Machines vs. ensembles: effective MAPK signaling through heterogeneous sets of protein complexes.

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Ryan Suderman

Full Text Available Despite the importance of intracellular signaling networks, there is currently no consensus regarding the fundamental nature of the protein complexes such networks employ. One prominent view involves stable signaling machines with well-defined quaternary structures. The combinatorial complexity of signaling networks has led to an opposing perspective, namely that signaling proceeds via heterogeneous pleiomorphic ensembles of transient complexes. Since many hypotheses regarding network function rely on how we conceptualize signaling complexes, resolving this issue is a central problem in systems biology. Unfortunately, direct experimental characterization of these complexes has proven technologically difficult, while combinatorial complexity has prevented traditional modeling methods from approaching this question. Here we employ rule-based modeling, a technique that overcomes these limitations, to construct a model of the yeast pheromone signaling network. We found that this model exhibits significant ensemble character while generating reliable responses that match experimental observations. To contrast the ensemble behavior, we constructed a model that employs hierarchical assembly pathways to produce scaffold-based signaling machines. We found that this machine model could not replicate the experimentally observed combinatorial inhibition that arises when the scaffold is overexpressed. This finding provides evidence against the hierarchical assembly of machines in the pheromone signaling network and suggests that machines and ensembles may serve distinct purposes in vivo. In some cases, e.g. core enzymatic activities like protein synthesis and degradation, machines assembled via hierarchical energy landscapes may provide functional stability for the cell. In other cases, such as signaling, ensembles may represent a form of weak linkage, facilitating variation and plasticity in network evolution. The capacity of ensembles to signal effectively

An Fgf-Shh signaling hierarchy regulates early specification of the zebrafish skull.

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McCarthy, Neil; Sidik, Alfire; Bertrand, Julien Y; Eberhart, Johann K

2016-07-15

The neurocranium generates most of the craniofacial skeleton and consists of prechordal and postchordal regions. Although development of the prechordal is well studied, little is known of the postchordal region. Here we characterize a signaling hierarchy necessary for postchordal neurocranial development involving Fibroblast growth factor (Fgf) signaling for early specification of mesodermally-derived progenitor cells. The expression of hyaluron synthetase 2 (has2) in the cephalic mesoderm requires Fgf signaling and Has2 function, in turn, is required for postchordal neurocranial development. While Hedgehog (Hh)-deficient embryos also lack a postchordal neurocranium, this appears primarily due to a later defect in chondrocyte differentiation. Inhibitor studies demonstrate that postchordal neurocranial development requires early Fgf and later Hh signaling. Collectively, our results provide a mechanistic understanding of early postchordal neurocranial development and demonstrate a hierarchy of signaling between Fgf and Hh in the development of this structure. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Early Warning Signals of Social Transformation: A Case Study from the US Southwest.

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Katherine A Spielmann

Full Text Available Recent research in ecology suggests that generic indicators, referred to as early warning signals (EWS, may occur before significant transformations, both critical and non-critical, in complex systems. Up to this point, research on EWS has largely focused on simple models and controlled experiments in ecology and climate science. When humans are considered in these arenas they are invariably seen as external sources of disturbance or management. In this article we explore ways to include societal components of socio-ecological systems directly in EWS analysis. Given the growing archaeological literature on 'collapses,' or transformations, in social systems, we investigate whether any early warning signals are apparent in the archaeological records of the build-up to two contemporaneous cases of social transformation in the prehistoric US Southwest, Mesa Verde and Zuni. The social transformations in these two cases differ in scope and severity, thus allowing us to explore the contexts under which warning signals may (or may not emerge. In both cases our results show increasing variance in settlement size before the transformation, but increasing variance in social institutions only before the critical transformation in Mesa Verde. In the Zuni case, social institutions appear to have managed the process of significant social change. We conclude that variance is of broad relevance in anticipating social change, and the capacity of social institutions to mitigate transformation is critical to consider in EWS research on socio-ecological systems.

Early Warning Signals of Social Transformation: A Case Study from the US Southwest.

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Spielmann, Katherine A; Peeples, Matthew A; Glowacki, Donna M; Dugmore, Andrew

2016-01-01

Recent research in ecology suggests that generic indicators, referred to as early warning signals (EWS), may occur before significant transformations, both critical and non-critical, in complex systems. Up to this point, research on EWS has largely focused on simple models and controlled experiments in ecology and climate science. When humans are considered in these arenas they are invariably seen as external sources of disturbance or management. In this article we explore ways to include societal components of socio-ecological systems directly in EWS analysis. Given the growing archaeological literature on 'collapses,' or transformations, in social systems, we investigate whether any early warning signals are apparent in the archaeological records of the build-up to two contemporaneous cases of social transformation in the prehistoric US Southwest, Mesa Verde and Zuni. The social transformations in these two cases differ in scope and severity, thus allowing us to explore the contexts under which warning signals may (or may not) emerge. In both cases our results show increasing variance in settlement size before the transformation, but increasing variance in social institutions only before the critical transformation in Mesa Verde. In the Zuni case, social institutions appear to have managed the process of significant social change. We conclude that variance is of broad relevance in anticipating social change, and the capacity of social institutions to mitigate transformation is critical to consider in EWS research on socio-ecological systems.

Complex Foot Injury: Early and Definite Management.

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Schepers, Tim; Rammelt, Stefan

2017-03-01

Complex foot injuries occur infrequently, but are life-changing events. They often present with other injuries as the result of a high-energy trauma. After initial stabilization, early assessment should be regarding salvagability. All treatment strategies are intensive. The initial treatment includes prevention of progression ischemia/necrosis, prevention of infection, and considering salvage or amputation. Definitive treatment for salvage includes anatomic reconstruction with stable internal fixation and early soft tissue coverage followed by aggressive rehabilitation. Prognosis after complex injuries is hard to predict. The various stages of the treatment are reviewed and recommendations are made. Copyright © 2016 Elsevier Inc. All rights reserved.

Ezh2 Controls an Early Hematopoietic Program and Growth and Survival Signaling in Early T Cell Precursor Acute Lymphoblastic Leukemia

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Etienne Danis

2016-03-01

Full Text Available Early T cell precursor acute lymphoblastic leukemia (ETP-ALL is an aggressive subtype of ALL distinguished by stem-cell-associated and myeloid transcriptional programs. Inactivating alterations of Polycomb repressive complex 2 components are frequent in human ETP-ALL, but their functional role is largely undefined. We have studied the involvement of Ezh2 in a murine model of NRASQ61K-driven leukemia that recapitulates phenotypic and transcriptional features of ETP-ALL. Homozygous inactivation of Ezh2 cooperated with oncogenic NRASQ61K to accelerate leukemia onset. Inactivation of Ezh2 accentuated expression of genes highly expressed in human ETP-ALL and in normal murine early thymic progenitors. Moreover, we found that Ezh2 contributes to the silencing of stem-cell- and early-progenitor-cell-associated genes. Loss of Ezh2 also resulted in increased activation of STAT3 by tyrosine 705 phosphorylation. Our data mechanistically link Ezh2 inactivation to stem-cell-associated transcriptional programs and increased growth/survival signaling, features that convey an adverse prognosis in patients.

Hydrogen Exchange Differences between Chemoreceptor Signaling Complexes Localize to Functionally Important Subdomains

Science.gov (United States)

2015-01-01

The goal of understanding mechanisms of transmembrane signaling, one of many key life processes mediated by membrane proteins, has motivated numerous studies of bacterial chemotaxis receptors. Ligand binding to the receptor causes a piston motion of an α helix in the periplasmic and transmembrane domains, but it is unclear how the signal is then propagated through the cytoplasmic domain to control the activity of the associated kinase CheA. Recent proposals suggest that signaling in the cytoplasmic domain involves opposing changes in dynamics in different subdomains. However, it has been difficult to measure dynamics within the functional system, consisting of extended arrays of receptor complexes with two other proteins, CheA and CheW. We have combined hydrogen exchange mass spectrometry with vesicle template assembly of functional complexes of the receptor cytoplasmic domain to reveal that there are significant signaling-associated changes in exchange, and these changes localize to key regions of the receptor involved in the excitation and adaptation responses. The methylation subdomain exhibits complex changes that include slower hydrogen exchange in complexes in a kinase-activating state, which may be partially consistent with proposals that this subdomain is stabilized in this state. The signaling subdomain exhibits significant protection from hydrogen exchange in complexes in a kinase-activating state, suggesting a tighter and/or larger interaction interface with CheA and CheW in this state. These first measurements of the stability of protein subdomains within functional signaling complexes demonstrate the promise of this approach for measuring functionally important protein dynamics within the various physiologically relevant states of multiprotein complexes. PMID:25420045

Synthesis of high-complexity rhythmic signals for closed-loop electrical neuromodulation.

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Zalay, Osbert C; Bardakjian, Berj L

2013-06-01

We propose an approach to synthesizing high-complexity rhythmic signals for closed-loop electrical neuromodulation using cognitive rhythm generator (CRG) networks, wherein the CRG is a hybrid oscillator comprised of (1) a bank of neuronal modes, (2) a ring device (clock), and (3) a static output nonlinearity (mapper). Networks of coupled CRGs have been previously implemented to simulate the electrical activity of biological neural networks, including in silico models of epilepsy, producing outputs of similar waveform and complexity to the biological system. This has enabled CRG network models to be used as platforms for testing seizure control strategies. Presently, we take the application one step further, envisioning therapeutic CRG networks as rhythmic signal generators creating neuromimetic signals for stimulation purposes, motivated by recent research indicating that stimulus complexity and waveform characteristics influence neuromodulation efficacy. To demonstrate this concept, an epileptiform CRG network generating spontaneous seizure-like events (SLEs) was coupled to a therapeutic CRG network, forming a closed-loop neuromodulation system. SLEs are associated with low-complexity dynamics and high phase coherence in the network. The tuned therapeutic network generated a high-complexity, multi-banded rhythmic stimulation signal with prominent theta and gamma-frequency power that suppressed SLEs and increased dynamic complexity in the epileptiform network, as measured by a relative increase in the maximum Lyapunov exponent and decrease in phase coherence. CRG-based neuromodulation outperformed both low and high-frequency periodic pulse stimulation, suggesting that neuromodulation using complex, biomimetic signals may provide an improvement over conventional electrical stimulation techniques for treating neurological disorders such as epilepsy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Body size shifts and early warning signals precede the historic collapse of whale stocks.

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Clements, Christopher F; Blanchard, Julia L; Nash, Kirsty L; Hindell, Mark A; Ozgul, Arpat

2017-06-22

Predicting population declines is a key challenge in the face of global environmental change. Abundance-based early warning signals have been shown to precede population collapses; however, such signals are sensitive to the low reliability of abundance estimates. Here, using historical data on whales harvested during the 20th century, we demonstrate that early warning signals can be present not only in the abundance data, but also in the more reliable body size data of wild populations. We show that during the period of commercial whaling, the mean body size of caught whales declined dramatically (by up to 4 m over a 70-year period), leading to early warning signals being detectable up to 40 years before the global collapse of whale stocks. Combining abundance and body size data can reduce the length of the time series required to predict collapse, and decrease the chances of false positive early warning signals.

Early detection of structual changes in random signal

International Nuclear Information System (INIS)

Kuroda, Yoshiteru; Yokota, Katsuhiro

1981-01-01

Early detection of structual changes in observed random signal is very important from the point of system diagnosis. In this paper, the following procedures are applied to this problem and the results are compared. (1) auto-regressive model to random signal to calculate the prediction error, i.e., the defference between observed and predicted values. (2) auto-regressive method to caluculate the sum of the prediction error. (3) a method is based on AIC (Akaike Information Criterion). Simulation is made of these procedures, indicating their merits and demerits as a diagostic tools. (author)

Complexity of EEG-signal in Time Domain - Possible Biomedical Application

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Klonowski, Wlodzimierz; Olejarczyk, Elzbieta; Stepien, Robert

2002-07-01

Human brain is a highly complex nonlinear system. So it is not surprising that in analysis of EEG-signal, which represents overall activity of the brain, the methods of Nonlinear Dynamics (or Chaos Theory as it is commonly called) can be used. Even if the signal is not chaotic these methods are a motivating tool to explore changes in brain activity due to different functional activation states, e.g. different sleep stages, or to applied therapy, e.g. exposure to chemical agents (drugs) and physical factors (light, magnetic field). The methods supplied by Nonlinear Dynamics reveal signal characteristics that are not revealed by linear methods like FFT. Better understanding of principles that govern dynamics and complexity of EEG-signal can help to find `the signatures' of different physiological and pathological states of human brain, quantitative characteristics that may find applications in medical diagnostics.

A functional TOC complex contributes to gravity signal transduction in Arabidopsis.

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Strohm, Allison K; Barrett-Wilt, Greg A; Masson, Patrick H

2014-01-01

Although plastid sedimentation has long been recognized as important for a plant's perception of gravity, it was recently shown that plastids play an additional function in gravitropism. The Translocon at the Outer envelope membrane of Chloroplasts (TOC) complex transports nuclear-encoded proteins into plastids, and a receptor of this complex, Toc132, was previously hypothesized to contribute to gravitropism either by directly functioning as a gravity signal transducer or by indirectly mediating the plastid localization of a gravity signal transducer. Here we show that mutations in multiple genes encoding TOC complex components affect gravitropism in a genetically sensitized background and that the cytoplasmic acidic domain of Toc132 is not required for its involvement in this process. Furthermore, mutations in TOC132 enhance the gravitropic defect of a mutant whose amyloplasts lack starch. Finally, we show that the levels of several nuclear-encoded root proteins are altered in toc132 mutants. These data suggest that the TOC complex indirectly mediates gravity signal transduction in Arabidopsis and support the idea that plastids are involved in gravitropism not only through their ability to sediment but also as part of the signal transduction mechanism.

Bio-Signal Complexity Analysis in Epileptic Seizure Monitoring: A Topic Review

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Zhenning Mei

2018-05-01

Full Text Available Complexity science has provided new perspectives and opportunities for understanding a variety of complex natural or social phenomena, including brain dysfunctions like epilepsy. By delving into the complexity in electrophysiological signals and neuroimaging, new insights have emerged. These discoveries have revealed that complexity is a fundamental aspect of physiological processes. The inherent nonlinearity and non-stationarity of physiological processes limits the methods based on simpler underlying assumptions to point out the pathway to a more comprehensive understanding of their behavior and relation with certain diseases. The perspective of complexity may benefit both the research and clinical practice through providing novel data analytics tools devoted for the understanding of and the intervention about epilepsies. This review aims to provide a sketchy overview of the methods derived from different disciplines lucubrating to the complexity of bio-signals in the field of epilepsy monitoring. Although the complexity of bio-signals is still not fully understood, bundles of new insights have been already obtained. Despite the promising results about epileptic seizure detection and prediction through offline analysis, we are still lacking robust, tried-and-true real-time applications. Multidisciplinary collaborations and more high-quality data accessible to the whole community are needed for reproducible research and the development of such applications.

Entropy for the Complexity of Physiological Signal Dynamics.

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Zhang, Xiaohua Douglas

2017-01-01

Recently, the rapid development of large data storage technologies, mobile network technology, and portable medical devices makes it possible to measure, record, store, and track analysis of biological dynamics. Portable noninvasive medical devices are crucial to capture individual characteristics of biological dynamics. The wearable noninvasive medical devices and the analysis/management of related digital medical data will revolutionize the management and treatment of diseases, subsequently resulting in the establishment of a new healthcare system. One of the key features that can be extracted from the data obtained by wearable noninvasive medical device is the complexity of physiological signals, which can be represented by entropy of biological dynamics contained in the physiological signals measured by these continuous monitoring medical devices. Thus, in this chapter I present the major concepts of entropy that are commonly used to measure the complexity of biological dynamics. The concepts include Shannon entropy, Kolmogorov entropy, Renyi entropy, approximate entropy, sample entropy, and multiscale entropy. I also demonstrate an example of using entropy for the complexity of glucose dynamics.

Stochastic effects as a force to increase the complexity of signaling networks

KAUST Repository

Kuwahara, Hiroyuki; Gao, Xin

2013-01-01

Cellular signaling networks are complex and appear to include many nonfunctional elements. Recently, it was suggested that nonfunctional interactions of proteins cause signaling noise, which, perhaps, shapes the signal transduction mechanism

DDX3 directly regulates TRAF3 ubiquitination and acts as a scaffold to co-ordinate assembly of signalling complexes downstream from MAVS.

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Gu, Lili; Fullam, Anthony; McCormack, Niamh; Höhn, Yvette; Schröder, Martina

2017-02-15

The human DEAD-box helicase 3 (DDX3) has been shown to contribute to type I interferon (IFN) induction downstream from antiviral pattern recognition receptors. It binds to TANK-binding kinase 1 and IκB-kinase-ε (IKKε), the two key kinases mediating activation of IFN regulatory factor (IRF) 3 and IRF7. We previously demonstrated that DDX3 facilitates IKKε activation downstream from RIG-I and then links the activated kinase to IRF3. In the present study, we probed the interactions between DDX3 and other key signalling molecules in the RIG-I pathway and identified a novel direct interaction between DDX3 and TNF receptor-associated factor 3 (TRAF3) mediated by a TRAF-interaction motif in the N-terminus of DDX3, which was required for TRAF3 ubiquitination. Interestingly, we observed two waves of K63-linked TRAF3 ubiquitination following RIG-I activation by Sendai virus (SeV) infection, both of which were suppressed by DDX3 knockdown. We also investigated the spatiotemporal formation of endogenous downstream signalling complexes containing the mitochondrial antiviral signalling (MAVS) adaptor, DDX3, IκB-kinase-ε (IKKε), TRAF3 and IRF3. DDX3 was recruited to MAVS early after SeV infection, suggesting that it might mediate subsequent recruitment of other molecules. Indeed, knockdown of DDX3 prevented the formation of TRAF3-MAVS and TRAF3-IKKε complexes. Based on our data, we propose that early TRAF3 ubiquitination is required for the formation of a stable MAVS-TRAF3 complex, while the second wave of TRAF3 ubiquitination mediates IRF3 recruitment and activation. Our study characterises DDX3 as a multifunctional adaptor molecule that co-ordinates assembly of different TRAF3, IKKε and IRF3-containing signalling complexes downstream from MAVS. Additionally, it provides novel insights into the role of TRAF3 in RIG-I signalling. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Exome localization of complex disease association signals

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Lewis Cathryn M

2011-02-01

Full Text Available Abstract Background Genome-wide association studies (GWAS of common diseases have had a tremendous impact on genetic research over the last five years; the field is now moving from microarray-based technology towards next-generation sequencing. To evaluate the potential of association studies for complex diseases based on exome sequencing we analysed the distribution of association signal with respect to protein-coding genes based on GWAS data for seven diseases from the Wellcome Trust Case Control Consortium. Results We find significant concentration of association signal in exons and genes for Crohn's Disease, Type 1 Diabetes and Bipolar Disorder, but also observe enrichment from up to 40 kilobases upstream to 40 kilobases downstream of protein-coding genes for Crohn's Disease and Type 1 Diabetes; the exact extent of the distribution is disease dependent. Conclusions Our work suggests that exome sequencing may be a feasible approach to find genetic variation associated with complex disease. Extending the exome sequencing to include flanking regions therefore promises further improvement of covering disease-relevant variants.

