.

  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 documents on…

  15. 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 documents on…

  16. 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.

  17. Automated Method of Frequency Determination in Software Metric Data Through the Use of the Multiple Signal Classification (MUSIC) Algorithm

    DTIC Science & Technology

    1998-06-26

    METHOD OF FREQUENCY DETERMINATION 4 IN SOFTWARE METRIC DATA THROUGH THE USE OF THE 5 MULTIPLE SIGNAL CLASSIFICATION ( MUSIC ) ALGORITHM 6 7 STATEMENT OF...graph showing the estimated power spectral 12 density (PSD) generated by the multiple signal classification 13 ( MUSIC ) algorithm from the data set used...implemented in this module; however, it is preferred to use 1 the Multiple Signal Classification ( MUSIC ) algorithm. The MUSIC 2 algorithm is

  18. 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

  19. 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.

  20. 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.

  1. [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.

  2. 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

  3. Statistical mechanics of learning multiple orthogonal signals: asymptotic theory and fluctuation effects.

    PubMed

    Hoyle, D C; Rattray, M

    2007-01-01

    The learning of signal directions in high-dimensional data through orthogonal decomposition or principal component analysis (PCA) has many important applications in physics and engineering disciplines, e.g., wireless communication, information theory, and econophysics. The accuracy of the orthogonal decomposition can be studied using mean-field theory. Previous analysis of data produced from a model with a single signal direction has predicted a retarded learning phase transition below which learning is not possible, i.e., if the signal is too weak or the data set is too small then it is impossible to learn anything about the signal direction or magnitude. In this contribution we show that the result can be generalized to the case where there are multiple signal directions. Each nondegenerate signal is associated with a retarded learning transition. However, fluctuations around the mean-field solution lead to large finite size effects unless the signal strengths are very well separated. We evaluate the one-loop contribution to the mean-field theory, which shows that signal directions are indistinguishable from one another if their corresponding population eigenvalues are separated by O(N(-tau)) with exponent tau>1/3, where N is the data dimension. Numerical simulations are consistent with the analysis and show that finite size effects can persist even for very large data sets.

  4. WNT/β-Catenin Signaling Regulates Multiple Steps of Myogenesis by Regulating Step-Specific Targets

    PubMed Central

    Suzuki, Akiko; Pelikan, Richard C.

    2015-01-01

    Molecules involved in WNT/β-catenin signaling show specific spatiotemporal expression and play vital roles in myogenesis; however, it is still largely unknown how WNT/β-catenin signaling regulates each step of myogenesis. Here, we show that WNT/β-catenin signaling can control diverse biological processes of myogenesis by regulating step-specific molecules. In order to identify the temporally specific roles of WNT/β-catenin signaling molecules in muscle development and homeostasis, we used in vitro culture systems for both primary mouse myoblasts and C2C12 cells, which can differentiate into myofibers. We found that a blockade of WNT/β-catenin signaling in the proliferating cells decreases proliferation activity, but does not induce cell death, through the regulation of genes cyclin A2 (Ccna2) and cell division cycle 25C (Cdc25c). During muscle differentiation, the inhibition of WNT/β-catenin signaling blocks myoblast fusion through the inhibition of the Fermitin family homolog 2 (Fermt2) gene. Blocking WNT/β-catenin signaling in the well-differentiated myofibers results in the failure of maintenance of their structure by disruption of cadherin/β-catenin/actin complex formation, which plays a crucial role in connecting a myofiber's cytoskeleton to the surrounding extracellular matrix. Thus, our results indicate that WNT/β-catenin signaling can regulate multiple steps of myogenesis, including cell proliferation, myoblast fusion, and homeostasis, by targeting step-specific molecules. PMID:25755281

  5. WNT/β-Catenin Signaling Regulates Multiple Steps of Myogenesis by Regulating Step-Specific Targets.

    PubMed

    Suzuki, Akiko; Pelikan, Richard C; Iwata, Junichi

    2015-05-01

    Molecules involved in WNT/β-catenin signaling show specific spatiotemporal expression and play vital roles in myogenesis; however, it is still largely unknown how WNT/β-catenin signaling regulates each step of myogenesis. Here, we show that WNT/β-catenin signaling can control diverse biological processes of myogenesis by regulating step-specific molecules. In order to identify the temporally specific roles of WNT/β-catenin signaling molecules in muscle development and homeostasis, we used in vitro culture systems for both primary mouse myoblasts and C2C12 cells, which can differentiate into myofibers. We found that a blockade of WNT/β-catenin signaling in the proliferating cells decreases proliferation activity, but does not induce cell death, through the regulation of genes cyclin A2 (Ccna2) and cell division cycle 25C (Cdc25c). During muscle differentiation, the inhibition of WNT/β-catenin signaling blocks myoblast fusion through the inhibition of the Fermitin family homolog 2 (Fermt2) gene. Blocking WNT/β-catenin signaling in the well-differentiated myofibers results in the failure of maintenance of their structure by disruption of cadherin/β-catenin/actin complex formation, which plays a crucial role in connecting a myofiber's cytoskeleton to the surrounding extracellular matrix. Thus, our results indicate that WNT/β-catenin signaling can regulate multiple steps of myogenesis, including cell proliferation, myoblast fusion, and homeostasis, by targeting step-specific molecules.

  6. 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

  7. 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

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

    PubMed

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

    2015-03-04

    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.

  9. A signaling and decision scheme with application to multiple-access communication

    NASA Astrophysics Data System (ADS)

    Longwell, B. C.; Arozullah, M.; Black, B. A.

    A decision directed detection method using a quasi-orthogonal set of signaling waveforms for detection-signals in the presence of random access interference is presented. In this method the spectra of a number of users in a random access scheme are allowed to overlap and decision is made by sequential elimination of interference. This method can achieve a larger throughput than that of frequency division multiple access. Performance of this detection scheme is evaluated in terms of probability of error and error propagation. This proposed detector outperforms the optimal linear detector for the same signal set in terms of signal-to-noise ratio needed for a given probability of error and data rate per unit bandwidth. This scheme may have application wherever a number of users need to communicate over a common channel e.g., tactical military communication system.

  10. 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.

  11. 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

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

    PubMed Central

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

    2016-01-01

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

  13. Neutron Detector Signal Processing to Calculate the Effective Neutron Multiplication Factor of Subcritical Assemblies

    SciTech Connect

    Talamo, Alberto; Gohar, Yousry

    2016-06-01

    This report describes different methodologies to calculate the effective neutron multiplication factor of subcritical assemblies by processing the neutron detector signals using MATLAB scripts. The subcritical assembly can be driven either by a spontaneous fission neutron source (e.g. californium) or by a neutron source generated from the interactions of accelerated particles with target materials. In the latter case, when the particle accelerator operates in a pulsed mode, the signals are typically stored into two files. One file contains the time when neutron reactions occur and the other contains the times when the neutron pulses start. In both files, the time is given by an integer representing the number of time bins since the start of the counting. These signal files are used to construct the neutron count distribution from a single neutron pulse. The built-in functions of MATLAB are used to calculate the effective neutron multiplication factor through the application of the prompt decay fitting or the area method to the neutron count distribution. If the subcritical assembly is driven by a spontaneous fission neutron source, then the effective multiplication factor can be evaluated either using the prompt neutron decay constant obtained from Rossi or Feynman distributions or the Modified Source Multiplication (MSM) method.

  14. Proposal for all-optical generation of multiple-frequency millimeter-wave signals for RoF system with multiple base stations using FWM in SOA.

    PubMed

    Zhang, Chongfu; Wang, Leyang; Qiu, Kun

    2011-07-18

    An approach for the multiple-frequency millimeter-wave (mm-wave) signals generation is proposed and demonstrated, specifically, which can be applied to a radio-over-fiber (RoF) system with multiple base stations (BSs). In this scheme, optical double sideband (ODSB) modulation is achieved using a Mach-Zehnder modulator (MZM) to generate the two-sideband signals. New frequencies of the optical signals are obtained by using four-wave mixing (FWM) in a semiconductor optical amplifier (SOA). At the BSs, two different frequencies are achieved using a comb optical filter (COF), and which then input a photodiode (PD) to generate the mm-wave signals with the frequencies of 20, 40 or 60 GHz for different BSs, by mixing of these frequencies components. Experimental results verify that the proposed multiple-frequency mm-wave signals generation scheme for a RoF system with multiple base stations can work properly.

  15. Multiple global suppressors of protein stability defects facilitate the evolution of extended-spectrum TEM β-lactamases

    PubMed Central

    Brown, Nicholas G.; Pennington, Jeanine M.; Huang, Wanzhi; Ayvaz, Tulin; Palzkill, Timothy

    2010-01-01

    The introduction of extended-spectrum cephalosporins and β-lactamase inhibitors has driven the evolution of extended–spectrum TEM β-lactamases (ESBLs) with the ability to hydrolyze these drugs. The evolved TEM ESBLs from clinical isolates of bacteria often contain substitutions that occur in the active site and alter the catalytic properties of the enzyme to provide increased hydrolysis of extended-spectrum cephalosporins or resistance to inhibitors. These active site substitutions often result in a cost in the form of reduced enzyme stability. The evolution of TEM ESBLs is facilitated by mutations that act as global suppressors of protein stability defects in that they allow the enzyme to absorb multiple amino acid changes despite incremental losses in stability associated with the substitutions. The best studied example is the M182T substitution that corrects protein stability defects and is commonly found in TEM-type ESBLs or inhibitor-resistant variants from clinical isolates. In this study, a genetic selection for second site mutations that could partially restore function to a severely destabilized primary mutant enabled the identification of A184V, T265M, R275Q, and N276D, which are known to occur in TEM ESBLs from clinical isolates, as suppressors of TEM-1 protein stability defects. Further characterization demonstrated that these substitutions increased the thermal stability of TEM-1 and were able to correct the stability defects of two different sets of destabilizing mutations. The acquisition of compensatory global suppressors of stability costs that are associated with active site mutations may be a common mechanism for the evolution of novel protein function. PMID:20955714

  16. Multiple Notch signaling events control Drosophila CNS midline neurogenesis, gliogenesis and neuronal identity

    PubMed Central

    Wheeler, Scott R.; Stagg, Stephanie B.; Crews, Stephen T.

    2009-01-01

    The study of how transcriptional control and cell signaling influence neurons and glia to acquire their differentiated properties is fundamental to understanding CNS development and function. The Drosophila CNS midline cells are an excellent system for studying these issues because they consist of a small population of diverse cells with well-defined gene expression profiles. In this paper, the origins and differentiation of midline neurons and glia were analyzed. Midline precursor (MP) cells each divide once giving rise to two neurons; here, we use a combination of single-cell gene expression mapping and time-lapse imaging to identify individual MPs, their locations, movements and stereotyped patterns of division. The role of Notch signaling was investigated by analyzing 37 midline-expressed genes in Notch pathway mutant and misexpression embryos. Notch signaling had opposing functions: it inhibited neurogenesis in MP1,3,4 and promoted neurogenesis in MP5,6. Notch signaling also promoted midline glial and median neuroblast cell fate. This latter result suggests that the median neuroblast resembles brain neuroblasts that require Notch signaling, rather than nerve cord neuroblasts, the formation of which is inhibited by Notch signaling. Asymmetric MP daughter cell fates also depend on Notch signaling. One member of each pair of MP3–6 daughter cells was responsive to Notch signaling. By contrast, the other daughter cell asymmetrically acquired Numb, which inhibited Notch signaling, leading to a different fate choice. In summary, this paper describes the formation and division of MPs and multiple roles for Notch signaling in midline cell development, providing a foundation for comprehensive molecular analyses. PMID:18701546

  17. Induction of Cancer Cell Death by Isoflavone: The Role of Multiple Signaling Pathways

    PubMed Central

    Li, Yiwei; Kong, Dejuan; Bao, Bin; Ahmad, Aamir; Sarkar, Fazlul H.

    2011-01-01

    Soy isoflavones have been documented as dietary nutrients broadly classified as “natural agents” which plays important roles in reducing the incidence of hormone-related cancers in Asian countries, and have shown inhibitory effects on cancer development and progression in vitro and in vivo, suggesting the cancer preventive or therapeutic activity of soy isoflavones against cancers. Emerging experimental evidence shows that isoflavones could induce cancer cell death by regulating multiple cellular signaling pathways including Akt, NF-κB, MAPK, Wnt, androgen receptor (AR), p53 and Notch signaling, all of which have been found to be deregulated in cancer cells. Therefore, homeostatic regulation of these important cellular signaling pathways by isoflavones could be useful for the activation of cell death signaling, which could result in the induction of apoptosis of both pre-cancerous and/or cancerous cells without affecting normal cells. In this article, we have attempted to summarize the current state-of-our-knowledge regarding the induction of cancer cell death pathways by isoflavones, which is believed to be mediated through the regulation of multiple cellular signaling pathways. The knowledge gained from this article will provide a comprehensive view on the molecular mechanism(s) by which soy isoflavones may exert their effects on the prevention of tumor progression and/or treatment of human malignancies, which would also aid in stimulating further in-depth mechanistic research and foster the initiation of novel clinical trials. PMID:22200028

  18. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids.

    PubMed

    Jardé, Thierry; Lloyd-Lewis, Bethan; Thomas, Mairian; Kendrick, Howard; Melchor, Lorenzo; Bougaret, Lauriane; Watson, Peter D; Ewan, Kenneth; Smalley, Matthew J; Dale, Trevor C

    2016-10-26

    The development of in vitro culture systems quantitatively and qualitatively recapitulating normal breast biology is key to the understanding of mammary gland biology. Current three-dimensional mammary culture systems have not demonstrated concurrent proliferation and functional differentiation ex vivo in any system for longer than 2 weeks. Here, we identify conditions including Neuregulin1 and R-spondin 1, allowing maintenance and expansion of mammary organoids for 2.5 months in culture. The organoids comprise distinct basal and luminal compartments complete with functional steroid receptors and stem/progenitor cells able to reconstitute a complete mammary gland in vivo. Alternative conditions are also described that promote enrichment of basal cells organized into multiple layers surrounding a keratinous core, reminiscent of structures observed in MMTV-Wnt1 tumours. These conditions comprise a unique tool that should further understanding of normal mammary gland development, the molecular mechanism of hormone action and signalling events whose deregulation leads to breast tumourigenesis.

  19. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids

    PubMed Central

    Jardé, Thierry; Lloyd-Lewis, Bethan; Thomas, Mairian; Kendrick, Howard; Melchor, Lorenzo; Bougaret, Lauriane; Watson, Peter D.; Ewan, Kenneth; Smalley, Matthew J.; Dale, Trevor C.

    2016-01-01

    The development of in vitro culture systems quantitatively and qualitatively recapitulating normal breast biology is key to the understanding of mammary gland biology. Current three-dimensional mammary culture systems have not demonstrated concurrent proliferation and functional differentiation ex vivo in any system for longer than 2 weeks. Here, we identify conditions including Neuregulin1 and R-spondin 1, allowing maintenance and expansion of mammary organoids for 2.5 months in culture. The organoids comprise distinct basal and luminal compartments complete with functional steroid receptors and stem/progenitor cells able to reconstitute a complete mammary gland in vivo. Alternative conditions are also described that promote enrichment of basal cells organized into multiple layers surrounding a keratinous core, reminiscent of structures observed in MMTV-Wnt1 tumours. These conditions comprise a unique tool that should further understanding of normal mammary gland development, the molecular mechanism of hormone action and signalling events whose deregulation leads to breast tumourigenesis. PMID:27782124

  20. 10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling.

    PubMed

    Honda, Yoko; Araki, Yoko; Hata, Taketoshi; Ichihara, Kenji; Ito, Masafumi; Tanaka, Masashi; Honda, Shuji

    2015-01-01

    Royal jelly (RJ) produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA), the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan of Caenorhabditis elegans. The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA further extended the lifespan of the daf-2 mutants, which exhibit long lifespan through reducing insulin-like signaling (ILS), indicating that 10-HDA extended lifespan independently of ILS. On the other hand, 10-HDA did not extend the lifespan of the eat-2 mutants, which show long lifespan through dietary restriction caused by a food-intake defect. This finding indicates that 10-HDA extends lifespan through dietary restriction signaling. We further found that 10-HDA did not extend the lifespan of the long-lived mutants in daf-15, which encodes Raptor, a target of rapamycin (TOR) components, indicating that 10-HDA shared some longevity control mechanisms with TOR signaling. Additionally, 10-HDA was found to confer tolerance against thermal and oxidative stress. 10-HDA increases longevity not through ILS but through dietary restriction and TOR signaling in C. elegans.

  1. Spatially Extended 21 cm Signal from Strongly Clustered Uv and X-Ray Sources in the Early Universe

    NASA Astrophysics Data System (ADS)

    Ahn, Kyungjin; Xu, Hao; Norman, Michael L.; Alvarez, Marcelo A.; Wise, John H.

    2015-03-01

    We present our prediction for the local 21 cm differential brightness temperature (δTb) from a set of strongly clustered sources of Population III (Pop III) and II (Pop II) objects in the early universe, by a numerical simulation of their formation and radiative feedback. These objects are located inside a highly biased environment, which is a rare, high-density peak (“Rarepeak”) extending to ∼7 comoving Mpc. We study the impact of ultraviolet and X-ray photons on the intergalactic medium (IGM) and the resulting δTb, when Pop III stars are assumed to emit X-ray photons by forming X-ray binaries very efficiently. We parameterize the rest-frame spectral energy distribution of X-ray photons, which regulates X-ray photon-trapping, IGM-heating, secondary Lyα pumping and the resulting morphology of δTb. A combination of emission (δTb > 0) and absorption (δTb < 0) regions appears in varying amplitudes and angular scales. The boost of the signal by the high-density environment (δ ∼ 0.64) and on a relatively large scale combines to make Rarepeak a discernible, spatially extended (θ ∼ 10‧) object for 21 cm observation at 13 ≲ z ≲ 17, which is found to be detectable as a single object by SKA with integration time of ∼1000 hr. Power spectrum analysis by some of the SKA precursors (Low Frequency Array, Murchison Widefield Array, Precision Array for Probing the Epoch of Reionization) of such rare peaks is found to be difficult due to the rarity of these peaks, and the contribution only by these rare peaks to the total power spectrum remains subdominant compared to that by all astrophysical sources.

  2. Capabilities of Multiplicative Array Processors as Signal Detector and Bearing Estimator

    DTIC Science & Technology

    1974-12-31

    demonstrated, a more reasonable approach perhaps is to recon- sider the entire configuration for these purposes. Stremler and Brown [54], for example...F. G. Stremler and T. Jensen, "Probability density function for the output of an analog cross correlator with bandpass inputs," IEEE Transactions...F. G. Stremler and W. M. Brown, "Phase analysis in multiple-sensor receivers with high signal-to-noise ratio," IEEE Transactions on Aerospace and

  3. 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

  4. p-21-Activated kinase 1 mediates gastrin-stimulated proliferation in the colorectal mucosa via multiple signaling pathways.

    PubMed

    Huynh, Nhi; Yim, Mildred; Chernoff, Jonathan; Shulkes, Arthur; Baldwin, Graham S; He, Hong

    2013-03-15

    Gastrins, including amidated (Gamide) and glycine-extended (Ggly) forms, function as growth factors for the gastrointestinal mucosa. The p-21-activated kinase 1 (PAK1) plays important roles in growth factor signaling networks that control cell motility, proliferation, differentiation, and transformation. PAK1, activated by both Gamide and Ggly, mediates gastrin-stimulated proliferation and migration, and activation of β-catenin, in gastric epithelial cells. The aim of this study was to investigate the role of PAK1 in the regulation by gastrin of proliferation in the normal colorectal mucosa in vivo. Mucosal proliferation was measured in PAK1 knockout (PAK1 KO) mice by immunohistochemistry. The expression of phosphorylated and unphosphorylated forms of the signaling molecules PAK1, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT), and the expression of β-catenin and its downstream targets c-Myc and cyclin D1, were measured in gastrin knockout (Gas KO) and PAK1 KO mice by Western blotting. The expression and activation of PAK1 are decreased in Gas KO mice, and these decreases are associated with reduced activation of ERK, AKT, and β-catenin. Proliferation in the colorectal mucosa of PAK1 KO mice is reduced, and the reduction is associated with reduced activation of ERK, AKT, and β-catenin. In compensation, antral gastrin mRNA and serum gastrin concentrations are increased in PAK1 KO mice. These results indicate that PAK1 mediates the stimulation of colorectal proliferation by gastrins via multiple signaling pathways involving activation of ERK, AKT, and β-catenin.

  5. DAG tales: the multiple faces of diacylglycerol--stereochemistry, metabolism, and signaling.

    PubMed

    Eichmann, Thomas Oliver; Lass, Achim

    2015-10-01

    The neutral lipids diacylglycerols (DAGs) are involved in a plethora of metabolic pathways. They function as components of cellular membranes, as building blocks for glycero(phospho)lipids, and as lipid second messengers. Considering their central role in multiple metabolic processes and signaling pathways, cellular DAG levels require a tight regulation to ensure a constant and controlled availability. Interestingly, DAG species are versatile in their chemical structure. Besides the different fatty acid species esterified to the glycerol backbone, DAGs can occur in three different stereo/regioisoforms, each with unique biological properties. Recent scientific advances have revealed that DAG metabolizing enzymes generate and distinguish different DAG isoforms, and that only one DAG isoform holds signaling properties. Herein, we review the current knowledge of DAG stereochemistry and their impact on cellular metabolism and signaling. Further, we describe intracellular DAG turnover and its stereochemistry in a 3-pool model to illustrate the spatial and stereochemical separation and hereby the diversity of cellular DAG metabolism.

  6. Multiple-Symbol combined differential detection for satellite-based AIS Signals

    NASA Astrophysics Data System (ADS)

    Hao, Jingsong; Ma, Shexiang; Wang, Junfeng; Meng, Xin

    2015-12-01

    In this paper, a multiple-symbol combined differential Viterbi decoding algorithm which is insensitive to frequency offset is proposed. According to the theories of multiple-symbol differential detection and maximum-likelihood detection, we combine the multiple-order differential information with the Viterbi algorithm. The phase shift caused by the frequency offset is estimated and compensated from the above information in the process of decoding. The simulation results show that the bit error rate (BER) of 2 bits combined differential Viterbi algorithm is below 10-3 when the normalized signal-to-noise ratio (NSNR) is 11 dB, and the decoding performances approach those of the coherent detection as the length of the combined differential symbols increases. The proposed method is simple and its performance remains stable under different frequency offsets.

  7. 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.

  8. [Extended medical quality management exemplified by the tracer diagnosis multiple trauma. Pilot study in the air rescue service].

    PubMed

    Helm, M; Hauke, J; Schlafer, O; Schlechtriemen, T; Lampl, L

    2012-02-01

    Adequate prehospital and inhospital primary care is a decisive factor in the successful treatment of multiple trauma patients. For optimization of treatment algorithms the implementation of a medical quality management is of utmost importance. The aim of this study was to extend quality management by including data on process quality. A retrospective study of primary rescue missions of the Helicopter Emergency Medical Service (HEMS) Christoph 22 in Ulm over a period of 2.5 years was performed. In a detailed analysis of filter criteria, in which relevant deviations from the recommendations (not fulfilled in  > 10% of the cases) occurred, process data was included (vital data, measurements and events). In the study population (n = 298, males 71.8%, mean age 39.8 ± 21.8 years) 2 filter criteria were identified in which relevant deviations where observed: time management where prehospital treatment time  ≤ 60 min in 36% of the cases was not fulfilled and circulatory management where the systolic blood pressure, detected with Riva-Rocci method (RR(sys))  ≥ 120 mmHg on hospital admission in patients with severe head trauma was not fulfilled in 45% of the cases. In patients with deviations in time management, prehospital treatment time was prolonged (75.6 ± 18.3 min versus 50.5 ± 6.7 min; p < 0.01) caused by a prolonged on scene attendance time (34.1 ± 22.1 min versus 20.6 ± 9.2 min; p < 0.01) and transport time (17.3 ± 9.4 min versus 13.3 ± 4.8 min; p < 0.01). In entrapment trauma prehospital treatment time was expanded (44% versus 10%; p < 0.01). Patients in whom circulatory management deviations were observed were more often in shock on arrival at the scene (RR(sys)  ≤ 90 mmHg: 60% versus 30%; p < 0.01), more often hypoxemic [pulse oximeter oxygen saturation (S(p)O(2)) ≤ 90%: 36% versus 19%; p < 0.05] and more often sustained a trauma to the chest as well as to chest and abdomen/pelvis (69% versus 52% and 42% versus 28%, respectively; p < 0

  9. Multiple functions and dynamic activation of MPK-1 extracellular signal-regulated kinase signaling in Caenorhabditis elegans germline development.

    PubMed

    Lee, Min-Ho; Ohmachi, Mitsue; Arur, Swathi; Nayak, Sudhir; Francis, Ross; Church, Diane; Lambie, Eric; Schedl, Tim

    2007-12-01

    The raison d'etre of the germline is to produce oocytes and sperm that pass genetic material and cytoplasmic constituents to the next generation. To achieve this goal, many developmental processes must be executed and coordinated. ERK, the terminal MAP kinase of a number of signaling pathways, controls many aspects of development. Here we present a comprehensive analysis of MPK-1 ERK in Caenorhabditis elegans germline development. MPK-1 functions in four developmental switches: progression through pachytene, oocyte meiotic maturation/ovulation, male germ cell fate specification, and a nonessential function of promoting the proliferative fate. MPK-1 also regulates multiple aspects of cell biology during oogenesis, including membrane organization and morphogenesis: organization of pachytene cells on the surface of the gonadal tube, oocyte organization and differentiation, oocyte growth control, and oocyte nuclear migration. MPK-1 activation is temporally/spatially dynamic and most processes appear to be controlled through sustained activation. MPK-1 thus may act not only in the control of individual processes but also in the coordination of contemporaneous processes and the integration of sequential processes. Knowledge of the dynamic activation and diverse functions of MPK-1 provides the foundation for identification of upstream signaling cascades responsible for region-specific activation and the downstream substrates that mediate the various processes.

