Co-Signaling by Neurotrophic Factors and the Extracellular Matrix for Axonal Growth and Neuronal Survival

Neurotrophic factors (NTFs) and the extracellular matrix (ECM) are important regulators of axonal growth and neuronal survival in mammalian nervous system. Understanding of the mechanisms of this regulation is crucial for the development of posttraumatic therapies and drug intervention in the injured nervous system. NTFs act as soluble, target-derived extracellular regulatory molecules for a wide range of physiological functions including axonal guidance and the regulation of programmed cell death in the nervous system. The ECM determines cell adhesion and regulates multiple physiological functions via short range cell-matrix interactions. The present work focuses on the mechanisms of the action of NTFs and the ECM on axonal growth and survival of cultured sensory neurons from dorsal root ganglia (DRG). We first examined signaling mechanisms of the action of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) on axonal growth. GDNF, neurturin (NRTN) and artemin (ART) but not persephin (PSPN) promoted axonal initiation in cultured DRG neurons from young adult mice. This effect required Src family kinase (SFK) activity. In neurons from GFRalpha2-deficient mice, NRTN did not significantly promote axonal initiation. GDNF and NRTN induced extensive lamellipodia formation on neuronal somata and growth cones. This study suggested that GDNF, NRTN and ARTN may serve as stimulators of nerve regeneration under posttraumatic conditions. Consequently we studied the convergence of signaling pathways induced by NTFs and the ECM molecule laminin in the intracellular signaling network that regulates axonal growth. We demonstrated that co-stimulation of DRG neurons with NTFs (GDNF, NRTN or nerve growth factor (NGF)) and laminin leads to axonal growth that requires activation of SFKs. A different, SFK-independent signaling pathway evoked axonal growth on laminin in the absence of the NTFs. In contrast, axonal branching was regulated by SFKs both in the presence and in the absence of NGF. We proposed and experimentally verified a Boolean model of the signaling network triggered by NTFs and laminin. Our results put forward an approach for predictable, Boolean logics-driven pharmacological manipulation of a complex signaling network. Finally we found that N-syndecan, the receptor for the ECM component HB-GAM was required for the survival of neonatal sensory neurons in vitro. We demonstrated massive cell death of cultured DRG neurons from mice deficient in the N-syndecan gene as compared to wild type controls. Importantly, this cell death could not be prevented by NGF the neurotrophin which activates multiple anti-apoptotic cascades in DRG neurons. The survival deficit was observed during first postnatal week. By contrast, DRG neurons from young adult N-syndecan knock-out mice exhibited normal survival. This study identifies a completely new syndecan-dependent type of signaling that regulates cell death in neurons.

ANC schemes for the enhancement of EEG signals in the presence of EOG artifacts

One of the most important applications of adaptive systems is in noise cancellation using adaptive filters. Ln this paper, we propose adaptive noise cancellation schemes for the enhancement of EEG signals in the presence of EOG artifacts. The effect of two reference inputs is studied on simulated as well as recorded EEG signals and it is found that one reference input is enough to get sufficient minimization of EOG artifacts. This has been verified through correlation analysis also. We use signal to noise ratio and linear prediction spectra, along with time plots, for comparing the performance of the proposed schemes for minimizing EOG artifacts from contaminated EEG signals. Results show that the proposed schemes are very effective (especially the one which employs Newton's method) in minimizing the EOG artifacts from contaminated EEG signals.