Dangerous mating systems: signal complexity, signal content and neural capacity in spiders.

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Herberstein, M E; Wignall, A E; Hebets, E A; Schneider, J M

2014-10-01

Spiders are highly efficient predators in possession of exquisite sensory capacities for ambushing prey, combined with machinery for launching rapid and determined attacks. As a consequence, any sexually motivated approach carries a risk of ending up as prey rather than as a mate. Sexual selection has shaped courtship to effectively communicate the presence, identity, motivation and/or quality of potential mates, which help ameliorate these risks. Spiders communicate this information via several sensory channels, including mechanical (e.g. vibrational), visual and/or chemical, with examples of multimodal signalling beginning to emerge in the literature. The diverse environments that spiders inhabit have further shaped courtship content and form. While our understanding of spider neurobiology remains in its infancy, recent studies are highlighting the unique and considerable capacities of spiders to process and respond to complex sexual signals. As a result, the dangerous mating systems of spiders are providing important insights into how ecology shapes the evolution of communication systems, with future work offering the potential to link this complex communication with its neural processes. Copyright © 2014 Elsevier Ltd. All rights reserved.

Important Text Characteristics for Early-Grades Text Complexity

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Fitzgerald, Jill; Elmore, Jeff; Koons, Heather; Hiebert, Elfrieda H.; Bowen, Kimberly; Sanford-Moore, Eleanor E.; Stenner, A. Jackson

2015-01-01

The Common Core set a standard for all children to read increasingly complex texts throughout schooling. The purpose of the present study was to explore text characteristics specifically in relation to early-grades text complexity. Three hundred fifty primary-grades texts were selected and digitized. Twenty-two text characteristics were identified…

Early spatiotemporal-specific changes in intermediate signals are predictive of cytotoxic sensitivity to TNFα and co-treatments

Science.gov (United States)

Loo, Lit-Hsin; Bougen-Zhukov, Nicola Michelle; Tan, Wei-Ling Cecilia

2017-03-01

Signaling pathways can generate different cellular responses to the same cytotoxic agents. Current quantitative models for predicting these differential responses are usually based on large numbers of intracellular gene products or signals at different levels of signaling cascades. Here, we report a study to predict cellular sensitivity to tumor necrosis factor alpha (TNFα) using high-throughput cellular imaging and machine-learning methods. We measured and compared 1170 protein phosphorylation events in a panel of human lung cancer cell lines based on different signals, subcellular regions, and time points within one hour of TNFα treatment. We found that two spatiotemporal-specific changes in an intermediate signaling protein, p90 ribosomal S6 kinase (RSK), are sufficient to predict the TNFα sensitivity of these cell lines. Our models could also predict the combined effects of TNFα and other kinase inhibitors, many of which are not known to target RSK directly. Therefore, early spatiotemporal-specific changes in intermediate signals are sufficient to represent the complex cellular responses to these perturbations. Our study provides a general framework for the development of rapid, signaling-based cytotoxicity screens that may be used to predict cellular sensitivity to a cytotoxic agent, or identify co-treatments that may sensitize or desensitize cells to the agent.

Complex Foot Injury: Early and Definite Management

NARCIS (Netherlands)

Schepers, Tim; Rammelt, Stefan

2017-01-01

Complex foot injuries occur infrequently, but are life-changing events. They often present with other injuries as the result of a high-energy trauma. After initial stabilization, early assessment should be regarding salvagability. All treatment strategies are intensive. The initial treatment

SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes

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Sebastian Kupka

2016-08-01

Full Text Available Recruitment of the deubiquitinase CYLD to signaling complexes is mediated by its interaction with HOIP, the catalytically active component of the linear ubiquitin chain assembly complex (LUBAC. Here, we identify SPATA2 as a constitutive direct binding partner of HOIP that bridges the interaction between CYLD and HOIP. SPATA2 recruitment to TNFR1- and NOD2-signaling complexes is dependent on HOIP, and loss of SPATA2 abolishes CYLD recruitment. Deficiency in SPATA2 exerts limited effects on gene activation pathways but diminishes necroptosis induced by tumor necrosis factor (TNF, resembling loss of CYLD. In summary, we describe SPATA2 as a previously unrecognized factor in LUBAC-dependent signaling pathways that serves as an adaptor between HOIP and CYLD, thereby enabling recruitment of CYLD to signaling complexes.

Phosphorylation site dynamics of early T-cell receptor signaling

DEFF Research Database (Denmark)

Chylek, Lily A; Akimov, Vyacheslav; Dengjel, Jörn

2014-01-01

In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack...... that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites...... a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found...

Simulation study on effects of signaling network structure on the developmental increase in complexity

Energy Technology Data Exchange (ETDEWEB)

Keranen, Soile V.E.

2003-04-02

The developmental increase in structural complexity in multicellular life forms depends on local, often non-periodic differences in gene expression. These depend on a network of gene-gene interactions coded within the organismal genome. To better understand how genomic information generates complex expression patterns, I have modeled the pattern forming behavior of small artificial genomes in virtual blastoderm embryos. I varied several basic properties of these genomic signaling networks, such as the number of genes, the distributions of positive (inductive) and negative (repressive) interactions, and the strengths of gene-gene interactions, and analyzed their effects on developmental pattern formation. The results show how even simple genomes can generate complex non-periodic patterns under suitable conditions. They also show how the frequency of complex patterns depended on the numbers and relative arrangements of positive and negative interactions. For example, negative co-regulation of signaling pathway components increased the likelihood of (complex) patterns relative to differential negative regulation of the pathway components. Interestingly, neither quantitative differences either in strengths of signaling interactions nor multiple response thresholds to signal concentration (as in morphogen gradients) were essential for formation of multiple, spatially unique cell types. Thus, with combinatorial code of gene regulation and hierarchical signaling interactions, it is theoretically possible to organize metazoan embryogenesis with just a small fraction of the metazoan genome. Because even small networks can generate complex patterns when they contain a suitable set of connections, evolution of metazoan complexity may have depended more on selection for favourable configurations of signaling interactions than on the increase in numbers of regulatory genes.

Resolving Early Signaling Events in T-Cell Activation Leading to IL-2 and FOXP3 Transcription

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Jeffrey P. Perley

2014-11-01

Full Text Available Signal intensity and feedback regulation are known to be major factors in the signaling events stemming from the T-cell receptor (TCR and its various coreceptors, but the exact nature of these relationships remains in question. We present a mathematical model of the complex signaling network involved in T-cell activation with cross-talk between the Erk, calcium, PKC and mTOR signaling pathways. The model parameters are adjusted to fit new and published data on TCR trafficking, Zap70, calcium, Erk and Isignaling. The regulation of the early signaling events by phosphatases, CD45 and SHP1, and the TCR dynamics are critical to determining the behavior of the model. Additional model corroboration is provided through quantitative and qualitative agreement with experimental data collected under different stimulating and knockout conditions. The resulting model is analyzed to investigate how signal intensity and feedback regulation affect TCR- and coreceptor-mediated signal transduction and their downstream transcriptional profiles to predict the outcome for a variety of stimulatory and knockdown experiments. Analysis of the model shows that: (1 SHP1 negative feedback is necessary for preventing hyperactivity in TCR signaling; (2 CD45 is required for TCR signaling, but also partially suppresses it at high expression levels; and (3 elevated FOXP3 and reduced IL-2 signaling, an expression profile often associated with T regulatory cells (Tregs, is observed when the system is subjected to weak TCR and CD28 costimulation or a severe reduction in CD45 activity.

Aliasing in the Complex Cepstrum of Linear-Phase Signals

DEFF Research Database (Denmark)

Bysted, Tommy Kristensen

1997-01-01

Assuming linear-phase of the associated time signal, this paper presents an approximated analytical description of the unavoidable aliasing in practical use of complex cepstrums. The linear-phase assumption covers two major applications of complex cepstrums which are linear- to minimum-phase FIR......-filter transformation and minimum-phase estimation from amplitude specifications. The description is made in the cepstrum domain, the Fourier transform of the complex cepstrum and in the frequency domain. Two examples are given, one for verification of the derived equations and one using the description to reduce...... aliasing in minimum-phase estimation...

Inhibition of the adrenomedullin/nitric oxide signaling pathway in early diabetic retinopathy.

Science.gov (United States)

Blom, Jan J; Giove, Thomas J; Favazza, Tara L; Akula, James D; Eldred, William D

2011-06-01

The nitric oxide (NO) signaling pathway is integrally involved in visual processing and changes in the NO pathway are measurable in eyes of diabetic patients. The small peptide adrenomedullin (ADM) can activate a signaling pathway to increase the enzyme activity of neuronal nitric oxide synthase (nNOS). ADM levels are elevated in eyes of diabetic patients and therefore, ADM may play a role in the pathology of diabetic retinopathy. The goal of this research was to test the effects of inhibiting the ADM/NO signaling pathway in early diabetic retinopathy. Inhibition of this pathway decreased NO production in high-glucose retinal cultures. Treating diabetic mice with the PKC β inhibitor ruboxistaurin for 5 weeks lowered ADM mRNA levels and ADM-like immunoreactivity and preserved retinal function as assessed by electroretinography. The results of this study indicate that inhibiting the ADM/NO signaling pathway prevents neuronal pathology and functional losses in early diabetic retinopathy.

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

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Hsu, Li-Jin; Hong, Qunying; Chen, Shur-Tzu; Kuo, Hsiang-Lin; Schultz, Lori; Heath, John; Lin, Sing-Ru; Lee, Ming-Hui; Li, Dong-Zhang; Li, Zih-Ling; Cheng, Hui-Ching; Armand, Gerard; Chang, Nan-Shan

2017-03-21

Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

Labor Inhibits Placental Mechanistic Target of Rapamycin Complex 1 Signaling

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LAGER, Susanne; AYE, Irving L.M.H.; GACCIOLI, Francesca; RAMIREZ, Vanessa I.; JANSSON, Thomas; POWELL, Theresa L.

2014-01-01

Introduction Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. Methods Placental tissue was collected from healthy, term pregnancies (n=15 no-labor; n=12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFκB p65 and PPARγ DNA binding activity was measured in isolated nuclei. Results Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFκB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Discussion and conclusion Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. PMID:25454472

Artificial Neural Network-Based Early-Age Concrete Strength Monitoring Using Dynamic Response Signals.

Science.gov (United States)

Kim, Junkyeong; Lee, Chaggil; Park, Seunghee

2017-06-07

Concrete is one of the most common materials used to construct a variety of civil infrastructures. However, since concrete might be susceptible to brittle fracture, it is essential to confirm the strength of concrete at the early-age stage of the curing process to prevent unexpected collapse. To address this issue, this study proposes a novel method to estimate the early-age strength of concrete, by integrating an artificial neural network algorithm with a dynamic response measurement of the concrete material. The dynamic response signals of the concrete, including both electromechanical impedances and guided ultrasonic waves, are obtained from an embedded piezoelectric sensor module. The cross-correlation coefficient of the electromechanical impedance signals and the amplitude of the guided ultrasonic wave signals are selected to quantify the variation in dynamic responses according to the strength of the concrete. Furthermore, an artificial neural network algorithm is used to verify a relationship between the variation in dynamic response signals and concrete strength. The results of an experimental study confirm that the proposed approach can be effectively applied to estimate the strength of concrete material from the early-age stage of the curing process.

Characterization of early autophagy signaling by quantitative phosphoproteomics

DEFF Research Database (Denmark)

Rigbolt, Kristoffer Tg; Zarei, Mostafa; Sprenger, Adrian

2014-01-01

. To elucidate the regulation of early signaling events upon autophagy induction, we applied quantitative phosphoproteomics characterizing the temporal phosphorylation dynamics after starvation and rapamycin treatment. We obtained a comprehensive atlas of phosphorylation kinetics within the first 30 min upon...... revealing regulated phosphorylation sites on proteins involved in a wide range of cellular processes and an impact of the treatments on the kinome. To approach the potential function of the identified phosphorylation sites we performed a screen for MAP1LC3-interacting proteins and identified a group...... induction of autophagy with both treatments affecting widely different cellular processes. The identification of dynamic phosphorylation already after 2 min demonstrates that the earliest events in autophagy signaling occur rapidly after induction. The data was subjected to extensive bioinformatics analysis...

Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

Science.gov (United States)

Hsu, Li-Jin; Hong, Qunying; Chen, Shur-Tzu; Kuo, Hsiang-Lin; Schultz, Lori; Heath, John; Lin, Sing-Ru; Lee, Ming-Hui; Li, Dong-Zhang; Li, Zih-Ling; Cheng, Hui-Ching; Armand, Gerard; Chang, Nan-Shan

2017-01-01

Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed. PMID:27845895

Age-Related Changes in Electroencephalographic Signal Complexity

Science.gov (United States)

Zappasodi, Filippo; Marzetti, Laura; Olejarczyk, Elzbieta; Tecchio, Franca; Pizzella, Vittorio

2015-01-01

The study of active and healthy aging is a primary focus for social and neuroscientific communities. Here, we move a step forward in assessing electrophysiological neuronal activity changes in the brain with healthy aging. To this end, electroencephalographic (EEG) resting state activity was acquired in 40 healthy subjects (age 16–85). We evaluated Fractal Dimension (FD) according to the Higuchi algorithm, a measure which quantifies the presence of statistical similarity at different scales in temporal fluctuations of EEG signals. Our results showed that FD increases from age twenty to age fifty and then decreases. The curve that best fits the changes in FD values across age over the whole sample is a parabola, with the vertex located around age fifty. Moreover, FD changes are site specific, with interhemispheric FD asymmetry being pronounced in elderly individuals in the frontal and central regions. The present results indicate that fractal dimension well describes the modulations of brain activity with age. Since fractal dimension has been proposed to be related to the complexity of the signal dynamics, our data demonstrate that the complexity of neuronal electric activity changes across the life span of an individual, with a steady increase during young adulthood and a decrease in the elderly population. PMID:26536036

Early warning signals of abrupt temperature change in different regions of China over the past 50 years

International Nuclear Information System (INIS)

Tong Ji-Long; Wu Hao; Hou Wei; He Wen-Ping; Zhou Jie

2014-01-01

In this paper, the early warning signals of abrupt temperature change in different regions of China are investigated. Seven regions are divided on the basis of different climate temperature patterns, obtained through the rotated empirical orthogonal function, and the signal-to-noise temperature ratios for each region are then calculated. Based on the concept of critical slowing down, the temperature data that contain noise in the different regions of China are preprocessed to study the early warning signals of abrupt climate change. First, the Mann–Kendall method is used to identify the instant of abrupt climate change in the temperature data. Second, autocorrelation coefficients that can identify critical slowing down are calculated. The results show that the critical slowing down phenomenon appeared in temperature data about 5–10 years before abrupt climate change occurred, which indicates that the critical slowing down phenomenon is a possible early warning signal for abrupt climate change, and that noise has less influence on the detection results of the early warning signals. Accordingly, this demonstrates that the model is reliable in identifying the early warning signals of abrupt climate change based on detecting the critical slowing down phenomenon, which provides an experimental basis for the actual application of the method. (geophysics, astronomy, and astrophysics)

Oscillation of Angiogenesis and Vascular Dropout in Progressive Human Vascular Disease. [Vascular Pattern as Useful Read-Out of Complex Molecular Signaling

Science.gov (United States)

Parsons-Wingerter, Patricia

2010-01-01

When analyzed by VESsel GENeration Analysis (VESGEN) software, vascular patterns provide useful integrative read-outs of complex, interacting molecular signaling pathways. Using VESGEN, we recently discovered and published our innovative, surprising findings that angiogenesis oscillated with vascular dropout throughout progression of diabetic retinopathy, a blinding vascular disease. Our findings provide a potential paradigm shift in the current prevailing view on progression and treatment of this disease, and a new early-stage window of regenerative therapeutic opportunities. The findings also suggest that angiogenesis may oscillate with vascular disease in a homeostatic-like manner during early stages of other inflammatory progressive diseases such as cancer and coronary vascular disease.

Aiding the Detection of QRS Complex in ECG Signals by Detecting S Peaks Independently.

Science.gov (United States)

Sabherwal, Pooja; Singh, Latika; Agrawal, Monika

2018-03-30

In this paper, a novel algorithm for the accurate detection of QRS complex by combining the independent detection of R and S peaks, using fusion algorithm is proposed. R peak detection has been extensively studied and is being used to detect the QRS complex. Whereas, S peaks, which is also part of QRS complex can be independently detected to aid the detection of QRS complex. In this paper, we suggest a method to first estimate S peak from raw ECG signal and then use them to aid the detection of QRS complex. The amplitude of S peak in ECG signal is relatively weak than corresponding R peak, which is traditionally used for the detection of QRS complex, therefore, an appropriate digital filter is designed to enhance the S peaks. These enhanced S peaks are then detected by adaptive thresholding. The algorithm is validated on all the signals of MIT-BIH arrhythmia database and noise stress database taken from physionet.org. The algorithm performs reasonably well even for the signals highly corrupted by noise. The algorithm performance is confirmed by sensitivity and positive predictivity of 99.99% and the detection accuracy of 99.98% for QRS complex detection. The number of false positives and false negatives resulted while analysis has been drastically reduced to 80 and 42 against the 98 and 84 the best results reported so far.