  10. Multiple Functions and Dynamic Activation of MPK-1 Extracellular Signal-Regulated Kinase Signaling in Caenorhabditis elegans Germline Development

    PubMed Central

    Lee, Min-Ho; Ohmachi, Mitsue; Arur, Swathi; Nayak, Sudhir; Francis, Ross; Church, Diane; Lambie, Eric; Schedl, Tim

    2007-01-01

    The raison d'etre of the germline is to produce oocytes and sperm that pass genetic material and cytoplasmic constituents to the next generation. To achieve this goal, many developmental processes must be executed and coordinated. ERK, the terminal MAP kinase of a number of signaling pathways, controls many aspects of development. Here we present a comprehensive analysis of MPK-1 ERK in Caenorhabditis elegans germline development. MPK-1 functions in four developmental switches: progression through pachytene, oocyte meiotic maturation/ovulation, male germ cell fate specification, and a nonessential function of promoting the proliferative fate. MPK-1 also regulates multiple aspects of cell biology during oogenesis, including membrane organization and morphogenesis: organization of pachytene cells on the surface of the gonadal tube, oocyte organization and differentiation, oocyte growth control, and oocyte nuclear migration. MPK-1 activation is temporally/spatially dynamic and most processes appear to be controlled through sustained activation. MPK-1 thus may act not only in the control of individual processes but also in the coordination of contemporaneous processes and the integration of sequential processes. Knowledge of the dynamic activation and diverse functions of MPK-1 provides the foundation for identification of upstream signaling cascades responsible for region-specific activation and the downstream substrates that mediate the various processes. PMID:18073423

  11. 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

  12. 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

  13. 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

  14. Multiple signals and male spacing affect female preference at cocktail parties in treefrogs

    PubMed Central

    Richardson, Christina; Lengagne, Thierry

    2010-01-01

    Effective acoustic communication in the face of intense conspecific background noise constitutes a constant sensory challenge in chorusing and colonial species. An evolutionary approach suggests that behavioural and environmental constraints in these species should have shaped signal design and signalling behaviour to enable communication in noisy conditions. This could be attained both through the use of multicomponent signals and through short-term adjustments in the spatial separation of calling males. We investigated these two hypotheses in a chorusing anuran, the hylid Hyla arborea, through a series of phonotaxis experiments conducted within a six-speaker arena in a high background noise situation, by presenting females with male calls containing either single or multiple attractive call components, and by modifying distances between speakers. We found that female ability to discriminate attractive calls increased when several attractive call components were available, providing novel evidence that the use of multicomponent signals enhances communication in complex acoustic conditions. Signal discrimination in females also improved with speaker separation, demonstrating that within natural choruses, spatial unmasking conditioned by male density and spatial separation probably improves female discrimination of competing males. Implications of these results for the accuracy of mate choice within choruses are discussed. PMID:20018785

  15. Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways.

    PubMed

    Xu, Chen; You, Xingji; Liu, Weina; Sun, Qianqian; Ding, Xiaoying; Huang, Ying; Ni, Xin

    2015-01-01

    Prostaglandin F2α (PGF2A) has multiple roles in the birth process in addition to its vital contractile role. Our previous study has demonstrated that PGF2A can modulate uterine activation proteins (UAPs) in cultured pregnant human myometrial smooth muscle cells (HMSMCs). The objective of this study was to define the signalling pathways responsible for PGF2A modulation of UAPs in myometrium. It was found that PGF2A stimulated the expression of (GJA1) connexin 43 (CX43), prostaglandin endoperoxide synthase 2 (PTGS2) and oxytocin receptor (OTR) in cultured HMSMCs. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked PGF2A-stimulated expression of CX43. The inhibitors of ERK, P38 and NFκB also blocked the effect of PGF2A on CX43 expression, whereas PI3K and calcineurin/nuclear factor of activated T-cells (NFAT) pathway inhibitors did not reverse the effect of PGF2A on CX43. For PTGS2 and OTR, PLC, PI3K, P38 and calcineurin/NFAT signalling pathways were involved in PGF2A action, whereas PKC and NFκB signalling were not involved. In addition, PGF2A activated NFAT, PI3K, NFκB, ERK and P38 signalling pathways. Our data suggest that PGF2A stimulates CX43, PTGS2 and OTR through divergent signalling pathways.

  16. 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.

  17. Multiple Novel Signals Mediate Thyroid Hormone Receptor Nuclear Import and Export*

    PubMed Central

    Mavinakere, Manohara S.; Powers, Jeremy M.; Subramanian, Kelly S.; Roggero, Vincent R.; Allison, Lizabeth A.

    2012-01-01

    Thyroid hormone receptor (TR) is a member of the nuclear receptor superfamily that shuttles between the cytosol and nucleus. The fine balance between nuclear import and export of TR has emerged as a critical control point for modulating thyroid hormone-responsive gene expression; however, sequence motifs of TR that mediate shuttling are not fully defined. Here, we characterized multiple signals that direct TR shuttling. Along with the known nuclear localization signal in the hinge domain, we identified a novel nuclear localization signal in the A/B domain of thyroid hormone receptor α1 that is absent in thyroid hormone receptor β1 and inactive in the oncoprotein v-ErbA. Our prior studies showed that thyroid hormone receptor α1 exits the nucleus through two pathways, one dependent on the export factor CRM1 and the other CRM1-independent. Here, we identified three novel CRM1-independent nuclear export signal (NES) motifs in the ligand-binding domain as follows: a highly conserved NES in helix 12 (NES-H12) and two additional NES sequences spanning helix 3 and helix 6, respectively. Mutations predicted to disrupt the α-helical structure resulted in a significant decrease in NES-H12 activity. The high degree of conservation of helix 12 suggests that this region may function as a key NES in other nuclear receptors. Furthermore, our mutagenesis studies on NES-H12 suggest that altered shuttling of thyroid hormone receptor β1 may be a contributing factor in resistance to thyroid hormone syndrome. Taken together, our findings provide a detailed mechanistic understanding of the multiple signals that work together to regulate TR shuttling and transcriptional activity, and they provide important insights into nuclear receptor function in general. PMID:22815488

  18. 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

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

    PubMed Central

    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

  20. Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration

    PubMed Central

    Peng, Yu-Ching; Levine, Charles M.; Zahid, Sarwar; Wilson, E. Lynette; Joyner, Alexandra L.

    2013-01-01

    The adult mouse prostate has a seemingly endless capacity for regeneration, and sonic hedgehog (SHH) signaling has been implicated in this stem cell-driven process. However, it is not clear whether SHH acts on the epithelium or stromal cells that secrete factors required for epithelial expansion. Because little is known about stromal stem cells compared with their epithelial counterparts, we used in vivo mouse genetics tools to characterize four prostate stromal subtypes and their stem cells. Using knockin reporter alleles, we uncovered that SHH signals from prostate basal epithelial cells to adjacent stromal cells. Furthermore, the SHH target gene Gli1 is preferentially expressed in subepithelial fibroblast-like cells, one of four prostate stromal subtypes and the subtype closest to the epithelial source of SHH. Using Genetic Inducible Fate Mapping to mark adult Gli1- or Smooth muscle actin-expressing cells and follow their fate during regeneration, we uncovered that Gli1-expressing cells exhibit long-term self-renewal capacity during multiple rounds of androgen-mediated regeneration after castration-induced involution, and depleted smooth muscle cells are mainly replenished by preexisting smooth muscle cells. Based on our Genetic Inducible Fate Mapping studies, we propose a model where SHH signals to multiple stromal stem cells, which are largely unipotent in vivo. PMID:24218555

  1. Classification of EEG Signals Using a Multiple Kernel Learning Support Vector Machine

    PubMed Central

    Li, Xiaoou; Chen, Xun; Yan, Yuning; Wei, Wenshi; Wang, Z. Jane

    2014-01-01

    In this study, a multiple kernel learning support vector machine algorithm is proposed for the identification of EEG signals including mental and cognitive tasks, which is a key component in EEG-based brain computer interface (BCI) systems. The presented BCI approach included three stages: (1) a pre-processing step was performed to improve the general signal quality of the EEG; (2) the features were chosen, including wavelet packet entropy and Granger causality, respectively; (3) a multiple kernel learning support vector machine (MKL-SVM) based on a gradient descent optimization algorithm was investigated to classify EEG signals, in which the kernel was defined as a linear combination of polynomial kernels and radial basis function kernels. Experimental results showed that the proposed method provided better classification performance compared with the SVM based on a single kernel. For mental tasks, the average accuracies for 2-class, 3-class, 4-class, and 5-class classifications were 99.20%, 81.25%, 76.76%, and 75.25% respectively. Comparing stroke patients with healthy controls using the proposed algorithm, we achieved the average classification accuracies of 89.24% and 80.33% for 0-back and 1-back tasks respectively. Our results indicate that the proposed approach is promising for implementing human-computer interaction (HCI), especially for mental task classification and identifying suitable brain impairment candidates. PMID:25036334

  2. Classification of EEG signals using a multiple kernel learning support vector machine.

    PubMed

    Li, Xiaoou; Chen, Xun; Yan, Yuning; Wei, Wenshi; Wang, Z Jane

    2014-07-17

    In this study, a multiple kernel learning support vector machine algorithm is proposed for the identification of EEG signals including mental and cognitive tasks, which is a key component in EEG-based brain computer interface (BCI) systems. The presented BCI approach included three stages: (1) a pre-processing step was performed to improve the general signal quality of the EEG; (2) the features were chosen, including wavelet packet entropy and Granger causality, respectively; (3) a multiple kernel learning support vector machine (MKL-SVM) based on a gradient descent optimization algorithm was investigated to classify EEG signals, in which the kernel was defined as a linear combination of polynomial kernels and radial basis function kernels. Experimental results showed that the proposed method provided better classification performance compared with the SVM based on a single kernel. For mental tasks, the average accuracies for 2-class, 3-class, 4-class, and 5-class classifications were 99.20%, 81.25%, 76.76%, and 75.25% respectively. Comparing stroke patients with healthy controls using the proposed algorithm, we achieved the average classification accuracies of 89.24% and 80.33% for 0-back and 1-back tasks respectively. Our results indicate that the proposed approach is promising for implementing human-computer interaction (HCI), especially for mental task classification and identifying suitable brain impairment candidates.

  3. Human glucocorticoid-induced TNF receptor ligand regulates its signaling activity through multiple oligomerization states

    PubMed Central

    Zhou, Zhaocai; Song, Xiaomin; Berezov, Alan; Zhang, Geng; Li, Yanjing; Zhang, Hongtao; Murali, Ramachandran; Li, Bin; Greene, Mark I.

    2008-01-01

    Ligation between glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) provides an undefined signal that renders CD4+CD25− effector T cells resistant to the inhibitory effects of CD4+CD25+ regulatory T cells. To understand the structural basis of GITRL function, we have expressed and purified the extracellular domain of human GITR ligand in Escherichia coli. Chromotography and cross-linking studies indicate that human GITRL (hGITRL) exists as dimers and trimers in solution and also can form a supercluster. To gain insight into the nature of GITRL oligomerization, we determined the crystallographic structures of hGITRL, which revealed a loosely associated open trimer with a deep cavity at the molecular center and a flexible C-terminal tail bent for trimerization. Moreover, a tetramer of trimers (i.e., supercluster) has also been observed in the crystal, consistent with the cross-linking analysis. Deletion of the C-terminal distal three residues disrupts the loosely assembled trimer and favors the formation of a dimer that has compromised receptor binding and signaling activity. Collectively, our studies identify multiple oligomeric species of hGITRL that possess distinct kinetics of ERK activation. The studies address the functional implications and structural models for a process by which hGITRL utilizes multiple oligomerization states to regulate GITR-mediated signaling during T cell costimulation. PMID:18378892

  4. Application of Bayes theorem to aminoglycoside-associated nephrotoxicity: comparison of extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing.

    PubMed

    Kim, Myong-Jin; Bertino, Joseph S; Erb, Tara A; Jenkins, Paul L; Nafziger, Anne N

    2004-07-01

    The objective of this study was to examine the incidence of aminoglycoside-associated nephrotoxicity related to extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing by applying Bayes theorem. An electronic literature search of MEDLINE (1966-2003) and a manual search of references from published meta-analyses and review articles were performed. Studies using extended-interval dosing, individualized pharmacokinetic monitoring, or multiple-daily dosing and reported aminoglycoside-associated nephrotoxicity for patients > or = 16 years of age were included. Quality scores were assigned based on the rigor of definition of aminoglycoside-associated nephrotoxicity, duration of therapy, and length of follow-up of renal function after completion of therapy. Inclusion criteria were then based on these quality scores. Quantitative data on the incidence of aminoglycoside-associated nephrotoxicity were abstracted. Twelve extended-interval dosing studies (n = 916), 10 individualized pharmacokinetic monitoring studies (n = 2066), and 27 multiple-daily dosing studies (n = 4251) met the inclusion criteria. Prior probabilities of aminoglycoside-associated nephrotoxicity were derived from a combination of a review of published studies and expert judgment. The maximum densities for the final posterior probabilities of aminoglycoside-associated nephrotoxicity for extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing were located at 12% to 13%, 10% to 11%, and 13% to 14%, respectively. Application of Bayes theorem demonstrates that aminoglycoside dosing by individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity than extended-interval dosing or multiple-daily dosing.

  5. Resolvin D1 Increases Mucin Secretion in Cultured Rat Conjunctival Goblet Cells via Multiple Signaling Pathways

    PubMed Central

    Lippestad, Marit; Hodges, Robin R.; Utheim, Tor P.; Serhan, Charles N.; Dartt, Darlene A.

    2017-01-01

    Purpose Goblet cells in the conjunctiva secrete mucin into the tear film protecting the ocular surface. The proresolution mediator resolvin D1 (RvD1) regulates mucin secretion to maintain homeostasis during physiological conditions and in addition, actively terminates inflammation. We determined the signaling mechanisms used by RvD1 in cultured rat conjunctival goblet cells to increase intracellular [Ca2+] ([Ca2+]i) and induce glycoconjugate secretion. Methods Increase in [Ca2+]i were measured using fura 2/AM and glycoconjugate secretion determined using an enzyme-linked lectin assay with the lectin Ulex Europaeus Agglutinin 1. Signaling pathways activated by RvD1 were studied after goblet cells were pretreated with signaling pathway inhibitors before stimulation with RvD1. The results were compared with results when goblet cells were stimulated with RvD1 alone and percent inhibition calculated. Results The increase in [Ca2+]i stimulated by RvD1 was blocked by inhibitors to phospholipases (PL-) -D, -C, -A2, protein kinase C (PKC), extracellular signal-regulated kinases (ERK)1/2 and Ca2+/calmodulin-dependent kinase (Ca2+/CamK). Glycoconjugate secretion was significantly inhibited by PLD, -C, -A2, ERK1/2 and Ca2+/CamK, but not PKC. Conclusions We conclude that RvD1 increases glycoconjugate secretion from goblet cells via multiple signaling pathways including PLC, PLD, and PLA2, as well as their signaling components ERK1/2 and Ca2+/CamK to preserve the mucous layer and maintain homeostasis by protecting the eye from desiccating stress, allergens, and pathogens. PMID:28892824

  6. Ras1 interacts with multiple new signaling and cytoskeletal loci in Drosophila eggshell patterning and morphogenesis.

    PubMed Central

    Schnorr, J D; Holdcraft, R; Chevalier, B; Berg, C A

    2001-01-01

    Little is known about the genes that interact with Ras signaling pathways to regulate morphogenesis. The synthesis of dorsal eggshell structures in Drosophila melanogaster requires multiple rounds of Ras signaling followed by dramatic epithelial sheet movements. We took advantage of this process to identify genes that link patterning and morphogenesis; we screened lethal mutations on the second chromosome for those that could enhance a weak Ras1 eggshell phenotype. Of 1618 lethal P-element mutations tested, 13 showed significant enhancement, resulting in forked and fused dorsal appendages. Our genetic and molecular analyses together with information from the Berkeley Drosophila Genome Project reveal that 11 of these lines carry mutations in previously characterized genes. Three mutations disrupt the known Ras1 cell signaling components Star, Egfr, and Blistered, while one mutation disrupts Sec61beta, implicated in ligand secretion. Seven lines represent cell signaling and cytoskeletal components that are new to the Ras1 pathway; these are Chickadee (Profilin), Tec29, Dreadlocks, POSH, Peanut, Smt3, and MESK2, a suppressor of dominant-negative Ksr. A twelfth insertion disrupts two genes, Nrk, a "neurospecific" receptor tyrosine kinase, and Tpp, which encodes a neuropeptidase. These results suggest that Ras1 signaling during oogenesis involves novel components that may be intimately associated with additional signaling processes and with the reorganization of the cytoskeleton. To determine whether these Ras1 Enhancers function upstream or downstream of the Egf receptor, four mutations were tested for their ability to suppress an activated Egfr construct (lambdatop) expressed in oogenesis exclusively in the follicle cells. Mutations in Star and l(2)43Bb had no significant effect upon the lambdatop eggshell defect whereas smt3 and dock alleles significantly suppressed the lambdatop phenotype. PMID:11606538

  7. Ras1 interacts with multiple new signaling and cytoskeletal loci in Drosophila eggshell patterning and morphogenesis.

    PubMed

    Schnorr, J D; Holdcraft, R; Chevalier, B; Berg, C A

    2001-10-01

    Little is known about the genes that interact with Ras signaling pathways to regulate morphogenesis. The synthesis of dorsal eggshell structures in Drosophila melanogaster requires multiple rounds of Ras signaling followed by dramatic epithelial sheet movements. We took advantage of this process to identify genes that link patterning and morphogenesis; we screened lethal mutations on the second chromosome for those that could enhance a weak Ras1 eggshell phenotype. Of 1618 lethal P-element mutations tested, 13 showed significant enhancement, resulting in forked and fused dorsal appendages. Our genetic and molecular analyses together with information from the Berkeley Drosophila Genome Project reveal that 11 of these lines carry mutations in previously characterized genes. Three mutations disrupt the known Ras1 cell signaling components Star, Egfr, and Blistered, while one mutation disrupts Sec61beta, implicated in ligand secretion. Seven lines represent cell signaling and cytoskeletal components that are new to the Ras1 pathway; these are Chickadee (Profilin), Tec29, Dreadlocks, POSH, Peanut, Smt3, and MESK2, a suppressor of dominant-negative Ksr. A twelfth insertion disrupts two genes, Nrk, a "neurospecific" receptor tyrosine kinase, and Tpp, which encodes a neuropeptidase. These results suggest that Ras1 signaling during oogenesis involves novel components that may be intimately associated with additional signaling processes and with the reorganization of the cytoskeleton. To determine whether these Ras1 Enhancers function upstream or downstream of the Egf receptor, four mutations were tested for their ability to suppress an activated Egfr construct (lambdatop) expressed in oogenesis exclusively in the follicle cells. Mutations in Star and l(2)43Bb had no significant effect upon the lambdatop eggshell defect whereas smt3 and dock alleles significantly suppressed the lambdatop phenotype.

  8. Scutellaria Barbata D Don Inhibits Colorectal Cancer Growth via Suppression of Multiple Signaling Pathways.

    PubMed

    Lin, Jiumao; Chen, Youqin; Cai, Qiaoyan; Wei, Lihui; Zhan, Youzhi; Shen, Aling; Sferra, Thomas J; Peng, Jun

    2014-05-01

    The pathogenic mechanisms underlying cancer development are complex and heterogeneous, involving multiple cellular signaling transduction pathways that usually function redundantly. In addition, crosstalk between these pathways generates a complicated and robust signaling network that is regulated by compensatory mechanisms. Given the complexity of cancer pathogenesis and progression, many of the currently used antitumor agents, which typically target a single intracellular pathway, might not always be effective on complex tumor systems. Moreover, long-term use of these agents often generates drug resistance and toxicity against normal cells. Therefore, the development of novel anticancer chemotherapies is urgently needed.Scutellaria barbataD Don (SB) is a medicinal herb that has long been used in China to treat various types of cancer. We previously reported that the ethanol extract of SB (EESB) is able to induce colon cancer cell apoptosis, inhibit cell proliferation and tumor angiogenesis via modulation of several pathways, including Hedgehog, Akt, and p53. To further elucidate the precise mechanisms of SB's antitumor activity, using a colorectal cancer (CRC) mouse xenograft model in the present study, we evaluated the therapeutic efficacy and molecular mechanisms of EESB against tumor growth. We found that EESB reduced tumor volume and tumor weight but had no effect on body weight gain in CRC mice, demonstrating that EESB could inhibit colon cancer growth in vivo without apparent adverse effect. In addition, EESB treatment could significantly suppress the activation of several CRC-related pathways, including STAT3, Erk, and p38 signalings in tumor tissues, and alter the expression of multiple critical target genes such as Bcl-2, Bax, Cyclin D1, CDK4, and p21. These molecular effects lead to the induction of cancer cell apoptosis and inhibition of cell proliferation. Our findings demonstrate that SB possesses a broad range of antitumor activities because of its

  9. The plant-unique cis-element that mediates signaling from multiple endoplasmic reticulum stress sensors

    PubMed Central

    Hayashi, Shimpei; Takaiwa, Fumio

    2013-01-01

    The accumulation of unfolded proteins in the ER lumen induces intracellular signaling mediated by the ER stress sensor protein IRE1. Our recent study identified a new common cis-element of ER stress-responsive genes (such as rice BiP paralogs and WRKY45) that were regulated via an IRE1-dependent pathway. ER stress-responsive cis-elements had been expected to be conserved between plants and mammals. However, contrary to expectations, sequences of the plant cis-element, pUPRE-II, were not identical to those of its mammalian counterpart. Additionally, pUPRE-II also interacted with another ER stress sensor protein and mediated multiple signaling pathways. Here, we provide a summary of the results that suggest the complicated mechanism underlying the regulation of ER stress-responsive gene expression in plants. PMID:23518586

  10. Specifics of signal generation in receivers based on thermoelastic effect at multiple impulse exposure

    NASA Astrophysics Data System (ADS)

    Shevnina, Elena I.; Maraev, Anton A.; Ishanin, Gennady G.

    2016-04-01

    To provide operating supervision of the process there is a need of means of control with high temporal stability and resistance to radiation excess. Receivers based on the thermoelastic effect in crystalline quartz are designed for energy measurement of lasers in single impulse mode or for average power measurement in operation monitoring of industrial lasers. In the research we analyze work of the receiver at single impulse exposure. The heat storage time of the receiver is defined. Specifics of signal generation in receivers on thermoelastic effect at multiple impulse exposure are also analyzed. An algorithm for voltage calculation of the receiver with given parameters is developed. The modelling shows that generated signal growth in the detector exposed to an impulse consequence can influence the power measurement result and thus the ways to reduce the effect are proposed.

  11. The plant-unique cis-element that mediates signaling from multiple endoplasmic reticulum stress sensors.

    PubMed

    Hayashi, Shimpei; Takaiwa, Fumio

    2013-06-01

    The accumulation of unfolded proteins in the ER lumen induces intracellular signaling mediated by the ER stress sensor protein IRE1. Our recent study identified a new common cis-element of ER stress-responsive genes (such as rice BiP paralogs and WRKY45) that were regulated via an IRE1-dependent pathway. ER stress-responsive cis-elements had been expected to be conserved between plants and mammals. However, contrary to expectations, sequences of the plant cis-element, pUPRE-II, were not identical to those of its mammalian counterpart. Additionally, pUPRE-II also interacted with another ER stress sensor protein and mediated multiple signaling pathways. Here, we provide a summary of the results that suggest the complicated mechanism underlying the regulation of ER stress-responsive gene expression in plants.

  12. 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

  13. TAK1 regulates caspase 8 activation and necroptotic signaling via multiple cell death checkpoints

    PubMed Central

    Guo, Xiaoyun; Yin, Haifeng; Chen, Yi; Li, Lei; Li, Jing; Liu, Qinghang

    2016-01-01

    Necroptosis has emerged as a new form of programmed cell death implicated in a number of pathological conditions such as ischemic injury, neurodegenerative disease, and viral infection. Recent studies indicate that TGFβ-activated kinase 1 (TAK1) is nodal regulator of necroptotic cell death, although the underlying molecular regulatory mechanisms are not well defined. Here we reported that TAK1 regulates necroptotic signaling as well as caspase 8-mediated apoptotic signaling through both NFκB-dependent and -independent mechanisms. Inhibition of TAK1 promoted TNFα-induced cell death through the induction of RIP1 phosphorylation/activation and necrosome formation. Further, inhibition of TAK1 triggered two caspase 8 activation pathways through the induction of RIP1-FADD-caspase 8 complex as well as FLIP cleavage/degradation. Mechanistically, our data uncovered an essential role for the adaptor protein TNF receptor-associated protein with death domain (TRADD) in caspase 8 activation and necrosome formation triggered by TAK1 inhibition. Moreover, ablation of the deubiqutinase CYLD prevented both apoptotic and necroptotic signaling induced by TAK1 inhibition. Finally, blocking the ubiquitin-proteasome pathway prevented the degradation of key pro-survival signaling proteins and necrosome formation. Thus, we identified new regulatory mechanisms underlying the critical role of TAK1 in cell survival through regulation of multiple cell death checkpoints. Targeting key components of the necroptotic pathway (e.g., TRADD and CYLD) and the ubiquitin-proteasome pathway may represent novel therapeutic strategies for pathological conditions driven by necroptosis. PMID:27685625

  14. Jasmonate signaling in plant development and defense response to multiple (a)biotic stresses.

    PubMed

    Santino, Angelo; Taurino, Marco; De Domenico, Stefania; Bonsegna, Stefania; Poltronieri, Palmiro; Pastor, Victoria; Flors, Victor

    2013-07-01

    Plants frequently live in environments characterized by the presence of simultaneous and different stresses. The intricate and finely tuned molecular mechanisms activated by plants in response to abiotic and biotic environmental factors are not well understood, and less is known about the integrative signals and convergence points activated by plants in response to multiple (a)biotic stresses. Phytohormones play a key role in plant development and response to (a)biotic stresses. Among these, one of the most important signaling molecules is an oxylipin, the plant hormone jasmonic acid. Oxylipins are derived from oxygenation of polyunsaturated fatty acids. Jasmonic acid and its volatile derivative methyl jasmonate have been considered for a long time to be the bioactive forms due to their physiological effects and abundance in the plant. However, more recent studies showed unambiguously that they are only precursors of the active forms represented by some amino acid conjugates. Upon developmental or environmental stimuli, jasmonates are synthesized and accumulate transiently. Upon perception, jasmonate signal transduction process is finely tuned by a complex mechanism comprising specific repressor proteins which in turn control a number of transcription factors regulating the expression of jasmonate responsive genes. We discuss the latest discoveries about the role of jasmonates in plants resistance mechanism against biotic and abiotic stresses. Finally, the deep interplay of different phytohormones in stresses signaling will be also discussed.

