Temporal Perturbations Research Articles

Comparative NMR-Based Metabonomic Investigation of the Metabolic Phenotype Associated with Tienilic Acid and Tienilic Acid Isomer

An NMR-based metabonomic approach was applied to study the systems level metabolic effects of two closely related thiophene compounds, tienilic acid (TA) and tienilic acid isomer (TAI). The metabonomic data were anchored with traditional clinical chemistry and histopathologic analyses. TA was removed from the market as a result of suspected immune-mediated hepatotoxicity, whereas TAI is an intrinsic hepatotoxin. Equimolar doses of TA and TAI were administered to Sprague-Dawley rats, and sampling was conducted at 2, 6, and 24 h post-treatment. Histopathologic analyses revealed development of a significant hepatic lesion 24 h post-TAI treatment with a parallel increase in plasma alanine aminotransferase (ALT) activity. In contrast, TA was not associated with the development of a hepatic lesion or an increase in plasma ALT activity. High-resolution NMR spectral metabolic profiles were generated for liver extracts, plasma, and urine at multiple time points. Multivariate statistical tools were applied to model the metabolic profiles and identify discriminatory metabolites that reflected both the adaptation to TA administration and the onset and progression of TAI-induced hepatotoxicity. TAI was shown to induce marked metabolic effects on the metabolome at all time points, with dramatic metabolic perturbations at 24 h post-treatment correlating with the histopathologic and clinical chemistry evidence of a hepatic lesion. The TAI-induced metabolic perturbations provided evidence for the generation of electrophilic reactive metabolites and a significant impairment of bioenergetic metabolic pathways. TA induced early metabolic perturbations that were largely resolved by 24 h post-treatment, suggesting the reestablishment of metabolic homeostasis and the ability to adapt to the intervention, with hepatic hypotaurine potentially representing a means of assessment of hepatic adaptation. This comparative metabonomic approach enabled the discrimination of metabolic perturbations that were common to both treatments and were interpreted as nontoxic thiophene-induced perturbations. Importantly, this approach enabled the identification of temporal metabolic perturbations that were unique to TAI or TA treatment and hence were of relevance to the development of toxicity or the ability to adapt. This approach is applicable to the future study of pharmacologically and structurally similar compounds and represents a refined means of identification of biomarkers of toxicity.

Error Modeling of Seebeck Coefficient Measurements Using Finite-Element Analysis

Using finite-element analysis, we have developed a metrology simulation to model errors in the measurement of the Seebeck coefficient. This physical parameter is the constant of proportionality relating the electric potential generated across a conductor to the applied thermal gradient. Its measurement requires careful attention to the electrical and thermal contact interfaces. Furthermore, it is essential that the electric potential and temperature difference be acquired at the same time and at the same location. We have performed Seebeck coefficient measurement simulations to quantitatively explore the effect of temporal perturbation to the voltage and temperature correspondence, by comparing simultaneous and staggered data acquisition techniques under the quasi-steady-state condition. Using a similar method, we have developed an error model to explore the effect of misalignment between the voltage and temperature probes on the measurement of the Seebeck coefficient. This approach enables the exploration of experimentally inaccessible data spaces under ideal conditions.

Complementary spatial interactions between binocular rivalry and stimulus rivalry

[1] Pearson, J., & Clifford, C. W. G. (2005). When your brain decides what you see: grouping across monocular, binocular, and stimulus rivalry. Psychological science, 16(7), 516–519. [2] Andrews, T. J., & Purves, D. (1997). Similarities in normal and binocularly rivalrous viewing. Proceedings of the National Academy of Sciences of the United States of America, 94(18), 9905–9908. [3] Blake, R., Westendorf, D., & Fox, R. (1990). Temporal perturbations of binocular rivalry. Perception and Psychophysics, 48(6), 593–602. [4] Mueller, T. J., & Blake, R. (1989). A fresh look at the temporal dynamics of binocular rivalry. Biological cybernetics, 61(3), 223–232. [5] Denison, R. N., & Silver, M. A. (2011). Distinct Contributions of the Magnocellular and Parvocellular Visual Streams to Perceptual Selection. Journal of Cognitive Neuroscience. doi:10.1162/jocn_a_00121 ¶ Supported by WCU program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R32-10142) and by NIH EY13358 References & Acknowledgement

Analysis of quantum coherence in bismuth-doped silicon: A system of strongly coupled spin qubits