Apartheid's Alcatraz: the Barberton prison complex during the early ...

African Journals Online (AJOL)

The purpose of this two-part article is to examine in detail the public discourse surrounding the Barberton Prison Complex during the early 1980s, at the height of the apartheid era. The prisons within the Barberton Prison Complex were notorious as being among the most punitive of the many prisons within apartheid South ...

Unraveling the Complexities of Androgen Receptor Signaling in Prostate Cancer Cells

OpenAIRE

Heemers, Hannelore V.; Tindall, Donald J.

2009-01-01

Androgen signaling is critical for proliferation of prostate cancer cells but cannot be fully inhibited by current androgen deprivation therapies. A study by Xu et al. in this issue of Cancer Cell provides insights into the complexities of androgen signaling in prostate cancer and suggests avenues to target a subset of androgen-sensitive genes.

Signalling fiscal stress in the euro area - a country-specific early warning system

OpenAIRE

Hernández de Cos, Pablo; Koester, Gerrit B.; Moral-Benito, Enrique; Nickel, Christiane

2014-01-01

The sovereign debt crisis in the euro area has increased the interest in early warning indicators, with the aim to indicate the build?up of fiscal stress early on and to facilitate crisis prevention by a timely counteraction of fiscal and macroeconomic policies. This paper presents possible improvements to enhance existing early warning indicators for fiscal stress, especially for the euro area. We show that a country?specific approach could strongly increase the signalling power of early war...

The primary cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation

DEFF Research Database (Denmark)

Clement, Christian A; Kristensen, Stine G; Møllgård, Kjeld

2009-01-01

Defects in the assembly or function of primary cilia, which are sensory organelles, are tightly coupled to developmental defects and diseases in mammals. Here, we investigated the function of the primary cilium in regulating hedgehog signaling and early cardiogenesis. We report that the pluripotent...... P19.CL6 mouse stem cell line, which can differentiate into beating cardiomyocytes, forms primary cilia that contain essential components of the hedgehog pathway, including Smoothened, Patched-1 and Gli2. Knockdown of the primary cilium by Ift88 and Ift20 siRNA or treatment with cyclopamine...... development. These data support the conclusion that cardiac primary cilia are crucial in early heart development, where they partly coordinate hedgehog signaling....

Disentangling the Complexity of HGF Signaling by Combining Qualitative and Quantitative Modeling.

Directory of Open Access Journals (Sweden)

Lorenza A D'Alessandro

2015-04-01

Full Text Available Signaling pathways are characterized by crosstalk, feedback and feedforward mechanisms giving rise to highly complex and cell-context specific signaling networks. Dissecting the underlying relations is crucial to predict the impact of targeted perturbations. However, a major challenge in identifying cell-context specific signaling networks is the enormous number of potentially possible interactions. Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF stimulated phosphoinositide-3-kinase (PI3K and mitogen activated protein kinase (MAPK signaling, which critically contribute to liver regeneration. By combining time-resolved quantitative experimental data generated in primary mouse hepatocytes with interaction graph and ordinary differential equation modeling, we identify and experimentally validate a network structure that represents the experimental data best and indicates specific crosstalk mechanisms. Whereas the identified network is robust against single perturbations, combinatorial inhibition strategies are predicted that result in strong reduction of Akt and ERK activation. Thus, by capitalizing on the advantages of the two modeling approaches, we reduce the high combinatorial complexity and identify cell-context specific signaling networks.

Effects of stressor characteristics on early warning signs of critical transitions and "critical coupling" in complex dynamical systems.

Science.gov (United States)

Blume, Steffen O P; Sansavini, Giovanni

2017-12-01

Complex dynamical systems face abrupt transitions into unstable and catastrophic regimes. These critical transitions are triggered by gradual modifications in stressors, which push the dynamical system towards unstable regimes. Bifurcation analysis can characterize such critical thresholds, beyond which systems become unstable. Moreover, the stochasticity of the external stressors causes small-scale fluctuations in the system response. In some systems, the decomposition of these signal fluctuations into precursor signals can reveal early warning signs prior to the critical transition. Here, we present a dynamical analysis of a power system subjected to an increasing load level and small-scale stochastic load perturbations. We show that the auto- and cross-correlations of bus voltage magnitudes increase, leading up to a Hopf bifurcation point, and further grow until the system collapses. This evidences a gradual transition into a state of "critical coupling," which is complementary to the established concept of "critical slowing down." Furthermore, we analyze the effects of the type of load perturbation and load characteristics on early warning signs and find that gradient changes in the autocorrelation provide early warning signs of the imminent critical transition under white-noise but not for auto-correlated load perturbations. Furthermore, the cross-correlation between all voltage magnitude pairs generally increases prior to and beyond the Hopf bifurcation point, indicating "critical coupling," but cannot provide early warning indications. Finally, we show that the established early warning indicators are oblivious to limit-induced bifurcations and, in the case of the power system model considered here, only react to an approaching Hopf bifurcation.

Complex Signal Kurtosis and Independent Component Analysis for Wideband Radio Frequency Interference Detection

Science.gov (United States)

Schoenwald, Adam; Mohammed, Priscilla; Bradley, Damon; Piepmeier, Jeffrey; Wong, Englin; Gholian, Armen

2016-01-01

Radio-frequency interference (RFI) has negatively implicated scientific measurements across a wide variation passive remote sensing satellites. This has been observed in the L-band radiometers SMOS, Aquarius and more recently, SMAP [1, 2]. RFI has also been observed at higher frequencies such as K band [3]. Improvements in technology have allowed wider bandwidth digital back ends for passive microwave radiometry. A complex signal kurtosis radio frequency interference detector was developed to help identify corrupted measurements [4]. This work explores the use of ICA (Independent Component Analysis) as a blind source separation technique to pre-process radiometric signals for use with the previously developed real and complex signal kurtosis detectors.

Generation of Long-time Complex Signals for Testing the Instruments for Detection of Voltage Quality Disturbances

Science.gov (United States)

Živanović, Dragan; Simić, Milan; Kokolanski, Zivko; Denić, Dragan; Dimcev, Vladimir

2018-04-01

Software supported procedure for generation of long-time complex test sentences, suitable for testing the instruments for detection of standard voltage quality (VQ) disturbances is presented in this paper. This solution for test signal generation includes significant improvements of computer-based signal generator presented and described in the previously published paper [1]. The generator is based on virtual instrumentation software for defining the basic signal parameters, data acquisition card NI 6343, and power amplifier for amplification of output voltage level to the nominal RMS voltage value of 230 V. Definition of basic signal parameters in LabVIEW application software is supported using Script files, which allows simple repetition of specific test signals and combination of more different test sequences in the complex composite test waveform. The basic advantage of this generator compared to the similar solutions for signal generation is the possibility for long-time test sequence generation according to predefined complex test scenarios, including various combinations of VQ disturbances defined in accordance with the European standard EN50160. Experimental verification of the presented signal generator capability is performed by testing the commercial power quality analyzer Fluke 435 Series II. In this paper are shown some characteristic complex test signals with various disturbances and logged data obtained from the tested power quality analyzer.

Fixed-Point Algorithms for the Blind Separation of Arbitrary Complex-Valued Non-Gaussian Signal Mixtures

Directory of Open Access Journals (Sweden)

Douglas Scott C

2007-01-01

Full Text Available We derive new fixed-point algorithms for the blind separation of complex-valued mixtures of independent, noncircularly symmetric, and non-Gaussian source signals. Leveraging recently developed results on the separability of complex-valued signal mixtures, we systematically construct iterative procedures on a kurtosis-based contrast whose evolutionary characteristics are identical to those of the FastICA algorithm of Hyvarinen and Oja in the real-valued mixture case. Thus, our methods inherit the fast convergence properties, computational simplicity, and ease of use of the FastICA algorithm while at the same time extending this class of techniques to complex signal mixtures. For extracting multiple sources, symmetric and asymmetric signal deflation procedures can be employed. Simulations for both noiseless and noisy mixtures indicate that the proposed algorithms have superior finite-sample performance in data-starved scenarios as compared to existing complex ICA methods while performing about as well as the best of these techniques for larger data-record lengths.

Isolation and structure–function characterization of a signaling-active rhodopsin–G protein complex

Science.gov (United States)

Gao, Yang; Westfield, Gerwin; Erickson, Jon W.; Cerione, Richard A.; Skiniotis, Georgios; Ramachandran, Sekar

2017-01-01

The visual photo-transduction cascade is a prototypical G protein–coupled receptor (GPCR) signaling system, in which light-activated rhodopsin (Rho*) is the GPCR catalyzing the exchange of GDP for GTP on the heterotrimeric G protein transducin (GT). This results in the dissociation of GT into its component αT–GTP and β1γ1 subunit complex. Structural information for the Rho*–GT complex will be essential for understanding the molecular mechanism of visual photo-transduction. Moreover, it will shed light on how GPCRs selectively couple to and activate their G protein signaling partners. Here, we report on the preparation of a stable detergent-solubilized complex between Rho* and a heterotrimer (GT*) comprising a GαT/Gαi1 chimera (αT*) and β1γ1. The complex was formed on native rod outer segment membranes upon light activation, solubilized in lauryl maltose neopentyl glycol, and purified with a combination of affinity and size-exclusion chromatography. We found that the complex is fully functional and that the stoichiometry of Rho* to GαT* is 1:1. The molecular weight of the complex was calculated from small-angle X-ray scattering data and was in good agreement with a model consisting of one Rho* and one GT*. The complex was visualized by negative-stain electron microscopy, which revealed an architecture similar to that of the β2-adrenergic receptor–GS complex, including a flexible αT* helical domain. The stability and high yield of the purified complex should allow for further efforts toward obtaining a high-resolution structure of this important signaling complex. PMID:28655769

Maize and Arabidopsis ARGOS Proteins Interact with Ethylene Receptor Signaling Complex, Supporting a Regulatory Role for ARGOS in Ethylene Signal Transduction[OPEN

Science.gov (United States)

Shi, Jinrui; Wang, Hongyu; Habben, Jeffrey E.

2016-01-01

The phytohormone ethylene regulates plant growth and development as well as plant response to environmental cues. ARGOS genes reduce plant sensitivity to ethylene when overexpressed in transgenic Arabidopsis (Arabidopsis thaliana) and maize (Zea mays). A previous genetic study suggested that the endoplasmic reticulum and Golgi-localized maize ARGOS1 targets the ethylene signal transduction components at or upstream of CONSTITUTIVE TRIPLE RESPONSE1, but the mechanism of ARGOS modulating ethylene signaling is unknown. Here, we demonstrate in Arabidopsis that ZmARGOS1, as well as the Arabidopsis ARGOS homolog ORGAN SIZE RELATED1, physically interacts with Arabidopsis REVERSION-TO-ETHYLENE SENSITIVITY1 (RTE1), an ethylene receptor interacting protein that regulates the activity of ETHYLENE RESPONSE1. The protein-protein interaction was also detected with the yeast split-ubiquitin two-hybrid system. Using the same yeast assay, we found that maize RTE1 homolog REVERSION-TO-ETHYLENE SENSITIVITY1 LIKE4 (ZmRTL4) and ZmRTL2 also interact with maize and Arabidopsis ARGOS proteins. Like AtRTE1 in Arabidopsis, ZmRTL4 and ZmRTL2 reduce ethylene responses when overexpressed in maize, indicating a similar mechanism for ARGOS regulating ethylene signaling in maize. A polypeptide fragment derived from ZmARGOS8, consisting of a Pro-rich motif flanked by two transmembrane helices that are conserved among members of the ARGOS family, can interact with AtRTE1 and maize RTL proteins in Arabidopsis. The conserved domain is necessary and sufficient to reduce ethylene sensitivity in Arabidopsis and maize. Overall, these results suggest a physical association between ARGOS and the ethylene receptor signaling complex via AtRTE1 and maize RTL proteins, supporting a role for ARGOS in regulating ethylene perception and the early steps of signal transduction in Arabidopsis and maize. PMID:27268962

6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-κB factors

International Nuclear Information System (INIS)

Tobón-Velasco, Julio C.; Limón-Pacheco, Jorge H.; Orozco-Ibarra, Marisol; Macías-Silva, Marina; Vázquez-Victorio, Genaro; Cuevas, Elvis; Ali, Syed F.

2013-01-01

6-Hydroxydopamine (6-OHDA) is a neurotoxin that generates an experimental model of Parkinson's disease in rodents and is commonly employed to induce a lesion in dopaminergic pathways. The characterization of those molecular mechanisms linked to 6-OHDA-induced early toxicity is needed to better understand the cellular events further leading to neurodegeneration. The present work explored how 6-OHDA triggers early downstream signaling pathways that activate neurotoxicity in the rat striatum. Mitochondrial function, caspases-dependent apoptosis, kinases signaling (Akt, ERK 1/2, SAP/JNK and p38) and crosstalk between nuclear factor kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) were evaluated at early times post-lesion. We found that 6-OHDA initiates cell damage via mitochondrial complex I inhibition, cytochrome c and apoptosis-inducing factor (AIF) release, as well as activation of caspases 9 and 3 to induce apoptosis, kinase signaling modulation and NF-κB-mediated inflammatory responses, accompanied by inhibition of antioxidant systems regulated by the Nrf2 pathway. Our results suggest that kinases SAP/JNK and p38 up-regulation may play a role in the early stages of 6-OHDA toxicity to trigger intrinsic pathways for apoptosis and enhanced NF-κB activation. In turn, these cellular events inhibit the activation of cytoprotective mechanisms, thereby leading to a condition of general damage

Isolation and structure-function characterization of a signaling-active rhodopsin-G protein complex.

Science.gov (United States)

Gao, Yang; Westfield, Gerwin; Erickson, Jon W; Cerione, Richard A; Skiniotis, Georgios; Ramachandran, Sekar

2017-08-25

The visual photo-transduction cascade is a prototypical G protein-coupled receptor (GPCR) signaling system, in which light-activated rhodopsin (Rho*) is the GPCR catalyzing the exchange of GDP for GTP on the heterotrimeric G protein transducin (G T ). This results in the dissociation of G T into its component α T -GTP and β 1 γ 1 subunit complex. Structural information for the Rho*-G T complex will be essential for understanding the molecular mechanism of visual photo-transduction. Moreover, it will shed light on how GPCRs selectively couple to and activate their G protein signaling partners. Here, we report on the preparation of a stable detergent-solubilized complex between Rho* and a heterotrimer (G T *) comprising a Gα T /Gα i1 chimera (α T *) and β 1 γ 1 The complex was formed on native rod outer segment membranes upon light activation, solubilized in lauryl maltose neopentyl glycol, and purified with a combination of affinity and size-exclusion chromatography. We found that the complex is fully functional and that the stoichiometry of Rho* to Gα T * is 1:1. The molecular weight of the complex was calculated from small-angle X-ray scattering data and was in good agreement with a model consisting of one Rho* and one G T *. The complex was visualized by negative-stain electron microscopy, which revealed an architecture similar to that of the β 2 -adrenergic receptor-G S complex, including a flexible α T * helical domain. The stability and high yield of the purified complex should allow for further efforts toward obtaining a high-resolution structure of this important signaling complex. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Fibroblast growth factor signaling is required for early somatic gonad development in zebrafish.

Science.gov (United States)

Leerberg, Dena M; Sano, Kaori; Draper, Bruce W

2017-09-01

The vertebrate ovary and testis develop from a sexually indifferent gonad. During early development of the organism, primordial germ cells (the gamete lineage) and somatic gonad cells coalesce and begin to undergo growth and morphogenesis to form this bipotential gonad. Although this aspect of development is requisite for a fertile adult, little is known about the genetic regulation of early gonadogenesis in any vertebrate. Here, we provide evidence that fibroblast growth factor (Fgf) signaling is required for the early growth phase of a vertebrate bipotential gonad. Based on mutational analysis in zebrafish, we show that the Fgf ligand 24 (Fgf24) is required for proliferation, differentiation, and morphogenesis of the early somatic gonad, and as a result, most fgf24 mutants are sterile as adults. Additionally, we describe the ultrastructural elements of the early zebrafish gonad and show that distinct somatic cell populations can be identified soon after the gonad forms. Specifically, we show that fgf24 is expressed in an epithelial population of early somatic gonad cells that surrounds an inner population of mesenchymal somatic gonad cells that are in direct contact with the germ cells, and that fgf24 is required for stratification of the somatic tissue. Furthermore, based on gene expression analysis, we find that differentiation of the inner mesenchymal somatic gonad cells into functional cell types in the larval and early juvenile-stage gonad is dependent on Fgf24 signaling. Finally, we argue that the role of Fgf24 in zebrafish is functionally analogous to the role of tetrapod FGF9 in early gonad development.

Analysis of the Influence of Complexity and Entropy of Odorant on Fractal Dynamics and Entropy of EEG Signal.

Science.gov (United States)

Namazi, Hamidreza; Akrami, Amin; Nazeri, Sina; Kulish, Vladimir V

2016-01-01

An important challenge in brain research is to make out the relation between the features of olfactory stimuli and the electroencephalogram (EEG) signal. Yet, no one has discovered any relation between the structures of olfactory stimuli and the EEG signal. This study investigates the relation between the structures of EEG signal and the olfactory stimulus (odorant). We show that the complexity of the EEG signal is coupled with the molecular complexity of the odorant, where more structurally complex odorant causes less fractal EEG signal. Also, odorant having higher entropy causes the EEG signal to have lower approximate entropy. The method discussed here can be applied and investigated in case of patients with brain diseases as the rehabilitation purpose.

Use of multiple singular value decompositions to analyze complex intracellular calcium ion signals

KAUST Repository

Martinez, Josue G.; Huang, Jianhua Z.; Burghardt, Robert C.; Barhoumi, Rola; Carroll, Raymond J.

2009-01-01

) to extract the signals from such movies, in a way that is semi-automatic and tuned closely to the actual data and their many complexities. These complexities include the following. First, the images themselves are of no interest: all interest focuses

Relation between stability and resilience determines the performance of early warning signals under different environmental drivers.