  15. 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.

  16. 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

  17. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

    PubMed Central

    Trynka, Gosia; Hunt, Karen A; Bockett, Nicholas A; Romanos, Jihane; Mistry, Vanisha; Szperl, Agata; Bakker, Sjoerd F; Bardella, Maria Teresa; Bhaw-Rosun, Leena; Castillejo, Gemma; de la Concha, Emilio G.; de Almeida, Rodrigo Coutinho; Dias, Kerith-Rae M; van Diemen, Cleo C.; Dubois, Patrick CA; Duerr, Richard H.; Edkins, Sarah; Franke, Lude; Fransen, Karin; Gutierrez, Javier; Heap, Graham AR; Hrdlickova, Barbara; Hunt, Sarah; Izurieta, Leticia Plaza; Izzo, Valentina; Joosten, Leo AB; Langford, Cordelia; Mazzilli, Maria Cristina; Mein, Charles A; Midah, Vandana; Mitrovic, Mitja; Mora, Barbara; Morelli, Marinita; Nutland, Sarah; Núñez, Concepción; Onengut-Gumuscu, Suna; Pearce, Kerra; Platteel, Mathieu; Polanco, Isabel; Potter, Simon; Ribes-Koninckx, Carmen; Ricaño-Ponce, Isis; Rich, Stephen S.; Rybak, Anna; Santiago, José Luis; Senapati, Sabyasachi; Sood, Ajit; Szajewska, Hania; Troncone, Riccardo; Varadé, Jezabel; Wallace, Chris; Wolters, Victorien M; Zhernakova, Alexandra; Thelma, B.K.; Cukrowska, Bozena; Urcelay, Elena; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Barrett, Jeffrey C; Plagnol, Vincent; Deloukas, Panos; Wijmenga, Cisca; van Heel, David A

    2011-01-01

    We densely genotyped, using 1000 Genomes Project pilot CEU and additional re-sequencing study variants, 183 reported immune-mediated disease non-HLA risk loci in 12,041 celiac disease cases and 12,228 controls. We identified 13 new celiac disease risk loci at genome wide significance, bringing the total number of known loci (including HLA) to 40. Multiple independent association signals are found at over a third of these loci, attributable to a combination of common, low frequency, and rare genetic variants. In comparison with previously available data such as HapMap3, our dense genotyping in a large sample size provided increased resolution of the pattern of linkage disequilibrium, and suggested localization of many signals to finer scale regions. In particular, 29 of 54 fine-mapped signals appeared localized to specific single genes - and in some instances to gene regulatory elements. We define a complex genetic architecture of risk regions, and refine risk signals, providing a next step towards elucidating causal disease mechanisms. PMID:22057235

  18. Laguerre-model blind system identification: cardiovascular dynamics estimated from multiple peripheral circulatory signals.

    PubMed

    McCombie, Devin B; Reisner, Andrew T; Asada, Haruhiko Harry

    2005-11-01

    This paper presents a method for comparing multiple circulatory waveforms measured at different locations to improve cardiovascular parameter estimation from these signals. The method identifies the distinct vascular dynamics that shape each waveform signal, and estimates the common cardiac flow input shared by them. This signal-processing algorithm uses the Laguerre function series expansion for modeling the hemodynamics of each arterial branch, and identifies unknown parameters in these models from peripheral waveforms using multichannel blind system identification. An effective technique for determining the Laguerre base pole is developed, so that the Laguerre expansion captures and quickly converges to the intrinsic arterial dynamics observed in the two circulatory signals. Furthermore, a novel deconvolution method is developed in order to stably invert the identified dynamic models for estimating the cardiac output (CO) waveform from peripheral pressure waveforms. The method is applied to experimental swine data. A mean error of less than 5% with the measured peripheral pressure waveforms has been achieved using the models and excellent agreement between the estimated CO waveforms and the gold standard measurements have been obtained.

  19. Recessive mutations in a common pathway block thymocyte apoptosis induced by multiple signals

    PubMed Central

    1994-01-01

    The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls genes necessary to initiate glucocorticoid-induced thymocyte apoptosis. We have performed a genetic analysis of thymocyte cell death by isolating and characterizing a panel of GR+ dexamethasone- resistant mutants of the murine WEHI7.2 thymocyte cell line. These apoptosis-defective (Apt-) mutants were used to identify previously unknown early steps in the apoptotic pathway. The Apt- mutants contain nonglucocorticoid receptor, recessive mutations in genes that represent multiple complementation groups. These mutations block apoptosis induced by dexamethasone, gamma irradiation, and c-AMP treatment before the point where Bcl-2 exerts its protective effect. We propose that different signals share a common apoptotic pathway, and that the induction of apoptosis involves multiple precommitment steps that can be blocked by recessive mutations. PMID:7798323

  20. New multiple-tap, general-response, reconfigurable photonic signal processor.

    PubMed

    Huang, Thomas X; Yi, Xiaoke; Minasian, Robert A

    2009-03-30

    A new photonic signal processor structure that can realize multiple-taps, with a general response capability, low-noise and widely tunable processor operation, is presented. It is based on a novel concept of employing positive and negative group delay slopes simultaneously by means of a dual-fed chirped fiber Bragg grating, and a new wavelength mapping scheme that enables wavelength re-use. The technique offers scalability, arbitrary responses with both positive and negative taps, tunability, and high frequency operation. Experimental results demonstrate widely tunable filters, with arbitrary bipolar tap generation, no PIIN noise, and with high FSR.

  1. A C*-based Extended Multiple Linear Regression Method to Determine Decadal Changes in Anthropogenic CO2 in the Ocean

    NASA Astrophysics Data System (ADS)

    Clement, Dominic; Gruber, Nicolas

    2017-04-01

    Major progress has been made by the international community (e.g., GO-SHIP, IOCCP, IMBER/SOLAS carbon working groups) in recent years by collecting and providing homogenized datasets for carbon and other biogeochemical variables in the surface ocean (SOCAT) and interior ocean (GLODAPv2). Together with previous efforts, this has enabled the community to develop methods to assess changes in the ocean carbon cycle through time. Of particular interest is the determination of the decadal change in the anthropogenic CO2 inventory solely based on in-situ measurements from at least two time periods in the interior ocean. However, all such methods face the difficulty of a scarce dataset in both space and time, making the use of appropriate interpolation techniques in time and space a crucial element of any method. Here we present a new method based on the parameter C*, whose variations reflect the total change in dissolved inorganic carbon (DIC) driven by the exchange of CO2 across the air-sea interface. We apply the extended Multiple Linear Regression method (Friis et al., 2005) on C* in order (1) to calculate the change in anthropogenic CO2 from the original DIC/C* measurements, and (2) to interpolate the result onto a spatial grid using other biogeochemical variables (T,S,AOU, etc.). These calculations are made on isopycnal slabs across whole ocean basins. In combination with the transient steady state assumption (Tanhua et al., 2007) providing a temporal correction factor, we address the spatial and temporal interpolation challenges. Using synthetic data from a hindcast simulation with a global ocean biogeochemistry model (NCAR-CCSM with BEC), we tested the method for robustness and accuracy in determining ΔCant. We will present data-based results for all ocean basins, with the most recent estimate of an global uptake of 32±6 Pg C between 1994 and 2007, indicating an uptake rate 2.5±0.5 Pg C yr-1 for this time period. These results are compared with regional and

  2. 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

  3. The role of toll-like receptor mediated signalling in the pathogenesis of multiple myeloma.

    PubMed

    Abdi, Jahangir; Engels, Ferdi; Garssen, Johan; Redegeld, Frank

    2011-11-01

    Toll-like receptors are critical structures in sensing the invading pathogens via conserved moieties termed pathogen associated molecular patterns and in directing the innate and adaptive immune responses. Studies have shown that Toll-like receptors are not limited to normal immune cells but are expressed on tumour cells as well, including those of lymphoid neoplasms particularly B-cell malignancies, multiple myeloma and chronic lymphocytic leukemia. Neoplastic plasma cells in multiple myeloma usually show a different pattern of Toll-like receptor expression compared to normal B cells. These receptors on multiple myeloma cells, have been indicated to have a role in their proliferation, differentiation and survival, probably through induction of autocrine IL-6 secretion, and in their immunomodulatory functions. Moreover, it is speculated that these molecules may contribute to osteolytic lesions through activation of osteoclasts, and to angiogenesis through induction of pro-angiogenic factors. Knowledge on Toll-like receptor signalling in the biology of malignant plasma cells or their cellular microenvironment may give new insights into pathogenesis of multiple myeloma and may open new avenues for the therapy of this disease. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. Signal Normalization Reduces Image Appearance Disparity Among Multiple Optical Coherence Tomography Devices

    PubMed Central

    Chen, Chieh-Li; Ishikawa, Hiroshi; Wollstein, Gadi; Bilonick, Richard A.; Kagemann, Larry; Schuman, Joel S.

    2017-01-01

    Purpose To assess the effect of the previously reported optical coherence tomography (OCT) signal normalization method on reducing the discrepancies in image appearance among spectral-domain OCT (SD-OCT) devices. Methods Healthy eyes and eyes with various retinal pathologies were scanned at the macular region using similar volumetric scan patterns with at least two out of three SD-OCT devices at the same visit (Cirrus HD-OCT, Zeiss, Dublin, CA; RTVue, Optovue, Fremont, CA; and Spectralis, Heidelberg Engineering, Heidelberg, Germany). All the images were processed with the signal normalization. A set of images formed a questionnaire with 24 pairs of cross-sectional images from each eye with any combination of the three SD-OCT devices either both pre- or postsignal normalization. Observers were asked to evaluate the similarity of the two displayed images based on the image appearance. The effects on reducing the differences in image appearance before and after processing were analyzed. Results Twenty-nine researchers familiar with OCT images participated in the survey. Image similarity was significantly improved after signal normalization for all three combinations (P ≤ 0.009) as Cirrus and RTVue combination became the most similar pair, followed by Cirrus and Spectralis, and RTVue and Spectralis. Conclusions The signal normalization successfully minimized the disparities in the image appearance among multiple SD-OCT devices, allowing clinical interpretation and comparison of OCT images regardless of the device differences. Translational Relevance The signal normalization would enable direct OCT images comparisons without concerning about device differences and broaden OCT usage by enabling long-term follow-ups and data sharing. PMID:28275528

  5. Bidirectional signaling between calcium channels of skeletal muscle requires multiple direct and indirect interactions

    PubMed Central

    Sheridan, David C.; Takekura, Hiroaki; Franzini-Armstrong, Clara; Beam, Kurt G.; Allen, Paul D.; Perez, Claudio F.

    2006-01-01

    We have defined regions of the skeletal muscle ryanodine receptor (RyR1) essential for bidirectional signaling with dihydropyridine receptors (DHPRs) and for the organization of DHPR into tetrad arrays by expressing RyR1–RyR3 chimerae in dyspedic myotubes. RyR1–RyR3 constructs bearing RyR1 residues 1–1681 restored wild-type DHPR tetrad arrays and, in part, skeletal-type excitation–contraction (EC) coupling (orthograde signaling) but failed to enhance DHPR Ca2+ currents (retrograde signaling) to WT RyR1 levels. Within this region, the D2 domain (amino acids 1272–1455), although ineffective on its own, dramatically enhanced the formation of tetrads and EC coupling rescue by constructs that otherwise are only partially effective. These findings suggest that the orthograde signal and DHPR tetrad formation require the contributions of numerous RyR regions. Surprisingly, we found that RyR3, although incapable of supporting EC coupling or tetrad formation, restored a significant level of Ca2+ current, revealing a functional interaction with the skeletal muscle DHPR. Thus, our data support the hypotheses that (i) the structural/functional link between RyR1 and the skeletal muscle DHPR requires multiple interacting regions, (ii) the D2 domain of RyR1 plays a key role in stabilizing this interaction, and (iii) a form of retrograde signaling from RyR3 to the DHPR occurs in the absence of direct protein–protein interactions. PMID:17172444

  6. 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

  7. Retrieval of Droplet size Density Distribution from Multiple field of view Cross polarized Lidar Signals: Theory and Experimental Validation

    DTIC Science & Technology

    2016-06-02

    Retrieval of droplet-size density distribution from multiple- field -of-view cross-polarized lidar signals: theory and experimental validation...Gilles Roy, Luc Bissonnette, Christian Bastille, and Gilles Vallee Multiple- field -of-view (MFOV) secondary-polarization lidar signals are used to...use secondary polarization. A mathematical relation among the PSD, the lidar fields of view, the scattering angles, and the angular depolarization

  8. Multiple disturbances classifier for electric signals using adaptive structuring neural networks

    NASA Astrophysics Data System (ADS)

    Lu, Yen-Ling; Chuang, Cheng-Long; Fahn, Chin-Shyurng; Jiang, Joe-Air

    2008-07-01

    This work proposes a novel classifier to recognize multiple disturbances for electric signals of power systems. The proposed classifier consists of a series of pipeline-based processing components, including amplitude estimator, transient disturbance detector, transient impulsive detector, wavelet transform and a brand-new neural network for recognizing multiple disturbances in a power quality (PQ) event. Most of the previously proposed methods usually treated a PQ event as a single disturbance at a time. In practice, however, a PQ event often consists of various types of disturbances at the same time. Therefore, the performances of those methods might be limited in real power systems. This work considers the PQ event as a combination of several disturbances, including steady-state and transient disturbances, which is more analogous to the real status of a power system. Six types of commonly encountered power quality disturbances are considered for training and testing the proposed classifier. The proposed classifier has been tested on electric signals that contain single disturbance or several disturbances at a time. Experimental results indicate that the proposed PQ disturbance classification algorithm can achieve a high accuracy of more than 97% in various complex testing cases.

  9. A new linear least squares method for T1 estimation from SPGR signals with multiple TRs

    NASA Astrophysics Data System (ADS)

    Chang, Lin-Ching; Koay, Cheng Guan; Basser, Peter J.; Pierpaoli, Carlo

    2009-02-01

    The longitudinal relaxation time, T1, can be estimated from two or more spoiled gradient recalled echo x (SPGR) images with two or more flip angles and one or more repetition times (TRs). The function relating signal intensity and the parameters are nonlinear; T1 maps can be computed from SPGR signals using nonlinear least squares regression. A widely-used linear method transforms the nonlinear model by assuming a fixed TR in SPGR images. This constraint is not desirable since multiple TRs are a clinically practical way to reduce the total acquisition time, to satisfy the required resolution, and/or to combine SPGR data acquired at different times. A new linear least squares method is proposed using the first order Taylor expansion. Monte Carlo simulations of SPGR experiments are used to evaluate the accuracy and precision of the estimated T1 from the proposed linear and the nonlinear methods. We show that the new linear least squares method provides T1 estimates comparable in both precision and accuracy to those from the nonlinear method, allowing multiple TRs and reducing computation time significantly.

  10. Cooperation of multiple signaling pathways in CD40-regulated gene expression in B lymphocytes

    PubMed Central

    Dadgostar, Hajir; Zarnegar, Brian; Hoffmann, Alexander; Qin, Xiao-Feng; Truong, Uyen; Rao, Govinda; Baltimore, David; Cheng, Genhong

    2002-01-01

    CD40/CD40L interaction is essential for multiple biological events in T dependent humoral immune responses, including B cell survival and proliferation, germinal center and memory B cell formation, and antibody isotype switching and affinity maturation. By using high-density microarrays, we examined gene expression in primary mouse B lymphocytes after multiple time points of CD40L stimulation. In addition to genes involved in cell survival and growth, which are also induced by other mitogens such as lipopolysaccharide, CD40L specifically activated genes involved in germinal center formation and T cell costimulatory molecules that facilitate T dependent humoral immunity. Next, by examining the roles of individual CD40-activated signal transduction pathways, we dissected the overall CD40-mediated response into genes independently regulated by the individual pathways or collectively by all pathways. We also found that gene down-regulation is a significant part of the overall response and that the p38 pathway plays an important role in this process, whereas the NF-κB pathway is important for the up-regulation of primary response genes. Our finding of overlapping independent control of gene expression modules by different pathways suggests, in principle, that distinct biological behaviors that depend on distinct gene expression subsets can be manipulated by targeting specific signaling pathways. PMID:11830667

  11. 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.

  12. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway.

    PubMed

    Wu, Ching-Shyi; Ouyang, Jian; Mori, Eiichiro; Nguyen, Hai Dang; Maréchal, Alexandre; Hallet, Alexander; Chen, David J; Zou, Lee

    2014-07-01

    The ATR (ATM [ataxia telangiectasia-mutated]- and Rad3-related) checkpoint is a crucial DNA damage signaling pathway. While the ATR pathway is known to transmit DNA damage signals through the ATR-Chk1 kinase cascade, whether post-translational modifications other than phosphorylation are important for this pathway remains largely unknown. Here, we show that protein SUMOylation plays a key role in the ATR pathway. ATRIP, the regulatory partner of ATR, is modified by SUMO2/3 at K234 and K289. An ATRIP mutant lacking the SUMOylation sites fails to localize to DNA damage and support ATR activation efficiently. Surprisingly, the ATRIP SUMOylation mutant is compromised in the interaction with a protein group, rather than a single protein, in the ATR pathway. Multiple ATRIP-interacting proteins, including ATR, RPA70, TopBP1, and the MRE11-RAD50-NBS1 complex, exhibit reduced binding to the ATRIP SUMOylation mutant in cells and display affinity for SUMO2 chains in vitro, suggesting that they bind not only ATRIP but also SUMO. Fusion of a SUMO2 chain to the ATRIP SUMOylation mutant enhances its interaction with the protein group and partially suppresses its localization and functional defects, revealing that ATRIP SUMOylation promotes ATR activation by providing a unique type of protein glue that boosts multiple protein interactions along the ATR pathway. © 2014 Wu et al.; Published by Cold Spring Harbor Laboratory Press.

  13. Microfluidic platform for real-time signaling analysis of multiple single T cells in parallel.

    PubMed

    Faley, Shannon; Seale, Kevin; Hughey, Jacob; Schaffer, David K; VanCompernolle, Scott; McKinney, Brett; Baudenbacher, Franz; Unutmaz, Derya; Wikswo, John P

    2008-10-01

    Deciphering the signaling pathways that govern stimulation of naïve CD4+ T helper cells by antigen-presenting cells via formation of the immunological synapse is key to a fundamental understanding of the progression of successful adaptive immune response. The study of T cell-APC interactions in vitro is challenging, however, due to the difficulty of tracking individual, non-adherent cell pairs over time. Studying single cell dynamics over time reveals rare, but critical, signaling events that might be averaged out in bulk experiments, but these less common events are undoubtedly important for an integrated understanding of a cellular response to its microenvironment. We describe a novel application of microfluidic technology that overcomes many limitations of conventional cell culture and enables the study of hundreds of passively sequestered hematopoietic cells for extended periods of time. This microfluidic cell trap device consists of 440 18 micromx18 micromx10 microm PDMS, bucket-like structures opposing the direction of flow which serve as corrals for cells as they pass through the cell trap region. Cell viability analysis revealed that more than 70% of naïve CD4+ T cells (TN), held in place using only hydrodynamic forces, subsequently remain viable for 24 hours. Cytosolic calcium transients were successfully induced in TN cells following introduction of chemical, antibody, or cellular forms of stimulation. Statistical analysis of TN cells from a single stimulation experiment reveals the power of this platform to distinguish different calcium response patterns, an ability that might be utilized to characterize T cell signaling states in a given population. Finally, we investigate in real time contact- and non-contact-based interactions between primary T cells and dendritic cells, two main participants in the formation of the immunological synapse. Utilizing the microfluidic traps in a daisy-chain configuration allowed us to observe calcium transients in TN

  14. Emodin inhibits coxsackievirus B3 replication via multiple signalling cascades leading to suppression of translation.

    PubMed

    Zhang, Huifang M; Wang, Fengping; Qiu, Ye; Ye, Xin; Hanson, Paul; Shen, Hongxing; Yang, Decheng

    2016-02-15

    CVB3 (coxsackievirus 3) is a primary causal agent of viral myocarditis. Emodin is a natural compound isolated from certain plant roots. In the present study, we found that emodin inhibited CVB3 replication in vitro and in mice, and now we report an unrecognized mechanism by which emodin inhibits CVB3 replication through suppression of viral protein translation via multiple pathways. On one hand, emodin treatment inhibited Akt/mTOR (mammalian target of rapamycin) signalling and activated 4EBP1 (eukaryotic initiation factor 4R-binding protein 1), leading to suppression of translation initiation of ribosomal protein L32 encoded by a 5'-TOP (terminal oligopyrimidine) mRNA. On the other hand, emodin treatment differentially regulated multiple signal cascades, including Akt/mTORC1/p70(S6K) (p70 S6 kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2)/p90(RSK) (p90 ribosomal S6 kinase) and Ca(2+)/calmodulin, leading to activation of eEF2K (eukaryotic elongation factor 2 kinase) and subsequent inactivation of eEF2 (eukaryotic elongation factor 2), resulting in inhibition of CVB3 VP1 (viral protein 1) synthesis. These data imply that eEF2K is a major factor mediating cross-talk of different arms of signalling cascades in this signal network. This notion was verified by either overexpressing eEF2K or treating the cells with siRNAs or eEF2K inhibitor A484954. We showed further that the emodin-induced decrease in p70(S6K) phosphorylation plays a dominant positive role in activation of eEF2K and in turn in conferring the antiviral effect of emodin. This finding was further solidified by expressing constitutively active and dominant-negative Akt. Collectively, our data reveal that emodin inhibits viral replication through impairing translational machinery and suppression of viral translation elongation. © 2016 Authors; published by Portland Press Limited.

  15. A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model

    PubMed Central

    Arima, Yasunobu; Kamimura, Daisuke; Atsumi, Toru; Harada, Masaya; Kawamoto, Tadafumi; Nishikawa, Naoki; Stofkova, Andrea; Ohki, Takuto; Higuchi, Kotaro; Morimoto, Yuji; Wieghofer, Peter; Okada, Yuka; Mori, Yuki; Sakoda, Saburo; Saika, Shizuya; Yoshioka, Yoshichika; Komuro, Issei; Yamashita, Toshihide; Hirano, Toshio; Prinz, Marco; Murakami, Masaaki

    2015-01-01

    Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target. DOI: http://dx.doi.org/10.7554/eLife.08733.001 PMID:26193120

  16. Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis.

    PubMed

    Fitzpatrick, John-Mark K; Downer, Eric J

    2017-02-01

    Toll-like receptors (TLRs) are the sensors of pathogen-associated molecules that trigger tailored innate immune intracellular signalling responses to initiate innate immune reactions. Data from the experimental autoimmune encephalomyelitis (EAE) model indicates that TLR signalling machinery is a pivotal player in the development of murine EAE. To compound this, data from human studies indicate that complex interplay exists between TLR signalling and Multiple Sclerosis (MS) pathogenesis. Cannabis-based therapies are in clinical development for the management of a variety of medical conditions, including MS. In particular Sativex(®), a combination of plant-derived cannabinoids, is an oromucosal spray with efficacy in MS patients, particularly those with neuropathic pain and spasticity. Despite this, the precise cellular and molecular mechanisms of action of Sativex(®) in MS patients remains unclear. This review will highlight evidence that novel interplay exists between the TLR and cannabinoid systems, both centrally and peripherally, with relevance to the pathogenesis of MS. This article is part of the Special Issue entitled 'Lipid Sensing G Protein-Coupled Receptors in the CNS'. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Homogeneously ultrasensitive electrochemical detection of adenosine triphosphate based on multiple signal amplification strategy.

    PubMed

    Chen, Xiaojun; Ge, Lingna; Guo, Buhua; Yan, Ming; Hao, Ning; Xu, Lin

    2014-08-15

    An ultrasensitive electrochemical aptasensor was successfully fabricated for the detection of adenosine triphosphate (ATP). For the first time, one detection system combined several elements: magnetic aptamer sequences for target recognition and separation, a DNAzyme assisted cyclic signal amplification strategy, layer-by-layer (LBL) quantum dots (QDs) composites for promoting square wave anodic stripping voltammetric (SWASV) analysis and Bi, Nafion (Nf) and three-dimensional ordered macroporous polyaniline-ionic liquid (Bi/Nf/3DOM PANI-IL) film modified glassy carbon electrode (GCE) for monitoring enhanced SWASV signal. The modification of Nf/3DOM PANI-IL on GCE showed that the preconcentration efficiency was improved by the electrostatic absorption of Cd(2+) with negative Nf layer with the enhanced analytical sensitivity due to a large active surface area of 3DOM structure. The increased SWASV peak current values of the label (CdS)4@SiO2 composites were found to be proportional to the logarithmic value of ATP concentrations in the range of 1pM-10nM and 10nM-1µM, with the detection limit as low as 0.5pM. The proposed aptasensor has shown an excellent performance such as high sensitivity, good selectivity and analytical application in real samples. The results demonstrated that the multiple signal amplified strategy we developed was feasible for clinical ATP assay and would provide a promising model for the detection of other small molecules.