There is growing interest in bismuth-doped silicon (Si:Bi) as an alternative to the well-studied proposals for silicon based quantum information processing (QIP) using phosphorus-doped silicon (Si:P). We focus here on the implications of its anomalously strong hyperfine coupling. In particular, we analyse in detail the regime where recent pulsed magnetic resonance experiments have demonstrated the potential for orders of magnitude speedup in quantum gates by exploiting transitions that are electron paramagnetic resonance (EPR) forbidden at high fields. We also present calculations using a phenomenological Markovian master equation which models the decoherence of the electron spin due to Gaussian temporal magnetic field perturbations. The model quantifies the advantages of certain "optimal working points" identified as the $df/dB=0$ regions, where $f$ is the transition frequency, which come in the form of frequency minima and maxima. We show that at such regions, dephasing due to the interaction of the electron spin with a fluctuating magnetic field in the $z$ direction (usually adiabatic) is completely removed.

Dynamic regulatory on/off minimization for biological systems under internal temporal perturbations

BackgroundFlux balance analysis (FBA) together with its extension, dynamic FBA, have proven instrumental for analyzing the robustness and dynamics of metabolic networks by employing only the stoichiometry of the included reactions coupled with adequately chosen objective function. In addition, under the assumption of minimization of metabolic adjustment, dynamic FBA has recently been employed to analyze the transition between metabolic states.ResultsHere, we propose a suite of novel methods for analyzing the dynamics of (internally perturbed) metabolic networks and for quantifying their robustness with limited knowledge of kinetic parameters. Following the biochemically meaningful premise that metabolite concentrations exhibit smooth temporal changes, the proposed methods rely on minimizing the significant fluctuations of metabolic profiles to predict the time-resolved metabolic state, characterized by both fluxes and concentrations. By conducting a comparative analysis with a kinetic model of the Calvin-Benson cycle and a model of plant carbohydrate metabolism, we demonstrate that the principle of regulatory on/off minimization coupled with dynamic FBA can accurately predict the changes in metabolic states.ConclusionsOur methods outperform the existing dynamic FBA-based modeling alternatives, and could help in revealing the mechanisms for maintaining robustness of dynamic processes in metabolic networks over time.

Detecting perturbations in polyrhythms: effects of complexity and attentional strategies

Jones et al. in Journal of Experimental Psychology Human Perception and Performance 21:293-307, 1995, showed that a temporal perturbation is easier to detect in a 3:2 polyrhythm than in a single-stream isochronous baseline condition if the two isochronous pulse streams forming the polyrhythm are perceptually integrated: integration creates shorter inter-onset interval (IOI) durations that facilitate perturbation detection. The present study examined whether this benefit of integration outweighs the potential costs imposed by the greater IOI heterogeneity and memory demands of more complex polyrhythms. In "Experiment 1", musically trained participants tried to detect perturbations in 3:5, 4:5, 6:5, and 7:5 polyrhythms having one of two different pitch separations between pulse streams, as well as in an isochronous baseline condition. "Experiment 2" included an additional 2:5 polyrhythm, additional pitch separations, and instructions to integrate or segregate the two pulse streams. In both experiments, perturbation detection scores for polyrhythms were below baseline, decreased as polyrhythm complexity increased, and tended to be lower at a smaller pitch separation, with little effect of instructions. Clearly, polyrhythm complexity was the main determinant of detection performance, which is attributed to the interval heterogeneity and/or memory demands of the pattern formed by the integrated pulse streams. In this task, perceptual integration was disadvantageous, but apparently could not be avoided.

Electroosmotic flows with simultaneous spatio-temporal modulations in zeta potential: cases of thick electrical double layers beyond the Debye Hückel limit

We devise a mathematical model for analyzing the effects of spatio-temporal perturbations in zeta potential on electroosmotic transport in narrow fluidic confinements, considering thick electrical double layer limits. The spatial perturbations in zeta potential may be attributed to surface charge patterning, either designed or manifested as a natural artifact of the surface inhomogeneities. The time-dependent variations in zeta potential, as considered in this work, may stem from the temporal perturbations in the bulk ionic concentrations in the end-channel reservoirs or ‘wells’. Overcoming the simplifications routinely employed in the literature, we develop here an improved analytical formalism, without imposing any constraints on the magnitude of the zeta potential. Using these solutions, we highlight the possibilities of obtaining designed rotationalities in the flow structure with simultaneous spatial variations in the zeta potential and temporal variations in the well concentrations. We show that such combinations of spatial and temporal variations, in effect, render the flow system to be capable of shedding vortex structures that are not otherwise obtainable with spatial variations in zeta potential alone.

