Complex Temporal Response Research Articles

Proteomic analysis of plasma at the preterminal stage of rhesus nonhuman primates exposed to a lethal total-body dose of gamma-radiation

The identification and validation of radiation biomarkers is critical for assessing the radiation dose received in exposed individuals and for developing radiation medical countermeasures that can be used to treat acute radiation syndrome (ARS). Additionally, a fundamental understanding of the effects of radiation injury could further aid in the identification and development of therapeutic targets for mitigating radiation damage. In this study, blood samples were collected from fourteen male nonhuman primates (NHPs) that were exposed to 7.2 Gy ionizing radiation at various time points (seven days prior to irradiation; 1, 13, and 25 days post-irradiation; and immediately prior to the euthanasia of moribund (preterminal) animals). Plasma was isolated from these samples and was analyzed using a liquid chromatography tandem mass spectrometry approach in an effort to determine the effects of radiation on plasma proteomic profiles. The primary objective was to determine if the radiation-induced expression of specific proteins could serve as an early predictor for health decline leading to a preterminal phenotype. Our results suggest that radiation induced a complex temporal response in which some features exhibit upregulation while others trend downward. These statistically significantly altered features varied from pre-irradiation levels by as much as tenfold. Specifically, we found the expression of integrin alpha and thrombospondin correlated in peripheral blood with the preterminal stage. The differential expression of these proteins implicates dysregulation of biological processes such as hemostasis, inflammation, and immune response that could be leveraged for mitigating radiation-induced adverse effects.

Projecting Antarctica's contribution to future sea level rise from basal ice shelf melt using linear response functions of 16 ice sheet models (LARMIP-2)

Abstract. The sea level contribution of the Antarctic ice sheet constitutes a large uncertainty in future sea level projections. Here we apply a linear response theory approach to 16 state-of-the-art ice sheet models to estimate the Antarctic ice sheet contribution from basal ice shelf melting within the 21st century. The purpose of this computation is to estimate the uncertainty of Antarctica's future contribution to global sea level rise that arises from large uncertainty in the oceanic forcing and the associated ice shelf melting. Ice shelf melting is considered to be a major if not the largest perturbation of the ice sheet's flow into the ocean. However, by computing only the sea level contribution in response to ice shelf melting, our study is neglecting a number of processes such as surface-mass-balance-related contributions. In assuming linear response theory, we are able to capture complex temporal responses of the ice sheets, but we neglect any self-dampening or self-amplifying processes. This is particularly relevant in situations in which an instability is dominating the ice loss. The results obtained here are thus relevant, in particular wherever the ice loss is dominated by the forcing as opposed to an internal instability, for example in strong ocean warming scenarios. In order to allow for comparison the methodology was chosen to be exactly the same as in an earlier study (Levermann et al., 2014) but with 16 instead of 5 ice sheet models. We include uncertainty in the atmospheric warming response to carbon emissions (full range of CMIP5 climate model sensitivities), uncertainty in the oceanic transport to the Southern Ocean (obtained from the time-delayed and scaled oceanic subsurface warming in CMIP5 models in relation to the global mean surface warming), and the observed range of responses of basal ice shelf melting to oceanic warming outside the ice shelf cavity. This uncertainty in basal ice shelf melting is then convoluted with the linear response functions of each of the 16 ice sheet models to obtain the ice flow response to the individual global warming path. The model median for the observational period from 1992 to 2017 of the ice loss due to basal ice shelf melting is 10.2 mm, with a likely range between 5.2 and 21.3 mm. For the same period the Antarctic ice sheet lost mass equivalent to 7.4 mm of global sea level rise, with a standard deviation of 3.7 mm (Shepherd et al., 2018) including all processes, especially surface-mass-balance changes. For the unabated warming path, Representative Concentration Pathway 8.5 (RCP8.5), we obtain a median contribution of the Antarctic ice sheet to global mean sea level rise from basal ice shelf melting within the 21st century of 17 cm, with a likely range (66th percentile around the mean) between 9 and 36 cm and a very likely range (90th percentile around the mean) between 6 and 58 cm. For the RCP2.6 warming path, which will keep the global mean temperature below 2 ∘C of global warming and is thus consistent with the Paris Climate Agreement, the procedure yields a median of 13 cm of global mean sea level contribution. The likely range for the RCP2.6 scenario is between 7 and 24 cm, and the very likely range is between 4 and 37 cm. The structural uncertainties in the method do not allow for an interpretation of any higher uncertainty percentiles. We provide projections for the five Antarctic regions and for each model and each scenario separately. The rate of sea level contribution is highest under the RCP8.5 scenario. The maximum within the 21st century of the median value is 4 cm per decade, with a likely range between 2 and 9 cm per decade and a very likely range between 1 and 14 cm per decade.