  18. 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

  19. A Multiple Kernel Learning approach for human behavioral task classification using STN-LFP signal.

    PubMed

    Golshan, Hosein M; Hebb, Adam O; Hanrahan, Sara J; Nedrud, Joshua; Mahoor, Mohammad H

    2016-08-01

    Deep Brain Stimulation (DBS) has gained increasing attention as an effective method to mitigate Parkinson's disease (PD) disorders. Existing DBS systems are open-loop such that the system parameters are not adjusted automatically based on patient's behavior. Classification of human behavior is an important step in the design of the next generation of DBS systems that are closed-loop. This paper presents a classification approach to recognize such behavioral tasks using the subthalamic nucleus (STN) Local Field Potential (LFP) signals. In our approach, we use the time-frequency representation (spectrogram) of the raw LFP signals recorded from left and right STNs as the feature vectors. Then these features are combined together via Support Vector Machines (SVM) with Multiple Kernel Learning (MKL) formulation. The MKL-based classification method is utilized to classify different tasks: button press, mouth movement, speech, and arm movement. Our experiments show that the lp-norm MKL significantly outperforms single kernel SVM-based classifiers in classifying behavioral tasks of five subjects even using signals acquired with a low sampling rate of 10 Hz. This leads to a lower computational cost.

  20. Pulse-grouping transmission of optical quadrature phase-shift keying signals with time diversity multiple-input and multiple-output detection and processing

    NASA Astrophysics Data System (ADS)

    Gao, Guanjun; Chen, Sai; Zhang, Jie

    2016-08-01

    We investigate an optical pulse-overlap transmission scheme where the orthogonal condition between neighbor pulses is violated. The interferences between the grouped optical pulses are mitigated at the optical coherent receiver with time diversity multiple-input and multiple-output-based digital signal processing. Numerical simulation investigates the performance of 50% return-to-zero (RZ)-quadrature phase-shift keying (QPSK) signals, where up to four pulses are overlapped and grouped for per pulse period. In the experiment demonstration, two 50% RZ-QPSK signals are combined with different time offset between neighbor pulses, and the Q-performance as a function of optical-signal-to-noise ratio (OSNR) is compared on each pulse channel basis, with minimum OSNR penalty of only 1-dB compared to the single pulse transmission.

  1. Multiple excitatory and inhibitory neural signals converge to fine-tune Caenorhabditis elegans feeding to food availability

    PubMed Central

    Dallière, Nicolas; Bhatla, Nikhil; Luedtke, Zara; Ma, Dengke K.; Woolman, Jonathan; Walker, Robert J.; Holden-Dye, Lindy; O’Connor, Vincent

    2016-01-01

    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.—Dallière, N., Bhatla, N., Luedtke, Z., Ma, D. K., Woolman, J., Walker, R. J., Holden-Dye, L., O’Connor, V. Multiple excitatory and inhibitory neural signals converge to fine-tune Caenorhabditis elegans feeding to food availability. PMID:26514165

  2. A new approach to sparse decomposition of nonstationary signals with multiple scale structures using self-consistent nonlinear waves

    NASA Astrophysics Data System (ADS)

    Young, Hsu-Wen Vincent; Hsu, Ke-Hsin; Pham, Van-Truong; Tran, Thi-Thao; Lo, Men-Tzung

    2017-09-01

    A new method for signal decomposition is proposed and tested. Based on self-consistent nonlinear wave equations with self-sustaining physical mechanisms in mind, the new method is adaptive and particularly effective for dealing with synthetic signals consisting of components of multiple time scales. By formulating the method into an optimization problem and developing the corresponding algorithm and tool, we have proved its usefulness not only for analyzing simulated signals, but, more importantly, also for real clinical data.

  3. 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

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

    PubMed

    Jackman, William R; Yoo, James J; Stock, David W

    2010-11-30

    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. 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. 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.

  5. Bone marrow microenvironment-derived signals induce Mcl-1 dependence in multiple myeloma.

    PubMed

    Gupta, Vikas A; Matulis, Shannon M; Conage-Pough, Jason E; Nooka, Ajay K; Kaufman, Jonathan L; Lonial, Sagar; Boise, Lawrence H

    2017-04-06

    Multiple myeloma is highly dependent on the bone marrow microenvironment until progressing to very advanced extramedullary stages of the disease such as plasma cell leukemia. Stromal cells in the bone marrow secrete a variety of cytokines that promote plasma cell survival by regulating antiapoptotic members of the Bcl-2 family including Mcl-1, Bcl-xL, and Bcl-2. Although the antiapoptotic protein on which a cell depends is typically consistent among normal cells of a particular phenotype, Bcl-2 family dependence is highly heterogeneous in multiple myeloma. Although normal plasma cells and most multiple myeloma cells require Mcl-1 for survival, a subset of myeloma is codependent on Bcl-2 and/or Bcl-xL We investigated the role of the bone marrow microenvironment in determining Bcl-2 family dependence in multiple myeloma. We used the Bcl-2/Bcl-xL inhibitor ABT-737 to study the factors regulating whether myeloma is Mcl-1 dependent, and thus resistant to ABT-737-induced apoptosis, or Bcl-2/Bcl-xL codependent, and thus sensitive to ABT-737. We demonstrate that bone marrow stroma is capable of inducing Mcl-1 dependence through the production of the plasma cell survival cytokine interleukin-6 (IL-6). IL-6 upregulates Mcl-1 transcription in a STAT3-dependent manner, although this occurred in a minority of the cells tested. In all cells, IL-6 treatment results in posttranslational modification of the proapoptotic protein Bim. Phosphorylation of Bim shifts its binding from Bcl-2 and Bcl-xL to Mcl-1, an effect reversed by MEK inhibition. Blocking IL-6 or downstream signaling restored Bcl-2/Bcl-xL dependence and may therefore represent a clinically useful strategy to enhance the activity of Bcl-2 inhibitors. © 2017 by The American Society of Hematology.

  6. 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…

  7. Are Luxury Brand Labels and “Green” Labels Costly Signals of Social Status? An Extended Replication

    PubMed Central

    2017-01-01

    Costly signaling theory provides an explanation for why humans are willing to a pay a premium for conspicuous products such as luxury brand-labeled clothing or conspicuous environmentally friendly cars. According to the theory, the extra cost of such products is a signal of social status and wealth and leads to advantages in social interactions for the signaler. A previous study found positive evidence for the case of luxury brand labels. However, an issue of this study was that some of the experiments were not conducted in a perfectly double-blind manner. I resolved this by replicating variations of the original design in a double-blind procedure. Additionally, besides the luxury label condition, I introduced a “green” label condition. Thus, the hypothesis that signaling theory is able to explain pro-environmental behavior was tested for the first time in a natural field setting. Further, I conducted experiments in both average and below-average socioeconomic neighborhoods, where, according to signaling theory, the effects of luxury signals should be even stronger. In contrast to the original study, I did not find positive effects of the luxury brand label in any of the five experiments. Nor did I find evidence for a green-signaling effect. Moreover, in poor neighborhoods a negative tendency of the luxury label actually became evident. This suggests that a signaling theory explanation of costly labels must take into account the characteristics of the observers, e.g. their social status. PMID:28170399

  8. Extended likelihood ratio test-based methods for signal detection in a drug class with application to FDA's adverse event reporting system database.

    PubMed

    Zhao, Yueqin; Yi, Min; Tiwari, Ram C

    2016-05-02

    A likelihood ratio test, recently developed for the detection of signals of adverse events for a drug of interest in the FDA Adverse Events Reporting System database, is extended to detect signals of adverse events simultaneously for all the drugs in a drug class. The extended likelihood ratio test methods, based on Poisson model (Ext-LRT) and zero-inflated Poisson model (Ext-ZIP-LRT), are discussed and are analytically shown, like the likelihood ratio test method, to control the type-I error and false discovery rate. Simulation studies are performed to evaluate the performance characteristics of Ext-LRT and Ext-ZIP-LRT. The proposed methods are applied to the Gadolinium drug class in FAERS database. An in-house likelihood ratio test tool, incorporating the Ext-LRT methodology, is being developed in the Food and Drug Administration.

  9. Predicting and Improving Recognition Memory Using Multiple Electrophysiological Signals in Real Time.

    PubMed

    Fukuda, Keisuke; Woodman, Geoffrey F

    2015-07-01

    Although people are capable of storing a virtually infinite amount of information in memory, their ability to encode new information is far from perfect. The quality of encoding varies from moment to moment and renders some memories more accessible than others. Here, we were able to forecast the likelihood that a given item will be later recognized by monitoring two dissociable fluctuations of the electroencephalogram during encoding. Next, we identified individual items that were poorly encoded, using our electrophysiological measures in real time, and we successfully improved the efficacy of learning by having participants restudy these items. Thus, our memory forecasts using multiple electrophysiological signals demonstrate the feasibility and the effectiveness of using real-time monitoring of the moment-to-moment fluctuations of the quality of memory encoding to improve learning. © The Author(s) 2015.

  10. Hedgehog Pathway Modulation by Multiple Lipid Binding Sites on the Smoothened Effector of Signal Response

    PubMed Central

    Myers, Benjamin R.; Sever, Navdar; Chong, Yong Chun; Kim, James; Belani, Jitendra D.; Rychnovsky, Scott; Bazan, J. Fernando; Beachy, Philip A.

    2014-01-01

    Summary Hedgehog (Hh) signaling during development and in postembryonic tissues requires activation of the 7TM oncoprotein Smoothened (Smo), by mechanisms that may involve endogenous lipidic modulators. Exogenous Smo ligands previously identified include the plant sterol cyclopamine (and its therapeutically useful synthetic mimics) and hydroxylated cholesterol derivatives (oxysterols); Smo is also highly sensitive to cellular sterol levels. The relationships between these effects are unclear because the relevant Smo structural determinants are unknown. We identify the conserved extracellular cysteine rich domain (CRD) as the site of action for oxysterols on Smo, involving residues structurally analogous to those contacting the Wnt lipid adduct in the homologous Frizzled CRD; this modulatory effect is distinct from that of cyclopamine mimics, from Hh-mediated regulation, and from the permissive action of cellular sterol pools. These results imply that Hh pathway activity is sensitive to lipid binding at several Smo sites, suggesting mechanisms for tuning by multiple physiological inputs. PMID:23954590

  11. Flat pancake distant dipolar fields for enhancement of intermolecular multiple-quantum coherence signals.

    PubMed

    Cai, Congbo; Lin, Yulan; Cai, Shuhui; Sun, Huijun; Zhong, Jianhui; Chen, Zhong

    2012-03-07

    Intermolecular multiple-quantum coherences (iMQCs) originated from distant dipolar field (DDF) possess some appealing unique properties for magnetic resonance imaging (MRI). DDF is usually induced with continuous wave (i.e., sine- or square-wave) magnetization modulation in the whole sample. In this article, a spatially localized and enhanced DDF was optimally tailored in a thin slice with an adiabatic inversion pulse. Evidence was provided to show that careful tailoring of the spatially localized DDF can generate highly efficient iMQC signals, with more than two-fold enhancement compared to the conventional sine-wave magnetization modulation method, and 1.5 times of that with the square-wave modulation under the similar condition. Theoretical predictions, simulation results, and experimental verifications agree well with each other. Practical implementation of this approach for efficient iMQC MRI was explored. © 2012 American Institute of Physics

  12. 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

  13. 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. Copyright © 2012 Elsevier B.V. All rights reserved.

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

    PubMed Central

    Wang, Baojun; Barahona, Mauricio; Buck, Martin

    2013-01-01

    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

  15. The thyroxine inactivating gene, type III deiodinase, suppresses multiple signaling centers in Dictyostelium discoideum.

    PubMed

    Singh, Shashi Prakash; Dhakshinamoorthy, Ranjani; Jaiswal, Pundrik; Schmidt, Stefanie; Thewes, Sascha; Baskar, Ramamurthy

    2014-12-15

    Thyroxine deiodinases, the enzymes that regulate thyroxine metabolism, are essential for vertebrate growth and development. In the genome of Dictyostelium discoideum, a single intronless gene (dio3) encoding type III thyroxine 5' deiodinase is present. The amino acid sequence of D. discoideum Dio3 shares 37% identity with human T4 deiodinase and is a member of the thioredoxin reductase superfamily. dio3 is expressed throughout growth and development and by generating a knockout of dio3, we have examined the role of thyroxine 5' deiodinase in D. discoideum. dio3(-) had multiple defects that affected growth, timing of development, aggregate size, cell streaming, and cell-type differentiation. A prominent phenotype of dio3(-) was the breaking of late aggregates into small signaling centers, each forming a fruiting body of its own. cAMP levels, its relay, photo- and chemo-taxis were also defective in dio3(-). Quantitative RT-PCR analyses suggested that expression levels of genes encoding adenylyl cyclase A (acaA), cAMP-receptor A (carA) and cAMP-phosphodiesterases were reduced. There was a significant reduction in the expression of CadA and CsaA, which are involved in cell-cell adhesion. The dio3(-) slugs had prestalk identity, with pronounced prestalk marker ecmA expression. Thus, Dio3 seems to have roles in mediating cAMP synthesis/relay, cell-cell adhesion and slug patterning. The phenotype of dio3(-) suggests that Dio3 may prevent the formation of multiple signaling centers during D. discoideum development. This is the first report of a gene involved in thyroxine metabolism that is also involved in growth and development in a lower eukaryote.

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

    PubMed

    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 (r(2)>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.

  17. 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

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

    PubMed

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

    2006-11-07

    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.

  19. Improving recovery of ECG signal with deterministic guarantees using split signal for multiple supports of matching pursuit (SS-MSMP) algorithm.

    PubMed

    Tawfic, Israa Shaker; Kayhan, Sema Koc

    2017-02-01

    Compressed sensing (CS) is a new field used for signal acquisition and design of sensor that made a large drooping in the cost of acquiring sparse signals. In this paper, new algorithms are developed to improve the performance of the greedy algorithms. In this paper, a new greedy pursuit algorithm, SS-MSMP (Split Signal for Multiple Support of Matching Pursuit), is introduced and theoretical analyses are given. The SS-MSMP is suggested for sparse data acquisition, in order to reconstruct analog and efficient signals via a small set of general measurements. This paper proposes a new fast method which depends on a study of the behavior of the support indices through picking the best estimation of the corrosion between residual and measurement matrix. The term multiple supports originates from an algorithm; in each iteration, the best support indices are picked based on maximum quality created by discovering correlation for a particular length of support. We depend on this new algorithm upon our previous derivative of halting condition that we produce for Least Support Orthogonal Matching Pursuit (LS-OMP) for clear and noisy signal. For better reconstructed results, SS-MSMP algorithm provides the recovery of support set for long signals such as signals used in WBAN. Numerical experiments demonstrate that the new suggested algorithm performs well compared to existing algorithms in terms of many factors used for reconstruction performance. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. 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

  1. Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance

    PubMed Central

    Alonso, Salvador; Hernandez, Daniela; Chang, Yu-ting; Gocke, Christian B.; McCray, Megan; Varadhan, Ravi; Matsui, William H.; Jones, Richard J.

    2016-01-01

    Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in bortezomib (BTZ) resistance. However, the mechanisms involved in these interactions are not completely understood. We previously showed that expression of CYP26 in BM stromal cells maintains a retinoic acid–low (RA-low) microenvironment that prevents the differentiation of normal and malignant hematopoietic cells. Since a low secretory B cell phenotype is associated with BTZ resistance in MM and retinoid signaling promotes plasma cell differentiation and Ig production, we investigated whether stromal expression of the cytochrome P450 monooxygenase CYP26 modulates BTZ sensitivity in the BM niche. CYP26-mediated inactivation of RA within the BM microenvironment prevented plasma cell differentiation and promoted a B cell–like, BTZ-resistant phenotype in human MM cells that were cocultured on BM stroma. Moreover, paracrine Hedgehog secretion by MM cells upregulated stromal CYP26 and further reinforced a protective microenvironment. These results suggest that crosstalk between Hedgehog and retinoid signaling modulates BTZ sensitivity in the BM niche. Targeting these pathological interactions holds promise for eliminating minimal residual disease in MM. PMID:27775549

  2. Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms

    PubMed Central

    Cohen, Michael; Kicheva, Anna; Ribeiro, Ana; Blassberg, Robert; Page, Karen M.; Barnes, Chris P.; Briscoe, James

    2015-01-01

    In the vertebrate neural tube, the morphogen Sonic Hedgehog (Shh) establishes a characteristic pattern of gene expression. Here we quantify the Shh gradient in the developing mouse neural tube and show that while the amplitude of the gradient increases over time, the activity of the pathway transcriptional effectors, Gli proteins, initially increases but later decreases. Computational analysis of the pathway suggests three mechanisms that could contribute to this adaptation: transcriptional upregulation of the inhibitory receptor Ptch1, transcriptional downregulation of Gli and the differential stability of active and inactive Gli isoforms. Consistent with this, Gli2 protein expression is downregulated during neural tube patterning and adaptation continues when the pathway is stimulated downstream of Ptch1. Moreover, the Shh-induced upregulation of Gli2 transcription prevents Gli activity levels from adapting in a different cell type, NIH3T3 fibroblasts, despite the upregulation of Ptch1. Multiple mechanisms therefore contribute to the intracellular dynamics of Shh signalling, resulting in different signalling dynamics in different cell types. PMID:25833741

  3. Multiple routes of endocytic internalization of PDGFRβ contribute to PDGF-induced STAT3 signaling.

    PubMed

    Jastrzębski, Kamil; Zdżalik-Bielecka, Daria; Mamińska, Agnieszka; Kalaidzidis, Yannis; Hellberg, Carina; Miaczynska, Marta

    2017-02-01

    Platelet-derived growth factor receptor β (PDGFRβ) is a receptor tyrosine kinase which upon activation by PDGF-BB stimulates cell proliferation, migration and angiogenesis. Ligand binding induces intracellular signaling cascades but also internalization of the receptor, eventually resulting in its lysosomal degradation. However, endocytic trafficking of receptors often modulates their downstream signaling. We previously reported that internalization of PDGFRβ occurs via dynamin-dependent and -independent pathways but their further molecular determinants remained unknown. Here we show that, in human fibroblasts expressing endogenous PDGFRβ and stimulated with 50 ng/ml PDGF-BB, ligand-receptor uptake proceeds via the parallel routes of clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE). CME involves the canonical AP2 complex as a clathrin adaptor, while CIE requires RhoA-ROCK, Cdc42 and galectin-3, the latter indicating lectin-mediated internalization via clathrin-independent carriers (CLICs). Although different uptake routes appear to be partly interdependent, they cannot fully substitute for each other. Strikingly, inhibition of any internalization mechanism impaired activation of STAT3 but not of other downstream effectors of PDGFRβ. Our data indicate that multiple routes of internalization of PDGFRβ contribute to a transcriptional and mitogenic response of cells to PDGF.

  4. 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.

  5. 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

  6. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma.

    PubMed

    Peacock, Craig D; Wang, Qiuju; Gesell, Gregory S; Corcoran-Schwartz, Ian M; Jones, Evan; Kim, Jynho; Devereux, Wendy L; Rhodes, Jonathan T; Huff, Carol A; Beachy, Philip A; Watkins, D Neil; Matsui, William

    2007-03-06

    The cancer stem cell hypothesis suggests that malignant growth depends on a subset of tumor cells with stem cell-like properties of self-renewal. Because hedgehog (Hh) signaling regulates progenitor cell fate in normal development and homeostasis, aberrant pathway activation might be involved in the maintenance of such a population in cancer. Indeed, mutational activation of the Hh pathway is associated with medulloblastoma and basal cell carcinoma; pathway activity is also critical for growth of other tumors lacking such mutations, although the mechanism of pathway activation is poorly understood. Here we study the role and mechanism of Hh pathway activation in multiple myeloma (MM), a malignancy with a well defined stem cell compartment. In this model, rare malignant progenitors capable of clonal expansion resemble B cells, whereas the much larger tumor cell population manifests a differentiated plasma cell phenotype that pathologically defines the disease. We show that the subset of MM cells that manifests Hh pathway activity is markedly concentrated within the tumor stem cell compartment. The Hh ligand promotes expansion of MM stem cells without differentiation, whereas the Hh pathway blockade, while having little or no effect on malignant plasma cell growth, markedly inhibits clonal expansion accompanied by terminal differentiation of purified MM stem cells. These data reveal that Hh pathway activation is heterogeneous across the spectrum of MM tumor stem cells and their more differentiated progeny. The potential existence of similar relationships in other adult cancers may have important biologic and clinical implications for the study of aberrant Hh signaling.

  7. 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.

  8. Distinct signaling mechanisms in multiple developmental pathways by the SCRAMBLED receptor of Arabidopsis.

    PubMed

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

    2014-10-01

    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.

  9. Multiple Kernel Based Region Importance Learning for Neural Classification of Gait States from EEG Signals

    PubMed Central

    Zhang, Yuhang; Prasad, Saurabh; Kilicarslan, Atilla; Contreras-Vidal, Jose L.

    2017-01-01

    With the development of Brain Machine Interface (BMI) systems, people with motor disabilities are able to control external devices to help them restore movement abilities. Longitudinal validation of these systems is critical not only to assess long-term performance reliability but also to investigate adaptations in electrocortical patterns due to learning to use the BMI system. In this paper, we decode the patterns of user's intended gait states (e.g., stop, walk, turn left, and turn right) from scalp electroencephalography (EEG) signals and simultaneously learn the relative importance of different brain areas by using the multiple kernel learning (MKL) algorithm. The region of importance (ROI) is identified during training the MKL for classification. The efficacy of the proposed method is validated by classifying different movement intentions from two subjects—an able-bodied and a spinal cord injury (SCI) subject. The preliminary results demonstrate that frontal and fronto-central regions are the most important regions for the tested subjects performing gait movements, which is consistent with the brain regions hypothesized to be involved in the control of lower-limb movements. However, we observed some regional changes comparing the able-bodied and the SCI subject. Moreover, in the longitudinal experiments, our findings exhibit the cortical plasticity triggered by the BMI use, as the classification accuracy and the weights for important regions—in sensor space—generally increased, as the user learned to control the exoskeleton for movement over multiple sessions. PMID:28420954

  10. 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.

  11. 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.

  12. Multiple Kernel Based Region Importance Learning for Neural Classification of Gait States from EEG Signals.

    PubMed

    Zhang, Yuhang; Prasad, Saurabh; Kilicarslan, Atilla; Contreras-Vidal, Jose L

    2017-01-01

    With the development of Brain Machine Interface (BMI) systems, people with motor disabilities are able to control external devices to help them restore movement abilities. Longitudinal validation of these systems is critical not only to assess long-term performance reliability but also to investigate adaptations in electrocortical patterns due to learning to use the BMI system. In this paper, we decode the patterns of user's intended gait states (e.g., stop, walk, turn left, and turn right) from scalp electroencephalography (EEG) signals and simultaneously learn the relative importance of different brain areas by using the multiple kernel learning (MKL) algorithm. The region of importance (ROI) is identified during training the MKL for classification. The efficacy of the proposed method is validated by classifying different movement intentions from two subjects-an able-bodied and a spinal cord injury (SCI) subject. The preliminary results demonstrate that frontal and fronto-central regions are the most important regions for the tested subjects performing gait movements, which is consistent with the brain regions hypothesized to be involved in the control of lower-limb movements. However, we observed some regional changes comparing the able-bodied and the SCI subject. Moreover, in the longitudinal experiments, our findings exhibit the cortical plasticity triggered by the BMI use, as the classification accuracy and the weights for important regions-in sensor space-generally increased, as the user learned to control the exoskeleton for movement over multiple sessions.

  13. Eukaryotic Elongation Factor 2 Kinase Activity Is Controlled by Multiple Inputs from Oncogenic Signaling

    PubMed Central

    Wang, Xuemin; Regufe da Mota, Sergio; Liu, Rui; Moore, Claire E.; Xie, Jianling; Lanucara, Francesco; Agarwala, Usha; Pyr dit Ruys, Sébastien; Vertommen, Didier; Rider, Mark H.; Eyers, Claire E.

    2014-01-01

    Eukaryotic elongation factor 2 kinase (eEF2K), an atypical calmodulin-dependent protein kinase, phosphorylates and inhibits eEF2, slowing down translation elongation. eEF2K contains an N-terminal catalytic domain, a C-terminal α-helical region and a linker containing several regulatory phosphorylation sites. eEF2K is expressed at high levels in certain cancers, where it may act to help cell survival, e.g., during nutrient starvation. However, it is a negative regulator of protein synthesis and thus cell growth, suggesting that cancer cells may possess mechanisms to inhibit eEF2K under good growth conditions, to allow protein synthesis to proceed. We show here that the mTORC1 pathway and the oncogenic Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway cooperate to restrict eEF2K activity. We identify multiple sites in eEF2K whose phosphorylation is regulated by mTORC1 and/or ERK, including new ones in the linker region. We demonstrate that certain sites are phosphorylated directly by mTOR or ERK. Our data reveal that glycogen synthase kinase 3 signaling also regulates eEF2 phosphorylation. In addition, we show that phosphorylation sites remote from the N-terminal calmodulin-binding motif regulate the phosphorylation of N-terminal sites that control CaM binding. Mutations in the former sites, which occur in cancer cells, cause the activation of eEF2K. eEF2K is thus regulated by a network of oncogenic signaling pathways. PMID:25182533

  14. Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells.

    PubMed

    Bauer, K; Kretzschmar, A K; Cvijic, H; Blumert, C; Löffler, D; Brocke-Heidrich, K; Schiene-Fischer, C; Fischer, G; Sinz, A; Clevenger, C V; Horn, F

    2009-08-06

    Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-gamma was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action.