Science.gov (United States)

Dai, Lei; Korolev, Kirill S; Gore, Jeff

2015-08-11

Shifting patterns of temporal fluctuations have been found to signal critical transitions in a variety of systems, from ecological communities to human physiology. However, failure of these early warning signals in some systems calls for a better understanding of their limitations. In particular, little is known about the generality of early warning signals in different deteriorating environments. In this study, we characterized how multiple environmental drivers influence the dynamics of laboratory yeast populations, which was previously shown to display alternative stable states [Dai et al., Science, 2012]. We observed that both the coefficient of variation and autocorrelation increased before population collapse in two slowly deteriorating environments, one with a rising death rate and the other one with decreasing nutrient availability. We compared the performance of early warning signals across multiple environments as "indicators for loss of resilience." We find that the varying performance is determined by how a system responds to changes in a specific driver, which can be captured by a relation between stability (recovery rate) and resilience (size of the basin of attraction). Furthermore, we demonstrate that the positive correlation between stability and resilience, as the essential assumption of indicators based on critical slowing down, can break down in this system when multiple environmental drivers are changed simultaneously. Our results suggest that the stability-resilience relation needs to be better understood for the application of early warning signals in different scenarios.

Study of the early signal perturbations due to GJ and Elves using the LWPC code

Science.gov (United States)

Nait Amor, Samir; Ghalila, Hassen; Bouderba, Yasmina

2015-04-01

Early events are a Very Low Frequencies (VLF) signal perturbations recorded during a lightning activity. The properties of these signal perturbations and their association to the lightning peak current and/or Transient Luminous Events (TLEs) were widely studied. In a recently analysis a new early signal perturbations whose recovery time persists for several minutes were discovered. The underlying cause of these events is still unclear. In a recently published work, these events were attributed to the lightning peak current and the type of associated TLE. In others, and newly published papers, analyzes were done where all kind of early events were considered. Statistical results showed that the occurrence of long recovery events is independent of the lightning current amplitude and/or TLEs type. To understand which is the main cause of these events, we analyzed two types of early signal perturbations: One was a typical event (~200s time duration) in association with a Gigantic Jet and the second was a long recovery event in association with an elve recorded on December 12 2009 during the EuroSprite campaign. In addition to the VLF signal analysis, we used the Long Wave Propagation Capability (LWPC) code to simulate the unperturbed and perturbed signal parameters (amplitude and phase), to determine the signal modes attenuation coefficient and then to infer the electron density increases in the disturbed region. The results showed that the reference height was reduced from its ambient value (87km) to 66.4 km in the case of the GJ and 74.3 km for the elve. These reference heights decreases affected the propagating signal at the disturbed region by increasing the modes attenuation coefficient. Effectively, the number of modes was reduced from 28 at ambient condition to 9 modes (in the case of GJ) and 17 (in the case of elve). This high attenuation of modes leads to the appearance of null signal perturbations positions due to the interferences. Between two null positions

Replicating the Ice-Volume Signal of the Early Pleistocene with a Complex Earth System Model

Science.gov (United States)

Tabor, C. R.; Poulsen, C. J.; Pollard, D.

2013-12-01

Milankovitch theory proposes high-latitude summer insolation intensity paces the ice ages by controlling perennial snow cover amounts (Milankovitch, 1941). According to theory, the ~21 kyr cycle of precession should dominate the ice-volume records since it has the greatest influence on high-latitude summer insolation. Modeling experiments frequently support Milankovitch theory by attributing the majority of Northern Hemisphere high-latitude summer snowmelt to changes in the cycle of precession (e.g. Jackson and Broccoli, 2003). However, ice-volume proxy records, especially those of the Early Pleistocene (2.6-0.8 Ma), display variability with a period of ~41 kyr (Raymo and Lisiecki, 2005), indicative of insolation forcing from obliquity, which has a much smaller influence on summer insolation intensity than precession. Several hypotheses attempt to explain the discrepancies between Milkankovitch theory and the proxy records by invoking phenomena such as insolation gradients (Raymo and Nisancioglu, 2003), hemispheric offset (Raymo et al., 2006; Lee and Poulsen, 2009), and integrated summer energy (Huybers, 2006); however, all of these hypotheses contain caveats (Ruddiman, 2006) and have yet to be supported by modeling studies that use a complex GCM. To explore potential solutions to this '41 kyr problem,' we use an Earth system model composed of the GENESIS GCM and Land Surface model, the BIOME4 vegetation model, and the Pennsylvania State ice-sheet model. Using an asynchronous coupling technique, we run four idealized transient combinations of obliquity and precession, representing the orbital extremes of the Pleistocene (Berger and Loutre, 1991). Each experiment is run through several complete orbital cycles with a dynamic ice domain spanning North America and Greenland, and fixed preindustrial greenhouse-gas concentrations. For all orbital configurations, model results produce greater ice-volume spectral power at the frequency of obliquity despite significantly

Identification of Anisomerous Motor Imagery EEG Signals Based on Complex Algorithms.

Science.gov (United States)

Liu, Rensong; Zhang, Zhiwen; Duan, Feng; Zhou, Xin; Meng, Zixuan

2017-01-01

Motor imagery (MI) electroencephalograph (EEG) signals are widely applied in brain-computer interface (BCI). However, classified MI states are limited, and their classification accuracy rates are low because of the characteristics of nonlinearity and nonstationarity. This study proposes a novel MI pattern recognition system that is based on complex algorithms for classifying MI EEG signals. In electrooculogram (EOG) artifact preprocessing, band-pass filtering is performed to obtain the frequency band of MI-related signals, and then, canonical correlation analysis (CCA) combined with wavelet threshold denoising (WTD) is used for EOG artifact preprocessing. We propose a regularized common spatial pattern (R-CSP) algorithm for EEG feature extraction by incorporating the principle of generic learning. A new classifier combining the K -nearest neighbor (KNN) and support vector machine (SVM) approaches is used to classify four anisomerous states, namely, imaginary movements with the left hand, right foot, and right shoulder and the resting state. The highest classification accuracy rate is 92.5%, and the average classification accuracy rate is 87%. The proposed complex algorithm identification method can significantly improve the identification rate of the minority samples and the overall classification performance.

Identification of Anisomerous Motor Imagery EEG Signals Based on Complex Algorithms

Science.gov (United States)

Zhang, Zhiwen; Duan, Feng; Zhou, Xin; Meng, Zixuan

2017-01-01

Motor imagery (MI) electroencephalograph (EEG) signals are widely applied in brain-computer interface (BCI). However, classified MI states are limited, and their classification accuracy rates are low because of the characteristics of nonlinearity and nonstationarity. This study proposes a novel MI pattern recognition system that is based on complex algorithms for classifying MI EEG signals. In electrooculogram (EOG) artifact preprocessing, band-pass filtering is performed to obtain the frequency band of MI-related signals, and then, canonical correlation analysis (CCA) combined with wavelet threshold denoising (WTD) is used for EOG artifact preprocessing. We propose a regularized common spatial pattern (R-CSP) algorithm for EEG feature extraction by incorporating the principle of generic learning. A new classifier combining the K-nearest neighbor (KNN) and support vector machine (SVM) approaches is used to classify four anisomerous states, namely, imaginary movements with the left hand, right foot, and right shoulder and the resting state. The highest classification accuracy rate is 92.5%, and the average classification accuracy rate is 87%. The proposed complex algorithm identification method can significantly improve the identification rate of the minority samples and the overall classification performance. PMID:28874909

A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes.

Science.gov (United States)

Tukachinsky, Hanna; Lopez, Lyle V; Salic, Adrian

2010-10-18

In vertebrates, Hedgehog (Hh) signaling initiated in primary cilia activates the membrane protein Smoothened (Smo) and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu). It is unclear how Hh activates Gli and whether it directly regulates SuFu. We find that Hh stimulation quickly recruits endogenous SuFu-Gli complexes to cilia, suggesting a model in which Smo activates Gli by relieving inhibition by SuFu. In support of this model, we find that Hh causes rapid dissociation of the SuFu-Gli complex, thus allowing Gli to enter the nucleus and activate transcription. Activation of protein kinase A (PKA), an inhibitor of Hh signaling, blocks ciliary localization of SuFu-Gli complexes, which in turn prevents their dissociation by signaling. Our results support a simple mechanism in which Hh signals at vertebrate cilia cause dissociation of inactive SuFu-Gli complexes, a process inhibited by PKA.

A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes

Science.gov (United States)

Tukachinsky, Hanna; Lopez, Lyle V.

2010-01-01

In vertebrates, Hedgehog (Hh) signaling initiated in primary cilia activates the membrane protein Smoothened (Smo) and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu). It is unclear how Hh activates Gli and whether it directly regulates SuFu. We find that Hh stimulation quickly recruits endogenous SuFu–Gli complexes to cilia, suggesting a model in which Smo activates Gli by relieving inhibition by SuFu. In support of this model, we find that Hh causes rapid dissociation of the SuFu–Gli complex, thus allowing Gli to enter the nucleus and activate transcription. Activation of protein kinase A (PKA), an inhibitor of Hh signaling, blocks ciliary localization of SuFu–Gli complexes, which in turn prevents their dissociation by signaling. Our results support a simple mechanism in which Hh signals at vertebrate cilia cause dissociation of inactive SuFu–Gli complexes, a process inhibited by PKA. PMID:20956384

Improved Empirical Mode Decomposition Algorithm of Processing Complex Signal for IoT Application

OpenAIRE

Yang, Xianzhao; Cheng, Gengguo; Liu, Huikang

2015-01-01

Hilbert-Huang transform is widely used in signal analysis. However, due to its inadequacy in estimating both the maximum and the minimum values of the signals at both ends of the border, traditional HHT is easy to produce boundary error in empirical mode decomposition (EMD) process. To overcome this deficiency, this paper proposes an enhanced empirical mode decomposition algorithm for processing complex signal. Our work mainly focuses on two aspects. On one hand, we develop a technique to obt...

Use of multiple singular value decompositions to analyze complex intracellular calcium ion signals

KAUST Repository

Martinez, Josue G.

2009-12-01

We compare calcium ion signaling (Ca(2+)) between two exposures; the data are present as movies, or, more prosaically, time series of images. This paper describes novel uses of singular value decompositions (SVD) and weighted versions of them (WSVD) to extract the signals from such movies, in a way that is semi-automatic and tuned closely to the actual data and their many complexities. These complexities include the following. First, the images themselves are of no interest: all interest focuses on the behavior of individual cells across time, and thus, the cells need to be segmented in an automated manner. Second, the cells themselves have 100+ pixels, so that they form 100+ curves measured over time, so that data compression is required to extract the features of these curves. Third, some of the pixels in some of the cells are subject to image saturation due to bit depth limits, and this saturation needs to be accounted for if one is to normalize the images in a reasonably un-biased manner. Finally, the Ca(2+) signals have oscillations or waves that vary with time and these signals need to be extracted. Thus, our aim is to show how to use multiple weighted and standard singular value decompositions to detect, extract and clarify the Ca(2+) signals. Our signal extraction methods then lead to simple although finely focused statistical methods to compare Ca(2+) signals across experimental conditions.

Network modeling reveals prevalent negative regulatory relationships between signaling sectors in Arabidopsis immune signaling.

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Masanao Sato

Full Text Available Biological signaling processes may be mediated by complex networks in which network components and network sectors interact with each other in complex ways. Studies of complex networks benefit from approaches in which the roles of individual components are considered in the context of the network. The plant immune signaling network, which controls inducible responses to pathogen attack, is such a complex network. We studied the Arabidopsis immune signaling network upon challenge with a strain of the bacterial pathogen Pseudomonas syringae expressing the effector protein AvrRpt2 (Pto DC3000 AvrRpt2. This bacterial strain feeds multiple inputs into the signaling network, allowing many parts of the network to be activated at once. mRNA profiles for 571 immune response genes of 22 Arabidopsis immunity mutants and wild type were collected 6 hours after inoculation with Pto DC3000 AvrRpt2. The mRNA profiles were analyzed as detailed descriptions of changes in the network state resulting from the genetic perturbations. Regulatory relationships among the genes corresponding to the mutations were inferred by recursively applying a non-linear dimensionality reduction procedure to the mRNA profile data. The resulting static network model accurately predicted 23 of 25 regulatory relationships reported in the literature, suggesting that predictions of novel regulatory relationships are also accurate. The network model revealed two striking features: (i the components of the network are highly interconnected; and (ii negative regulatory relationships are common between signaling sectors. Complex regulatory relationships, including a novel negative regulatory relationship between the early microbe-associated molecular pattern-triggered signaling sectors and the salicylic acid sector, were further validated. We propose that prevalent negative regulatory relationships among the signaling sectors make the plant immune signaling network a "sector

The Hrs/Stam complex acts as a positive and negative regulator of RTK signaling during Drosophila development.

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Hélène Chanut-Delalande

Full Text Available BACKGROUND: Endocytosis is a key regulatory step of diverse signalling pathways, including receptor tyrosine kinase (RTK signalling. Hrs and Stam constitute the ESCRT-0 complex that controls the initial selection of ubiquitinated proteins, which will subsequently be degraded in lysosomes. It has been well established ex vivo and during Drosophila embryogenesis that Hrs promotes EGFR down regulation. We have recently isolated the first mutations of stam in flies and shown that Stam is required for air sac morphogenesis, a larval respiratory structure whose formation critically depends on finely tuned levels of FGFR activity. This suggest that Stam, putatively within the ESCRT-0 complex, modulates FGF signalling, a possibility that has not been examined in Drosophila yet. PRINCIPAL FINDINGS: Here, we assessed the role of the Hrs/Stam complex in the regulation of signalling activity during Drosophila development. We show that stam and hrs are required for efficient FGFR signalling in the tracheal system, both during cell migration in the air sac primordium and during the formation of fine cytoplasmic extensions in terminal cells. We find that stam and hrs mutant cells display altered FGFR/Btl localisation, likely contributing to impaired signalling levels. Electron microscopy analyses indicate that endosome maturation is impaired at distinct steps by hrs and stam mutations. These somewhat unexpected results prompted us to further explore the function of stam and hrs in EGFR signalling. We show that while stam and hrs together downregulate EGFR signalling in the embryo, they are required for full activation of EGFR signalling during wing development. CONCLUSIONS/SIGNIFICANCE: Our study shows that the ESCRT-0 complex differentially regulates RTK signalling, either positively or negatively depending on tissues and developmental stages, further highlighting the importance of endocytosis in modulating signalling pathways during development.

Precise signal amplitude retrieval for a non-homogeneous diagnostic beam using complex interferometry approach

Science.gov (United States)

Krupka, M.; Kalal, M.; Dostal, J.; Dudzak, R.; Juha, L.

2017-08-01

Classical interferometry became widely used method of active optical diagnostics. Its more advanced version, allowing reconstruction of three sets of data from just one especially designed interferogram (so called complex interferogram) was developed in the past and became known as complex interferometry. Along with the phase shift, which can be also retrieved using classical interferometry, the amplitude modifications of the probing part of the diagnostic beam caused by the object under study (to be called the signal amplitude) as well as the contrast of the interference fringes can be retrieved using the complex interferometry approach. In order to partially compensate for errors in the reconstruction due to imperfections in the diagnostic beam intensity structure as well as for errors caused by a non-ideal optical setup of the interferometer itself (including the quality of its optical components), a reference interferogram can be put to a good use. This method of interferogram analysis of experimental data has been successfully implemented in practice. However, in majority of interferometer setups (especially in the case of the ones employing the wavefront division) the probe and the reference part of the diagnostic beam would feature different intensity distributions over their respective cross sections. This introduces additional error into the reconstruction of the signal amplitude and the fringe contrast, which cannot be resolved using the reference interferogram only. In order to deal with this error it was found that additional separately recorded images of the intensity distribution of the probe and the reference part of the diagnostic beam (with no signal present) are needed. For the best results a sufficient shot-to-shot stability of the whole diagnostic system is required. In this paper, efficiency of the complex interferometry approach for obtaining the highest possible accuracy of the signal amplitude reconstruction is verified using the computer

The fidelity of synaptonemal complex assembly is regulated by a signaling mechanism that controls early meiotic progression.

Science.gov (United States)

Silva, Nicola; Ferrandiz, Nuria; Barroso, Consuelo; Tognetti, Silvia; Lightfoot, James; Telecan, Oana; Encheva, Vesela; Faull, Peter; Hanni, Simon; Furger, Andre; Snijders, Ambrosius P; Speck, Christian; Martinez-Perez, Enrique

2014-11-24

Proper chromosome segregation during meiosis requires the assembly of the synaptonemal complex (SC) between homologous chromosomes. However, the SC structure itself is indifferent to homology, and poorly understood mechanisms that depend on conserved HORMA-domain proteins prevent ectopic SC assembly. Although HORMA-domain proteins are thought to regulate SC assembly as intrinsic components of meiotic chromosomes, here we uncover a key role for nuclear soluble HORMA-domain protein HTP-1 in the quality control of SC assembly. We show that a mutant form of HTP-1 impaired in chromosome loading provides functionality of an HTP-1-dependent checkpoint that delays exit from homology search-competent stages until all homolog pairs are linked by the SC. Bypassing of this regulatory mechanism results in premature meiotic progression and licensing of homology-independent SC assembly. These findings identify nuclear soluble HTP-1 as a regulator of early meiotic progression, suggesting parallels with the mode of action of Mad2 in the spindle assembly checkpoint. Copyright © 2014 Elsevier Inc. All rights reserved.

Analysis of the Influence of Complexity and Entropy of Odorant on Fractal Dynamics and Entropy of EEG Signal

OpenAIRE

Hamidreza Namazi; Amin Akrami; Sina Nazeri; Vladimir V. Kulish

2016-01-01

An important challenge in brain research is to make out the relation between the features of olfactory stimuli and the electroencephalogram (EEG) signal. Yet, no one has discovered any relation between the structures of olfactory stimuli and the EEG signal. This study investigates the relation between the structures of EEG signal and the olfactory stimulus (odorant). We show that the complexity of the EEG signal is coupled with the molecular complexity of the odorant, where more structurally ...

MiRNA-mediated regulation of cell signaling and homeostasis in the early mouse embryo.