Time series gene expression profiling and temporal regulatory pathway analysis of BMP6 induced osteoblast differentiation and mineralization

BackgroundBMP6 mediated osteoblast differentiation plays a key role in skeletal development and bone disease. Unfortunately, the signaling pathways regulated by BMP6 are largely uncharacterized due to both a lack of data and the complexity of the response.ResultsTo better characterize the signaling pathways responsive to BMP6, we conducted a time series microarray study to track BMP6 induced osteoblast differentiation and mineralization. These temporal data were analyzed using a customized gene set analysis approach to identify temporally coherent sets of genes that act downstream of BMP6. Our analysis identified BMP6 regulation of previously reported pathways, such as the TGF-beta pathway. We also identified previously unknown connections between BMP6 and pathways such as Notch signaling and the MYB and BAF57 regulatory modules. In addition, we identify a super-network of pathways that are sequentially activated following BMP6 induction.ConclusionIn this work, we carried out a microarray-based temporal regulatory pathway analysis of BMP6 induced osteoblast differentiation and mineralization using GAGE method. This novel temporal analysis is more informative and powerful than the classical static pathway analysis in that: (1) it captures the interconnections between signaling pathways or functional modules and demonstrates the even higher level organization of molecular biological systems; (2) it describes the temporal perturbation patterns of each pathway or module and their dynamic roles in osteoblast differentiation. The same set of experimental and computational strategies employed in our work could be useful for studying other complex biological processes.

Characterization of atypical vocal source excitation, temporal dynamics and prosody for objective measurement of dysarthric word intelligibility

Objective measurement of dysarthric speech intelligibility can assist clinicians in the diagnosis of speech disorder severity as well as in the evaluation of dysarthria treatments. In this paper, several objective measures are proposed and tested as correlates of subjective intelligibility. More specifically, the kurtosis of the linear prediction residual is proposed as a measure of vocal source excitation oddity. Additionally, temporal perturbations resultant from imprecise articulation and atypical speech rates are characterized by short- and long-term temporal dynamics measures, which in turn, are based on log-energy dynamics and on an auditory-inspired modulation spectral signal representation, respectively. Motivated by recent insights in the communication disorders literature, a composite measure is developed based on linearly combining a salient subset of the proposed measures with conventional prosodic parameters. Experiments with the publicly-available ‘Universal Access’ database of spastic dysarthric speech (10 patient speakers; 300 words spoken in isolation, per speaker) show that the proposed composite measure can achieve correlation with subjective intelligibility ratings as high as 0.97; thus the measure can serve as an accurate indicator of dysarthric speech intelligibility.

Global stability of swept flow around a parabolic body: features of the global spectrum

The global temporal stability of three-dimensional compressible flow about a yawed parabolic body of infinite span is investigated using an iterative eigenvalue technique in combination with direct numerical simulations. The computed global spectrum provides a comprehensive picture of the temporal perturbation dynamics of the flow, and a wide and rich variety of modes has been uncovered for the investigated parameter choices: stable and unstable boundary-layer modes, different types of stable and unstable acoustic modes, and stable wavepacket modes have been found. A parameter study varying the spanwise perturbation wavenumber and the sweep Reynolds number reproduced a preferred spanwise length scale and a critical Reynolds number for a boundary-layer or acoustic instability. Convex leading-edge curvature has been found to have a strongly stabilizing effect on boundary-layer modes but only a weakly stabilizing effect on acoustic modes. Furthermore, for certain parameter choices, the acoustic modes have been found to dominate the boundary-layer modes.