  15. Lipopolysaccharide activates innate immune responses in murine intestinal myofibroblasts through multiple signaling pathways

    PubMed Central

    Walton, Kristen L. W.; Holt, Lisa; Sartor, R. Balfour

    2009-01-01

    Myofibroblasts (MF) play an important role in intestinal wound healing. A compromised epithelial barrier exposes intestinal subepithelial MF to luminal bacterial products. However, responses of murine intestinal MF to bacterial adjuvants and potential roles of intestinal MF in innate immune responses are not well defined. Our aims in this study were to determine innate immune responses and intracellular signaling pathways of intestinal MF exposed to LPS, a prototypic Toll-like receptor (TLR) ligand. Expression of TLR4 in primary murine intestinal MF cultures was confirmed by RT-PCR and Western blotting. LPS-induced secretion of prostaglandin E2 (PGE2), interleukin (IL)-6, and keratinocyte-derived chemokines (KC) was measured by ELISA. Intracellular responses to LPS were assessed by Western blotting for NF-κB p65, Iκ-Bα, Akt, p38 MAP kinase, and cyclooxygenase-2 (COX-2). LPS induced rapid phosphorylation of NF-κB p65, Akt, and p38 MAPK and degradation of Iκ-Bα. LPS induced expression of COX-2 and secretion of PGE2 (2.0 ± 0.8-fold induction vs. unstimulated cells), IL-6 (6.6 ± 0.4-fold induction), and KC (12.5 ± 0.4-fold induction). Inhibition of phosphoinositide-3 (PI3)-kinase, p38 MAPK, or NF-κB pathways reduced LPS-induced PGE2, IL-6, and KC secretion. These studies show that primary murine intestinal MF respond to LPS, evidenced by activation of NF-κB, PI3-kinase, and MAPK signaling pathways and secretion of proinflammatory molecules. Inhibition of these pathways attenuated LPS-dependent PGE2, IL-6, and KC production, indicating that LPS activates MF by multiple signaling pathways. These data support the hypothesis that MF are a component of the innate immune system and may exert paracrine effects on adjacent epithelial and immune cells by responding to luminal bacterial adjuvants. PMID:19136385

  16. Multiple follicle culture supports primary follicle growth through paracrine-acting signals.

    PubMed

    Hornick, J E; Duncan, F E; Shea, L D; Woodruff, T K

    2013-01-01

    In vitro follicle growth in alginate hydrogels is a unique and versatile method for studying ovarian and follicle biology that may also have implications for fertility preservation. Current culture systems support the development of isolated mouse follicles from the secondary stage onward. However, it has been a challenge to grow smaller follicles in vitro due to the dissociation of the oocyte from companion somatic cells. Recent work has demonstrated that coculturing primary follicles with mouse embryonic fibroblasts or ovarian stromal cells supports follicle survival and growth. In this study, we demonstrate that follicles themselves can exert a beneficial coculture effect. When primary follicles were cultured in groups of five or ten (multiple follicle culture), there was increased growth and survival. The multiple follicle culture approach maintained follicle integrity and resulted in the formation of antral stage follicles containing meiotically competent gametes. The growth and survival of primary follicles were highly number dependent, with the most significant enhancement observed when the largest number of follicles was grown together. Our data suggest that the follicle unit is necessary to produce the secreted factors responsible for the supportive effects of multiple follicle culture, as neither denuded oocytes, oocyte-secreted factors, nor granulosa cells alone were sufficient to support early follicle growth in vitro. Therefore, there may be signaling from both the oocyte and the follicle that enhances growth but requires both components in a feedback mechanism. This work is consistent with current in vivo models for follicle growth and thus advances the movement to recapitulate the ovarian environment in vitro.

  17. Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways.

    PubMed

    Lin, Jiumao; Chen, Youqin; Wei, Lihui; Hong, Zhenfeng; Sferra, Thomas J; Peng, Jun

    2013-11-01

    Angiogenesis plays a critical role in the development of solid tumors by supplying nutrients and oxygen to support continuous growth of tumor as well as providing an avenue for hematogenous metastasis. Tumor angiogenesis is highly regulated by multiple intracellular signaling transduction cascades such as Hedgehog, STAT3, Akt and p70S6K pathways that are known to malfunction in many types of cancer including colorectal cancer (CRC). Therefore, suppression of tumor angiogenesis through targeting these signaling pathways has become a promising strategy for cancer chemotherapy. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used in China for the clinical treatment of various types of cancer. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its anti-angiogenic activity are not well understood. To further elucidate the mechanism(s) of the tumorcidal activity of UA, using a CRC mouse xenograft model, chick embryo chorioallantoic membrane (CAM) model, the human colon carcinoma cell line HT-29 and human umbilical vein endothelial cells (HUVECs), in the present study we evaluated the efficacy of UA against tumor growth and angiogenesis in vivo and in vitro and investigated the underlying molecular mechanisms. We found that administration of UA significantly inhibited tumor volume but had no effect on body weight changes in CRC mice, suggesting that UA can suppress colon cancer growth in vivo without noticeable signs of toxicity. In addition, UA treatment reduced intratumoral microvessel density (MVD) in CRC mice, decreased the total number of blood vessels in the CAM model, and dose and time-dependently inhibited the proliferation, migration and tube formation of HUVECs, demonstrating UA's antitumor angiogenesis in vivo and in vitro. Moreover, UA treatment inhibited the expression of critical angiogenic factors, such as VEGF-A and bFGF. Furthermore, UA suppressed the

  18. Two zebrafish G2A homologs activate multiple intracellular signaling pathways in acidic environment

    SciTech Connect

    Ichijo, Yuta; Mochimaru, Yuta; Azuma, Morio; Satou, Kazuhiro; Negishi, Jun; Nakakura, Takashi; Oshima, Natsuki; Mogi, Chihiro; Sato, Koichi; Matsuda, Kouhei; Okajima, Fumikazu; Tomura, Hideaki

    2016-01-01

    Human G2A is activated by various stimuli such as lysophosphatidylcholine (LPC), 9-hydroxyoctadecadienoic acid (9-HODE), and protons. The receptor is coupled to multiple intracellular signaling pathways, including the G{sub s}-protein/cAMP/CRE, G{sub 12/13}-protein/Rho/SRE, and G{sub q}-protein/phospholipase C/NFAT pathways. In the present study, we examined whether zebrafish G2A homologs (zG2A-a and zG2A-b) could respond to these stimuli and activate multiple intracellular signaling pathways. We also examined whether histidine residue and basic amino acid residue in the N-terminus of the homologs also play roles similar to those played by human G2A residues if the homologs sense protons. We found that the zG2A-a showed the high CRE, SRE, and NFAT activities, however, zG2A-b showed only the high SRE activity under a pH of 8.0. Extracellular acidification from pH 7.4 to 6.3 ameliorated these activities in zG2A-a-expressing cells. On the other hand, acidification ameliorated the SRE activity but not the CRE and NFAT activities in zG2A-b-expressing cells. LPC or 9-HODE did not modify any activity of either homolog. The substitution of histidine residue at the 174{sup th} position from the N-terminus of zG2A-a to asparagine residue attenuated proton-induced CRE and NFAT activities but not SRE activity. The substitution of arginine residue at the 32nd position from the N-terminus of zG2A-a to the alanine residue also attenuated its high and the proton-induced CRE and NFAT activities. On the contrary, the substitution did not attenuate SRE activity. The substitution of the arginine residue at the 10th position from the N-terminus of zG2A-b to the alanine residue also did not attenuate its high or the proton-induced SRE activity. These results indicate that zebrafish G2A homologs were activated by protons but not by LPC and 9-HODE, and the activation mechanisms of the homologs were similar to those of human G2A. - Highlights: • Zebrafish two G2A homologs are proton

  19. 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.

  20. Signal to Noise Ratio in Digital Lock-in Detection for Multiple Intensity-Modulated Signals in CO2 Laser Absorption Spectrometer

    NASA Astrophysics Data System (ADS)

    CHEN, S.; Lin, B.; Harrison, F. W.; Nehrir, A. R.; Campbell, J. F.; Refaat, T.; Abedin, N. M.; Obland, M. D.; Ismail, S.; Meadows, B. L.

    2013-12-01

    NASA Langley Research Center is investigating Intensity-Modulated, Continuous-Wave Laser Absorption Spectrometers (LASs) for the measurement of atmospheric carbon dioxide (CO2) column mixing ratio from both air- and space-borne platforms. The LAS system uses high-power fiber lasers/amplifiers in the 1.57-um CO2 absorption band and the 1.26-um O2 absorption band in the transmitters and simultaneous digital lock-in detection for the multiple intensity-modulated signals with different modulation waveforms , such as simple sinusoidal waves at different frequencies, associated with different wavelengths in the receivers. The Signal to Noise Ratio (SNR) of the simultaneous digital lock-in detection in the system is of interest for the system designs and the performance prediction of airborne and space-borne implementations in the future. This paper will discuss the properties of the signals and various noises in the LAS system, especially for the simultaneous digital lock-in detection with a single detector for the multiple intensity-modulated signals at different frequencies. The numerical simulation of the SNR for the simultaneous digital lock-in detection in terms of relative intensity of the multiple modulated signals and the integration time, and an initial experimental verification will be presented.

  1. 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…

  2. 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…

  3. 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

  4. 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

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

    PubMed

    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.

  6. 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

  7. Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma

    PubMed Central

    Cui, Grace; Senpan, Angana; Yang, Xiaoxia; Lu, Lan; Weilbaecher, Katherine N.; Prochownik, Edward V.; Lanza, Gregory M.; Tomasson, Michael H.

    2015-01-01

    Multiple myeloma pathogenesis is driven by the MYC oncoprotein, its dimerization with MAX, and the binding of this heterodimer to E-Boxes in the vicinity of target genes. The systemic utility of potent small molecule inhibitors of MYC-MAX dimerization was limited by poor bioavailability, rapid metabolism, and inadequate target site penetration. We hypothesized that new lipid-based MYC-MAX dimerization inhibitor prodrugs delivered via integrin-targeted nanoparticles (NP) would overcome prior shortcomings of MYC inhibitor approaches and prolong survival in a mouse model of cancer. An Sn 2 lipase-labile prodrug inhibitor of MYC-MAX dimerization (MI1-PD) was developed which decreased cell proliferation and induced apoptosis in cultured multiple myeloma cell lines alone (P < 0.05) and when incorporated into integrin-targeted lipid-encapsulated NPs (P < 0.05). Binding and efficacy of NPs closely correlated with integrin expression of the target multiple myeloma cells. Using a KaLwRij metastatic multiple myeloma mouse model, VLA-4–targeted NPs (20 nm and 200 nm) incorporating MI1-PD (D) NPs conferred significant survival benefits compared with respective NP controls, targeted (T) no-drug (ND), and untargeted (NT) control NPs (T/D 200: 46 days vs. NT/ND: 28 days, P < 0.05 and T/D 20: 52 days vs. NT/ND: 29 days, P = 0.001). The smaller particles performed better of the two sizes. Neither MI1 nor MI1-PD provided survival benefit when administered systemically as free compounds. These results demonstrate for the first time that a small molecule inhibitor of the MYC transcription factor can be an effective anticancer agent when delivered using a targeted nanotherapy approach. PMID:25824336

  8. 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.

  9. Multiple recent horizontal transfers of the cox1 intron in Solanaceae and extended co-conversion of flanking exons

    PubMed Central

    2011-01-01

    Background The most frequent case of horizontal transfer in plants involves a group I intron in the mitochondrial gene cox1, which has been acquired via some 80 separate plant-to-plant transfer events among 833 diverse angiosperms examined. This homing intron encodes an endonuclease thought to promote the intron's promiscuous behavior. A promising experimental approach to study endonuclease activity and intron transmission involves somatic cell hybridization, which in plants leads to mitochondrial fusion and genome recombination. However, the cox1 intron has not yet been found in the ideal group for plant somatic genetics - the Solanaceae. We therefore undertook an extensive survey of this family to find members with the intron and to learn more about the evolutionary history of this exceptionally mobile genetic element. Results Although 409 of the 426 species of Solanaceae examined lack the cox1 intron, it is uniformly present in three phylogenetically disjunct clades. Despite strong overall incongruence of cox1 intron phylogeny with angiosperm phylogeny, two of these clades possess nearly identical intron sequences and are monophyletic in intron phylogeny. These two clades, and possibly the third also, contain a co-conversion tract (CCT) downstream of the intron that is extended relative to all previously recognized CCTs in angiosperm cox1. Re-examination of all published cox1 genes uncovered additional cases of extended co-conversion and identified a rare case of putative intron loss, accompanied by full retention of the CCT. Conclusions We infer that the cox1 intron was separately and recently acquired by at least three different lineages of Solanaceae. The striking identity of the intron and CCT from two of these lineages suggests that one of these three intron captures may have occurred by a within-family transfer event. This is consistent with previous evidence that horizontal transfer in plants is biased towards phylogenetically local events. The discovery

  10. 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

  11. Seismic random noise attenuation and signal-preserving by multiple directional time-frequency peak filtering

    NASA Astrophysics Data System (ADS)

    Zhang, Chao; Li, Yue; Lin, Hong-bo; Yang, Bao-jun

    2015-01-01

    Time-frequency peak filtering (TFPF) is an effective method for seismic random noise attenuation. The linearity of the signal has a significant influence on the accuracy of the TFPF method. The higher the linearity of the signal to be filtered is, the better the denoising result is. With this in mind, and taking the lateral coherence of reflected events into account, we do TFPF along the reflected events to improve the degree of linearity and enhance the continuity of these events. The key factor to realize this idea is to find the traces of the reflected events. However, the traces of the events are too hard to obtain in the complicated field seismic data. In this paper, we propose a Multiple Directional TFPF (MD-TFPF), in which the filtering is performed in certain direction components of the seismic data. These components are obtained by a directional filter bank. In each direction component, we do TFPF along these decomposed reflected events (the local direction of the events) instead of the channel direction. The final result is achieved by adding up the filtering results of all decomposition directions of seismic data. In this way, filtering along the reflected events is implemented without accurately finding the directions. The effectiveness of the proposed method is tested on synthetic and field seismic data. The experimental results demonstrate that MD-TFPF can more effectively eliminate random noise and enhance the continuity of the reflected events with better preservation than the conventional TFPF, curvelet denoising method and F-X deconvolution method.

  12. Silence of MCL-1 upstream signaling by shRNA abrogates multiple myeloma growth.

    PubMed

    Wang, Mengchang; Wu, Di; Liu, Pengbo; Deng, Jiusheng

    2014-01-01

    Multiple myeloma (MM) is an incurable B-cell cancer with accumulated clonal abnormal plasma cells in bone marrow of patients. MCL-1 (myeloid cell leukemia sequence 1) protein is an anti-apoptotic molecule in MM cells and regulated by pro-inflammatory cytokine IL-6 and downstream signaling molecules STAT3, PI3K and MAPK. The purpose of this study is to investigate the effect of STAT3, PI3K and MAPK gene silence on MCL-1 expression in human MM cells and the consequence of cell survival. Lentivirus small hairpin RNA (shRNA) interference techniques were utilized to knock down STAT3, PI3K or MAPK genes. Gene and protein expression was quantified by quantitative real-time PCR and Western Blot. MM cell apoptosis was examined by annexin-V FITC/propidium iodide staining. Efficient silence of STAT3, PI3K, MAPK1 or MAPK2 gene robustly abrogated IL-6 enhanced MCL-1 expression and suppressed MM cell growth. Silencing STAT3 gene inhibited PI3K expression, silencing PI3K markedly abrogated STAT3 and MAPK production. Inhibition of MAPK2 gene by shMAPK2 suppressed STAT3, PI3K and MAPK1 expression in the cells. Silencing of STAT3, PI3K and MAPK2 together completely blocked MCL-1 expression in MM cells. There is a syngeneic effect among the three independent STAT3, PI3K and MAPK2 survival-signaling pathways related to MCL-1 expression in MM cells. shRNAs silencing of STAT3, PI3K and MAPK2 together could provide an effective strategy to treat MM.

  13. 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. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. 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.

  15. Study of orexins signal transduction pathways in rat olfactory mucosa and in olfactory sensory neurons-derived cell line Odora: multiple orexin signalling pathways.

    PubMed

    Gorojankina, Tatiana; Grébert, Denise; Salesse, Roland; Tanfin, Zahra; Caillol, Monique

    2007-06-07

    Orexins A and B (OxA and OxB) are multifunctional neuropeptides implicated in the regulation of energy metabolism, wakefulness but also in a broad range of motivated behaviours. They signal through two G-protein-coupled receptors: orexin receptor 1 and 2 (Ox1R and Ox2R). The orexins and their receptors are present at all levels of the rat olfactory system: epithelium, bulb, piriform cortex but their signalling mechanisms remain unknown. We have studied orexins signal transduction pathways in the rat olfactory mucosa (OM) and in the Odora cell line derived from olfactory sensory neurons and heterologously expressing Ox1R or Ox2R. We have demonstrated by western blot and RT-PCR that multiple components of adenylyl cyclase (AC) and phospholipase C (PLC) signalling pathways were identical in OM and Odora cells. OxA and OxB induced a weak increase in IP3 in OM; they induced a significant rise in cAMP and IP3 in Odora transfected cells, suggesting the activation of AC and PLC pathways. Both OxA and OxB induced intracellular calcium elevation and transient activation of MAP kinases (ERK42/44) in Odora/Ox1R and Odora/Ox2R cells. These results suggest the existence of multiple orexins signalling pathways in Odora cells and probably in OM, corresponding to different possible roles of these peptides.

  16. Relationship between EMG signals and force in human vastus lateralis muscle using multiple bipolar wire electrodes.

    PubMed

    Onishi, H; Yagi, R; Akasaka, K; Momose, K; Ihashi, K; Handa, Y

    2000-02-01

    This paper describes the relationship between knee extension force and EMG signals detected by multiple bipolar wire electrodes inserted into the human vastus lateralis muscle under isometric conditions. Six healthy male volunteers participated in this study. Eight pairs of bipolar wire electrodes were inserted into the right vastus lateralis muscle and the EMG data were simultaneously detected and analyzed. The EMG raw data and individual force-IEMG relations were influenced by the location of the electrode inserted into the muscle. The force and IEMG relationship averaged across subjects detected from the eight electrodes, however, showed almost the same linear correlation in spite of different electrode locations. No linear correlation was observed between MdF and the knee extension force. This result suggests that, if all of the muscle fibers participate in the same action at the same time, the averaged normalized IEMG from any places using wire electrodes could reflect the total activities of that muscle even if the muscle is large.

  17. Ethacrynic acid inhibits multiple steps in the NF-kappaB signaling pathway.

    PubMed

    Han, Yusheng; Englert, Joshua A; Delude, Russell L; Fink, Mitchell P

    2005-01-01

    Ethacrynic acid has been used as a safe and effective diuretic for more than 30 years. In this study, we tested the hypothesis that ethacrynic acid is also an anti-inflammatory agent that inhibits signaling by the proinflammatory transcription factor NF-kappaB. We showed that ethacrynic acid inhibited luciferase expression in lipopolysaccharide-stimulated macrophage-like RAW 264.7 cells transfected with an NF-kappaB-dependent luciferase reporter vector and also inhibited NF-kappaB DNA binding in lipopolysaccharide-stimulated RAW 264.7 cells (electrophoretic mobility shift assay). Ethacrynic acid inhibited degradation of IkappaBalpha and IkappaBbeta in lipopolysaccharide-stimulated RAW 264.7 cells. Ethacrynic acid impaired DNA binding of wild-type p65 subunits of NF-kappaB in cells. However, DNA binding of a Cys--> Ser p65 mutant was not inhibited by ethacrynic acid, suggesting that ethacrynic acid inhibits DNA binding by alkylating p65 at Cys. In a cell-free system, binding of p50 homodimers to an NF-kappaB consensus sequence was inhibited by ethacrynic acid at concentrations from 10 to 100 microM, indicating that ethacrynic acid probably also covalently modifies the p50 subunit. These data indicate that ethacrynic acid inhibits activation of the NF-kappaB pathway at multiple points and suggest that this well-studied drug warrants further investigation as a potential therapeutic for various conditions that are associated with excessive inflammation.

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

    PubMed Central

    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

    2015-01-01

    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

  19. TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling.

    PubMed

    Woodfield, George W; Horan, Annamarie D; Chen, Yizhen; Weigel, Ronald J

    2007-09-15

    Breast cancers expressing estrogen receptor-alpha (ERalpha) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ERalpha, other pathways of estrogen response have been identified including ERbeta and GPR30, a membrane receptor for estrogen, and the key mechanisms regulating expression of ERs and hormone response remain controversial. Herein, we show that TFAP2C is the key regulator of hormone responsiveness in breast carcinoma cells through the control of multiple pathways of estrogen signaling. TFAP2C regulates the expression of ERalpha directly by binding to the ERalpha promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ERalpha target genes, including pS2, MYB, and RERG. Furthermore, TFAP2C controlled the expression of GPR30. In distinct contrast, TFAP2A, a related factor expressed in breast cancer, was not involved in estrogen-mediated pathways but regulated expression of genes controlling cell cycle arrest and apoptosis including p21(CIP1) and IGFBP-3. Knockdown of TFAP2C abrogated the mitogenic response to estrogen exposure and decreased hormone-responsive tumor growth of breast cancer xenografts. We conclude that TFAP2C is a central control gene of hormone response and is a novel therapeutic target in the design of new drug treatments for breast cancer.

  20. Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis

    PubMed Central

    Tan, Yossan-Var; Waschek, James A

    2011-01-01

    MS (multiple sclerosis) is a chronic autoimmune and neurodegenerative pathology of the CNS (central nervous system) affecting approx. 2.5 million people worldwide. Current and emerging DMDs (disease-modifying drugs) predominantly target the immune system. These therapeutic agents slow progression and reduce severity at early stages of MS, but show little activity on the neurodegenerative component of the disease. As the latter determines permanent disability, there is a critical need to pursue alternative modalities. VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating peptide) have potent anti-inflammatory and neuroprotective actions, and have shown significant activity in animal inflammatory disease models including the EAE (experimental autoimmune encephalomyelitis) MS model. Thus, their receptors have become candidate targets for inflammatory diseases. Here, we will discuss the immunomodulatory and neuroprotective actions of VIP and PACAP and their signalling pathways, and then extensively review the structure–activity relationship data and biophysical interaction studies of these peptides with their cognate receptors. PMID:21895607

  1. Polymodal Responses in C. elegans Phasmid Neurons Rely on Multiple Intracellular and Intercellular Signaling Pathways

    PubMed Central

    Zou, Wenjuan; Cheng, Hankui; Li, Shitian; Yue, Xiaomin; Xue, Yadan; Chen, Sixi; Kang, Lijun

    2017-01-01

    Animals utilize specialized sensory neurons enabling the detection of a wide range of environmental stimuli from the presence of toxic chemicals to that of touch. However, how these neurons discriminate between different kinds of stimuli remains poorly understood. By combining in vivo calcium imaging and molecular genetic manipulation, here we investigate the response patterns and the underlying mechanisms of the C. elegans phasmid neurons PHA/PHB to a variety of sensory stimuli. Our observations demonstrate that PHA/PHB neurons are polymodal sensory neurons which sense harmful chemicals, hyperosmotic solutions and mechanical stimulation. A repulsive concentration of IAA induces calcium elevations in PHA/PHB and both OSM-9 and TAX-4 are essential for IAA-sensing in PHA/PHB. Nevertheless, the PHA/PHB neurons are inhibited by copper and post-synaptically activated by copper removal. Neuropeptide is likely involved in copper removal-induced calcium elevations in PHA/PHB. Furthermore, mechanical stimulation activates PHA/PHB in an OSM-9-dependent manner. Our work demonstrates how PHA/PHB neurons respond to multiple environmental stimuli and lays a foundation for the further understanding of the mechanisms of polymodal signaling, such as nociception, in more complex organisms. PMID:28195191

  2. 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.

  3. Multiple input detection and digital signal processing for uncooled ONUs in a TWDM-PON with a commercial WDM demultiplexer

    NASA Astrophysics Data System (ADS)

    Liu, Jie; Gao, Zhen; Guo, Changjian; Lu, Chao

    2014-08-01

    A simple uplink transmission scheme with multiple-input direct detection and digital signal processing has been proposed and experimentally demonstrated for the time and wavelength division multiplexed passive optical networks (TWDM-PONs), to allow wavelength drift of lasers at the uncooled optical network units (ONUs). In our experiment, after passing by the commercial 100-GHz WDM demultiplexer, three 10-Gb/s NRZ signals with minimum signal wavelength separation of 50-GHz can be recovered successfully after 50-km standard single-mode fiber (SSMF) transmission. Simulation results are also obtained to analysis the receiver sensitivity at different wavelength separations and discuss methods improving power budget.

  4. 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.

  5. 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.

  6. Swimming of Xenopus laevis sperm exhibits multiple gears and its duration is extended by egg jelly constituents.

    PubMed

    Tholl, Nathan; Naqvi, Sumera; McLaughlin, Ericka; Boyles, Serenity; Bieber, Allan L; Chandler, Douglas E

    2011-06-01

    The motility of Xenopus sperm is initiated by the osmotic shock experienced when these cells are ejaculated into low-salinity pond water. Motility is brief and is required for the sperm to penetrate the jelly layers and fertilize the egg. In this study we demonstrate that extracts of egg jelly contain factors that extend the period of sperm motility as well as providing a chemoattractant activity as previously reported. Both activities are partially dependent on extracellular calcium. Time-lapse and video microscopy show that after activation of motility the number of motile sperm decreases rapidly, with a half-time of about 2 min. Addition of 10% v/v egg jelly extract ("egg water") increased the number of motile sperm 2-fold over controls at 20 s and about 4- to 10-fold over controls at 10 min after initiation of motility. Extension of motility lifetime was not mediated by a nonspecific protein or by allurin, the egg-water protein that has chemoattractant activity. The helical path of Xenopus sperm exhibited tight coupling between rotational and forward velocities in egg jelly, but coupling changed rapidly from moment to moment in low-salinity buffer. Our observations suggest that jelly-derived factors regulate both the longevity and directionality of sperm propulsion.

  7. Heparanase Enhances the Insulin Receptor Signaling Pathway to Activate Extracellular Signal-regulated Kinase in Multiple Myeloma*

    PubMed Central

    Purushothaman, Anurag; Babitz, Stephen K.; Sanderson, Ralph D.