Death pathways activated in the neurotrophic factor-deprived neurons

Programed cell death (PCD) is a fundamental biological process that is as essential for the development and tissue homeostasis as cell proliferation, differentiation and adaptation. The main mode of PCD - apoptosis - occurs via specifi c pathways, such as mitochondrial or death receptor pathway. In the developing nervous system, programed death broadly occurs, mainly triggered by the defi ciency of different survival-promoting neurotrophic factors, but the respective death pathways are poorly studied. In one of the best-characterized models, sympathetic neurons deprived of nerve growth factor (NGF) die via the classical mitochondrial apoptotic pathway. The main aim of this study was to describe the death programs activated in these and other neuronal populations by using neuronal cultures deprived of other neurotrophic factors. First, this study showed that the cultured sympathetic neurons deprived of glial cell line-derived neurotrophic factor (GDNF) die via a novel non-classical death pathway, in which mitochondria and death receptors are not involved. Indeed, cytochrome c was not released into the cytosol, Bax, caspase-9, and caspase-3 were not involved, and Bcl-xL overexpression did not prevent the death. This pathway involved activation of mixed lineage kinases and c-jun, and crucially requires caspase-2 and -7. Second, it was shown that deprivation of neurotrophin-3 (NT-3) from cultured sensory neurons of the dorsal root ganglia kills them via a dependence receptor pathway, including cleavage of the NT- 3 receptor TrkC and liberation of a pro-apoptotic dependence domain. Indeed, death of NT-3-deprived neurons was blocked by a dominant-negative construct interfering with TrkC cleavage. Also, the uncleavable mutant of TrkC, replacing the siRNA-silenced endogeneous TrkC, was not able to trigger death upon NT-3 removal. Such a pathway was not activated in another subpopulation of sensory neurons deprived of NGF. Third, it was shown that cultured midbrain dopaminergic neurons deprived of GDNF or brainderived neurotrophic factor (BDNF) kills them by still a different pathway, in which death receptors and caspases, but not mitochondria, are activated. Indeed, cytochrome c was not released into the cytosol, Bax was not activated, and Bcl-xL did not block the death, but caspases were necessary for the death of these neurons. Blocking the components of the death receptor pathway - caspase-8, FADD, or Fas - blocked the death, whereas activation of Fas accelerated it. The activity of Fas in the dopaminergic neurons could be controlled by the apoptosis inhibitory molecule FAIML. For these studies we developed a novel assay to study apoptosis in the transfected dopaminergic neurons. Thus, a novel death pathway, characteristic for the dopaminergic neurons was described. The study suggests death receptors as possible targets for the treatment of Parkinson s disease, which is caused by the degeneration of dopaminergic neurons.

Real-time kinematic positioning over long baselines using triple-frequency BeiDou signals

The BeiDou system is the first global navigation satellite system in which all satellites transmit triple-frequency signals that can provide the positioning, navigation, and timing independently. A benefit of triple-frequency signals is that more useful combinations can be formed, including some extrawide-lane combinations whose ambiguities can generally be instantaneously fixed without distance restriction, although the narrow-lane ambiguity resolution (NL AR) still depends on the interreceiver distance or requires a long time to achieve. In this paper, we synthetically study decimeter and centimeter kinematic positioning using BeiDou triple-frequency signals. It starts with AR of two extrawide-lane signals based on the ionosphere-free or ionosphere-reduced geometry-free model. For decimeter positioning, one can immediately use two ambiguity-fixed extrawide-lane observations without pursuing NL AR. To achieve higher accuracy, NL AR is the necessary next step. Despite the fact that long-baseline NL AR is still challenging, some NL ambiguities can indeed be fixed with high reliability. Partial AR for NL signals is acceptable, because as long as some ambiguities for NL signals are fixed, positioning accuracy will be certainly improved.With accumulation of observations, more and more NL ambiguities are fixed and the positioning accuracy continues to improve. An efficient Kalman-filtering system is established to implement the whole process. The formulated system is flexible, since the additional constraints can be easily applied to enhance the model's strength. Numerical results from a set of real triple-frequency BeiDou data on a 50 km baseline show that decimeter positioning is achievable instantaneously.With only five data epochs, 84% of NL ambiguities can be fixed so that the real-time kinematic accuracies are 4.5, 2.5, and 16 cm for north, east, and height components (respectively), while with 10 data epochs more than 90% of NL ambiguities are fixed, and the rea- -time kinematic solutions are improved to centimeter level for all three coordinate components.