Design of an Optimal Wing-Body Configuration to Delay Onset of Vortex Asymmetry

O NE important phenomenon associated with high-angle-ofattack aerodynamics is the sudden onset of vortex asymmetry on the forebody of an air vehicle in symmetric flight. One of the first observations of the onset of vortex asymmetry was reported in 1951 by Allen and Perkins [1]. Interest in the phenomenon has been intensified since the late 1970s as concepts for highly maneuverable aircraft have been developed. These high-performance aircraft are expected to operate routinely at angles of attack at which vortex asymmetry is likely to occur. When vortex asymmetry occurs, the aerodynamic, stability, and control characteristics of the vehicle change dramatically. In themeantime, the conventional aerodynamic controls become ineffective due to the vortex wakes generated by the forebody. The subject was reviewed by Hunt [2], Ericsson and Reding [3], and Champigny [4]. High-angle-of-attack flow control is most effective when applied in the region close to the tip of the forebody. The presence of two closely spaced vortices around the pointed forebody at high angles of attack enhances the effectiveness. Compared with that on wings, control on the forebody is required over a much smaller area; thus, physical requirements such as size and weight should be much smaller. The lengthy forebody of a modern fighter further enhances the control effectiveness by providing a long moment arm. Excellent reviews of this activity can be found in papers by Malcolm [5,6] and Williams [7]. Recently, Liu et al. [8] successfully demonstrated linear proportional control of the side forces over a slender circular cone using duty-cycled single-dielectric-barrier-discharge plasma actuators. One of the devices to suppress the flow asymmetry are the horizontal nose strakes. Coe et al. [9] showed, by wind-tunnel tests, the alleviating effects of horizontal and symmetrical strakes placed close to the apex of a slender ogive forebody and a slender circular cone. It is observed that the effect of the strakes is to produce a welldefined point of separation at the leading edges of the strakes, which results in a symmetrical flowfield over a wide range of high angles of attack. Two sharp side edges on an otherwise smooth body can also serve to define the point of separation. Siclari [10] used a Navier– Stokes solver to study the natural occurrence of separated flows over biparabolic and biwedge cones at a freestream Mach number of 1.8 and an angle of attack of 20 . As the thickness ratiowas increased, the originally symmetric vortex pair separated from the sharp side edges, becoming asymmetric at thickness ratios of 0.5 and 0.6 for the biparabolic and biwedge cones, respectively. Cai et al. developed a stability analysis method [11] and used it to study high angle-of-attack flow about slender conical wing and wing–body combinations [12,13]. The analytic method is based on an eigenvalue analysis on the motion of the vortices under small temporal perturbations. The theoretical results agree well with available experimental observations and are corroborated by numerical computations [14]. The aim of the present paper is to manipulate the aerodynamic configuration for the purpose of keeping the stationary symmetric vortex pair stable at high angles of attack. In the following sections, the analyticmethod in [11] is summarized and a numerical conformal mapping technique is described. A series of configurations are analyzed for the stability of the symmetric vortex pair. A most effective configuration of thewing–body combination is obtained by the analytic method and validated by an Euler solver. In the last section, conclusions are drawn.

Carrier Dynamics in Tunneling Injection Quantum Dot Lasers

We describe a detailed model for carrier dynamics in tunneling injection quantum dot lasers. The model includes the spatial dependence of the mobile carriers and the coupling between mobile carriers and confined carriers. The Poisson and Schrodinger equations are solved together, which enables consideration of band structure modification due to an electron-hole interaction. The model is solved both in steady state and for temporal perturbations. Steady-state carrier distributions and the band structure are presented, as well as large and small signal modulation responses.

A generalized model for metabolomic analyses: application to dose and time dependent toxicity

As metabolomic technology expands, validated techniques for analyzing highly dimensional categorical data are becoming increasingly important. This manuscript presents a novel latent vector-based methodology for analyzing complex data sets with multiple groups that include both high and low doses using orthogonal projections to latent structures (OPLS) coupled with hierarchical clustering. This general methodology allows complex experimental designs (e.g., multiple dose and time combinations) to be encoded and directly compared. Further, it allows for the inclusion of low dose samples that do not exhibit a strong enough individual response to be modeled independently. A dose- and time-responsive metabolomic study was completed to evaluate and demonstrate this methodology. Single doses (0.1–100 mg/kg body weight) of α-naphthylisothiocyanate (ANIT), a common model of hepatic cholestasis, were administered orally in corn oil to male Fischer 344 rats. Urine samples were collected pre-dose and daily through day-4 post-dose. Blood samples were collected pre and post-dose to assess indices of clinical toxicity. Urine samples were analyzed by 1H-NMR spectroscopy, and the spectra were adaptively binned to reduce dimensionality. The proposed methodology for NMR-based urinary metabolomics was sensitive enough to detect ANIT-induced effects with respect to both dose and time at doses below the threshold of clinical toxicity. A pattern of ANIT-dependent effects established at the highest dose was seen in the 50 and 20 mg/kg dose groups, an effect not directly identifiable with individual principal component analysis (PCA). Coupling the pattern found by the OPLS algorithm and hierarchical clustering revealed a relationship between the 100, 50 and 20 mg/kg dose groups, suggesting a characteristic effect of ANIT exposure. These studies demonstrate that the use of a metabolomics approach with flexible binning of 1H spectra and appropriate application of multivariate analyses can reveal biologically relevant information about the temporal metabolic perturbations caused by exposure and toxicity.