    2012-01-01

    ERK signaling regulates proliferation, survival, drug resistance, and angiogenesis in cancer. Although the mechanisms regulating ERK activation are not fully understood, we previously demonstrated that ERK phosphorylation is elevated by heparanase, an enzyme associated with aggressive behavior of many cancers. In the present study, myeloma cell lines expressing either high or low levels of heparanase were utilized to determine how heparanase stimulates ERK signaling. We discovered that the insulin receptor was abundant on cells expressing either high or low levels of heparanase, but the receptor was highly phosphorylated in heparanase-high cells compared with heparanase-low cells. In addition, protein kinase C activity was elevated in heparanase-high cells, and this enhanced expression of insulin receptor substrate-1 (IRS-1), the principle intracellular substrate for phosphorylation by the insulin receptor. Blocking insulin receptor function with antibody or a small molecule inhibitor or knockdown of IRS-1 expression using shRNA diminished heparanase-mediated ERK activation in the tumor cells. In addition, up-regulation of the insulin signaling pathway by heparanase and the resulting ERK activation were dependent on heparanase retaining its enzyme activity. These results reveal a novel mechanism whereby heparanase enhances activation of the insulin receptor signaling pathway leading to ERK activation and modulation of myeloma behavior. PMID:23048032

  8. Dispersion-Tolerant Multiple WDM Channel Millimeter-Wave Signal Generation Using a Single Monolithic Mode-Locked Semiconductor Laser

    NASA Astrophysics Data System (ADS)

    Attygalle, M.; Lim, C.; Nirmalathas, A.

    2005-01-01

    This paper presents a scheme by which multiple wavelength-division-multiplexed millimeter-wave (mm-wave) signals in the range of 30 GHz can be generated from a single monolithic semiconductor laser for applications in optically fed mm-wave networks or fiber radio networks. The mm-wave signals are generated using dual optical modes separated by a mm-wave frequency, obtained from spectrum slicing the output from a stable multimode hybrid mode-locked semiconductor laser. In this scheme, self-heterodyne detection at a high-speed photodetector achieves the photonic upconversion of low-data-rate signals to mm-wave frequencies without the need for electronic mixing. Experimental results show the generation of up to 14 WDM channels using a single laser. The phase noise of electrical signals generated by photonic upconversion of these signals is less than -94 dBc/Hz at 100-kHz offset frequency across the wavelengths. Also presented is the transmission of 155-Mb/s binary-phase-shift-keyed data signals at 30-GHz frequency over 10 km of single-mode fiber at different wavelengths using dual-mode signals. The results confirm that a bit-error rate of 10-^9 can be easily achieved. The dispersion tolerance of the dual-mode signals is evaluated using simulation and an analytical model and compared with other mm-wave signal generation techniques.

  9. Gene microarray assessment of multiple genes and signal pathways involved in androgen-dependent prostate cancer becoming androgen independent.

    PubMed

    Liu, Jun-Bao; Dai, Chun-Mei; Su, Xiao-Yun; Cao, Lu; Qin, Rui; Kong, Qing-Bo

    2014-01-01

    To study the gene expression change and possible signal pathway during androgen-dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down-regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-β signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs.

  10. Efficacy and safety of multiple doses of levomilnacipran extended-release for the treatment of major depressive disorder

    PubMed Central

    Huang, Qunlian; Zhong, Xiaoyan; Yun, Ye; Yu, Bin; Huang, Yilan

    2016-01-01

    Objective The aim of this meta-analysis was to evaluate the efficacy and safety of levomilnacipran extended-release (ER) in the treatment of major depressive disorder (MDD). Methods Randomized controlled trials were searched by electronic databases. Unpublished data were also searched by the relevant websites. Weighted mean difference (WMD) and risk ratio (RR) with 95% confidence interval (CI) were calculated and pooled using fixed-effects model or random-effects model. Results Five randomized placebo-controlled trials including 2,637 patients were analyzed. Compared with placebo, levomilnacipran ER had a greater reduction in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score and Sheehan Disability Scale (SDS) total score (MADRS: WMD −3.49 [95% CI −4.28, −2.70; P<0.00001]; SDS: WMD −2.41 [95% CI −3.05, −1.77; P<0.00001]). Significantly more patients in levomilnacipran ER achieved MADRS response rate (RR 1.35 [95% CI 1.23, 1.47; P<0.00001]) and MADRS remission rate (RR 1.30 [95% CI 1.06, 1.59; P=0.01]). In terms of safety, more patients discontinued due to adverse events (AEs) in levomilnacipran ER compared with placebo (RR 3.15 [95% CI 2.26, 4.39; P<0.00001]), but it was generally well tolerated in each eligible trial. The most common AEs were nausea, delay in ejaculation, erectile dysfunction, tachycardia, headache and increase in heart rate. Conclusion Levomilnacipran ER is a safe and effective short-term treatment for MDD (≤10 weeks). Long-term and head-to-head trials comparing levomilnacipran ER with other antidepressants are needed to confirm the conclusion. PMID:27822042

  11. Extending the eigCG algorithm to non-symmetric linear systems with multiple right-hand sides

    SciTech Connect

    Abdou Abdel-Rehim, Kostas Orginos, Andreas Stathopoulos

    2009-11-01

    For Hermitian positive definite linear systems and eigenvalue problems, the eigCG algorithm is a memory efficient algorithm that solves the linear system and simultaneously computes some of its eigenvalues. The algorithm is based on the Conjugate-Gradient (CG) algorithm, however, it uses only a window of the vectors generated by the CG algorithm to compute approximate eigenvalues. The number and accuracy of the eigenvectors can be increased by solving more right-hand sides. For Hermitian systems with multiple right-hand sides, the computed eigenvectors can be used to speed up the solution of subsequent systems. The algorithm was tested on Lattice QCD problems by solving the normal equations and was shown to give large speed up factors and to remove the critical slowing down as we approach light quark masses. Here, an extension to the non-symmetric case based on the two-sided Lanczos algorithm is given. The new algorithm is tested on Lattice QCD problems and is shown to give promising results. We also study the removal of the critical slowing down and compare results with those of the eigCG algorithm. We also discuss the case when the system is gamma5-Hermitian.

  12. 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.

  13. 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.

  14. Extended and Structurally Supported Insights into Extracellular Hormone Binding, Signal Transduction and Organization of the Thyrotropin Receptor

    PubMed Central

    Krause, Gerd; Kreuchwig, Annika; Kleinau, Gunnar

    2012-01-01

    The hormone thyrotropin (TSH) and its receptor (TSHR) are crucial for the growth and function of the thyroid gland. The TSHR is evolutionary linked with the receptors of follitropin (FSHR) and lutropin/choriogonadotropin (LHR) and their sequences and structures are similar. The extracellular region of TSHR contains more than 350 amino acids and binds hormone and antibodies. Several important questions related to functions and mechanisms of TSHR are still not comprehensively understood. One major reason for these open questions is the lack of any structural information about the extracellular segment of TSHR that connects the N-terminal leucine-rich repeat domain (LRRD) with the transmembrane helix (TMH) 1, the hinge region. It has been shown experimentally that this segment is important for fine tuning of signaling and ligand interactions. A new crystal structure containing most of the extracellular hFSHR region in complex with hFSH has recently been published. Now, we have applied these new structural insights to the homologous TSHR and have generated a structural model of the TSHR LRRD/hinge-region/TSH complex. This structural model is combined and evaluated with experimental data including hormone binding (bTSH, hTSH, thyrostimulin), super-agonistic effects, antibody interactions and signaling regulation. These studies and consideration of significant and non-significant amino acids have led to a new description of mechanisms at the TSHR, including ligand-induced displacements of specific hinge region fragments. This event triggers conformational changes at a convergent center of the LRRD and the hinge region, activating an “intramolecular agonistic unit” close to the transmembrane domain. PMID:23300822

  15. Female preference for multi-modal courtship: multiple signals are important for male mating success in peacock spiders

    PubMed Central

    Girard, Madeline B.; Elias, Damian O.; Kasumovic, Michael M.

    2015-01-01

    A long-standing goal for biologists has been to understand how female preferences operate in systems where males have evolved numerous sexually selected traits. Jumping spiders of the Maratus genus are exceptionally sexually dimorphic in appearance and signalling behaviour. Presumably, strong sexual selection by females has played an important role in the evolution of complex signals displayed by males of this group; however, this has not yet been demonstrated. In fact, despite apparent widespread examples of sexual selection in nature, empirical evidence is relatively sparse, especially for species employing multiple modalities for intersexual communication. In order to elucidate whether female preference can explain the evolution of multi-modal signalling traits, we ran a series of mating trials using Maratus volans. We used video recordings and laser vibrometry to characterize, quantify and examine which male courtship traits predict various metrics of mating success. We found evidence for strong sexual selection on males in this system, with success contingent upon a combination of visual and vibratory displays. Additionally, independently produced, yet correlated suites of multi-modal male signals are linked to other aspects of female peacock spider behaviour. Lastly, our data provide some support for both the redundant signal and multiple messages hypotheses for the evolution of multi-modal signalling. PMID:26631566

  16. Female preference for multi-modal courtship: multiple signals are important for male mating success in peacock spiders.

    PubMed

    Girard, Madeline B; Elias, Damian O; Kasumovic, Michael M

    2015-12-07

    A long-standing goal for biologists has been to understand how female preferences operate in systems where males have evolved numerous sexually selected traits. Jumping spiders of the Maratus genus are exceptionally sexually dimorphic in appearance and signalling behaviour. Presumably, strong sexual selection by females has played an important role in the evolution of complex signals displayed by males of this group; however, this has not yet been demonstrated. In fact, despite apparent widespread examples of sexual selection in nature, empirical evidence is relatively sparse, especially for species employing multiple modalities for intersexual communication. In order to elucidate whether female preference can explain the evolution of multi-modal signalling traits, we ran a series of mating trials using Maratus volans. We used video recordings and laser vibrometry to characterize, quantify and examine which male courtship traits predict various metrics of mating success. We found evidence for strong sexual selection on males in this system, with success contingent upon a combination of visual and vibratory displays. Additionally, independently produced, yet correlated suites of multi-modal male signals are linked to other aspects of female peacock spider behaviour. Lastly, our data provide some support for both the redundant signal and multiple messages hypotheses for the evolution of multi-modal signalling. © 2015 The Author(s).

  17. Reconstruction of the first-derivative EPR spectrum from multiple harmonics of the field-modulated continuous wave signal.

    PubMed

    Tseitlin, Mark; Eaton, Sandra S; Eaton, Gareth R

    2011-04-01

    Selection of the amplitude of magnetic field modulation for continuous wave electron paramagnetic resonance (EPR) often is a trade-off between sensitivity and resolution. Increasing the modulation amplitude improves the signal-to-noise ratio, S/N, at the expense of broadening the signal. Combining information from multiple harmonics of the field-modulated signal is proposed as a method to obtain the first derivative spectrum with minimal broadening and improved signal-to-noise. The harmonics are obtained by digital phase-sensitive detection of the signal at the modulation frequency and its integer multiples. Reconstruction of the first-derivative EPR line is done in the Fourier conjugate domain where each harmonic can be represented as the product of the Fourier transform of the 1st derivative signal with an analytical function. The analytical function for each harmonic can be viewed as a filter. The Fourier transform of the 1st derivative spectrum can be calculated from all available harmonics by solving an optimization problem with the goal of maximizing the S/N. Inverse Fourier transformation of the result produces the 1st derivative EPR line in the magnetic field domain. The use of modulation amplitude greater than linewidth improves the S/N, but does not broaden the reconstructed spectrum. The method works for an arbitrary EPR line shape, but is limited to the case when magnetization instantaneously follows the modulation field, which is known as the adiabatic approximation. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Reconstruction of the first derivative EPR spectrum from multiple harmonics of the field-modulated continuous wave signal

    PubMed Central

    Tseitlin, Mark; Eaton, Sandra S.; Eaton, Gareth R.

    2011-01-01

    Selection of the amplitude of magnetic field modulation for continuous wave electron paramagnetic resonance (EPR) often is a trade-off between sensitivity and resolution. Increasing the modulation amplitude improves the signal-to-noise ratio, S/N, at the expense of broadening the signal. Combining information from multiple harmonics of the field-modulated signal is proposed as a method to obtain the first derivative spectrum with minimal broadening and improved signal-to-noise. The harmonics are obtained by digital phase-sensitive detection of the signal at the modulation frequency and its integer multiples. Reconstruction of the first derivative EPR line is done in the Fourier conjugate domain where each harmonic can be represented as the product of the Fourier transform of the 1st derivative signal with an analytical function. The analytical function for each harmonic can be viewed as a filter. The Fourier transform of the 1st derivative spectrum can be calculated from all available harmonics by solving an optimization problem with the goal of maximizing the S/N. Inverse Fourier transformation of the result produces the 1st derivative EPR line in the magnetic field domain. The use of modulation amplitude greater than linewidth improves the S/N, but does not broaden the reconstructed spectrum. The method works for an arbitrary EPR line shape, but is limited to the case when magnetization instantaneously follows the modulation field, which is known as the adiabatic approximation. PMID:21349750

  19. 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.

  20. Combinatorial regulation of the Saccharomyces cerevisiae CAR1 (arginase) promoter in response to multiple environmental signals.

    PubMed Central

    Smart, W C; Coffman, J A; Cooper, T G

    1996-01-01

    CAR1 (arginase) gene expression responds to multiple environmental signals; expression is induced in response to the intracellular accumulation of arginine and repressed when readily transported and catabolized nitrogen sources are available in the environment. Up to 14 cis-acting sites and 9 trans-acting factors have been implicated in regulated CAR1 transcription. In all but one case, the sites are redundant. To test whether these sites actually participate in CAR1 expression, each class of sites was inactivated by substitution mutations that retained the native spacing of the CAR1 cis-acting elements. Three types of sites function independently of the nitrogen source: two clusters of Abflp- and Rap1p-binding sites, and a GC-rich sequence. Two different sets of nitrogen source-dependent sites are also required: the first consists of two GATAA-containing UASNTR sites that mediate nitrogen catabolite repression-sensitive transcription, and the second is arginine dependent and consists of three UAS1 elements that activate transcription only when arginine is present. A single URS1 site mediates repression of CAR1 arginine-independent upstream activator site (UAS) activity in the absence of arginine and the presence of a poor nitrogen source (a condition under which the inducer-independent Gln3p can function in association with the UASNTR sites). When arginine is present, the combined activity of the UAS elements overcomes the negative effects mediated by URS1. Mutation of the classes of sites either singly or in combination markedly alters CAR1 promoter operation and control, supporting the idea that they function synergistically to regulate expression of the gene. PMID:8816501

  1. MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways.

    PubMed

    Rao, X; Di Leva, G; Li, M; Fang, F; Devlin, C; Hartman-Frey, C; Burow, M E; Ivan, M; Croce, C M; Nephew, K P

    2011-03-03

    Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the overexpression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two 'oncomirs' may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer.

  2. MicroRNA-221/222 confers breast cancer fulvestrant resistance by regulating multiple signaling pathways

    PubMed Central

    Rao, X; Di Leva, G; Li, M; Fang, F; Devlin, C; Hartman-Frey, C; Burow, ME; Ivan, M; Croce, CM; Nephew, KP

    2012-01-01

    Fulvestrant is a selective estrogen receptor downregulator (SERD) and highly effective antagonist to hormone-sensitive breast cancers following failure of previous tamoxifen or aromatase inhibitor therapies. However, after prolonged fulvestrant therapy, acquired resistance eventually occurs in the majority of breast cancer patients, due to poorly understood mechanisms. To examine a possible role(s) of aberrantly expressed microRNAs (miRNAs) in acquired fulvestrant resistance, we compared antiestrogen-resistant and -sensitive breast cancer cells, revealing the over-expression of miR-221/222 in the SERD-resistant cell lines. Fulvestrant treatment of estradiol (E2)- and fulvestrant-sensitive MCF7 cells resulted in increased expression of endogenous miR-221/222. Ectopic upregulation of miR-221/222 in estrogen receptor-α (ERα)-positive cell lines counteracted the effects of E2 depletion or fulvestrant-induced cell death, thus also conferring hormone-independent growth and fulvestrant resistance. In cells with acquired resistance to fulvestrant, miR-221/222 expression was essential for cell growth and cell cycle progression. To identify possible miR-221/222 targets, miR-221- or miR-222- induced alterations in global gene expression profiles and target gene expression at distinct time points were determined, revealing that miR-221/222 overexpression resulted in deregulation of multiple oncogenic signaling pathways previously associated with drug resistance. Activation of β-catenin by miR-221/222 contributed to estrogen-independent growth and fulvestrant resistance, whereas TGF-β-mediated growth inhibition was repressed by the two miRNAs. This first in-depth investigation into the role of miR-221/222 in acquired fulvestrant resistance, a clinically important problem, demonstrates that these two ‘oncomirs’ may represent promising therapeutic targets for treating hormone-independent, SERD-resistant breast cancer. PMID:21057537

  3. Morbillivirus V Proteins Exhibit Multiple Mechanisms to Block Type 1 and Type 2 Interferon Signalling Pathways

    PubMed Central

    Chinnakannan, Senthil K.; Nanda, Sambit K.; Baron, Michael D.

    2013-01-01

    Morbilliviruses form a closely related group of pathogenic viruses which encode three non-structural proteins V, W and C in their P gene. Previous studies with rinderpest virus (RPV) and measles virus (MeV) have demonstrated that these non-structural proteins play a crucial role in blocking type I (IFNα/β) and type II (IFNγ) interferon action, and various mechanisms have been proposed for these effects. We have directly compared four important morbilliviruses, rinderpest (RPV), measles virus (MeV), peste des petits ruminants virus (PPRV) and canine distemper virus (CDV). These viruses and their V proteins could all block type I IFN action. However, the viruses and their V proteins had varying abilities to block type II IFN action. The ability to block type II IFN-induced gene transcription correlated with co-precipitation of STAT1 with the respective V protein, but there was no correlation between co-precipitation of either STAT1 or STAT2 and the abilities of the V proteins to block type I IFN-induced gene transcription or the creation of the antiviral state. Further study revealed that the V proteins of RPV, MeV, PPRV and CDV could all interfere with phosphorylation of the interferon-receptor-associated kinase Tyk2, and the V protein of highly virulent RPV could also block the phosphorylation of another such kinase, Jak1. Co-precipitation studies showed that morbillivirus V proteins all form a complex containing Tyk2 and Jak1. This study highlights the ability of morbillivirus V proteins to target multiple components of the IFN signalling pathways to control both type I and type II IFN action. PMID:23431397

  4. Profiling of multiple signal pathway activities by multiplexing antibody and GFP-based translocation assays.

    PubMed

    Henriksen, Ulla; Fog, Jacob; Loechel, Frosty; Praestegaard, Morten

    2008-08-01

    Multiplexing of GFP based and immunofluorescence translocation assays enables easy acquisition of multiple readouts from the same cell in a single assay run. Immunofluorescence assays monitor translocation, phosphorylation, and up/down regulation of endogenous proteins. GFP-based assays monitor translocation of stably expressed GFP-fusion proteins. Such assays may be multiplexed along (vertical), across (horizontal), and between (branch) signal pathways. Examples of these strategies are presented: 1) The MK2-GFP assay monitors translocation of MK2-GFP from the nucleus to the cytoplasm in response to stimulation of the p38 pathway. By applying different immunofluorescent assays to the MK2 assay, a multiplexed HCA system is created for deconvolution of p38 pathway activation including assay readouts for MK2, p38, NFkappaB, and c-Jun. 2) A method for evaluating GPCR activation and internalization in a single assay run has been established by multiplexing GFP-based internalization assays with immunofluorescence assays for downstream transducers of GPCR activity: pCREB (cAMP sensor), NFATc1 (Ca(2+) sensor), and ERK (G-protein activation). Activation of the AT1 receptor is given as an example. 3) Cell toxicity readouts can be linked to primary readouts of interest via acquisition of secondary parameters describing cellular morphology. This approach is used to flag cytotoxic compounds and deselect false positives. The ATF6 Redistribution assay is provided as an example. These multiplex strategies provide a unique opportunity to enhance HCA data quality and save time during drug discovery. From a single assay run, several assay readouts are obtained that help the user to deconvolute the mode of action of test compounds.

  5. The representation of inflammatory signals in the brain - a model for subjective fatigue in multiple sclerosis.

    PubMed

    Hanken, Katrin; Eling, Paul; Hildebrandt, Helmut

    2014-01-01

    In multiple sclerosis (MS) patients, fatigue is rated as one of the most common and disabling symptoms. However, the pathophysiology underlying this fatigue is not yet clear. Several lines of evidence suggest that immunological factors, such as elevated levels of pro-inflammatory cytokines, may contribute to subjective fatigue in MS patients. Pro-inflammatory cytokines represent primary mediators of immune-to-brain-communication, modulating changes in the neurophysiology of the central nervous system. Recently, we proposed a model arguing that fatigue in MS patients is a subjective feeling, which is related to inflammation. Moreover, it implies that fatigue can be measured behaviorally only by applying specific cognitive tasks related to alertness and vigilance. In the present review, we focus on the subjective feeling of MS-related fatigue. We examine the hypothesis that the subjective feeling of MS-related fatigue may be a variant of inflammation-induced sickness behavior, resulting from cytokine-mediated activity changes within brain areas involved in interoception and homeostasis including the insula, the anterior cingulate, and the hypothalamus. We first present studies demonstrating a relationship between pro-inflammatory cytokines and subjective fatigue in healthy individuals, in people with inflammatory disorders, and particularly in MS patients. Subsequently, we discuss studies analyzing the impact of anti-inflammatory treatment on fatigue. In the next part of this review, we present studies on the transmission and neural representation of inflammatory signals, with a special focus on possible neural concomitants of inflammation-induced fatigue. We also present two of our studies on the relationship between local gray and white matter atrophy and fatigue in MS patients. Finally, we discuss some implications of our findings and future perspectives.

  6. Multiple nuclear localization signals function in the nuclear import of the transcription factor Nrf2.

    PubMed

    Theodore, Melanie; Kawai, Yumiko; Yang, Jianqi; Kleshchenko, Yuliya; Reddy, Sekhar P; Villalta, Fernando; Arinze, Ifeanyi J

    2008-04-04

    Nuclear factor erythroid 2-related factor 2 (Nrf2) mediates the transcriptional response of cells to oxidative stress and is translocated into the nucleus following, or concomitant with, its activation by electrophiles or reactive oxygen species. The mechanism of its translocation into the nucleus is not entirely elucidated. Here we have identified two novel nuclear localization signal (NLS) motifs in murine Nrf2, one located near the N-terminal region (amino acid residues 42-53) and the other (residues 587-593) located near the C-terminal region. Imaging of green fluorescent protein (GFP)-tagged Nrf2 revealed that mutation(s) in any of these sequences resulted in decreased nuclear fluorescence intensity compared with the wild-type Nrf2 when Nrf2 activation was induced with the electrophile tert-butylhydroquinone. The mutations also impaired Nrf2-induced transactivation of antioxidant response element-driven reporter gene expression to the same extent as the Nrf2 construct bearing mutation in a previously identified bipartite NLS that maps at residues 494-511. When linked to GFP or to GFP-PEPCK-C each of the novel NLS motifs was sufficient to drive nuclear translocation of the fusion proteins. Co-immunoprecipitation assays demonstrated that importins alpha5 and beta1 associate with Nrf2, an interaction that was blocked by the nuclear import inhibitor SN50. SN50 also blocked tert-butylhydroquinone-induced nuclear fluorescence of GFP-Nrf2 in cells transfected with wild-type GFP-Nrf2. Overall these results reveal that multiple NLS motifs in Nrf2 function in its nuclear translocation in response to pro-oxidant stimuli and that the importin alpha-beta heterodimer nuclear import receptor system plays a critical role in the import process.

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

    PubMed

    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. 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. 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.

  8. 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

  9. T1 Signal Measurements in Pediatric Brain: Findings after Multiple Exposures to Gadobenate Dimeglumine for Imaging of Nonneurologic Disease.

    PubMed

    Schneider, G K; Stroeder, J; Roditi, G; Colosimo, C; Armstrong, P; Martucci, M; Buecker, A; Raczeck, P

    2017-09-01

    Signal intensity increases possibly suggestive of gadolinium retention have recently been reported on unenhanced T1-weighted images of the pediatric brain following multiple exposures to gadolinium-based MR contrast agents. Our aim was to determine whether T1 signal changes suggestive of gadolinium deposition occur in the brains of pediatric nonneurologic patients after multiple exposures to gadobenate dimeglumine. Thirty-four nonneurologic patients (group 1; 17 males/17 females; mean age, 7.18 years) who received between 5 and 15 injections (mean, 7.8 injections) of 0.05 mmol/kg of gadobenate during a mean of 2.24 years were compared with 24 control patients (group 2; 16 males/8 females; mean age, 8.78 years) who had never received gadolinium-based contrast agents. Exposure to gadobenate was for diagnosis and therapy monitoring. Five blinded readers independently determined the signal intensity at ROIs in the dentate nucleus, globus pallidus, pons, and thalamus on unenhanced T1-weighted spin-echo images from both groups. Unpaired t tests were used to compare signal-intensity values and dentate nucleus-pons and globus pallidus-thalamus signal-intensity ratios between groups 1 and 2. Mean signal-intensity values in the dentate nucleus, globus pallidus, pons, and thalamus of gadobenate-exposed patients ranged from 366.4 to 389.2, 360.5 to 392.9, 370.5 to 374.9, and 356.9 to 371.0, respectively. Corresponding values in gadolinium-based contrast agent-naïve subjects were not significantly different (P > .05). Similarly, no significant differences were noted by any reader for comparisons of the dentate nucleus-pons signal-intensity ratios. One reader noted a difference in the mean globus pallidus-thalamus signal-intensity ratios (1.06 ± 0.006 versus 1.02 ± 0.009, P = .002), but this reflected nonsignificantly higher T1 signal in the thalamus of control subjects. The number of exposures and the interval between the first and last exposures did not influence signal

  10. Lenalidomide restores the osteogenic differentiation of bone marrow mesenchymal stem cells from multiple myeloma patients via deactivating Notch signaling pathway

    PubMed Central

    Guo, Juan; Fei, Chengming; Zhao, Youshan; Zhao, Sida; Zheng, Qingqing; Su, Jiying; Wu, Dong; Li, Xiao; Chang, Chunkang

    2017-01-01

    Multiple myeloma (MM) always presents osteolytic bone lesions, resulting from the abnormal osteoblastic and osteoclastic function in patients. MM patients exhibit the impairment of osteogenic differentiation of BMMSCs (bone marrow mesenchymal stem cells) and osteoblast deficiency. Effects of the drug, lenalidomide on the osteoblastic functions and the involved mechanisms remain unexplored. In the present study, it is observed that the osteogenic differentiation of BMMSCs from MM patients (MM-MSCs) is impaired and activation of Notch signaling pathway in MM-MSCs is abnormal. Notch signaling activation inhibits BMMSCs osteogenesis. Knockdown of Notch1 expression and DAPT application reverse the osteogenic differentiation from MM-MSCs. Furthermore, it is shown that the gene expression of Notch signaling molecules, including receptors, ligands and downstream factors are significantly decreased in MM-MSCs following lenalidomide treatment, compared with non-treated MM-MSCs. Taken together, treatment with lenalidomide restores the osteogenic differentiation of MM-MSCs via deactivating Notch signaling pathway.