Science.gov (United States)

Pernaute, Barbara; Spruce, Thomas; Rodriguez, Tristan A; Manzanares, Miguel

2011-02-15

At the time of implantation the mouse embryo is composed of three tissues the epiblast, trophectoderm and primitive endoderm. As development progresses the epiblast goes on to form the foetus whilst the trophectoderm and primitive endoderm give rise to extra-embryonic structures with important roles in embryo patterning and nutrition. Dramatic changes in gene expression occur during early embryo development and these require regulation at different levels. miRNAs are small non coding RNAs that have emerged over the last decade as important post-transcriptional repressors of gene expression. The roles played by miRNAs during early mammalian development are only starting to be elucidated. In order to gain insight into the function of miRNAs in the different lineages of the early mouse embryo we have analysed in depth the phenotype of embryos and extra-embryonic stem cells mutant for the miRNA maturation protein Dicer. This study revealed that miRNAs are involved in regulating cell signaling and homeostasis in the early embryo. Specifically, we identified a role for miRNAs in regulating the Erk signaling pathway in the extra-embryonic endoderm, cell cycle progression in extra-embryonic tissues and apoptosis in the epiblast.

Strong Start Wraparound: Addressing the Complex Needs of Mothers in Early Recovery

Science.gov (United States)

Teel, M. Kay

2014-01-01

The Strong Start Study tested an innovative, High-Fidelity Wraparound intervention with families in early recovery from substance use. The Strong Start Wraparound model addressed the complex needs of pregnant and parenting women who were in early recovery to increase the protective factors of parental resilience, social connections, concrete…

Application of «Sensor signal analysis network» complex for distributed, time synchronized analysis of electromagnetic radiation

Science.gov (United States)

Mochalov, Vladimir; Mochalova, Anastasia

2017-10-01

The paper considers a developing software-hardware complex «Sensor signal analysis network» for distributed and time synchronized analysis of electromagnetic radiations. The areas of application and the main features of the complex are described. An example of application of the complex to monitor natural electromagnetic radiation sources is considered based on the data recorded in VLF range. A generalized functional scheme of stream analysis of signals by a complex functional node is suggested and its application for stream detection of atmospherics, whistlers and tweaks is considered.

Biphasic activation of liver regeneration-associated signals in an early stage after portal vein branch ligation

International Nuclear Information System (INIS)

Yokoyama, Shinya; Yokoyama, Yukihiro; Kawai, Toru; Kobayashi, Satoshi; Nagino, Masato; Oda, Koji; Nimura, Yuji; Sokabe, Masahiro

2006-01-01

At an early stage in liver regeneration, a variety of factors including transcriptional factors, proinflammatory cytokines, and proto-oncogenes are activated or expressed. However, these responses are affected by surgical stress in the conventional portal vein branch ligation model (PVL). We sought to determine the net activation of early regeneration-associated signals after PVL using a newly developed non-surgical stress PVL model. Male Wistar rats were assigned into two groups, a stress-PVL (sPVL) model with laparotomy and portal vein branch ligation, and a non-stress-PVL (nsPVL) one subjected to portal vein branch ligation 1 week after laparotomy in which the effects of surgical stress were subsided. The activation of transcriptional factors and expression of immediate early genes were analyzed at an early time point (within 24 h) by Western blotting and RT-PCR, respectively. A monophasic upregulation of nuclear factor-κB (NF-κB) and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) peaked at 3 h after sPVL was observed. In contrast, the expression pattern of these factors was biphasic (first peak at 0.5-1 h, second peak at 3-6 h) in nsPVL group. The expression pattern of immediate early genes showed a similar trend between sPVL and nsPVL. cDNA array analysis for the non-ligated lobe at 2 h after PVL revealed a much higher gene activation in sPVL than in nsPVL. These results indicate that previously observed activation pattern of regeneration-associated signals after PVL is significantly affected by the effect of laparotomy and our results using nsPVL model may more accurately represent liver regeneration-associated signal pattern

Close relationship between fMRI signals and transient heart rate changes accompanying K-complex. Simultaneous EEG/fMRI study

International Nuclear Information System (INIS)

Kan, Shigeyuki; Koike, Takahiko; Miyauchi, Satoru; Misaki, Masaya

2009-01-01

Combining functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) allows the investigation of spontaneous activities in the human brain. Recently, by using this technique, increases in fMRI signal accompanying transient EEG activities such as sleep spindles and slow waves were reported. Although these fMRI signal increases appear to arise as a result of the neural activities being reflected in the EEG, when the influence of physiological activities upon fMRI signals are taken into consideration, it is highly controversial that fMRI signal increases accompanying transient EEG activities reflect actual neural activities. In the present study, we conducted simultaneous fMRI and polysomnograph recording of 18 normal adults, to study the effect of transient heart rate changes after a K-complex on fMRI signals. Significant fMRI signal increase was observed in the cerebellum, the ventral thalamus, the dorsal part of the brainstem, the periventricular white matter and the ventricle (quadrigeminal cistern). On the other hand, significant fMRI signal decrease was observed only in the right insula. Moreover, intensities of fMRI signal increase that was accompanied by a K-complex correlated positively with the magnitude of heart rate changes after a K-complex. Previous studies have reported that K-complex is closely related with sympathetic nervous activity and that the attributes of perfusion regulation in the brain differ during wakefulness and sleep. By taking these findings into consideration, our present results indicate that a close relationship exists between a K-complex and the changes in cardio- and neurovascular regulations that are mediated by the autonomic nervous system during sleep; further, these results indicate that transient heart rate changes after a K-complex can affect the fMRI signal generated in certain brain regions. (author)

Nitric Oxide Synthase and Cyclooxygenase Pathways: A Complex Interplay in Cellular Signaling.

Science.gov (United States)

Sorokin, Andrey

2016-01-01

The cellular reaction to external challenges is a tightly regulated process consisting of integrated processes mediated by a variety of signaling molecules, generated as a result of modulation of corresponding biosynthetic systems. Both, nitric oxide synthase (NOS) and cyclooxygenase (COX) systems, consist of constitutive forms (NOS1, NOS3 and COX-1), which are mostly involved in housekeeping tasks, and inducible forms (NOS2 and COX-2), which shape the cellular response to stress and variety of bioactive agents. The complex interplay between NOS and COX pathways can be observed at least at three levels. Firstly, products of NOS and Cox systems can mediate the regulation and the expression of inducible forms (NOS2 and COX-2) in response of similar and dissimilar stimulus. Secondly, the reciprocal modulation of cyclooxygenase activity by nitric oxide and NOS activity by prostaglandins at the posttranslational level has been shown to occur. Mechanisms by which nitric oxide can modulate prostaglandin synthesis include direct S-nitrosylation of COX and inactivation of prostaglandin I synthase by peroxynitrite, product of superoxide reaction with nitric oxide. Prostaglandins, conversely, can promote an increased association of dynein light chain (DLC) (also known as protein inhibitor of neuronal nitric oxide synthase) with NOS1, thereby reducing its activity. The third level of interplay is provided by intracellular crosstalk of signaling pathways stimulated by products of NOS and COX which contributes significantly to the complexity of cellular signaling. Since modulation of COX and NOS pathways was shown to be principally involved in a variety of pathological conditions, the dissection of their complex relationship is needed for better understanding of possible therapeutic strategies. This review focuses on implications of interplay between NOS and COX for cellular function and signal integration.

n-Order and maximum fuzzy similarity entropy for discrimination of signals of different complexity: Application to fetal heart rate signals.

Science.gov (United States)

Zaylaa, Amira; Oudjemia, Souad; Charara, Jamal; Girault, Jean-Marc

2015-09-01

This paper presents two new concepts for discrimination of signals of different complexity. The first focused initially on solving the problem of setting entropy descriptors by varying the pattern size instead of the tolerance. This led to the search for the optimal pattern size that maximized the similarity entropy. The second paradigm was based on the n-order similarity entropy that encompasses the 1-order similarity entropy. To improve the statistical stability, n-order fuzzy similarity entropy was proposed. Fractional Brownian motion was simulated to validate the different methods proposed, and fetal heart rate signals were used to discriminate normal from abnormal fetuses. In all cases, it was found that it was possible to discriminate time series of different complexity such as fractional Brownian motion and fetal heart rate signals. The best levels of performance in terms of sensitivity (90%) and specificity (90%) were obtained with the n-order fuzzy similarity entropy. However, it was shown that the optimal pattern size and the maximum similarity measurement were related to intrinsic features of the time series. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of GFL–GFRα complexes: further evidence relating GFL bend angle to RET signalling

International Nuclear Information System (INIS)

Parkash, Vimal; Goldman, Adrian

2009-01-01

The second crystal structure of the GDNF-GFRα1 complex provides further evidence that GFL signalling through RET is determined by the bend angle in the GFL. Glial cell line-derived neurotrophic factor (GDNF) activates the receptor tyrosine kinase RET by binding to the GDNF-family receptor α1 (GFRα1) and forming the GDNF 2 –GFRα1 2 –RET 2 heterohexamer complex. A previous crystal structure of the GDNF 2 –GFRα1 2 complex suggested that differences in signalling in GDNF-family ligand (GFL) complexes might arise from differences in the bend angle between the two monomers in the GFL homodimer. Here, a 2.35 Å resolution structure of the GDNF 2 –GFRα1 2 complex crystallized with new cell dimensions is reported. The structure was refined to a final R factor of 22.5% (R free = 28%). The structures of both biological tetrameric complexes in the asymmetric unit are very similar to 2v5e and different from the artemin–GFRα3 structure, even though there is a small change in the structure of the GDNF. By comparison of all known GDNF and artemin structures, it is concluded that GDNF is more bent and more flexible than artemin and that this may be related to RET signalling. Comparisons also suggest that the differences between artemin and GDNF arise from the increased curvature of the artemin ‘fingers’, which both increases the buried surface area in the monomer–monomer interface and changes the intermonomer bend angle. From sequence comparison, it is suggested that neuturin (the second GFL) adopts an artemin-like conformation, while persephin has a different conformation to the other three

Stochastic effects as a force to increase the complexity of signaling networks

KAUST Repository

Kuwahara, Hiroyuki

2013-07-29

Cellular signaling networks are complex and appear to include many nonfunctional elements. Recently, it was suggested that nonfunctional interactions of proteins cause signaling noise, which, perhaps, shapes the signal transduction mechanism. However, the conditions under which molecular noise influences cellular information processing remain unclear. Here, we explore a large number of simple biological models of varying network sizes to understand the architectural conditions under which the interactions of signaling proteins can exhibit specific stochastic effects - called deviant effects - in which the average behavior of a biological system is substantially altered in the presence of molecular noise. We find that a small fraction of these networks does exhibit deviant effects and shares a common architectural feature whereas most of the networks show only insignificant levels of deviations. Interestingly, addition of seemingly unimportant interactions into protein networks gives rise to deviant effects.

Discrimination of Rock Fracture and Blast Events Based on Signal Complexity and Machine Learning

Directory of Open Access Journals (Sweden)

Zilong Zhou

2018-01-01

Full Text Available The automatic discrimination of rock fracture and blast events is complex and challenging due to the similar waveform characteristics. To solve this problem, a new method based on the signal complexity analysis and machine learning has been proposed in this paper. First, the permutation entropy values of signals at different scale factors are calculated to reflect complexity of signals and constructed into a feature vector set. Secondly, based on the feature vector set, back-propagation neural network (BPNN as a means of machine learning is applied to establish a discriminator for rock fracture and blast events. Then to evaluate the classification performances of the new method, the classifying accuracies of support vector machine (SVM, naive Bayes classifier, and the new method are compared, and the receiver operating characteristic (ROC curves are also analyzed. The results show the new method obtains the best classification performances. In addition, the influence of different scale factor q and number of training samples n on discrimination results is discussed. It is found that the classifying accuracy of the new method reaches the highest value when q = 8–15 or 8–20 and n=140.

Detection of early warning signals of forest mortality in California

Science.gov (United States)

Liu, Y.; Kumar, M.; Katul, G. G.; Porporato, A. M.

2017-12-01

Massive forest mortality was observed in California during the most recent drought. Owing to complex interactions of physiological mechanisms under stress, prediction of climate-induced forest mortality using dynamic global vegetation models remains fraught with uncertainty. Given that forest ecosystems approaching mortality tend to exhibit reduction in resilience, we evaluate the time-varying resilience from time series of satellite images to detect early warning signals (EWSs) of mortality. Four metrics of EWSs are used: (1) low greenness, (2) high empirical autocorrelation of greenness, (3) high autocorrelation inferred using a Bayesian dynamic linear model considering the influence of seasonality and climate conditions, and (4) low recovery rate inferred from the drift term in the Langevin equation describing stochastic dynamics. Spatial accuracy and lead-time of these EWSs are evaluated by comparing the EWSs against observed mortality from aerial surveys conducted by the US Forest Service. Our results show that most forested areas in California that underwent mortality exhibit a EWS with a lead time of three months to two years ahead of observed mortality. Notably, EWS is also detected in some areas without mortality, suggesting reduced resilience during drought. Furthermore, the influence of the previous drought (2007-2009) may have propagated into the recent drought (2012-2016) through reduced resilience, hence contributing to the massive forest mortality observed recently. Methodologies developed in this study for detection of EWS will improve the near-term predictability of forest mortality, thus providing crucial information for forest and water resource management.

A simple iterative independent component analysis algorithm for vibration source signal identification of complex structures

Directory of Open Access Journals (Sweden)

Dong-Sup Lee

2015-01-01

Full Text Available Independent Component Analysis (ICA, one of the blind source separation methods, can be applied for extracting unknown source signals only from received signals. This is accomplished by finding statistical independence of signal mixtures and has been successfully applied to myriad fields such as medical science, image processing, and numerous others. Nevertheless, there are inherent problems that have been reported when using this technique: insta- bility and invalid ordering of separated signals, particularly when using a conventional ICA technique in vibratory source signal identification of complex structures. In this study, a simple iterative algorithm of the conventional ICA has been proposed to mitigate these problems. The proposed method to extract more stable source signals having valid order includes an iterative and reordering process of extracted mixing matrix to reconstruct finally converged source signals, referring to the magnitudes of correlation coefficients between the intermediately separated signals and the signals measured on or nearby sources. In order to review the problems of the conventional ICA technique and to vali- date the proposed method, numerical analyses have been carried out for a virtual response model and a 30 m class submarine model. Moreover, in order to investigate applicability of the proposed method to real problem of complex structure, an experiment has been carried out for a scaled submarine mockup. The results show that the proposed method could resolve the inherent problems of a conventional ICA technique.

Complex Interplay of Hormonal Signals during Grape Berry Ripening

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Ana Margarida Fortes

2015-05-01

Full Text Available Grape and wine production and quality is extremely dependent on the fruit ripening process. Sensory and nutritional characteristics are important aspects for consumers and their development during fruit ripening involves complex hormonal control. In this review, we explored data already published on grape ripening and compared it with the hormonal regulation of ripening of other climacteric and non-climacteric fruits. The roles of abscisic acid, ethylene, and brassinosteroids as promoters of ripening are discussed, as well as the role of auxins, cytokinins, gibberellins, jasmonates, and polyamines as inhibitors of ripening. In particular, the recently described role of polyamine catabolism in grape ripening is discussed, together with its putative interaction with other hormones. Furthermore, other recent examples of cross-talk among the different hormones are presented, revealing a complex interplay of signals during grape development and ripening.

β-Catenin destruction complex-independent regulation of Hippo–YAP signaling by APC in intestinal tumorigenesis

Science.gov (United States)

Cai, Jing; Maitra, Anirban; Anders, Robert A.; Taketo, Makoto M.; Pan, Duojia

2015-01-01

Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the β-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo–YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the β-catenin destruction complex. PMID:26193883

GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation

Directory of Open Access Journals (Sweden)

Li Wang

2018-01-01

Full Text Available Precise control of gene expression during development is orchestrated by transcription factors and co-regulators including chromatin modifiers. How particular chromatin-modifying enzymes affect specific developmental processes is not well defined. Here, we report that GCN5, a histone acetyltransferase essential for embryonic development, is required for proper expression of multiple genes encoding components of the fibroblast growth factor (FGF signaling pathway in early embryoid bodies (EBs. Gcn5−/− EBs display deficient activation of ERK and p38, mislocalization of cytoskeletal components, and compromised capacity to differentiate toward mesodermal lineage. Genomic analyses identified seven genes as putative direct targets of GCN5 during early differentiation, four of which are cMYC targets. These findings established a link between GCN5 and the FGF signaling pathway and highlighted specific GCN5-MYC partnerships in gene regulation during early differentiation.

Fuzzy approximate entropy analysis of chaotic and natural complex systems: detecting muscle fatigue using electromyography signals.

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Xie, Hong-Bo; Guo, Jing-Yi; Zheng, Yong-Ping

2010-04-01

In the present contribution, a complexity measure is proposed to assess surface electromyography (EMG) in the study of muscle fatigue during sustained, isometric muscle contractions. Approximate entropy (ApEn) is believed to provide quantitative information about the complexity of experimental data that is often corrupted with noise, short data length, and in many cases, has inherent dynamics that exhibit both deterministic and stochastic behaviors. We developed an improved ApEn measure, i.e., fuzzy approximate entropy (fApEn), which utilizes the fuzzy membership function to define the vectors' similarity. Tests were conducted on independent, identically distributed (i.i.d.) Gaussian and uniform noises, a chirp signal, MIX processes, Rossler equation, and Henon map. Compared with the standard ApEn, the fApEn showed better monotonicity, relative consistency, and more robustness to noise when characterizing signals with different complexities. Performance analysis on experimental EMG signals demonstrated that the fApEn significantly decreased during the development of muscle fatigue, which is a similar trend to that of the mean frequency (MNF) of the EMG signal, while the standard ApEn failed to detect this change. Moreover, fApEn of EMG demonstrated a better robustness to the length of the analysis window in comparison with the MNF of EMG. The results suggest that the fApEn of an EMG signal may potentially become a new reliable method for muscle fatigue assessment and be applicable to other short noisy physiological signal analysis.