Unraveling the metabolic response of Brassica oleracea exposed to Xanthomonas campestris pv. campestris.

Brassica crops together with cereals represent the basis of world supplies. Due to their importance, the production losses caused by Xanthomonas campestris pv. campestris (Xcc) infection represent a high economic impact. Understanding molecular and biochemical mechanisms of plants is essential to develop resistant crops with durable protection against diseases. In this regard, metabolomics has emerged as a valuable technology to provide an overview of the biological status of a plant exposed to a disease. This study investigated the dynamic changes in the metabolic profile of Brassica oleracea plants during an Xcc infection from leaves collected at five different days post infection using a mass spectrometry approach. Results showed that Xcc infection causes dynamic changes in the metabolome of B. oleracea. Moreover, induction/repression pattern of the metabolites implicated in the response follows a complex dynamics during infection progression, indicating a complex temporal response. Specific metabolic pathways such as alkaloids, coumarins or sphingolipids are postulated as promising key role candidates in the infection response. This work tries to decipher the changes produced on Brassica crops metabolome under Xcc infection and represents a step forward in the understanding of B. oleracea-Xcc interaction. © 2018 Society of Chemical Industry.

Correlation-based iterative clustering methods for time course data: The identification of temporal gene response modules for influenza infection in humans

Many pragmatic clustering methods have been developed to group data vectors or objects into clusters so that the objects in one cluster are very similar and objects in different clusters are distinct based on some similarity measure. The availability of time course data has motivated researchers to develop methods, such as mixture and mixed-effects modelling approaches, that incorporate the temporal information contained in the shape of the trajectory of the data. However, there is still a need for the development of time-course clustering methods that can adequately deal with inhomogeneous clusters (some clusters are quite large and others are quite small). Here we propose two such methods, hierarchical clustering (IHC) and iterative pairwise-correlation clustering (IPC). We evaluate and compare the proposed methods to the Markov Cluster Algorithm (MCL) and the generalised mixed-effects model (GMM) using simulation studies and an application to a time course gene expression data set from a study containing human subjects who were challenged by a live influenza virus. We identify four types of temporal gene response modules to influenza infection in humans, i.e., single-gene modules (SGM), small-size modules (SSM), medium-size modules (MSM) and large-size modules (LSM). The LSM contain genes that perform various fundamental biological functions that are consistent across subjects. The SSM and SGM contain genes that perform either different or similar biological functions that have complex temporal responses to the virus and are unique to each subject. We show that the temporal response of the genes in the LSM have either simple patterns with a single peak or trough a consequence of the transient stimuli sustained or state-transitioning patterns pertaining to developmental cues and that these modules can differentiate the severity of disease outcomes. Additionally, the size of gene response modules follows a power-law distribution with a consistent exponent across all subjects, which reveals the presence of universality in the underlying biological principles that generated these modules.

Time-Resolved Investigations of the Cooling Dynamics of Metal Nanoparticles: Impact of Environment

Tunable two-color ultrafast pump–probe experiments are performed on colloidal metal nanospheres in water and ethanol, and the results are interpreted through a model including thermal dynamics in both the nanoparticle and its environment. Transient optical signals measured for gold nanoparticles in ethanol display a complex temporal response strongly dependent on the wavelength of the probe beam. We demonstrate that its origin is related to a large contribution of liquid environment transient heating to the optical response, in contrast to the usual assumption that optical transmission changes reflect the evolution of nanoparticle temperature only. Accounting for this contribution enables an accurate measurement of thermal conductances at gold–ethanol and gold–water interfaces. Moreover, the thermal dynamics of the solvent can be selectively probed through a specific choice of probe wavelength.

Ethanol Regulation of Serum Glucocorticoid Kinase 1 Expression in DBA2/J Mouse Prefrontal Cortex