Assessment of code bias variations of BDS triple-frequency signals and their impacts on ambiguity resolution for long baselines

Carrier phase ambiguity resolution over long baselines is challenging in BDS data processing. This is partially due to the variations of the hardware biases in BDS code signals and its dependence on elevation angles. We present an assessment of satellite-induced code bias variations in BDS triple-frequency signals and the ambiguity resolutions procedures involving both geometry-free and geometry-based models. First, since the elevation of a GEO satellite remains unchanged, we propose to model the single-differenced fractional cycle bias with widespread ground stations. Second, the effects of code bias variations induced by GEO, IGSO and MEO satellites on ambiguity resolution of extra-wide-lane, wide-lane and narrow-lane combinations are analyzed. Third, together with the IGSO and MEO code bias variations models, the effects of code bias variations on ambiguity resolution are examined using 30-day data collected over the baselines ranging from 500 to 2600 km in 2014. The results suggest that although the effect of code bias variations on the extra-wide-lane integer solution is almost ignorable due to its long wavelength, the wide-lane integer solutions are rather sensitive to the code bias variations. Wide-lane ambiguity resolution success rates are evidently improved when code bias variations are corrected. However, the improvement of narrow-lane ambiguity resolution is not obvious since it is based on geometry-based model and there is only an indirect impact on the narrow-lane ambiguity solutions.

Geometry-free stochastic analysis of BDS triple frequency signals

The paper presents a geometry-free approach to assess the variation of covariance matrices of undifferenced triple frequency GNSS measurements and its impact on positioning solutions. Four independent geometryfree/ ionosphere-free (GFIF) models formed from original triple-frequency code and phase signals allow for effective computation of variance-covariance matrices using real data. Variance Component Estimation (VCE) algorithms are implemented to obtain the covariance matrices for three pseudorange and three carrier-phase signals epoch-by-epoch. Covariance results from the triple frequency Beidou System (BDS) and GPS data sets demonstrate that the estimated standard deviation varies in consistence with the amplitude of actual GFIF error time series. The single point positioning (SPP) results from BDS ionosphere-free measurements at four MGEX stations demonstrate an improvement of up to about 50% in Up direction relative to the results based on a mean square statistics. Additionally, a more extensive SPP analysis at 95 global MGEX stations based on GPS ionosphere-free measurements shows an average improvement of about 10% relative to the traditional results. This finding provides a preliminary confirmation that adequate consideration of the variation of covariance leads to the improvement of GNSS state solutions.

Wide area kinematic positioning with BeiDou triple frequency signals

A key challenge of wide area kinematic positioning is to overcome the effects of the varying hardware biases in code signals of the BeiDou system. Based on three geometryfree/ionosphere-free combinations, the elevation-dependent code biases are modelled for all BeiDou satellites. Results from the data sets of 30-day for 5 baselines of 533 to 2545 km demonstrate that the wide-lane (WL) integer-fixing success rates of 98% to 100% can be achieved within 25 min. Under the condition of HDOP of less than 2, the overall RMS statistics show that ionospheric-free WL single-epoch solutions achieve 24 to 50 cm in the horizontal direction. Smoothing processing over the moving window of 20 min reduces the RMS values by a factor of about 2. Considering distance-independent nature, the above results show the potential that reliable and high precision positioning services could be provided in a wide area based on a sparsely distributed ground network.

Detection of SFBC-OFDM signals in frequency- and time-selective MIMO channels

Use of space-frequency block coded (SFBC) OFDM signals is advantageous in high-mobility broadband wireless access, where the channel is highly time- as well as frequency-selective because of which the receiver experiences both inter-symbol interference (ISI) as well as inter-carrier interference (10). ISI occurs due to the violation of the 'quasi-static' fading assumption caused due to frequency- and/or time-selectivity of the channel. In addition, ICI occurs due to time-selectivity of the channel which results in loss of orthogonality among the subcarriers. In this paper, we are concerned with the detection of SFBC-OFDM signals on time- and frequency-selective MIMO channels. Specifically, we propose and evaluate the performance of an interference cancelling receiver for SFBC-OFDM which alleviates the effects of ISI and ICI in highly time- and frequency-selective channels.