Guard Cell Signal Transduction Network: Advances in Understanding Abscisic Acid, CO2, and Ca2+ Signaling

KAUST Repository

Kim, Tae-Houn

2010-05-04

Stomatal pores are formed by pairs of specialized epidermal guard cells and serve as major gateways for both CO2 influx into plants from the atmosphere and transpirational water loss of plants. Because they regulate stomatal pore apertures via integration of both endogenous hormonal stimuli and environmental signals, guard cells have been highly developed as a model system to dissect the dynamics and mechanisms of plant-cell signaling. The stress hormone ABA and elevated levels of CO2 activate complex signaling pathways in guard cells that are mediated by kinases/phosphatases, secondary messengers, and ion channel regulation. Recent research in guard cells has led to a new hypothesis for how plants achieve specificity in intracellular calcium signaling: CO2 and ABA enhance (prime) the calcium sensitivity of downstream calcium-signaling mechanisms. Recent progress in identification of early stomatal signaling components are reviewed here, including ABA receptors and CO2-binding response proteins, as well as systems approaches that advance our understanding of guard cell-signaling mechanisms.

Guard Cell Signal Transduction Network: Advances in Understanding Abscisic Acid, CO2, and Ca2+ Signaling

KAUST Repository

Kim, Tae-Houn; Bö hmer, Maik; Hu, Honghong; Nishimura, Noriyuki; Schroeder, Julian I.

2010-01-01

Stomatal pores are formed by pairs of specialized epidermal guard cells and serve as major gateways for both CO2 influx into plants from the atmosphere and transpirational water loss of plants. Because they regulate stomatal pore apertures via integration of both endogenous hormonal stimuli and environmental signals, guard cells have been highly developed as a model system to dissect the dynamics and mechanisms of plant-cell signaling. The stress hormone ABA and elevated levels of CO2 activate complex signaling pathways in guard cells that are mediated by kinases/phosphatases, secondary messengers, and ion channel regulation. Recent research in guard cells has led to a new hypothesis for how plants achieve specificity in intracellular calcium signaling: CO2 and ABA enhance (prime) the calcium sensitivity of downstream calcium-signaling mechanisms. Recent progress in identification of early stomatal signaling components are reviewed here, including ABA receptors and CO2-binding response proteins, as well as systems approaches that advance our understanding of guard cell-signaling mechanisms.

Assembly of Slx4 signaling complexes behind DNA replication forks.

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Balint, Attila; Kim, TaeHyung; Gallo, David; Cussiol, Jose Renato; Bastos de Oliveira, Francisco M; Yimit, Askar; Ou, Jiongwen; Nakato, Ryuichiro; Gurevich, Alexey; Shirahige, Katsuhiko; Smolka, Marcus B; Zhang, Zhaolei; Brown, Grant W

2015-08-13

Obstructions to replication fork progression, referred to collectively as DNA replication stress, challenge genome stability. In Saccharomyces cerevisiae, cells lacking RTT107 or SLX4 show genome instability and sensitivity to DNA replication stress and are defective in the completion of DNA replication during recovery from replication stress. We demonstrate that Slx4 is recruited to chromatin behind stressed replication forks, in a region that is spatially distinct from that occupied by the replication machinery. Slx4 complex formation is nucleated by Mec1 phosphorylation of histone H2A, which is recognized by the constitutive Slx4 binding partner Rtt107. Slx4 is essential for recruiting the Mec1 activator Dpb11 behind stressed replication forks, and Slx4 complexes are important for full activity of Mec1. We propose that Slx4 complexes promote robust checkpoint signaling by Mec1 by stably recruiting Dpb11 within a discrete domain behind the replication fork, during DNA replication stress. © 2015 The Authors.

Kurtosis based blind source extraction of complex noncircular signals with application in EEG artifact removal in real-time

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Soroush eJavidi

2011-10-01

Full Text Available A new class of complex domain blind source extraction (BSE algorithms suitable for the extraction of both circular and noncircular complex signals is proposed. This is achieved through sequential extraction based on the degree of kurtosis and in the presence of noncircular measurement noise. The existence and uniqueness analysis of the solution is followed by a study of fast converging variants of the algorithm. The performance is first assessed through simulations on well understood benchmark signals, followed by a case study on real-time artifact removal from EEG signals, verified using both qualitative and quantitative metrics. The results illustrate the power of the proposed approach in real-time blind extraction of general complex-valued sources.

Ethylene Regulates Levels of Ethylene Receptor/CTR1 Signaling Complexes in Arabidopsis thaliana*

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Shakeel, Samina N.; Gao, Zhiyong; Amir, Madiha; Chen, Yi-Feng; Rai, Muneeza Iqbal; Haq, Noor Ul; Schaller, G. Eric

2015-01-01

The plant hormone ethylene is perceived by a five-member family of receptors in Arabidopsis thaliana. The receptors function in conjunction with the Raf-like kinase CTR1 to negatively regulate ethylene signal transduction. CTR1 interacts with multiple members of the receptor family based on co-purification analysis, interacting more strongly with receptors containing a receiver domain. Levels of membrane-associated CTR1 vary in response to ethylene, doing so in a post-transcriptional manner that correlates with ethylene-mediated changes in levels of the ethylene receptors ERS1, ERS2, EIN4, and ETR2. Interactions between CTR1 and the receptor ETR1 protect ETR1 from ethylene-induced turnover. Kinetic and dose-response analyses support a model in which two opposing factors control levels of the ethylene receptor/CTR1 complexes. Ethylene stimulates the production of new complexes largely through transcriptional induction of the receptors. However, ethylene also induces turnover of receptors, such that levels of ethylene receptor/CTR1 complexes decrease at higher ethylene concentrations. Implications of this model for ethylene signaling are discussed. PMID:25814663

Normalization of informatisation parameter on airfield light-signal bar at flights in complex meteorological conditions

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П.В. Попов

2005-03-01

Full Text Available  The technique of maintenance of the set level of flights safetivness is developed by normalization of informatisation parameters functional groups of light-signal lightings at technological stages of interaction of crew of the airplane with the airfield light-signals bar at flights in a complex weathercast conditions.

Zebrafish foxo3b negatively regulates canonical Wnt signaling to affect early embryogenesis.

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Xun-wei Xie

Full Text Available FOXO genes are involved in many aspects of development and vascular homeostasis by regulating cell apoptosis, proliferation, and the control of oxidative stress. In addition, FOXO genes have been showed to inhibit Wnt/β-catenin signaling by competing with T cell factor to bind to β-catenin. However, how important of this inhibition in vivo, particularly in embryogenesis is still unknown. To demonstrate the roles of FOXO genes in embryogenesis will help us to further understand their relevant physiological functions. Zebrafish foxo3b gene, an orthologue of mammalian FOXO3, was expressed maternally and distributed ubiquitously during early embryogenesis and later restricted to brain. After morpholino-mediated knockdown of foxo3b, the zebrafish embryos exhibited defects in axis and neuroectoderm formation, suggesting its critical role in early embryogenesis. The embryo-developmental marker gene staining at different stages, phenotype analysis and rescue assays revealed that foxo3b acted its role through negatively regulating both maternal and zygotic Wnt/β-catenin signaling. Moreover, we found that foxo3b could interact with zebrafish β-catenin1 and β-catenin2 to suppress their transactivation in vitro and in vivo, further confirming its role relevant to the inhibition of Wnt/β-catenin signaling. Taken together, we revealed that foxo3b played a very important role in embryogenesis and negatively regulated maternal and zygotic Wnt/β-catenin signaling by directly interacting with both β-catenin1 and β-catenin2. Our studies provide an in vivo model for illustrating function of FOXO transcription factors in embryogenesis.

Excessive Leucine-mTORC1-Signalling of Cow Milk-Based Infant Formula: The Missing Link to Understand Early Childhood Obesity.

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Melnik, Bodo C

2012-01-01

Increased protein supply by feeding cow-milk-based infant formula in comparison to lower protein content of human milk is a well-recognized major risk factor of childhood obesity. However, there is yet no conclusive biochemical concept explaining the mechanisms of formula-induced childhood obesity. It is the intention of this article to provide the biochemical link between leucine-mediated signalling of mammalian milk proteins and adipogenesis as well as early adipogenic programming. Leucine has been identified as the predominant signal transducer of mammalian milk, which stimulates the nutrient-sensitive kinase mammalian target of rapamycin complex 1 (mTORC1). Leucine thus functions as a maternal-neonatal relay for mTORC1-dependent neonatal β-cell proliferation and insulin secretion. The mTORC1 target S6K1 plays a pivotal role in stimulation of mesenchymal stem cells to differentiate into adipocytes and to induce insulin resistance. It is of most critical concern that infant formulas provide higher amounts of leucine in comparison to human milk. Exaggerated leucine-mediated mTORC1-S6K1 signalling induced by infant formulas may thus explain increased adipogenesis and generation of lifelong elevated adipocyte numbers. Attenuation of mTORC1 signalling of infant formula by leucine restriction to physiologic lower levels of human milk offers a great chance for the prevention of childhood obesity and obesity-related metabolic diseases.

Association between increased EEG signal complexity and cannabis dependence.

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Laprevote, Vincent; Bon, Laura; Krieg, Julien; Schwitzer, Thomas; Bourion-Bedes, Stéphanie; Maillard, Louis; Schwan, Raymund

2017-12-01

Both acute and regular cannabis use affects the functioning of the brain. While several studies have demonstrated that regular cannabis use can impair the capacity to synchronize neural assemblies during specific tasks, less is known about spontaneous brain activity. This can be explored by measuring EEG complexity, which reflects the spontaneous variability of human brain activity. A recent study has shown that acute cannabis use can affect that complexity. Since the characteristics of cannabis use can affect the impact on brain functioning, this study sets out to measure EEG complexity in regular cannabis users with or without dependence, in comparison with healthy controls. We recruited 26 healthy controls, 25 cannabis users without cannabis dependence and 14 cannabis users with cannabis dependence, based on DSM IV TR criteria. The EEG signal was extracted from at least 250 epochs of the 500ms pre-stimulation phase during a visual evoked potential paradigm. Brain complexity was estimated using Lempel-Ziv Complexity (LZC), which was compared across groups by non-parametric Kruskall-Wallis ANOVA. The analysis revealed a significant difference between the groups, with higher LZC in participants with cannabis dependence than in non-dependent cannabis users. There was no specific localization of this effect across electrodes. We showed that cannabis dependence is associated to an increased spontaneous brain complexity in regular users. This result is in line with previous results in acute cannabis users. It may reflect increased randomness of neural activity in cannabis dependence. Future studies should explore whether this effect is permanent or diminishes with cannabis cessation. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Metal Dependence of Signal Transmission through MolecularQuantum-Dot Cellular Automata (QCA: A Theoretical Studyon Fe, Ru, and Os Mixed-Valence Complexes

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Ken Tokunaga

2010-08-01

Full Text Available Dynamic behavior of signal transmission through metal complexes [L5M-BL-ML5]5+ (M=Fe, Ru, Os, BL=pyrazine (py, 4,4’-bipyridine (bpy, L=NH3, which are simplified models of the molecular quantum-dot cellular automata (molecular QCA, is discussed from the viewpoint of one-electron theory, density functional theory. It is found that for py complexes, the signal transmission time (tst is Fe(0.6 fs < Os(0.7 fs < Ru(1.1 fs and the signal amplitude (A is Fe(0.05 e < Os(0.06 e < Ru(0.10 e. For bpy complexes, tst and A are Fe(1.4 fs < Os(1.7 fs < Ru(2.5 fs and Os(0.11 e < Ru(0.12 e complexes generally have stronger signal amplitude, but waste longer time for signal transmission than py complexes. Among all complexes, Fe complex with bpy BL shows the best result. These results are discussed from overlap integral and energy gap of molecular orbitals.

Weak signal transmission in complex networks and its application in detecting connectivity.

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Liang, Xiaoming; Liu, Zonghua; Li, Baowen

2009-10-01

We present a network model of coupled oscillators to study how a weak signal is transmitted in complex networks. Through both theoretical analysis and numerical simulations, we find that the response of other nodes to the weak signal decays exponentially with their topological distance to the signal source and the coupling strength between two neighboring nodes can be figured out by the responses. This finding can be conveniently used to detect the topology of unknown network, such as the degree distribution, clustering coefficient and community structure, etc., by repeatedly choosing different nodes as the signal source. Through four typical networks, i.e., the regular one dimensional, small world, random, and scale-free networks, we show that the features of network can be approximately given by investigating many fewer nodes than the network size, thus our approach to detect the topology of unknown network may be efficient in practical situations with large network size.

Assembly of Oligomeric Death Domain Complexes during Toll Receptor Signaling*

OpenAIRE

Moncrieffe, Martin C.; Grossmann, J. Günter; Gay, Nicholas J.

2008-01-01

The Drosophila Toll receptor is activated by the endogenous protein ligand Spätzle in response to microbial stimuli in immunity and spatial cues during embryonic development. Downstream signaling is mediated by the adaptor proteins Tube, the kinase Pelle, and the Drosophila homologue of myeloid differentiation primary response protein (dMyD88). Here we have characterized heterodimeric (dMyD88-Tube) and heterotrimeric (dMyD88-Tube-Pelle) death domain complexes. We show ...

Early-warning signals for an outbreak of the influenza pandemic

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Ren, Di; Gao, Jie

2011-12-01

Over the course of human history, influenza pandemics have been seen as major disasters, so studies on the influenza virus have become an important issue for many experts and scholars. Comprehensive research has been performed over the years on the biological properties, chemical characteristics, external environmental factors and other aspects of the virus, and some results have been achieved. Based on the chaos game representation walk model, this paper uses the time series analysis method to study the DNA sequences of the influenza virus from 1913 to 2010, and works out the early-warning signals indicator value for the outbreak of an influenza pandemic. The variances in the CGR walk sequences for the pandemic years (or + -1 to 2 years) are significantly higher than those for the adjacent years, while those in the non-pandemic years are usually smaller. In this way we can provide an influenza early-warning mechanism so that people can take precautions and be well prepared prior to a pandemic.

Early warning signals of desertification transitions in semiarid ecosystems.

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Corrado, Raffaele; Cherubini, Anna Maria; Pennetta, Cecilia

2014-12-01

The identification of early warning signals for regime shifts in ecosystems is of crucial importance given their impact in terms of economic and social effects. We present here the results of a theoretical study on the desertification transition in semiarid ecosystems under external stress. We performed numerical simulations based on a stochastic cellular automaton model, and we studied the dynamics of the vegetation clusters in terms of percolation theory, assumed as an effective tool for analyzing the geometrical properties of the clusters. Focusing on the role played by the strength of external stresses, measured by the mortality rate m, we followed the progressive degradation of the ecosystem for increasing m, identifying different stages: first, the fragmentation transition occurring at relatively low values of m, then the desertification transition at higher mortality rates, and finally the full desertification transition corresponding to the extinction of the vegetation and the almost complete degradation of the soil, attained at the maximum value of m. For each transition we calculated the spanning probabilities as functions of m and the percolation thresholds according to different spanning criteria. The identification of the different thresholds is proposed as an useful tool for monitoring the increasing degradation of real-world finite-size systems. Moreover, we studied the time fluctuations of the sizes of the biggest clusters of vegetated and nonvegetated cells over the entire range of mortality values. The change of sign in the skewness of the size distributions, occurring at the fragmentation threshold for the biggest vegetation cluster and at the desertification threshold for the nonvegetated cluster, offers new early warning signals for desertification. Other new and robust indicators are given by the maxima of the root-mean-square deviation of the distributions, which are attained respectively inside the fragmentation interval, for the vegetated

The mediator complex in genomic and non-genomic signaling in cancer.

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Weber, Hannah; Garabedian, Michael J

2018-05-01

Mediator is a conserved, multi-subunit macromolecular machine divided structurally into head, middle, and tail modules, along with a transiently associating kinase module. Mediator functions as an integrator of transcriptional regulatory activity by interacting with DNA-bound transcription factors and with RNA polymerase II (Pol II) to both activate and repress gene expression. Mediator has been shown to affect multiple steps in transcription, including chromatin looping between enhancers and promoters, pre-initiation complex formation, transcriptional elongation, and mRNA splicing. Individual Mediator subunits participate in regulation of gene expression by the estrogen and androgen receptors and are altered in a number of endocrine cancers, including breast and prostate cancer. In addition to its role in genomic signaling, MED12 has been implicated in non-genomic signaling by interacting with and activating TGF-beta receptor 2 in the cytoplasm. Recent structural studies have revealed extensive inter-domain interactions and complex architecture of the Mediator-Pol II complex, suggesting that Mediator is capable of reorganizing its conformation and composition to fit cellular needs. We propose that alterations in Mediator subunit expression that occur in various cancers could impact the organization and function of Mediator, resulting in changes in gene expression that promote malignancy. A better understanding of the role of Mediator in cancer could reveal new approaches to the diagnosis and treatment of Mediator-dependent endocrine cancers, especially in settings of therapy resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene expression profiling reveals different molecular patterns in G-protein coupled receptor signaling pathways between early- and late-onset preeclampsia.

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Liang, Mengmeng; Niu, Jianmin; Zhang, Liang; Deng, Hua; Ma, Jian; Zhou, Weiping; Duan, Dongmei; Zhou, Yuheng; Xu, Huikun; Chen, Longding

2016-04-01

Early-onset preeclampsia and late-onset preeclampsia have been regarded as two different phenotypes with heterogeneous manifestations; To gain insights into the pathogenesis of the two traits, we analyzed the gene expression profiles in preeclamptic placentas. A whole genome-wide microarray was used to determine the gene expression profiles in placental tissues from patients with early-onset (n = 7; 36 weeks) preeclampsia and their controls who delivered preterm (n = 5; 36 weeks). Genes were termed differentially expressed if they showed a fold-change ≥ 2 and q-value preeclampsia (177 genes were up-regulated and 450 were down-regulated). Gene ontology analysis identified significant alterations in several biological processes; the top two were immune response and cell surface receptor linked signal transduction. Among the cell surface receptor linked signal transduction-related, differentially expressed genes, those involved in the G-protein coupled receptor protein signaling pathway were significantly enriched. G-protein coupled receptor signaling pathway related genes, such as GPR124 and MRGPRF, were both found to be down-regulated in early-onset preeclampsia. The results were consistent with those of western blotting that the abundance of GPR124 was lower in early-onset compared with late-onset preeclampsia. The different gene expression profiles reflect the different levels of transcription regulation between the two conditions and supported the hypothesis that they are separate disease entities. Moreover, the G-protein coupled receptor signaling pathway related genes may contribute to the mechanism underlying early- and late-onset preeclampsia. Copyright © 2016 Elsevier Ltd. All rights reserved.