BackgroundWe previously identified a group of glucocorticoid-responsive genes, including Serum Glucocorticoid kinase 1 (Sgk1), regulated by acute ethanol in prefrontal cortex of DBA2/J mice. Acute ethanol activates the hypothalamic pituitary adrenal axis (HPA) causing release of glucocorticoids. Chronic ethanol dysregulates the HPA response in both humans and rodents, possibly contributing to important interactions between stress and alcoholism. Because Sgk1 regulates ion channels and learning and memory, we hypothesized that Sgk1 contributes to HPA-dependent acute and adaptive neuronal responses to ethanol. These studies characterized acute and chronic ethanol regulation of Sgk1 mRNA and protein and their relationship with ethanol actions on the HPA axis.ResultsAcute ethanol increased Sgk1 mRNA expression in a dose and time dependent manner. Three separate results suggested that ethanol regulated Sgk1 via circulating glucocorticoids: acute ethanol increased glucocorticoid receptor binding to the Sgk1 promoter; adrenalectomy blocked ethanol induction of Sgk1 mRNA; and chronic ethanol exposure during locomotor sensitization down-regulated HPA axis activation and Sgk1 induction by acute ethanol. SGK1 protein had complex temporal responses to acute ethanol with rapid and transient increases in Ser422 phosphorylation at 15 min. following ethanol administration. This activating phosphorylation had functional consequences, as suggested by increased phosphorylation of the known SGK1 target, N-myc downstream-regulated gene 1 (NDRG1). After repeated ethanol administration during locomotor sensitization, basal SGK1 protein phosphorylation increased despite blunting of Sgk1 mRNA induction by ethanol.ConclusionsThese results suggest that HPA axis and glucocorticoid receptor signaling mediate acute ethanol induction of Sgk1 transcription in mouse prefrontal cortex. However, acute ethanol also causes complex changes in SGK1 protein expression and activity. Chronic ethanol modifies both SGK1 protein and HPA-mediated induction of Sgk1 mRNA. These adaptive molecular responses of glucocorticoid-responsive gene expression and SGK1 in prefrontal cortex may contribute to mechanisms underlying behavioral responses to chronic ethanol exposure.

Full Waveform Analysis for Long-Range 3D Imaging Laser Radar

The new generation of 3D imaging systems based on laser radar (ladar) offers significant advantages in defense and security applications. In particular, it is possible to retrieve 3D shape information directly from the scene and separate a target from background or foreground clutter by extracting a narrow depth range from the field of view by range gating, either in the sensor or by postprocessing. We discuss and demonstrate the applicability of full-waveform ladar to produce multilayer 3D imagery, in which each pixel produces a complex temporal response that describes the scene structure. Such complexity caused bymultiple and distributed reflection arises inmany relevant scenarios, for example in viewing partially occluded targets, through semitransparent materials (e.g., windows) and through distributed reflective media such as foliage. We demonstrate our methodology on 3D image data acquired by a scanning time-of-flight system, developed in our own laboratories, which uses the time-correlated single-photon counting technique.

Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca 2+ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

Although angiotensin II (Ang II) plays an important role in heart disease associated with pump dysfunction, its direct effects on cardiac pump function remain controversial. We found that after Ang II infusion, the developed pressure and +dP/dt(max) in isolated Langendorff-perfused mouse hearts showed a complex temporal response, with a rapid transient decrease followed by an increase above baseline. Similar time-dependent changes in cell shortening and L-type Ca(2+) currents were observed in isolated ventricular myocytes. Previous studies have established that Ang II signaling involves phosphoinositide 3-kinases (PI3K). Dominant-negative inhibition of PI3Kalpha in the myocardium selectively eliminated the rapid negative inotropic action of Ang II (inhibited by approximately 90%), whereas the loss of PI3Kgamma had no effect on the response to Ang II. Consistent with a link between PI3Kalpha and protein kinase C (PKC), PKC inhibition (with GF 109203X) reduced the negative inotropic effects of Ang II by approximately 50%. Although PI3Kalpha and PKC activities are associated with glycogen synthase kinase-3beta and NADPH oxidase, genetic ablation of either glycogen synthase kinase-3beta or p47(phox) (an essential subunit of NOX2-NADPH oxidase) had no effect on the inotropic actions of Ang II. Our results establish that Ang II has complex temporal effects on contractility and L-type Ca(2+) channels in normal mouse myocardium, with the negative inotropic effects requiring PI3Kalpha and PKC activities.

Evaluation of the irising effect of a slow-gating intensified charge-coupled device on laser-induced incandescence measurements of soot

Intensified charge-coupled devices (ICCDs) are used extensively in many scientific and engineering environments to image weak or temporally short optical events. To optimize the quantum efficiency of light collection, many of these devices are chosen to have characteristic intensifier gate times that are relatively slow, on the order of tens of nanoseconds. For many measurements associated with nanosecond laser sources, such as scattering-based diagnostics and most laser-induced fluorescence applications, the signals rise and decay sufficiently fast during and after the laser pulse that the intensifier gate may be set to close after the cessation of the signal and still effectively reject interferences associated with longer time scales. However, the relatively long time scale and complex temporal response of laser-induced incandescence (LII) of nanometer-sized particles (such as soot) offer a difficult challenge to the use of slow-gating ICCDs for quantitative measurements. In this paper, ultraviolet Rayleigh scattering imaging is used to quantify the irising effect of a slow-gating scientific ICCD camera, and an analysis is conducted of LII image data collected with this camera as a function of intensifier gate width. The results demonstrate that relatively prompt LII detection, generally desirable to minimize the influences of particle size and local gas pressure and temperature on measurements of the soot volume fraction, is strongly influenced by the irising effect of slow-gating ICCDs.