Detection of multicode STBC signals in frequency selective fading

Multicode operation in space-time block coded (STBC) multiple input multiple output (MIMO) systems can provide additional degrees of freedom in code domain to achieve high data rates. In such multicode STBC systems, the receiver experiences code domain interference (CDI) in frequency selective fading. In this paper, we propose a linear parallel interference cancellation (LPIC) approach to cancel the CDI in multicode STBC in frequency selective fading. The proposed detector first performs LPIC followed by STBC decoding. We evaluate the bit error performance of the detector and show that it effectively cancels the CDI and achieves improved error performance. Our results further illustrate how the combined effect of interference cancellation, transmit diversity, and RAKE diversity affect the bit error performance of the system.

Parametric analysis of acoustic emission signals for evaluating damage in composites using a PVDF film sensor

With the increased utilization of advanced composites in strategic industries, the concept of Structural Health Monitoring (SHM) with its inherent advantages is gaining ground over the conventional methods of NDE and NDI. The most attractive feature of this concept is on-line evaluation using embedded sensors. Consequently, development of methodologies with identification of appropriate sensors such as PVDF films becomes the key for exploiting the new concept. And, of the methods used for on-line evaluation acoustic emission has been most effective. Thus, Acoustic Emission (AE) generated during static tensile loading of glass fiber reinforced plastic composites was monitored using a Polyvinylidene fluoride (PVDF) film sensor. The frequency response of the film sensor was obtained with pencil lead breakage tests to choose the appropriate band of operation. The specimen considered for the experiments were chosen to characterize the differences in the operation of the failure mechanisms through AE parametric analysis. The results of the investigations can be characterized using AE parameter indicating that a PVDF film sensor was effective as an AE sensor used in structural health monitoring on-line.

Phonetic tone signals quantity and word structure

Many languages exploit suprasegmental devices in signaling word meaning. Tone languages exploit fundamental frequency whereas quantity languages rely on segmental durations to distinguish otherwise similar words. Traditionally, duration and tone have been taken as mutually exclusive. However, some evidence suggests that, in addition to durational cues, phonological quantity is associated with and co-signaled by changes in fundamental frequency in quantity languages such as Finnish, Estonian, and Serbo-Croat. The results from the present experiment show that the structure of disyllabic word stems in Finnish are indeed signaled tonally and that the phonological length of the stressed syllable is further tonally distinguished within the disyllabic sequence. The results further indicate that the observed association of tone and duration in perception is systematically exploited in speech production in Finnish.

Part I: Enzyme replacement versus neurotrophic factor viral vector-mediated gene therapy of Parkinson’s disease, Part II: The effects of orally dosed tolcapone and entacapone on dopamine metabolism in the dorsal striatum and nucleus accumbens in rats