Palaeomagnetism of the Early Permian Mount Leyshon Intrusive Complex and Tuckers Igneous Complex, North Queensland, Australia

Science.gov (United States)

Clark, D. A.; Lackie, M. A.

2003-06-01

This study provides reliable, precisely defined and well-dated Early Permian (286 +/- 6 Ma) palaeomagnetic poles for Australia from the Mount Leyshon Intrusive Complex (MLIC) and the Tuckers Igneous Complex (TIC). Both complexes are associated with prominent negative magnetic anomalies, indicating the presence of rocks carrying stable remanence of reverse polarity, with a Koenigsberger ratio greater than unity. The characteristic remanence carried by the intrusive phases and by locally remagnetized, contact-metamorphosed host rocks is always of reverse polarity, consistent with acquisition during the Permo-Carboniferous (Kiaman) Reverse Superchron. The corresponding palaeopoles confirm that Australia occupied high latitudes in the Early Permian. The pole positions are: MLIC: lat. = 43.2 °S, long. = 137.3 °E dp = 6.0°, dm = 6.4° Q= 6; TIC: lat. = 47.5 °S, long. = 143.0 °E, dp = 6.0°, dm = 6.6° Q= 6. Permian palaeomagnetic overprinting is detectable at considerable distances from the MLIC (2-3 km), well beyond the zone of visible alteration. The primary nature of the Early Permian palaeomagnetic signature is established by full baked contact/aureole tests at both localities. Other new data from Australia are consistent with the poles reported here. Comparison of the Australian, African and South American Apparent Polar Wander Paths (APWP) suggests that mean Permian and Triassic poles from West Gondwana, particularly from South America, are biased by remagnetization in the Jurassic-Cretaceous and that the Late Palaeozoic-Mesozoic APWP for Gondwana is best defined by Australian data. The Australian APWP exhibits substantial movement through the Mesozoic. Provided only that the time-averaged palaeofield was zonal, the Early Triassic palaeomagnetic data from Australia provide an important palaeogeographic constraint that the south geographic pole was within, or very close to, SE Australia around 240 Ma. The new Early Permian poles are apparently more consistent

Enabling complex genetic circuits to respond to extrinsic environmental signals.

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Hoynes-O'Connor, Allison; Shopera, Tatenda; Hinman, Kristina; Creamer, John Philip; Moon, Tae Seok

2017-07-01

Genetic circuits have the potential to improve a broad range of metabolic engineering processes and address a variety of medical and environmental challenges. However, in order to engineer genetic circuits that can meet the needs of these real-world applications, genetic sensors that respond to relevant extrinsic and intrinsic signals must be implemented in complex genetic circuits. In this work, we construct the first AND and NAND gates that respond to temperature and pH, two signals that have relevance in a variety of real-world applications. A previously identified pH-responsive promoter and a temperature-responsive promoter were extracted from the E. coli genome, characterized, and modified to suit the needs of the genetic circuits. These promoters were combined with components of the type III secretion system in Salmonella typhimurium and used to construct a set of AND gates with up to 23-fold change. Next, an antisense RNA was integrated into the circuit architecture to invert the logic of the AND gate and generate a set of NAND gates with up to 1168-fold change. These circuits provide the first demonstration of complex pH- and temperature-responsive genetic circuits, and lay the groundwork for the use of similar circuits in real-world applications. Biotechnol. Bioeng. 2017;114: 1626-1631. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Complexity Analysis of Resting-State MEG Activity in Early-Stage Parkinson's Disease Patients

NARCIS (Netherlands)

Gómez, C.; Olde Dubbelink, K.T.E.; Stam, C.J.; Abasolo, D.; Berendse, H.W.; Hornero, R.

2011-01-01

The aim of the present study was to analyze resting-state brain activity in patients with Parkinson's disease (PD), a degenerative disorder of the nervous system. Magnetoencephalography (MEG) signals were recorded with a 151-channel whole-head radial gradiometer MEG system in 18 early-stage

Complex motion of a vehicle through a series of signals controlled by power-law phase

Science.gov (United States)

Nagatani, Takashi

2017-07-01

We study the dynamic motion of a vehicle moving through the series of traffic signals controlled by the position-dependent phase of power law. All signals are controlled by both cycle time and position-dependent phase. The dynamic model of the vehicular motion is described in terms of the nonlinear map. The vehicular motion varies in a complex manner by varying cycle time for various values of the power of the position-dependent phase. The vehicle displays the periodic motion with a long cycle for the integer power of the phase, while the vehicular motion exhibits the very complex behavior for the non-integer power of the phase.

An Adaptive Noise Cancellation System Based on Linear and Widely Linear Complex Valued Least Mean Square Algorithms for Removing Electrooculography Artifacts from Electroencephalography Signals

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Engin Cemal MENGÜÇ

2018-03-01

Full Text Available In this study, an adaptive noise cancellation (ANC system based on linear and widely linear (WL complex valued least mean square (LMS algorithms is designed for removing electrooculography (EOG artifacts from electroencephalography (EEG signals. The real valued EOG and EEG signals (Fp1 and Fp2 given in dataset are primarily expressed as a complex valued signal in the complex domain. Then, using the proposed ANC system, the EOG artifacts are eliminated in the complex domain from the EEG signals. Expression of these signals in the complex domain allows us to remove EOG artifacts from two EEG channels simultaneously. Moreover, in this study, it has been shown that the complex valued EEG signal exhibits noncircular behavior, and in the case, the WL-CLMS algorithm enhances the performance of the ANC system compared to real-valued LMS and CLMS algorithms. Simulation results support the proposed approach.

RssAB signaling coordinates early development of surface multicellularity in Serratia marcescens.

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Yu-Huan Tsai

Full Text Available Bacteria can coordinate several multicellular behaviors in response to environmental changes. Among these, swarming and biofilm formation have attracted significant attention for their correlation with bacterial pathogenicity. However, little is known about when and where the signaling occurs to trigger either swarming or biofilm formation. We have previously identified an RssAB two-component system involved in the regulation of swarming motility and biofilm formation in Serratia marcescens. Here we monitored the RssAB signaling status within single cells by tracing the location of the translational fusion protein EGFP-RssB following development of swarming or biofilm formation. RssAB signaling is specifically activated before surface migration in swarming development and during the early stage of biofilm formation. The activation results in the release of RssB from its cognate inner membrane sensor kinase, RssA, to the cytoplasm where the downstream gene promoters are located. Such dynamic localization of RssB requires phosphorylation of this regulator. By revealing the temporal activation of RssAB signaling following development of surface multicellular behavior, our findings contribute to an improved understanding of how bacteria coordinate their lifestyle on a surface.

Transcriptomic signatures of transfer cells in early developing nematode feeding cells of Arabidopsis focused on auxin and ethylene signalling.

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Javier eCabrera

2014-03-01

Full Text Available Phyto-endoparasitic nematodes induce specialized feeding cells (NFCs in their hosts, termed syncytia and giant cells (GCs for cyst and root-knot nematodes, respectively. They differ in their ontogeny and global transcriptional signatures, but both develop cell wall ingrowths to facilitate high rates of apoplastic/symplastic solute exchange showing transfer cell (TC characteristics. Regulatory signals for TC differentiation are not still well known. The two-component signalling system (2CS and reactive oxygen species are proposed as inductors of TC identity, while, 2CSs-related genes are not major contributors to differential gene expression in early developing NFCs. Additionally, transcriptomic and functional studies have assigned a major role to auxin and ethylene as regulatory signals on early developing TCs. Genes encoding proteins with similar functions expressed in both early developing NFCs and typical TCs are putatively involved in upstream or downstream responses mediated by auxin and ethylene. Yet, no function directly associated to the TCs identity of NFCs, such as the formation of cell wall ingrowths is described for most of them. Thus we reviewed similarities between transcriptional changes observed during the early stages of NFCs formation and those described during differentiation of TCs to hypothesize about putative signals leading to TC-like differentiation of NFCs with particular emphasis on auxin an ethylene.

Receptor density balances signal stimulation and attenuation in membrane-assembled complexes of bacterial chemotaxis signaling proteins

Science.gov (United States)

Besschetnova, Tatiana Y.; Montefusco, David J.; Asinas, Abdalin E.; Shrout, Anthony L.; Antommattei, Frances M.; Weis, Robert M.

2008-01-01

All cells possess transmembrane signaling systems that function in the environment of the lipid bilayer. In the Escherichia coli chemotaxis pathway, the binding of attractants to a two-dimensional array of receptors and signaling proteins simultaneously inhibits an associated kinase and stimulates receptor methylation—a slower process that restores kinase activity. These two opposing effects lead to robust adaptation toward stimuli through a physical mechanism that is not understood. Here, we provide evidence of a counterbalancing influence exerted by receptor density on kinase stimulation and receptor methylation. Receptor signaling complexes were reconstituted over a range of defined surface concentrations by using a template-directed assembly method, and the kinase and receptor methylation activities were measured. Kinase activity and methylation rates were both found to vary significantly with surface concentration—yet in opposite ways: samples prepared at high surface densities stimulated kinase activity more effectively than low-density samples, whereas lower surface densities produced greater methylation rates than higher densities. FRET experiments demonstrated that the cooperative change in kinase activity coincided with a change in the arrangement of the membrane-associated receptor domains. The counterbalancing influence of density on receptor methylation and kinase stimulation leads naturally to a model for signal regulation that is compatible with the known logic of the E. coli pathway. Density-dependent mechanisms are likely to be general and may operate when two or more membrane-related processes are influenced differently by the two-dimensional concentration of pathway elements. PMID:18711126

Early intervention services of children with physical disabilities: complexity of child and family needs.

Science.gov (United States)

Ziviani, Jenny; Darlington, Yvonne; Feeney, Rachel; Rodger, Sylvia; Watter, Pauline

2014-04-01

To gain insight into the special issues confronting parents when accessing early intervention for children with physical disabilities where child and/or family characteristics indicate complex needs within the unique Australian context. Qualitative interviews with families receiving early intervention for their children with physical disabilities (N=10). Families with complex circumstances such as having children with high support needs, those from culturally and linguistically diverse backgrounds, and single-parent families were recruited to the study. Families where parents had mental or health issues, parents/other family members had an identified disability, and/or where families lived in regional or rural locations were also purposively sampled. Participants highlighted issues around (i) the nature of early intervention services provided; (ii) the ways in which services were structured; and (ii) managing their child's needs/planning into the future. Parents stressed the importance of having access to a variety of early intervention services aside from therapy. They also emphasised the need for greater clarity about what to expect from services, the intensity of therapy, other services they could access and how long they would be able to receive these. Despite their complex circumstances and needs, participants' experiences of accessing early intervention services were largely consistent with the broader research literature. Of the parents interviewed, those with health problems and single mothers expressed most apprehension about managing their child's needs and planning for the future. © 2013 Occupational Therapy Australia.

Maternal xNorrin, a canonical Wnt signaling agonist and TGF-β antagonist, controls early neuroectoderm specification in Xenopus.

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Suhong Xu

Full Text Available Dorsal-ventral specification in the amphibian embryo is controlled by β-catenin, whose activation in all dorsal cells is dependent on maternal Wnt11. However, it remains unknown whether other maternally secreted factors contribute to β-catenin activation in the dorsal ectoderm. Here, we show that maternal Xenopus Norrin (xNorrin promotes anterior neural tissue formation in ventralized embryos. Conversely, when xNorrin function is inhibited, early canonical Wnt signaling in the dorsal ectoderm and the early expression of the zygotic neural inducers Chordin, Noggin, and Xnr3 are severely suppressed, causing the loss of anterior structures. In addition, xNorrin potently inhibits BMP- and Nodal/Activin-related functions through direct binding to the ligands. Moreover, a subset of Norrin mutants identified in humans with Norrie disease retain Wnt activation but show defective inhibition of Nodal/Activin-related signaling in mesoderm induction, suggesting that this disinhibition causes Norrie disease. Thus, xNorrin is an unusual molecule that acts on two major signaling pathways, Wnt and TGF-β, in opposite ways and is essential for early neuroectoderm specification.

Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway.

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Nakada, Daisuke; Hirano, Yukinori; Sugimoto, Katsunori

2004-11-01

The large protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), orchestrate DNA damage checkpoint pathways. In budding yeast, ATM and ATR homologs are encoded by TEL1 and MEC1, respectively. The Mre11 complex consists of two highly related proteins, Mre11 and Rad50, and a third protein, Xrs2 in budding yeast or Nbs1 in mammals. The Mre11 complex controls the ATM/Tel1 signaling pathway in response to double-strand break (DSB) induction. We show here that the Mre11 complex functions together with exonuclease 1 (Exo1) in activation of the Mec1 signaling pathway after DNA damage and replication block. Mec1 controls the checkpoint responses following UV irradiation as well as DSB induction. Correspondingly, the Mre11 complex and Exo1 play an overlapping role in activation of DSB- and UV-induced checkpoints. The Mre11 complex and Exo1 collaborate in producing long single-stranded DNA (ssDNA) tails at DSB ends and promote Mec1 association with the DSBs. The Ddc1-Mec3-Rad17 complex associates with sites of DNA damage and modulates the Mec1 signaling pathway. However, Ddc1 association with DSBs does not require the function of the Mre11 complex and Exo1. Mec1 controls checkpoint responses to stalled DNA replication as well. Accordingly, the Mre11 complex and Exo1 contribute to activation of the replication checkpoint pathway. Our results provide a model in which the Mre11 complex and Exo1 cooperate in generating long ssDNA tracts and thereby facilitate Mec1 association with sites of DNA damage or replication block.

Jasmonate signalling in Arabidopsis involves SGT1b-HSP70-HSP90 chaperone complexes.

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Zhang, Xue-Cheng; Millet, Yves A; Cheng, Zhenyu; Bush, Jenifer; Ausubel, Frederick M

Plant hormones play pivotal roles in growth, development and stress responses. Although it is essential to our understanding of hormone signalling, how plants maintain a steady state level of hormone receptors is poorly understood. We show that mutation of the Arabidopsis thaliana co-chaperone SGT1b impairs responses to the plant hormones jasmonate, auxin and gibberellic acid, but not brassinolide and abscisic acid, and that SGT1b and its homologue SGT1a are involved in maintaining the steady state levels of the F-box proteins COI1 and TIR1, receptors for jasmonate and auxin, respectively. The association of SGT1b with COI1 is direct and is independent of the Arabidopsis SKP1 protein, ASK1. We further show that COI1 is a client protein of SGT1b-HSP70-HSP90 chaperone complexes and that the complexes function in hormone signalling by stabilizing the COI1 protein. This study extends the SGT1b-HSP90 client protein list and broadens the functional scope of SGT1b-HSP70-HSP90 chaperone complexes.

Signaling and Adaptation Modulate the Dynamics of the Photosensoric Complex of Natronomonas pharaonis.

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Philipp S Orekhov

2015-10-01

Full Text Available Motile bacteria and archaea respond to chemical and physical stimuli seeking optimal conditions for survival. To this end transmembrane chemo- and photoreceptors organized in large arrays initiate signaling cascades and ultimately regulate the rotation of flagellar motors. To unravel the molecular mechanism of signaling in an archaeal phototaxis complex we performed coarse-grained molecular dynamics simulations of a trimer of receptor/transducer dimers, namely NpSRII/NpHtrII from Natronomonas pharaonis. Signaling is regulated by a reversible methylation mechanism called adaptation, which also influences the level of basal receptor activation. Mimicking two extreme methylation states in our simulations we found conformational changes for the transmembrane region of NpSRII/NpHtrII which resemble experimentally observed light-induced changes. Further downstream in the cytoplasmic domain of the transducer the signal propagates via distinct changes in the dynamics of HAMP1, HAMP2, the adaptation domain and the binding region for the kinase CheA, where conformational rearrangements were found to be subtle. Overall these observations suggest a signaling mechanism based on dynamic allostery resembling models previously proposed for E. coli chemoreceptors, indicating similar properties of signal transduction for archaeal photoreceptors and bacterial chemoreceptors.

The SH2 Domain–Containing Proteins in 21 Species Establish the Provenance and Scope of Phosphotyrosine Signaling in Eukaryotes

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Liu, Bernard A.; Shah, Eshana; Jablonowski, Karl; Stergachis, Andrew; Engelmann, Brett; Nash, Piers D.

2014-01-01

The Src homology 2 (SH2) domains are participants in metazoan signal transduction, acting as primary mediators for regulated protein-protein interactions with tyrosine-phosphorylated substrates. Here, we describe the origin and evolution of SH2 domain proteins by means of sequence analysis from 21 eukaryotic organisms from the basal unicellular eukaryotes, where SH2 domains first appeared, through the multicellular animals and increasingly complex metazoans. On the basis of our results, SH2 domains and phosphotyrosine signaling emerged in the early Unikonta, and the numbers of SH2 domains expanded in the choanoflagellate and metazoan lineages with the development of tyrosine kinases, leading to rapid elaboration of phosphotyrosine signaling in early multicellular animals. Our results also indicated that SH2 domains coevolved and the number of the domains expanded alongside protein tyrosine kinases and tyrosine phosphatases, thereby coupling phosphotyrosine signaling to downstream signaling networks. Gene duplication combined with domain gain or loss produced novel SH2-containing proteins that function within phosphotyrosine signaling, which likely have contributed to diversity and complexity in metazoans. We found that intra- and intermolecular interactions within and between SH2 domain proteins increased in prevalence along with organismal complexity and may function to generate more highly connected and robust phosphotyrosine signaling networks. PMID:22155787

Early-warning signals for an outbreak of the influenza pandemic

International Nuclear Information System (INIS)

Ren Di; Gao Jie

2011-01-01

Over the course of human history, influenza pandemics have been seen as major disasters, so studies on the influenza virus have become an important issue for many experts and scholars. Comprehensive research has been performed over the years on the biological properties, chemical characteristics, external environmental factors and other aspects of the virus, and some results have been achieved. Based on the chaos game representation walk model, this paper uses the time series analysis method to study the DNA sequences of the influenza virus from 1913 to 2010, and works out the early-warning signals indicator value for the outbreak of an influenza pandemic. The variances in the CGR walk sequences for the pandemic years (or + −1 to 2 years) are significantly higher than those for the adjacent years, while those in the non-pandemic years are usually smaller. In this way we can provide an influenza early-warning mechanism so that people can take precautions and be well prepared prior to a pandemic. (interdisciplinary physics and related areas of science and technology)

Pseudo-stokes vector from complex signal representation of a speckle pattern and its applications to micro-displacement measurement

DEFF Research Database (Denmark)

Wang, W.; Ishijima, R.; Matsuda, A.