  11. Effect of sod (superoxide dismutase) protein supplementation in semen extenders on motility, viability, acrosome status and ERK (extracellular signal-regulated kinase) protein phosphorylation of chilled stallion spermatozoa.

    PubMed

    Cocchia, N; Pasolini, M P; Mancini, R; Petrazzuolo, O; Cristofaro, I; Rosapane, I; Sica, A; Tortora, G; Lorizio, R; Paraggio, G; Mancini, A

    2011-04-15

    New studies are underway to find new methods for supporting longer storage of cooled stallion semen. It is known that high concentrations of reactive oxygen species (ROS) cause sperm pathology. The metalloprotein superoxide dismutase (SOD) is responsible for H(2)O(2) and O(2) production, by dismutation of superoxide radicals. The aim of this study is to assess the quality of chilled stallion semen processed with extenders containing SOD at different concentrations as antioxidant additives. A total of 80 ejaculates collected from 5 standardbred stallions was divided into 5 aliquots treated as: native semen (control 1); native semen diluted 1:3 with Kenney semen extender (control 2); spermatozoa diluted after centrifugation in extender without (control 3) or with SOD at 25 IU/ml (experimental 1) or 50 IU/ml (experimental 2). Each sample was analyzed for motility, viability and acrosome status, immediately after semen preparation and again after storage at 5 °C for 24 h, 48 h and 7 2h. Acrosome integrity was evaluated by Chlortetracycline (CTC) and Fluorescent-labeled peanut lectin agglutinin (PNA-FITC conjugated staining). A proteomic approach of quantifying extracellular signal regulated kinase (ERK) was also evaluated as an indirect indicator of oxidative stress. In all samples sperm progressive motility and sperm acrosomal integrity showed a significant reduction between fresh and cooled spermatozoa at 24 h, 48 h and 72 h. Quality parameters of sperm were significantly higher (Progressive Motility P < 0.01; Viability P < 0.001) in aliquots supplemented with SOD. ERK phosphorylation was statistically higher (P < 0.01) in aliquots without SOD. The Authors concluded that addition of SOD to semen extenders improves the quality of chilled equine semen and reduces ERK activation.

  12. 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.

  13. 2,5-Dimethyl-Celecoxib Extends Drosophila Life Span via a Mechanism That Requires Insulin and Target of Rapamycin Signaling.

    PubMed

    Wu, Qi; Lian, Ting; Fan, Xiaolan; Song, Chaochun; Gaur, Uma; Mao, Xueping; Yang, Deying; Piper, Matthew D W; Yang, Mingyao

    2017-10-01

    The search for antiaging drugs is a key component of gerontology research. A few drugs with positive effects on life span in model organisms have been found. Here, we report that 2,5-dimethyl-celecoxib, a derivative of the anti-inflammatory drug celecoxib, can extend Drosophila life span and delay aging by a mechanism involving insulin signaling and target of rapamycin signaling. Importantly, its positive effects were apparent when the treatment window was restricted to the beginning of life or the later half. 2,5-Dimethyl-celecoxib-induced longevity was also associated with improvements in physical activity, intestinal integrity, and increased autophagy. In addition, 2,5-dimethyl-celecoxib exhibited protective effects against several kinds of stress such as starvation and heat. The generally positive effects of 2,5-dimethyl-celecoxib on both health and life span, combined with its mode of action via evolutionarily conserved signaling pathways, indicate that it has the potential to become an effective antiaging drug. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. 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.

  15. Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

    PubMed Central

    van Andel, Harmen; Ren, Zemin; Koopmans, Iris; Joosten, Sander P. J.; Kocemba, Kinga A.; de Lau, Wim; Kersten, Marie José; de Bruin, Alexander M.; Guikema, Jeroen E. J.; Clevers, Hans; Spaargaren, Marcel; Pals, Steven T.

    2017-01-01

    The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto- and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM. PMID:28028233

  16. Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins.

    PubMed

    van Andel, Harmen; Ren, Zemin; Koopmans, Iris; Joosten, Sander P J; Kocemba, Kinga A; de Lau, Wim; Kersten, Marie José; de Bruin, Alexander M; Guikema, Jeroen E J; Clevers, Hans; Spaargaren, Marcel; Pals, Steven T

    2017-01-10

    The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto- and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.

  17. 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

    2012-02-03

    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.

  18. 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

  19. Multiple signaling pathways coordinate to induce a threshold response in a chordate embryo.

    PubMed

    Ohta, Naoyuki; Satou, Yutaka

    2013-01-01

    In animal development, secreted signaling molecules evoke all-or-none threshold responses of target gene transcription to specify cell fates. In the chordate Ciona intestinalis, the neural markers Otx and Nodal are induced at early embryonic stages by Fgf9/16/20 signaling. Here we show that three additional signaling molecules act negatively to generate a sharp expression boundary for neural genes. EphrinA signaling antagonizes FGF signaling by inhibiting ERK phosphorylation more strongly in epidermal cells than in neural cells, which accentuates differences in the strength of ERK activation. However, even weakly activated ERK activates Otx and Nodal transcription occasionally, probably because of the inherently stochastic nature of signal transduction processes and binding of transcription factors to target sequences. This occasional and undesirable activation of neural genes by weak residual ERK activity is directly repressed by Smad transcription factors activated by Admp and Gdf1/3-like signaling, further sharpening the differential responses of cells to FGF signaling. Thus, these signaling pathways coordinate to evoke a threshold response that delineates a sharp expression boundary.

  20. Particle identification in a LKr ionization chamber by multiple induced current measurements using the shape analysis of the signal

    NASA Astrophysics Data System (ADS)

    Diaferia, R.; Lanni, F.; Maggi, B.; Palombo, F.; Sala, A.; Cantoni, P.; Frabetti, P. L.; Stagni, L.

    1996-01-01

    Charged particle (π/K) separation in the momentum range 0.5-0.7 GeV/c using a new method of shape analysis of the signal from a liquid krypton ionization chamber has been studied experimentally. The detector has been exposed to pions and protons at the T11 test beam at CERN PS. The shape of preamplifier output signal has been recorded by a waveform digitizer and differentiated to obtain multiple measurements of induced current inside a 2 cm gap. Results on particle separation are presented and compared with a Monte Carlo simulation.

  1. Particle identification in a LKr ionization chamber by multiple induced current measurements using the shape analysis of the signal

    NASA Astrophysics Data System (ADS)

    Cantoni, P.; Frabetti, P. L.; Stagni, L.; Diaferia, R.; Lanni, F.; Maggi, B.; Palombo, F.; Sala, A.; Manfredi, P. F.; Re, V.; Speziali, V.

    1995-02-01

    Charged particle ( {π}/{K}) separation in the momentum range 0.5-0.7 GeV/ c using a new method of shape analysis of the signal from a liquid krypton ionization chamber has been studied experimentally. The detector has been exposed to the T11 test beam at CERN PS. The shape of the preamplifier output signal has been recorded by a waveform digitizer and differentiated to obtain multiple measurements of induced current inside a 2 cm gap. Results on particle separation are presented.

  2. 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

  3. 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.

  4. 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.

  5. Extended daily on-line high-volume haemodiafiltration in septic multiple organ failure: a well-tolerated and feasible procedure.

    PubMed

    Kron, Joachim; Kron, Susanne; Wenkel, Reinhard; Schuhmacher, Hans-Uwe; Thieme, Ulrike; Leimbach, Til; Kern, Hartmut; Neumayer, Hans-H; Slowinski, Torsten

    2012-01-01

    The outcome of patients with septic multiple organ failure (MOF) remains poor. There are experimental and clinical data indicating a beneficial effect of high-volume haemofiltration. Delivering high-volume therapy is only cost effective using on-line devices because of high costs for additional solution bags in conventional continuous renal replacement therapy (CRRT). We investigated feasibility and effectiveness of extended daily on-line high-volume haemodiafiltration (HDF) with technically maximum convective volume in patients with septic MOF in a pilot study. We included 21 consecutive critically ill patients with septic MOF having a mortality risk >50% (SAPS II >50, APACHE II >25). Renal replacement therapy (RRT) was applied with extended daily HDF for 6-23 h using the AK 200 Ultra S dialysis machine in the ultracontrol pre-dilution mode. Dialysate and substitution fluid were prepared on-line. Patients underwent 289 treatments. The mean convective volume was 17.8 ± 3.7 L/h and 208 ± 66 mL/kg/h, respectively, median treatment time was 10:15 h/day. Seventeen of 21 patients survived 28 days (81%). The 90-day survival rate was 52% (11/21) versus 19% compared to the survival rate predicted by APACHE II (33.6 mean) and SAPS II (68.6 mean) scores. Haemodynamics improved significantly during the treatment procedures. Material costs per treatment amounted to 35 €. Extended daily on-line HDF using maximum convective volume seems to improve the outcome of septic MOF, especially in the early phase. The investigated mode of treatment proved to be feasible, well tolerated and highly cost effective compared to conventional CRRT. At present, this procedure would be applicable at every ICU facility with nephrological support.

  6. Highly stable RF signal from a mode-locked laser stabilized to multiple saturated absorption lines

    NASA Astrophysics Data System (ADS)

    Kovalev, Anton V.; Uskov, Alexander V.; Polyakov, Vadim M.

    2017-02-01

    We control the optical comb in Nd:YVO4 mode-locked lasers with intracavity frequency doubling based on KTP crystals via changing the cavity length and its dispersion properties and achieve high-purity radiofrequency (RF) signals. The laser output wavelength (532 nm) is in the range of the molecular iodine absorption spectrum with narrow (1.5 kHz) homogeneously broadened lines. We propose to stabilize the two longitudinal modes on two narrow iodine absorption lines. The third derivative of the absorption line could be obtained by heterodyning the absorption signal with the third harmonic of the modulation signal. The resulting RF error signal could be used to stabilize two locked longitudinal modes separated by 1.37 GHz which results in stabilized beat note signal.

  7. Towards a physiological signal-based access solution for a non-verbal adolescent with severe and multiple disabilities.

    PubMed

    Memarian, Negar; Blain-Moraes, Stefanie; Chau, Tom

    2014-08-01

    To find physiologically arousing stimuli and labile physiological channels in a non-verbal adolescent with severe and multiple congenital disabilities, who did not have a reliable means of communication. The client was repeatedly presented with visual and audiovisual stimuli, representing variations of six contextual factors over three sessions in a one month period. For each stimulus, reactions were detected in the client's four peripheral autonomic nervous system signals using a rule-based classification algorithm. During the presentation of audiovisual stimuli, the number of physiological reactions significantly differed from that observed in baseline (χ(2) = 3.93, p = 0.0476). Aural stimuli articulated in an unfamiliar voice, and aural stimuli containing anticipatory patterns were also physiologically arousing. Fingertip temperature was the client's most labile physiological signal. The results of this case study suggest that physiological data may complement caregiver acumen in deciphering the reactions of non-verbal clients with severe and multiple disabilities.

  8. Parameter Estimation and Modeling of Interference Cancellation Technique for Multiple Signal Recovery

    DTIC Science & Technology

    2013-06-01

    Miridakis and D. D. Vergados, “A survey on the successive interference cancellation performance for single-antenna and multiple-antenna OFDM ...antenna and multiple-antenna OFDM systems,” IEEE Comms. Surveys & Tutorials, vol.15, no. 1, pp. 312–335, 2013. [2] J. G. Andrews, “Interference

  9. Pigment Translocation in Caridean Shrimp Chromatophores: Receptor Type, Signal Transduction, Second Messengers, and Cross Talk Among Multiple Signaling Cascades.

    PubMed

    Milograna, Sarah Ribeiro; Ribeiro, Márcia Regina; Bell, Fernanda Tinti; McNamara, John Campbell

    2016-11-01

    Pigment aggregation in shrimp chromatophores is triggered by red pigment concentrating hormone (RPCH), a neurosecretory peptide whose plasma membrane receptor may be a G-protein coupled receptor (GPCR). While RPCH binding activates the Ca(2+) /cGMP signaling cascades, a role for cyclic AMP (cAMP) in pigment aggregation is obscure, as are the steps governing Ca(2+) release from the smooth endoplasmic reticulum (SER). A role for the antagonistic neuropeptide, pigment dispersing homone (α-PDH) is also unclear. In red, ovarian chromatophores from the freshwater shrimp Macrobrachium olfersi, we show that a G-protein antagonist (AntPG) strongly inhibits RPCH-triggered pigment aggregation, suggesting that RPCH binds to a GPCR, activating an inhibitory G-protein. Decreasing cAMP levels may cue pigment aggregation, since cytosolic cAMP titers, when augmented by cholera toxin, forskolin or vinpocentine, completely or partially impair pigment aggregation. Triggering opposing Ca(2+) /cGMP and cAMP cascades by simultaneous perfusion with lipid-soluble cyclic nucleotide analogs induces a "tug-of-war" response, pigments aggregating in some chromatosomes with unpredictable, oscillatory movements in others. Inhibition of cAMP-dependent protein kinase accelerates aggregation and reduces dispersion velocities, suggesting a role in phosphorylation events, possibly regulating SER Ca(2+) release and pigment aggregation. The second messengers IP3 and cADPR do not stimulate SER Ca(2+) release. α-PDH does not sustain pigment dispersion, suggesting that pigment translocation in caridean chromatophores may be regulated solely by RPCH, since PDH is not required. We propose a working hypothesis to further unravel key steps in the mechanisms of pigment translocation within crustacean chromatophores that have remained obscure for nearly a century.

  10. An Extended ΔCT-Method Facilitating Normalisation with Multiple Reference Genes Suited for Quantitative RT-PCR Analyses of Human Hepatocyte-Like Cells

    PubMed Central

    Fekete-Drimusz, Nora; Manns, Michael P.; Vondran, Florian W. R.; Bock, Michael

    2014-01-01

    Reference genes (RG) as sample internal controls for gene transcript level analyses by quantitative RT-PCR (RT-qPCR) must be stably expressed within the experimental range. A variety of in vitro cell culture settings with primary human hepatocytes, and Huh-7 and HepG2 cell lines, were used to determine candidate RG expression stability in RT-qPCR analyses. Employing GeNorm, BestKeeper and Normfinder algorithms, this study identifies PSMB6, MDH1 and some more RG as sufficiently unregulated, thus expressed at stable levels, in hepatocyte-like cells in vitro. Inclusion of multiple RG, quenching occasional regulations of single RG, greatly stabilises gene expression level calculations from RT-qPCR data. To further enhance validity and reproducibility of relative RT-qPCR quantifications, the ΔCT calculation can be extended (e-ΔCT) by replacing the CT of a single RG in ΔCT with an averaged CT-value from multiple RG. The use of two or three RG - here identified suited for human hepatocyte-like cells - for normalisation with the straightforward e-ΔCT calculation, should improve reproducibility and robustness of comparative RT-qPCR-based gene expression analyses. PMID:24658132

  11. Multiple stellar populations in Magellanic Cloud clusters - III. The first evidence of an extended main sequence turn-off in a young cluster: NGC 1856

    NASA Astrophysics Data System (ADS)

    Milone, A. P.; Bedin, L. R.; Piotto, G.; Marino, A. F.; Cassisi, S.; Bellini, A.; Jerjen, H.; Pietrinferni, A.; Aparicio, A.; Rich, R. M.

    2015-07-01

    Recent studies have shown that the extended main-sequence turn-off (eMSTO) is a common feature of intermediate-age star clusters in the Magellanic Clouds (MCs). The most simple explanation is that these stellar systems harbour multiple generations of stars with an age difference of a few hundred million years. However, while an eMSTO has been detected in a large number of clusters with ages between ˜1-2 Gyr, several studies of young clusters in both MCs and in nearby galaxies do not find any evidence for a prolonged star formation history, i. e. for multiple stellar generations. These results have suggested alternative interpretation of the eMSTOs observed in intermediate-age star clusters. The eMSTO could be due to stellar rotation mimicking an age spread or to interacting binaries. In these scenarios, intermediate-age MC clusters would be simple stellar populations, in close analogy with younger clusters. Here, we provide the first evidence for an eMSTO in a young stellar cluster. We exploit multiband Hubble Space Telescope photometry to study the ˜300-Myr old star cluster NGC 1856 in the Large Magellanic Cloud and detected a broadened MSTO that is consistent with a prolonged star formation which had a duration of about 150 Myr. Below the turn-off, the main sequence (MS) of NGC 1856 is split into a red and blue component, hosting 33 ± 5 and 67 ± 5 per cent of the total number of MS stars, respectively. We discuss these findings in the context of multiple-stellar-generation, stellar-rotation, and interacting-binary hypotheses.

  12. Microbial effectors target multiple steps in the salicylic acid production and signaling pathway

    PubMed Central

    Tanaka, Shigeyuki; Han, Xiaowei; Kahmann, Regine

    2015-01-01

    Microbes attempting to colonize plants are recognized through the plant immune surveillance system. This leads to a complex array of global as well as specific defense responses, which are often associated with plant cell death and subsequent arrest of the invader. The responses also entail complex changes in phytohormone signaling pathways. Among these, salicylic acid (SA) signaling is an important pathway because of its ability to trigger plant cell death. As biotrophic and hemibiotrophic pathogens need to invade living plant tissue to cause disease, they have evolved efficient strategies to downregulate SA signaling by virulence effectors, which can be proteins or secondary metabolites. Here we review the strategies prokaryotic pathogens have developed to target SA biosynthesis and signaling, and contrast this with recent insights into how plant pathogenic eukaryotic fungi and oomycetes accomplish the same goal. PMID:26042138

  13. Multiple roles for membrane-associated protein trafficking and signaling in gravitropism.

    PubMed

    Strohm, Allison K; Baldwin, Katherine L; Masson, Patrick H

    2012-01-01

    Gravitropism is a process that allows plant organs to guide their growth relative to the gravity vector. It requires them to sense changes in their orientation and generate a biochemical signal that they transmit to the tissues that drive organ curvature. Trafficking between the plasma membrane and endosomal compartments is important for all of these phases of the gravitropic response. The sedimentation of starch-filled organelles called amyloplasts plays a key role in sensing reorientation, and vacuolar integrity is required for amyloplast sedimentation in shoots. Other proteins associated with the vesicle trafficking pathway contribute to early gravity signal transduction independently of amyloplast sedimentation in both roots and hypocotyls. Phosphatidylinositol signaling, which starts at the plasma membrane and later affects the localization of auxin efflux facilitators, is a likely second messenger in the signal transduction phase of gravitropism. Finally, membrane-localized auxin influx and efflux facilitators contribute to a differential auxin gradient across the gravistimulated organs, which directs root curvature.

  14. Multiple roles for membrane-associated protein trafficking and signaling in gravitropism

    PubMed Central

    Strohm, Allison K.; Baldwin, Katherine L.; Masson, Patrick H.

    2012-01-01

    Gravitropism is a process that allows plant organs to guide their growth relative to the gravity vector. It requires them to sense changes in their orientation and generate a biochemical signal that they transmit to the tissues that drive organ curvature. Trafficking between the plasma membrane and endosomal compartments is important for all of these phases of the gravitropic response. The sedimentation of starch-filled organelles called amyloplasts plays a key role in sensing reorientation, and vacuolar integrity is required for amyloplast sedimentation in shoots. Other proteins associated with the vesicle trafficking pathway contribute to early gravity signal transduction independently of amyloplast sedimentation in both roots and hypocotyls. Phosphatidylinositol signaling, which starts at the plasma membrane and later affects the localization of auxin efflux facilitators, is a likely second messenger in the signal transduction phase of gravitropism. Finally, membrane-localized auxin influx and efflux facilitators contribute to a differential auxin gradient across the gravistimulated organs, which directs root curvature. PMID:23248632

  15. The Multiple Roles of FGF Signaling in the Developing Spinal Cord

    PubMed Central

    Diez del Corral, Ruth; Morales, Aixa V.

    2017-01-01

    During vertebrate embryonic development, the spinal cord is formed by the neural derivatives of a neuromesodermal population that is specified at early stages of development and which develops in concert with the caudal regression of the primitive streak. Several processes related to spinal cord specification and maturation are coupled to this caudal extension including neurogenesis, ventral patterning and neural crest specification and all of them seem to be crucially regulated by Fibroblast Growth Factor (FGF) signaling, which is prominently active in the neuromesodermal region and transiently in its derivatives. Here we review the role of FGF signaling in those processes, trying to separate its different functions and highlighting the interactions with other signaling pathways. Finally, these early functions of FGF signaling in spinal cord development may underlay partly its ability to promote regeneration in the lesioned spinal cord as well as its action promoting specific fates in neural stem cell cultures that may be used for therapeutical purposes. PMID:28626748

  16. 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.

  17. 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

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

    PubMed

    Westcott, Erika B; Segal, Steven S

    2013-04-01

    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. Although 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. © 2013 John Wiley & Sons Ltd.

  19. 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. ©2015 American Association for Cancer Research.

  20. The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways.

    PubMed

    Youns, Mаhmoud; Abdel Halim Hegazy, Wael

    2017-01-01

    Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines. Gene expression results showed that 1307 genes were significantly regulated in their expression in hepatic and pancreatic cell lines. 350 genes were commonly up-regulated and 353 genes were commonly down-regulated. Additionally, 604 genes were oppositely expressed in both tumor cells. CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling were among most prominent signaling pathways modulating the growth inhibitory effects of fisetin on hepatic and pancreatic cancer cells. The present analysis showed, for the first time, that the anti-tumor effect of fisetin was mediated mainly through modulation of multiple signaling pathways and via activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes.

  1. Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling.

    PubMed

    Ohnishi, Hidenori; Tochio, Hidehito; Kato, Zenichiro; Orii, Kenji E; Li, Ailian; Kimura, Takeshi; Hiroaki, Hidekazu; Kondo, Naomi; Shirakawa, Masahiro

    2009-06-23

    Myeloid differentiating factor 88 (MyD88) and MyD88 adaptor-like (Mal) are adaptor molecules critically involved in the Toll-like receptor (TLR) 4 signaling pathway. While Mal has been proposed to serve as a membrane-sorting adaptor, MyD88 mediates signal transduction from activated TLR4 to downstream components. The Toll/Interleukin-1 receptor (TIR) domain of MyD88 is responsible for sorting and signaling via direct or indirect TIR-TIR interactions between Mal and TLR4. However, the molecular mechanisms involved in multiple interactions of the TIR domain remain unclear. The present study describes the solution structure of the MyD88 TIR domain. Reporter gene assays revealed that 3 discrete surface sites in the TIR domain of MyD88 are important for TLR4 signaling. Two of these sites were shown to mediate direct binding to the TIR domain of Mal. Interestingly, Mal-TIR, but not MyD88-TIR, directly binds to the cytosolic TIR domain of TLR4. These observations suggested that the heteromeric assembly of TIR domains of the receptor and adaptors constitutes the initial step of TLR4 intracellular signal transduction.

  2. The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways

    PubMed Central

    Youns, Mаhmoud; Abdel Halim Hegazy, Wael

    2017-01-01

    Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines. Gene expression results showed that 1307 genes were significantly regulated in their expression in hepatic and pancreatic cell lines. 350 genes were commonly up-regulated and 353 genes were commonly down-regulated. Additionally, 604 genes were oppositely expressed in both tumor cells. CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling were among most prominent signaling pathways modulating the growth inhibitory effects of fisetin on hepatic and pancreatic cancer cells. The present analysis showed, for the first time, that the anti-tumor effect of fisetin was mediated mainly through modulation of multiple signaling pathways and via activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes. PMID:28052097

  3. 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.