Real-time complex temporal response measurements of ultrahigh-speed optical modulators

We demonstrate a technique for direct, real-time characterization of the complex (amplitude and phase) temporal response of ultrahigh-speed (GHz-bandwidth) optical modulators. The demonstrated technique is based on pulse interferometry combined with time-frequency mapping processes using fiber linear dispersion. A new mechanism is incorporated to overcome the temporal resolution (bandwidth) limitation of the detectable modulation response in our previously reported setup. This mechanism, referred to as 'common-path temporal image magnification', lowers the required detection bandwidth by a factor of more than 10, enabling real-time single-shot waveform acquisition without loss of information using a conventional temporal digitizer. The design specifications of the proposed measurement setup are derived and discussed in detail. As a proof-of-concept experiment, real-time characterization of a complex electro-op c modulation temporal response with time features as fast as approximately 35 ps (modulation bandwidth > 40-GHz) was obtained and displayed at a video rate of 30 frames/sec.

SPATIAL AND TEMPORAL ASPECTS OF cAMP SIGNALLING IN CARDIAC MYOCYTES

1. beta(1)-Adrenoceptor and M(2) muscarinic receptor regulation of cAMP production plays a pivotal role in autonomic regulation of cardiac myocyte function. However, not all responses are easily explained by a uniform increase or decrease in cAMP activity throughout the entire cell. 2. Adenovirus expression of fluorescence resonance energy transfer (FRET)-based biosensors can be used to monitor cAMP activity in protein kinase A (PKA) signalling domains, as well as the bulk cytoplasmic domain of intact adult cardiac myocytes. 3. Data obtained using FRET-based biosensors expressed in different cellular microdomains have been used to develop a computational model of compartmentalized cAMP signalling. 4. A systems biology approach that uses quantitative computational modelling together with experimental data obtained using FRET-based biosensors has been used to provide evidence for the idea that compartmentation of cAMP signalling is necessary to explain the stimulatory responses to beta(1)-adrenoceptor activation as well as the complex temporal responses to M(2) muscarinic receptor activation.

Direct time-response measurement of high-speed optical modulators based on stretched-pulse interferometry

A simple technique for the direct measurement of the complex temporal response of a high-speed electro-optic (EO) modulator is proposed. This technique recovers the amplitude and phase temporal profiles of an instantaneous modulation over the duration of a chirped pulse (obtained by linear dispersion) using Fourier-transform interferometry, and it exploits the time-to-frequency mapping induced by the pulse dispersion process. The method can be implemented by using either time- or frequency-domain interferometric detection, allowing the characterization of modulation bandwidths in the tens-of-gigahertz range. The concept is demonstrated by accurately measuring the complex temporal response of a 2.5 Gbps intensity EO modulator.

Temporal Representations of Odors in an Olfactory Network

The responses of projection neurons in the antennal lobe of the locust brain (the functional analog of mitral-tufted cells in the vertebrate olfactory bulb) to natural blends and simple odors were studied with multiple intra- and extracellular recordings in vivo. Individual odors evoked complex temporal response patterns in many neurons. These patterns differed across odors for a given neuron and across neurons for a given odor, but were stable for each neuron over repeated presentations (separated by seconds to minutes) of the same odor. The response of individual neurons to an odor was superimposed on an odor-specific coherent oscillatory population activity. Each neuron usually participated in the coherent oscillations during one or more specific epochs of the ensemble activity. These epochs of phase locking were reliable for each neuron over tens of repeated presentations of one odor. The timing of these epochs of synchronization differed across neurons and odors. Correlated activity of specific pairs of neurons, hence, generally occurred transiently during the population response, at times that were specific to these pairs and to the odor smelled. The field potential oscillations, therefore, fail to reveal a progressive transformation of the synchronized ensemble as the response to the odor unfolds. We propose that (1) odors are represented by spatially and temporally distributed ensembles of coherently firing neurons, and (2) the field potential oscillations that characterize odor responses in the olfactory system occur, at least in this animal, in parallel with a slower dynamic odor representation.

Response pattern complexity of auditory cells in the cortex of unanesthetized monkeys

Complex temporal response patterns of neurons in auditory cortex were studied in unanesthetized, alert monkeys under controlled behavioral conditions. Responses to various frequencies and intensities of pure tones and various intensities of white noise stimuli were studied. Approximately 48% of the cells studied exhibited multiple, temporally discrete response components. In about one-third of these cells the temporally discrete components varied independently of one another in their response to changes in stimulus parameters. These observations bear on questions of the structural and functional organization of the auditory system and neural coding.