Part I: Parkinson’s disease is a slowly progressive neurodegenerative disorder in which particularly the dopaminergic neurons of the substantia nigra pars compacta degenerate and die. Current conventional treatment is based on restraining symptoms but it has no effect on the progression of the disease. Gene therapy research has focused on the possibility of restoring the lost brain function by at least two means: substitution of critical enzymes needed for the synthesis of dopamine and slowing down the progression of the disease by supporting the functions of the remaining nigral dopaminergic neurons by neurotrophic factors. The striatal levels of enzymes such as tyrosine hydroxylase, dopadecarboxylase and GTP-CH1 are decreased as the disease progresses. By replacing one or all of the enzymes, dopamine levels in the striatum may be restored to normal and behavioral impairments caused by the disease may be ameliorated especially in the later stages of the disease. The neurotrophic factors glial cell derived neurotrophic factor (GDNF) and neurturin have shown to protect and restore functions of dopaminergic cell somas and terminals as well as improve behavior in animal lesion models. This therapy may be best suited at the early stages of the disease when there are more dopaminergic neurons for neurotrophic factors to reach. Viral vector-mediated gene transfer provides a tool to deliver proteins with complex structures into specific brain locations and provides long-term protein over-expression. Part II: The aim of our study was to investigate the effects of two orally dosed COMT inhibitors entacapone (10 and 30 mg/kg) and tolcapone (10 and 30 mg/kg) with a subsequent administration of a peripheral dopadecarboxylase inhibitor carbidopa (30 mg/kg) and L- dopa (30 mg/kg) on dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens of freely moving rats using dual-probe in vivo microdialysis. Earlier similarly designed studies have only been conducted in the dorsal striatum. We also confirmed the result of earlier ex vivo studies regarding the effects of intraperitoneally dosed tolcapone (30 mg/kg) and entacapone (30 mg/kg) on striatal and hepatic COMT activity. The results obtained from the dorsal striatum were generally in line with earlier studies, where tolcapone tended to increase dopamine and DOPAC levels and decrease HVA levels. Entacapone tended to keep striatal dopamine and HVA levels elevated longer than in controls and also tended to elevate the levels of DOPAC. Surprisingly in the nucleus accumbens, dopamine levels after either dose of entacapone or tolcapone were not elevated. Accumbal DOPAC levels, especially in the tolcapone 30 mg/kg group, were elevated nearly to the same extent as measured in the dorsal striatum. Entacapone 10 mg/kg elevated accumbal HVA levels more than the dose of 30 mg/kg and the effect was more pronounced in the nucleus accumbens than in the dorsal striatum. This suggests that entacapone 30 mg/kg has minor central effects. Also our ex vivo study results obtained from the dorsal striatum suggest that entacapone 30 mg/kg has minor and transient central effects, even though central HVA levels were not suppressed below those of the control group in either brain area in the microdialysis study. Both entacapone and tolcapone suppressed hepatic COMT activity more than striatal COMT activity. Tolcapone was more effective than entacapone in the dorsal striatum. The differences between dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens may be due to different properties of the two brain areas.

Denoising signals corrupted by chaotic noise

We consider the problem of signal estimation where the observed time series is modeled as y(i) = x(i) + s(i) with {x(i)} being an orbit of a chaotic self-map on a compact subset of R-d and {s(i)} a sequence in R-d converging to zero. This model is motivated by experimental results in the literature where the ocean ambient noise and the ocean clutter are found to be chaotic. Making use of observations up to time n, we propose an estimate of s(i) for i < n and show that it approaches s(i) as n -> infinity for typical asymptotic behaviors of orbits. (C) 2010 Elsevier B.V. All rights reserved.

Estimation of signals in colored non gaussian noise based on Gaussian Mixture models

Non-Gaussianity of signals/noise often results in significant performance degradation for systems, which are designed using the Gaussian assumption. So non-Gaussian signals/noise require a different modelling and processing approach. In this paper, we discuss a new Bayesian estimation technique for non-Gaussian signals corrupted by colored non Gaussian noise. The method is based on using zero mean finite Gaussian Mixture Models (GMMs) for signal and noise. The estimation is done using an adaptive non-causal nonlinear filtering technique. The method involves deriving an estimator in terms of the GMM parameters, which are in turn estimated using the EM algorithm. The proposed filter is of finite length and offers computational feasibility. The simulations show that the proposed method gives a significant improvement compared to the linear filter for a wide variety of noise conditions, including impulsive noise. We also claim that the estimation of signal using the correlation with past and future samples leads to reduced mean squared error as compared to signal estimation based on past samples only.

Comparative study of filter-bank mean-energy distance for automated segmentation of speech signals

This paper describes a method of automated segmentation of speech assuming the signal is continuously time varying rather than the traditional short time stationary model. It has been shown that this representation gives comparable if not marginally better results than the other techniques for automated segmentation. A formulation of the 'Bach' (music semitonal) frequency scale filter-bank is proposed. A comparative study has been made of the performances using Mel, Bark and Bach scale filter banks considering this model. The preliminary results show up to 80 % matches within 20 ms of the manually segmented data, without any information of the content of the text and without any language dependence. 'Bach' filters are seen to marginally outperform the other filters.