  4. 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

  5. Involvement of the Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathway in Multiple Sclerosis and the Animal Model of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Liu, Yudong; McFarland, Braden C.; Qin, Hongwei

    2014-01-01

    Multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE) are characterized by focal inflammatory infiltrates into the central nervous system, demyelinating lesions, axonal damage, and abundant production of cytokines that activate immune cells and damage neurons and oligodendrocytes, including interleukin-12 (IL-12), IL-6, IL-17, IL-21, IL-23, granulocyte macrophage-colony stimulating factor, and interferon-gamma. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway mediates the biological activities of these cytokines and is essential for the development and regulation of immune responses. Dysregulation of the JAK/STAT pathway contributes to numerous autoimmune diseases, including MS/EAE. The JAK/STAT pathway is aberrantly activated in MS/EAE because of excessive production of cytokines, loss of expression of negative regulators such as suppressors of cytokine signaling proteins, and significant enrichment of genes encoding components of the JAK/STAT pathway, including STAT3. Specific JAK/STAT inhibitors have been used in numerous preclinical models of MS and demonstrate beneficial effects on the clinical course of disease and attenuation of innate and adaptive immune responses. In addition, other drugs such as statins, glatiramer acetate, laquinimod, and fumarates have beneficial effects that involve inhibition of the JAK/STAT pathway. We conclude by discussing the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases. PMID:25084174

  6. Activated IL-1RI Signaling Pathway Induces Th17 Cell Differentiation via Interferon Regulatory Factor 4 Signaling in Patients with Relapsing-Remitting Multiple Sclerosis

    PubMed Central

    Sha, Yonggang; Markovic-Plese, Silva

    2016-01-01

    IL-1β plays a crucial role in the differentiation of human Th17 cells. We report here that IL-1RI expression is significantly increased in both naive and memory CD4+ T cells derived from relapsing-remitting multiple sclerosis (RR MS) patients in comparison to healthy controls. Interleukin 1 receptor (IL-1R)I expression is upregulated in the in vitro-differentiated Th17 cells from RR MS patients in comparison to the Th1 and Th2 cell subsets, indicating the role of IL-1R signaling in the Th17 cell differentiation in RR MS. When IL-1RI gene expression was silenced using siRNA, human naive CD4+ T cells cultured in the presence of Th17-polarizing cytokines had a significantly decreased expression of interleukin regulatory factor 4 (IRF4), RORc, IL-17A, IL-17F, IL-21, IL-22, and IL-23R genes, confirming that IL-1RI signaling induces Th17 cell differentiation. Since IL-1R gene expression silencing inhibited IRF4 expression and Th17 differentiation, and IRF4 gene expression silencing inhibited Th17 cell differentiation, our results indicate that IL-1RI induces human Th17 cell differentiation in an IRF4-dependant manner. Our study has identified that IL-1RI-mediated signaling pathway is constitutively activated, leading to an increased Th17 cell differentiation in IRF4-dependent manner in patients with RR MS. PMID:27965670

  7. 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.

  8. Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy.

    PubMed

    Žiberna, Lovro; Šamec, Dunja; Mocan, Andrei; Nabavi, Seyed Fazel; Bishayee, Anupam; Farooqi, Ammad Ahmad; Sureda, Antoni; Nabavi, Seyed Mohammad

    2017-03-16

    Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5' adenosine monophosphate-activated protein kinase, extracellular signal-regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical.

  9. Multiple roles for mTOR signaling in both glutamatergic and GABAergic synaptic transmission

    PubMed Central

    Weston, Matthew C.; Chen, Hongmei; Swann, John W.

    2012-01-01

    Summary The mammalian target of rapamycin (mTOR) signaling pathway in neurons integrates a variety of extracellular signals to produce appropriate translational responses. mTOR signaling is hyperactive in neurological syndromes in both humans and mouse models that are characterized by epilepsy, autism and cognitive disturbances. In addition, rapamycin, a clinically important immunosuppressant, is a specific and potent inhibitor of mTOR signaling. While mTOR is known to regulate growth and synaptic plasticity of glutamatergic neurons, its effects on basic parameters of synaptic transmission are less well studied, and its role in regulating GABAergic transmission is unexplored. We therefore performed an electrophysiological and morphological comparison of glutamatergic and GABAergic neurons in which mTOR signaling was either increased by loss of the repressor Pten or decreased by treatment with rapamycin. We found that hyperactive mTOR signaling increased evoked synaptic responses in both glutamatergic and GABAergic neurons by approximately 50%, due to an increase in the number of synaptic vesicles available for release, the number of synapses formed and the miniature event size. Prolonged (72 hours) rapamycin treatment prevented these abnormalities and also decreased synaptic transmission in wild-type glutamatergic, but not GABAergic, neurons. Further analyses suggested that hyperactivation of the mTOR pathway also impairs presynaptic function, possibly by interfering with vesicle fusion. Despite this presynaptic impairment, the net effect of Pten loss is enhanced synaptic transmission in both GABAergic and glutamatergic neurons, which has numerous implications – depending on where in the brain mutations of an mTOR suppressor gene takes place during development. PMID:22895726

  10. 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.

  11. Integrating multiple types of data for signaling research: challenges and opportunities.

    PubMed

    Wiley, H Steven

    2011-02-15

    New technologies promise to provide unprecedented amounts of information that can build 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.

  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.

  13. An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes

    PubMed Central

    Huard, Jérémy; Mueller, Stephanie; Gilles, Ernst D; Klingmüller, Ursula; Klamt, Steffen

    2012-01-01

    During liver regeneration, quiescent hepatocytes re-enter the cell cycle to proliferate and compensate for lost tissue. Multiple signals including hepatocyte growth factor, epidermal growth factor, tumor necrosis factor α, interleukin-6, insulin and transforming growth factor β orchestrate these responses and are integrated during the G1 phase of the cell cycle. To investigate how these inputs influence DNA synthesis as a measure for proliferation, we established a large-scale integrated logical model connecting multiple signaling pathways and the cell cycle. We constructed our model based upon established literature knowledge, and successively improved and validated its structure using hepatocyte-specific literature as well as experimental DNA synthesis data. Model analyses showed that activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways was sufficient and necessary for triggering DNA synthesis. In addition, we identified key species in these pathways that mediate DNA replication. Our model predicted oncogenic mutations that were compared with the COSMIC database, and proposed intervention targets to block hepatocyte growth factor-induced DNA synthesis, which we validated experimentally. Our integrative approach demonstrates that, despite the complexity and size of the underlying interlaced network, logical modeling enables an integrative understanding of signaling-controlled proliferation at the cellular level, and thus can provide intervention strategies for distinct perturbation scenarios at various regulatory levels. PMID:22443451

  14. Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways.

    PubMed

    Lin, Jiumao; Chen, Youqin; Wei, Lihui; Shen, Aling; Sferra, Thomas J; Hong, Zhenfeng; Peng, Jun

    2013-10-01

    The development of colorectal cancer (CRC) is strongly correlated with the aberrant activation of multiple intracellular signaling transduction cascades including STAT3, ERK, JNK and p38 pathways which usually function redundantly. In addition, crosstalk between these pathways forms a complicated signaling network that is regulated by compensatory mechanisms. Therefore, most of the currently used and single-target-based antitumor agents might not always be therapeutically effective. Moreover, long-term use of these agents often generates drug resistance. These problems highlight the urgent need for the development of novel anticancer chemotherapies. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used for the clinical treatment of CRC. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its tumoricidal activity are not well understood. In the present study, using CRC mouse xenograft model and the HT-29 human colon carcinoma cell line, we evaluated the efficacy of UA against tumor growth in vivo and in vitro and investigated the underlying molecular mechanisms. We found that UA inhibits cancer growth without apparent toxicity. Furthermore, UA significantly suppresses the activation of several CRC-related signaling pathways and alters the expression of critical target genes. These molecular effects lead to the induction of apoptosis and inhibition of cellular proliferation. These data demonstrate that UA possesses a broad range of anticancer activities due to its ability to affect multiple intracellular targets, suggesting that UA could be a novel multipotent therapeutic agent for cancer treatment.

  15. 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.

  16. Multiple roles of the prostaglandin D2 signaling pathway in reproduction.

    PubMed

    Rossitto, Moïra; Ujjan, Safdar; Poulat, Francis; Boizet-Bonhoure, Brigitte

    2015-01-01

    Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are catalyzed by two cyclooxygenases and prostaglandin synthases. In particular, the prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2 α) have been shown to be involved in female reproductive mechanisms. Furthermore, widespread expression of lipocalin- and hematopoietic-PGD2 synthases in the male reproductive tract supports the purported roles of PGD2 in the development of both embryonic and adult testes, sperm maturation, and spermatogenesis. In this review, we summarize the putative roles of PGD2 signaling and the roles of both PGD2 synthases in testicular formation and function. We review the data reporting the involvement of PGD2 signaling in the differentiation of Sertoli and germ cells of the embryonic testis. Furthermore, we discuss the roles of lipocalin-PGD2 synthase in steroidogenesis and spermatogenesis, in terms of lipid molecule transport and PGD2 production. Finally, we discuss the hypothesis that PGD2 signaling may be affected in certain reproductive diseases, such as infertility, cryptorchidism, and testicular cancer.

  17. Multiple-scale neuroendocrine signals connect brain and pituitary hormone rhythms

    PubMed Central

    Romanò, Nicola; Guillou, Anne; Martin, Agnès O; Mollard, Patrice

    2017-01-01

    Small assemblies of hypothalamic “parvocellular” neurons release their neuroendocrine signals at the median eminence (ME) to control long-lasting pituitary hormone rhythms essential for homeostasis. How such rapid hypothalamic neurotransmission leads to slowly evolving hormonal signals remains unknown. Here, we show that the temporal organization of dopamine (DA) release events in freely behaving animals relies on a set of characteristic features that are adapted to the dynamic dopaminergic control of pituitary prolactin secretion, a key reproductive hormone. First, locally generated DA release signals are organized over more than four orders of magnitude (0.001 Hz–10 Hz). Second, these DA events are finely tuned within and between frequency domains as building blocks that recur over days to weeks. Third, an integration time window is detected across the ME and consists of high-frequency DA discharges that are coordinated within the minutes range. Thus, a hierarchical combination of time-scaled neuroendocrine signals displays local–global integration to connect brain–pituitary rhythms and pace hormone secretion. PMID:28193889

  18. Low antioxidant concentrations impact on multiple signalling pathways in Arabidopsis thaliana partly through NPR1

    PubMed Central

    Brosché, Mikael; Kangasjärvi, Jaakko

    2012-01-01

    Production of reactive oxygen species (ROS) is linked to signalling in both developmental and stress responses. The level of ROS is controlled by both production and removal through various scavengers including ascorbic acid and glutathione. Here, the role of low ascorbic acid or glutathione concentrations was investigated on ozone-induced cell death, defence signalling, and developmental responses. Low ascorbic acid concentrations in vtc1 activated expression of salicylic acid (SA)-regulated genes, a response found to be dependent on the redox-regulated transcriptional co-regulator NPR1. In contrast, low glutathione concentrations in cad2 or pad2 reduced expression of SA-regulated genes. Testing different responses to jasmonic acid (JA) revealed the presence of at least two separate JA signalling pathways. Treatment of the vtc1 mutant with JA led to hyper-induction of MONODEHYDROASCORBATE REDUCTASE3, indicating that low ascorbic acid concentrations prime the response to JA. Furthermore, NPR1 was found to be a positive regulator of JA-induced expression of MDHAR3 and TAT3. The vtc1 and npr1 mutants were sensitive to glucose inhibition of seed germination; an opposite response was found in cad2 and pad2. Overall, low ascorbic acid concentrations mostly led to opposite phenotypes to low glutathione concentrations, and both antioxidants interacted with SA and JA signalling pathways. PMID:22213815

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

    PubMed

    Henry, J Q; Martindale, M Q

    2001-10-01

    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.

  20. Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy

    PubMed Central

    Žiberna, Lovro; Šamec, Dunja; Mocan, Andrei; Nabavi, Seyed Fazel; Bishayee, Anupam; Farooqi, Ammad Ahmad; Sureda, Antoni; Nabavi, Seyed Mohammad

    2017-01-01

    Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5′ adenosine monophosphate-activated protein kinase, extracellular signal–regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical. PMID:28300756

  1. 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

  2. The HAMP signal relay domain adopts multiple conformational states through collective piston and tilt motions.

    PubMed

    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.

  3. 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

  4. Multiplicity

    DTIC Science & Technology

    1991-04-01

    practice as a "[descent] into that inner circle of the Inferno where the damned endlessly degate multiplicity for sentencing." United States v. Barnard...select the charges to be brought in a particular case"). 19 Brown v. Ohio, 432 U.S. 161, 165 (1977). 20 Whalen v. United States, 445 U.S. at 689. 21...parte Lange, 8-5 U.S. (19 Wall.) 163 (1874). Cf. Brown v. Ohio, 432 U.S. at 165 ("once the legislature has acted courts may not impose more than one

  5. Determination of the acid dissociation constant of bromocresol green and cresol red in water/AOT/isooctane reverse micelles by multiple linear regression and extended principal component analysis.

    PubMed

    Caselli, Maurizio; Mangone, Annarosa; Paolillo, Paola; Traini, Angela

    2002-01-01

    The pKa of 3',3",5',5"tetrabromo-m-cresolsulfonephtalein (Bromocresol Green) and o-cresolsulphonephtalein (Cresol Red) was spectrophotometrically measured in a water/AOT/isooctane microemulsion in the presence of a series of buffers carrying different charges at different water/surfactant ratios. Extended Principal Component Analysis was used for a precise determination of the apparent pKa and of the spectra of the acid and base forms of the dye. The apparent pKa of dyes in water-in-oil microemulsions depends on the charge of the acid and base forms of the buffers present in the water pool. Combination with multiple linear regression increases the precision. Results are discussed taking into account the profile of the electrostatic potential in the water pool and the possible partition of the indicator between the aqueous core and the surfactant. The pKa corrected for these effects are independent of w0 and are close to the value of the pKa in bulk water. On the basis of a tentative hypothesis it is possible to calculate the true pKa of the buffer in the pool.

  6. Power-Aware Asynchronous Peer-to-Peer Duplex Communication System Based on Multiple-Valued One-Phase Signaling

    NASA Astrophysics Data System (ADS)

    Mizusawa, Kazuyasu; Onizawa, Naoya; Hanyu, Takahiro

    This paper presents a design of an asynchronous peer-to-peer half-duplex/full-duplex-selectable data-transfer system on-chip interconnected. The data-transfer method between channels is based on a 1-phase signaling scheme realized by using multiple-valued current-mode (MVCM) circuits and encoding, which performs high-speed communication. A data transmission is selectable by adding a mode-detection circuit that observes data-transmission modes; full-duplex, half duplex and standby modes. Especially, since current sources are completely cut off during the standby mode, the power dissipation can be greatly reduced. Moreover, both half-duplex and full-duplex communication can be realized by sharing a common circuit except a signal-level conversion circuit. The proposed interface is implemented using 0.18-μm CMOS, and its performance improvement is discussed in comparison with those of the other ordinary asynchronous methods.

  7. An ecological method for the sampling of nonverbal signalling behaviours of young children with profound and multiple learning disabilities (PMLD).

    PubMed

    Atkin, Keith; Lorch, Marjorie Perlman

    2016-08-01

    Profound and multiple learning disabilities (PMLD) are a complex range of disabilities that affect the general health and well-being of the individual and their capacity to interact and learn. We developed a new methodology to capture the non-symbolic signalling behaviours of children with PMLD within the context of a face-to-face interaction with a caregiver to provide analysis at a micro-level of descriptive detail incorporating the use of the ELAN digital video software. The signalling behaviours of participants in a natural, everyday interaction can be better understood with the use of this innovation in methodology, which is predicated on the ecology of communication. Recognition of the developmental ability of the participants is an integral factor within that ecology. The method presented establishes an advanced account of the modalities through which a child affected by PMLD is able to communicate.

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

    PubMed

    Fu, Rong; Chen, Yan; 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

    2016-02-02

    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.

  9. 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

  10. A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway.

    PubMed

    Salašová, Alena; Yokota, Chika; Potěšil, David; Zdráhal, Zbyněk; Bryja, Vítězslav; Arenas, Ernest

    2017-07-11

    /PCP signaling pathway through its interaction to multiple WNT/PCP components. We suggest that LRRK2 regulates the balance between WNT/β-catenin and WNT/PCP signaling, depending on the binding partners. Since this balance is crucial for homeostasis of midbrain dopaminergic neurons, we hypothesize that its alteration may contribute to the pathophysiology of Parkinson's disease.

  11. Miniature stereo radio transmitter for simultaneous recording of multiple single-neuron signals from behaving owls.

    PubMed

    Nieder, A

    2000-09-15

    Wireless radiotelemetric transmission of neuronal activity is an elegant technique to study brain-behavior interaction in unrestrained animals. In the current study, a miniature FM-stereo radio transmitter is described that permitted simultaneous recordings from two microelectrodes in behaving barn owls. Input from two independent channels is multiplexed to form a stereo composite signal that modulates a radio frequency carrier. The high quality of broadcasted extracellular signals enabled separation of single units based on differences in spike waveforms. Recording several single cells from different electrodes allows the possibility of investigating correlations between small, distributed neuronal ensembles. Multi-channel radiotelemetry that meets the demands of modern electrophysiology might open a new perspective for combined behavioral/neurophysiological approaches in freely-behaving animals.

  12. 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

  13. Cyclophilin A as a downstream effector of PI3K/Akt signalling pathway in multiple myeloma cells.

    PubMed

    Lin, Zuo-Lin; Wu, Hsin-Jou; Chen, Jin-An; Lin, Kuo-Chih; Hsu, Jung-Hsin

    2015-12-01

    Cyclophilin A (Cyp A), a member of the peptidyl-prolyl isomerase (PPI) family, may function as a molecular signalling switch. Comparative proteomic studies have identified Cyp A as a potential downstream target of protein kinase B (Akt). This study confirmed that Cyp A is a downstream effector of the phosphatidylinositide 3-kinase (PI3K)/Akt signalling pathway. Cyp A was highly phosphorylated in response to interleukin-6 treatment, which was consistent with the accumulation of phosphorylated Akt, suggesting that Cyp A is a phosphorylation target of Akt and downstream effector of the PI3K/Akt pathway. Cyclosporine A (CsA), a PPI inhibitor, inhibited the growth of multiple myeloma (MM) U266 cells. Moreover, CsA treatment inhibited the activation of the signal transducer and activator of transcription 3 (STAT3) in MM U266 cells. Several Cyp A mutants were generated. Mutants with mutated AKT phosphorylation sites increased the G1 phase arrest in MM U266 cells. The other mutants that mimicked the phosphorylated state of Cyp A decreased the percentage of G1 phase. These results demonstrated that the states of phosphorylation of Cyp A by Akt can influence the progress of the cell cycle in MM U266 cells and that this effect is probably mediated through the Janus-activated kinase 2/STAT3 signalling pathway.

  14. 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.

  15. 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.

  16. Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human β-Cells

    PubMed Central

    Kleinberger, Jeffrey W.; Takane, Karen K.; Salim, Fatimah; Fiaschi-Taesch, Nathalie; Pappas, Kyrie; Parsons, Ramon; Jiang, Jing; Zhang, Yue; Liu, Hongtao; Wang, Peng; Bender, Aaron S.; Frank, Stuart J.

    2015-01-01

    Pregnancy in rodents is associated with a two- to threefold increase in β-cell mass, which is attributable to large increases in β-cell proliferation, complimented by increases in β-cell size, survival, and function and mediated mainly by the lactogenic hormones prolactin (PRL) and placental lactogens. In humans, however, β-cell mass does not increase as dramatically during pregnancy, and PRL fails to activate proliferation in human islets in vitro. To determine why, we explored the human PRL–prolactin receptor (hPRLR)–Janus kinase 2 (JAK2)–signal transducer and activator of transcription 5 (STAT5)–cyclin–cdk signaling cascade in human β-cells. Surprisingly, adult human β-cells express little or no PRLR. As expected, restoration of the hPRLR in human β-cells rescued JAK2-STAT5 signaling in response to PRL. However, rescuing hPRLR-STAT5 signaling nevertheless failed to confer proliferative ability on adult human β-cells in response to PRL. Surprisingly, mouse (but not human) Stat5a overexpression led to upregulation of cyclins D1–3 and cdk4, as well as their nuclear translocation, all of which are associated with β-cell cycle entry. Collectively, the findings show that human β-cells fail to proliferate in response to PRL for multiple reasons, one of which is a paucity of functional PRL receptors, and that murine Stat5 overexpression is able to bypass these impediments. PMID:26159175

  17. Multiple signalling modalities mediated by dendritic exocytosis of oxytocin and vasopressin.

    PubMed

    Ludwig, Mike; Stern, Javier

    2015-07-05

    The mammalian hypothalamic magnocellular neurons of the supraoptic and paraventricular nuclei are among the best understood of all peptidergic neurons. Through their anatomical features, vasopressin- and oxytocin-containing neurons have revealed many important aspects of dendritic functions. Here, we review our understanding of the mechanisms of somato-dendritic peptide release, and the effects of autocrine, paracrine and hormone-like signalling on neuronal networks and behaviour.

  18. Potent activation of multiple signalling pathways by C-peptide in opossum kidney proximal tubular cells.

    PubMed

    Al-Rasheed, N M; Meakin, F; Royal, E L; Lewington, A J; Brown, J; Willars, G B; Brunskill, N J

    2004-06-01

    Proinsulin C-peptide is generally believed to be inert without any appreciable biological functions. However, it has been shown to modulate a variety of cellular processes important in the pathophysiology of diabetic complications. We therefore investigated the ability of C-peptide to stimulate intracellular signalling pathways in kidney proximal tubular cells, the altered activation of which may possibly be related to the development of diabetic nephropathy. Extracellular signal-regulated kinase (ERK) and Akt phosphorylation were evaluated by western blotting. ERK activity was measured by in vitro kinase assay. Intracellular Ca(2+) was evaluated by confocal imaging. The membrane and cytosol-associated fractions of protein kinase C (PKC) isoforms were evaluated by western blotting. Proliferation was assessed by thymidine incorporation assay. Using the opossum proximal tubular kidney cell line as a model, we demonstrated that at high picomolar to low nanomolar concentrations, C-peptide stimulates extracellular signal-regulated mitogen-activated kinase (3.3+/-0.1-fold over basal at 3 minutes) and phosphatidylinositol 3-kinase (4.1+/-0.05-fold over basal at 5 minutes). ERK activation was attenuated by pre-treatment with a PKC inhibitor and abolished by pertussis toxin. Elevations of intracellular [Ca(2+)] are seen in response to 5 nmol/l C-peptide with consequent activation of PKC-alpha. Pre-treatment with pertussis toxin abolished PKC-alpha. C-peptide is also a functional mitogen in this cell type, stimulating significantly increased cell proliferation. Proliferation was attenuated by wortmannin and pertussis toxin pre-treatments. None of these effects is reproduced by scrambled C-peptide. This study provides evidence that C-peptide, within physiological concentration ranges, stimulates many signalling pathways in opossum kidney cells.

  19. Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3.

    PubMed

    Lin, Liang; Yan, Fan; Zhao, Dandan; Lv, Meng; Liang, Xiaodong; Dai, Hui; Qin, Xiaodan; Zhang, Yan; Hao, Jie; Sun, Xiuyuan; Yin, Yanhui; Huang, Xiaojun; Zhang, Jun; Lu, Jin; Ge, Qing

    2016-03-01

    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.

  20. Multiple Mobile mRNA Signals Regulate Tuber Development in Potato.

    PubMed

    Hannapel, David J; Banerjee, Anjan K

    2017-02-10

    Included among the many signals that traffic through the sieve element system are full-length mRNAs that function to respond to the environment and to regulate development. In potato, several mRNAs that encode transcription factors from the three-amino-loop-extension (TALE) superfamily move from leaves to roots and stolons via the phloem to control growth and signal the onset of tuber formation. This RNA transport is enhanced by short-day conditions and is facilitated by RNA-binding proteins from the polypyrimidine tract-binding family of proteins. Regulation of growth is mediated by three mobile mRNAs that arise from vasculature in the leaf. One mRNA, StBEL5, functions to activate growth, whereas two other, sequence-related StBEL's, StBEL11 and StBEL29, function antagonistically to repress StBEL5 target genes involved in promoting tuber development. This dynamic system utilizes closely-linked phloem-mobile mRNAs to control growth in developing potato tubers. In creating a complex signaling pathway, potato has evolved a long-distance transport system that regulates underground organ development through closely-associated, full-length mRNAs that function as either activators or repressors.

  1. A smart flow measurement system for flow evaluation with multiple signals in different operation modes

    NASA Astrophysics Data System (ADS)

    Kaltsas, G.; Katsikogiannis, P.; Asimakopoulos, P.; Nassiopoulou, A. G.

    2007-11-01

    This paper presents the development and evaluation of a smart flow measurement system based on an integrated thermal flow sensor that implements a heater and two pairs of thermopiles, symmetrically situated on both sides of the heater. A specially designed interface circuit monitors and controls sensor operation, allowing three different operational modes: constant voltage (CV), constant power (CP) and constant temperature (CT). It also simultaneously monitors the heater resistance and the thermopile signal. Communication with a PC is implemented through a USB connection, and a developed Java program controls the system and data representation and storage. Transfer rates in the order of 20 000 sps are achieved, which allow detailed flow monitoring. For system evaluation, flow measurements were performed in both the calorimetric and hot-wire principles with the three different modes of operation and the corresponding results are presented comparatively. Flow velocity was determined by different sensor signals (heater resistance and power, thermopile signal) and the related sensitivities were extracted. Furthermore, it was verified that the system could detect the flow direction as well as the transition point from laminar to turbulent region.

  2. 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

  3. Multiple Mobile mRNA Signals Regulate Tuber Development in Potato

    PubMed Central

    Hannapel, David J.; Banerjee, Anjan K.

    2017-01-01

    Included among the many signals that traffic through the sieve element system are full-length mRNAs that function to respond to the environment and to regulate development. In potato, several mRNAs that encode transcription factors from the three-amino-loop-extension (TALE) superfamily move from leaves to roots and stolons via the phloem to control growth and signal the onset of tuber formation. This RNA transport is enhanced by short-day conditions and is facilitated by RNA-binding proteins from the polypyrimidine tract-binding family of proteins. Regulation of growth is mediated by three mobile mRNAs that arise from vasculature in the leaf. One mRNA, StBEL5, functions to activate growth, whereas two other, sequence-related StBEL’s, StBEL11 and StBEL29, function antagonistically to repress StBEL5 target genes involved in promoting tuber development. This dynamic system utilizes closely-linked phloem-mobile mRNAs to control growth in developing potato tubers. In creating a complex signaling pathway, potato has evolved a long-distance transport system that regulates underground organ development through closely-associated, full-length mRNAs that function as either activators or repressors. PMID:28208608