A Role for the Geomagnetic Field in Cell Regulation

We advance the hypothesis that biological systems utilize the geomagnetic field (GMF) for functional purposes by means of ion cyclotron resonance-like (ICR) mechanisms. Numerous ICR-designed experiments have demonstrated that living things are sensitive, in varying degrees, to magnetic fields that are equivalent to both changes in the general magnetostatic intensity of the GMF, as well as its temporal perturbations. We propose the existence of ICR-like cell regulation processes, homologous to the way that biochemical messengers alter the net biological state through competing processes of enhancement and inhibition. In like manner, combinations of different resonance frequencies all coupled to the same local magnetic field provide a unique means for cell regulation. Recent work on ultraweak ICR magnetic fields by Zhadin and others fits into our proposed framework if one assumes that cellular systems generate time-varying electric fields of the order 100 mV/cm with bandwidths that include relevant ICR frequencies.

Analytical description of gain depletion and recovery in quantum dot optical amplifiers

We present an analytical description of ultrashort femtosecond pump–probe experiments and investigate the gain response of quantum dot (QD) semiconductor optical amplifiers. The calculation provides a full analytical solution of numerical studies to recent experiments in such structures (Gomis-Bresco et al 2008 Phys. Rev. Lett.101 256803). Our approach is based on QD Bloch equations, which are analytically evaluated within the third-order temporal perturbation theory (χ(3) level). In particular, we study the influence of the coherence and the population dynamics of two confined QD levels on the gain as a function of the delay time between the pump and the probe pulse. We discuss how to engineer optimal conditions for high-performance QD amplifiers, which are characterized by an ultrafast gain recovery and a pronounced gain depletion.

Temporal Proteome and Lipidome Profiles Reveal Hepatitis C Virus-Associated Reprogramming of Hepatocellular Metabolism and Bioenergetics

Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV) infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins) predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis.

The Development of Period Correction Processes in Motor Coordination: Adaptation to Temporal Perturbation

The third in a series of studies investigating the development of multilimb coordination in children, this study investigates the ability to period correct, or resynchronize limbs after a temporal perturbation. Participants performed single (clap, walk) and dual (simultaneously clap and walk) motor tasks to a metronome, which was randomly perturbed (either increase or decrease in speed). In the walk/metronome coupling, a significant interaction existed in relative phase error between age group and cycle with less relative phase error on the third and forth cycle with increased age. In the clap/metronome, a main effect existed for cycle (increasing with cycle) and age (decreasing with age), but no interactions existed. Neither task (single or dual) nor direction of perturbation (speed increase/decrease) had a statistical effect. The results suggested that developmental trajectories may exist in period correction processes; further research examining continuous data over longer collection periods should be performed to confirm this finding.

Temporal patterns and oscillatory voltage perturbation during an electrochemical process

The response of electrodissolution dynamics of nickel in sulfuric acid electrolyte was studied and categorized using efficient signal processing techniques. Time-frequency and phase analysis revealed complex dynamical patterns in anodic currents observed in the system. These patterns which respond to three-dimensional changes in the electrolyte and surface conditions, have a multitude of spatio-temporal properties which proved sensitive to oscillatory voltage perturbations, allowing signal recognition through distinct response patterns. Experimental work included studies on identification of control parameters, characterization of subsequent temporal patterns and examination of system response to information in the form of oscillatory voltage perturbations. Various data processing and pattern recognition techniques revealed the complexity and dynamics of these distinctive responses, which illustrate the capacity of the system to store information, with varying memory lengths. These patterns can be recalled upon excitation with particular perturbation cues.

Modeling Interacting Galaxies: NGC 4449 revisited

Observing nearby interacting galaxies is a key to understanding galactic physics provided that we know the spatial and temporal perturbations acting on these galaxies. Thus, we have to know the orbits and the gross internal properties of the galaxies. In order to cope with the related extended parameter space, we developed the code MINGA which combines a genetic algorithm with a fast N-body method. As an example for this method, we present a re-analysis of the prototypical system NGC 4449 which is now based on both, the full HI data cube of the NGC 4449 system and on improved determinations of the galactic orbits within a restricted N-body calculation.

Temporal perturbation of neural activity in Drosophila larvae undergoing locomotion

Temporal perturbation of neural activity in Drosophila larvae undergoing locomotion