2010-01-01

As an improvement of the intensity correlation used widely in conventional electronic speckle photography, we propose a new technique for displacement measurement based on correlating Stokes-like parameters derivatives for transformed speckle patterns. The method is based on a Riesz transform of ...... are presented that demonstrate the validity and advantage of the proposed pseudo-Stokes vector correlation technique over conventional intensity correlation technique....... of the intensity speckle pattern, which converts the original real-valued signal into a complex signal. In closest analogy to the polarisation of a vector wave, the Stokes-like vector constructed from the spatial derivative of the generated complex signal has been applied for correlation. Experimental results...

A lossless multichannel bio-signal compression based on low-complexity joint coding scheme for portable medical devices.

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Kim, Dong-Sun; Kwon, Jin-San

2014-09-18

Research on real-time health systems have received great attention during recent years and the needs of high-quality personal multichannel medical signal compression for personal medical product applications are increasing. The international MPEG-4 audio lossless coding (ALS) standard supports a joint channel-coding scheme for improving compression performance of multichannel signals and it is very efficient compression method for multi-channel biosignals. However, the computational complexity of such a multichannel coding scheme is significantly greater than that of other lossless audio encoders. In this paper, we present a multichannel hardware encoder based on a low-complexity joint-coding technique and shared multiplier scheme for portable devices. A joint-coding decision method and a reference channel selection scheme are modified for a low-complexity joint coder. The proposed joint coding decision method determines the optimized joint-coding operation based on the relationship between the cross correlation of residual signals and the compression ratio. The reference channel selection is designed to select a channel for the entropy coding of the joint coding. The hardware encoder operates at a 40 MHz clock frequency and supports two-channel parallel encoding for the multichannel monitoring system. Experimental results show that the compression ratio increases by 0.06%, whereas the computational complexity decreases by 20.72% compared to the MPEG-4 ALS reference software encoder. In addition, the compression ratio increases by about 11.92%, compared to the single channel based bio-signal lossless data compressor.

CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Complexes to Regulate Innate Immune Signaling

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Matous Hrdinka

2016-03-01

Full Text Available Innate immune signaling relies on the deposition of non-degradative polyubiquitin at receptor-signaling complexes, but how these ubiquitin modifications are regulated by deubiquitinases remains incompletely understood. Met1-linked ubiquitin (Met1-Ub is assembled by the linear ubiquitin assembly complex (LUBAC, and this is counteracted by the Met1-Ub-specific deubiquitinase OTULIN, which binds to the catalytic LUBAC subunit HOIP. In this study, we report that HOIP also interacts with the deubiquitinase CYLD but that CYLD does not regulate ubiquitination of LUBAC components. Instead, CYLD limits extension of Lys63-Ub and Met1-Ub conjugated to RIPK2 to restrict signaling and cytokine production. Accordingly, Met1-Ub and Lys63-Ub were individually required for productive NOD2 signaling. Our study thus suggests that LUBAC, through its associated deubiquitinases, coordinates the deposition of not only Met1-Ub but also Lys63-Ub to ensure an appropriate response to innate immune receptor activation.

Switch I-dependent allosteric signaling in a G-protein chaperone-B12 enzyme complex.

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Campanello, Gregory C; Lofgren, Michael; Yokom, Adam L; Southworth, Daniel R; Banerjee, Ruma

2017-10-27

G-proteins regulate various processes ranging from DNA replication and protein synthesis to cytoskeletal dynamics and cofactor assimilation and serve as models for uncovering strategies deployed for allosteric signal transduction. MeaB is a multifunctional G-protein chaperone, which gates loading of the active 5'-deoxyadenosylcobalamin cofactor onto methylmalonyl-CoA mutase (MCM) and precludes loading of inactive cofactor forms. MeaB also safeguards MCM, which uses radical chemistry, against inactivation and rescues MCM inactivated during catalytic turnover by using the GTP-binding energy to offload inactive cofactor. The conserved switch I and II signaling motifs used by G-proteins are predicted to mediate allosteric regulation in response to nucleotide binding and hydrolysis in MeaB. Herein, we targeted conserved residues in the MeaB switch I motif to interrogate the function of this loop. Unexpectedly, the switch I mutations had only modest effects on GTP binding and on GTPase activity and did not perturb stability of the MCM-MeaB complex. However, these mutations disrupted multiple MeaB chaperone functions, including cofactor editing, loading, and offloading. Hence, although residues in the switch I motif are not essential for catalysis, they are important for allosteric regulation. Furthermore, single-particle EM analysis revealed, for the first time, the overall architecture of the MCM-MeaB complex, which exhibits a 2:1 stoichiometry. These EM studies also demonstrate that the complex exhibits considerable conformational flexibility. In conclusion, the switch I element does not significantly stabilize the MCM-MeaB complex or influence the affinity of MeaB for GTP but is required for transducing signals between MeaB and MCM. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Klotho Regulates 14-3-3ζ Monomerization and Binding to the ASK1 Signaling Complex in Response to Oxidative Stress.

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Reynolds K Brobey

Full Text Available The reactive oxygen species (ROS-sensitive apoptosis signal-regulating kinase 1 (ASK1 signaling complex is a key regulator of p38 MAPK activity, a major modulator of stress-associated with aging disorders. We recently reported that the ratio of free ASK1 to the complex-bound ASK1 is significantly decreased in Klotho-responsive manner and that Klotho-deficient tissues have elevated levels of free ASK1 which coincides with increased oxidative stress. Here, we tested the hypothesis that: 1 covalent interactions exist among three identified proteins constituting the ASK1 signaling complex; 2 in normal unstressed cells the ASK1, 14-3-3ζ and thioredoxin (Trx proteins simultaneously engage in a tripartite complex formation; 3 Klotho's stabilizing effect on the complex relied solely on 14-3-3ζ expression and its apparent phosphorylation and dimerization changes. To verify the hypothesis, we performed 14-3-3ζ siRNA knock-down experiments in conjunction with cell-based assays to measure ASK1-client protein interactions in the presence and absence of Klotho, and with or without an oxidant such as rotenone. Our results show that Klotho activity induces posttranslational modifications in the complex targeting 14-3-3ζ monomer/dimer changes to effectively protect against ASK1 oxidation and dissociation. This is the first observation implicating all three proteins constituting the ASK1 signaling complex in close proximity.

Spatial early warning signals in a lake manipulation

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Butitta, Vince L.; Carpenter, Stephen R.; Loken, Luke; Pace, Michael L.; Stanley, Emily H.

2017-01-01

Rapid changes in state have been documented for many of Earth's ecosystems. Despite a growing toolbox of methods for detecting declining resilience or early warning indicators (EWIs) of ecosystem transitions, these methods have rarely been evaluated in whole-ecosystem trials using reference ecosystems. In this study, we experimentally tested EWIs of cyanobacteria blooms based on changes in the spatial structure of a lake. We induced a cyanobacteria bloom by adding nutrients to an experimental lake and mapped fine-resolution spatial patterning of cyanobacteria using a mobile sensor platform. Prior to the bloom, we detected theoretically predicted spatial EWIs based on variance and spatial autocorrelation, as well as a new index based on the extreme values. Changes in EWIs were not discernible in an unenriched reference lake. Despite the fluid environment of a lake where spatial heterogeneity driven by biological processes may be overwhelmed by physical mixing, spatial EWIs detected an approaching bloom suggesting the utility of spatial metrics for signaling ecological thresholds.

A complex symbol signal-to-noise ratio estimator and its performance

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Feria, Y.

1994-01-01

This article presents an algorithm for estimating the signal-to-noise ratio (SNR) of signals that contain data on a downconverted suppressed carrier or the first harmonic of a square-wave subcarrier. This algorithm can be used to determine the performance of the full-spectrum combiner for the Galileo S-band (2.2- to 2.3-GHz) mission by measuring the input and output symbol SNR. A performance analysis of the algorithm shows that the estimator can estimate the complex symbol SNR using 10,000 symbols at a true symbol SNR of -5 dB with a mean of -4.9985 dB and a standard deviation of 0.2454 dB, and these analytical results are checked by simulations of 100 runs with a mean of -5.06 dB and a standard deviation of 0.2506 dB.

Involvement of ethylene biosynthesis and signalling in fruit set and early fruit development in zucchini squash (Cucurbita pepo L.).

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Martínez, Cecilia; Manzano, Susana; Megías, Zoraida; Garrido, Dolores; Picó, Belén; Jamilena, Manuel

2013-09-22

We have identified a kind of parthenocarpy in zucchini squash which is associated with an incomplete andromonoecy, i.e. a partial conversion of female into bisexual flowers. Given that andromonoecy in this and other cucurbit species is caused by a reduction of ethylene production in the female flower, the associated parthenocarpic development of the fruit suggested the involvement of ethylene in fruit set and early fruit development. We have compared the production of ethylene as well as the expression of 13 ethylene biosynthesis and signalling genes in pollinated and unpollinated ovaries/fruits of two cultivars, one of which is parthenocarpic (Cavili), while the other is non-parthenocarpic (Tosca). In the latter, unpollinated ovaries show an induction of ethylene biosynthesis and ethylene signal transduction pathway genes three days after anthesis, which is concomitant with the initiation of fruit abortion and senescence. Fruit set and early fruit development in pollinated flowers of both cultivars and unpollinated flowers of Cavili is coupled with low ethylene biosynthesis and signalling, which would also explain the partial andromonoecy in the parthenocarpic genotype. The reduction of ethylene production in the ovary cosegregates with parthenocarpy and partial andromonoecy in the selfing progeny of Cavili. Moreover, the induction of ethylene in anthesis (by ethephon treatments) reduced the percentage of bisexual parthenocarpic flowers in Cavili, while the inhibition of ethylene biosynthesis or response (by AVG and STS treatments) induces not only andromonoecy but also the parthenocarpic development of the fruit in both cultivars. Results demonstrate that a reduction of ethylene production or signalling in the zucchini flower is able to induce fruit set and early fruit development, and therefore that ethylene is actively involved in fruit set and early fruit development. Auxin and TIBA treatments, inducing fruit set and early fruit development in this species

Parent-offspring conflict theory, signaling of need, and weight gain in early life.

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Wells, Jonathan C

2003-06-01

Human growth in early life has major implications for fitness. During this period, the mother regulates the growth of her offspring through placental nutrition and lactation. However, parent-offspring conflict theory predicts that offspring are selected to demand more resources than the mother is selected to provide. This general issue has prompted the development of begging theory, which attempts to find the optimal levels of offspring demand and parental provisioning. Several models have been proposed to account for begging behavior, whether by biochemical or behavioral pathways, including: (1) blackmail of parents; (2) scramble competition between multiple offspring; (3) honest signaling of nutritional need; and (4) honest signaling of offspring worth. These models are all supported by data from nonhuman animals, with species varying according to which model is relevant. This paper examines the evidence that human suckling and crying signal nutritional demand, need, and worth to the mother. While suckling provides hormonal stimulation of breast milk production and signals hunger, crying fulfills a different role, with evidence suggesting that it signals both worth and need for resources (nutrition and thermoregulation). The role of signaling in nutritional demand is examined in the context of three common health problems that have traditionally been assumed to have physiological rather than behavioral causes: excess weight gain, failure to thrive, and colic. The value of such an evolutionary approach lies in its potential to enhance behavioral management of these conditions.

A curcumin-based TPA four-branched copper(II) complex probe for in vivo early tumor detection

Energy Technology Data Exchange (ETDEWEB)

Pi, Zongxin [Department of Chemical and Chemical Engineering, Hefei Normal University, Hefei 230001 (China); Wang, Jiafeng; Jiang, Bo [Department of Pharmacy, Anhui University of Chinese Medicine, Hefei 230038 (China); Cheng, Gang [Department of Chemical and Chemical Engineering, Hefei Normal University, Hefei 230001 (China); Zhou, Shuangsheng, E-mail: zshuangsheng@126.com [Department of Pharmacy, Anhui University of Chinese Medicine, Hefei 230038 (China); Center of Modern Experimental Technology, Anhui University, Hefei 230038 (China)

2015-01-01

A multibranched Cu(II) complex CuL{sub 2} curcumin-based was synthesized and characterized by single-crystal X-ray diffraction analysis. The photophysical properties of the complex have been investigated both experimentally and theoretically. The results show that the target complex exhibits higher quantum yield and larger two-photon absorption (TPA) cross-section in the near infrared (NIR) region compared with its free ligand. The cell imaging studies in vitro and in vivo reveal that the complex shows good photostability and excellent tumor targeting capability to tested cancerous cells, which can be potentially used for early tumor detection. - Graphical abstract: A multibranched Cu(II) complex was prepared from curcumin. The photophysical properties of the obtained complex have been investigated. The results exhibit that the complex has high capability to test cancerous cells and can distinguish between the cancerous and noncancerous cells, which should be potentially used for early tumor detection. - Highlights: • A novel multi-branched copper complex was synthesized. • The obtained compounds exhibited obvious TPA in high polar solvents. • The complex is a low toxicity at low-micromolar concentrations. • The complex exhibits larger TPA cross-section and brighter TPF imaging. • The complex has excellent targeting capability to tested cancerous cells.

FGF signaling via MAPK is required early and improves Activin A-induced definitive endoderm formation from human embryonic stem cells

International Nuclear Information System (INIS)

Sui, Lina; Mfopou, Josué K.; Geens, Mieke; Sermon, Karen; Bouwens, Luc

2012-01-01

Highlights: ► Deep study the FGF signaling role during DE specification in the context of hESCs. ► DE differentiation from hESCs has an early dependence on FGF signaling. ► A serum-free DE protocol is developed based on the findings. ► The DE cells showed potential to differentiate into pancreatic progenitor cells. -- Abstract: Considering their unlimited proliferation and pluripotency properties, human embryonic stem cells (hESCs) constitute a promising resource applicable for cell replacement therapy. To facilitate this clinical translation, it is critical to study and understand the early stage of hESCs differentiation wherein germ layers are defined. In this study, we examined the role of FGF signaling in Activin A-induced definitive endoderm (DE) differentiation in the absence of supplemented animal serum. We found that activated FGF/MAPK signaling is required at the early time point of Activin A-induced DE formation. In addition, FGF activation increased the number of DE cells compared to Activin A alone. These DE cells could further differentiate into PDX1 and NKX6.1 positive pancreatic progenitors in vitro. We conclude that Activin A combined with FGF/MAPK signaling efficiently induce DE cells in the absence of serum. These findings improve our understanding of human endoderm formation, and constitute a step forward in the generation of clinical grade hESCs progenies for cell therapy.

Hurst Exponent Analysis of Resting-State fMRI Signal Complexity across the Adult Lifespan

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Jianxin Dong

2018-02-01

Full Text Available Exploring functional information among various brain regions across time enables understanding of healthy aging process and holds great promise for age-related brain disease diagnosis. This paper proposed a method to explore fractal complexity of the resting-state functional magnetic resonance imaging (rs-fMRI signal in the human brain across the adult lifespan using Hurst exponent (HE. We took advantage of the examined rs-fMRI data from 116 adults 19 to 85 years of age (44.3 ± 19.4 years, 49 females from NKI/Rockland sample. Region-wise and voxel-wise analyses were performed to investigate the effects of age, gender, and their interaction on complexity. In region-wise analysis, we found that the healthy aging is accompanied by a loss of complexity in frontal and parietal lobe and increased complexity in insula, limbic, and temporal lobe. Meanwhile, differences in HE between genders were found to be significant in parietal lobe (p = 0.04, corrected. However, there was no interaction between gender and age. In voxel-wise analysis, the significant complexity decrease with aging was found in frontal and parietal lobe, and complexity increase was found in insula, limbic lobe, occipital lobe, and temporal lobe with aging. Meanwhile, differences in HE between genders were found to be significant in frontal, parietal, and limbic lobe. Furthermore, we found age and sex interaction in right parahippocampal gyrus (p = 0.04, corrected. Our findings reveal HE variations of the rs-fMRI signal across the human adult lifespan and show that HE may serve as a new parameter to assess healthy aging process.

Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes.

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Baltensperger, K; Kozma, L M; Cherniack, A D; Klarlund, J K; Chawla, A; Banerjee, U; Czech, M P

1993-06-25

Signal transmission by insulin involves tyrosine phosphorylation of a major insulin receptor substrate (IRS-1) and exchange of Ras-bound guanosine diphosphate for guanosine triphosphate. Proteins containing Src homology 2 and 3 (SH2 and SH3) domains, such as the p85 regulatory subunit of phosphatidylinositol-3 kinase and growth factor receptor-bound protein 2 (GRB2), bind tyrosine phosphate sites on IRS-1 through their SH2 regions. Such complexes in COS cells were found to contain the heterologously expressed putative guanine nucleotide exchange factor encoded by the Drosophila son of sevenless gene (dSos). Thus, GRB2, p85, or other proteins with SH2-SH3 adapter sequences may link Sos proteins to IRS-1 signaling complexes as part of the mechanism by which insulin activates Ras.

Microscopic insight into thermodynamics of conformational changes of SAP-SLAM complex in signal transduction cascade

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Samanta, Sudipta; Mukherjee, Sanchita

2017-04-01

The signalling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, associate with SLAM-associated protein (SAP)-related molecules, composed of single SH2 domain architecture. SAP activates Src-family kinase Fyn after SLAM ligation, resulting in a SLAM-SAP-Fyn complex, where, SAP binds the Fyn SH3 domain that does not involve canonical SH3 or SH2 interactions. This demands insight into this SAP mediated signalling cascade. Thermodynamics of the conformational changes are extracted from the histograms of dihedral angles obtained from the all-atom molecular dynamics simulations of this structurally well characterized SAP-SLAM complex. The results incorporate the binding induced thermodynamic changes of individual amino acid as well as the secondary structural elements of the protein and the solvent. Stabilization of the peptide partially comes through a strong hydrogen bonding network with the protein, while hydrophobic interactions also play a significant role where the peptide inserts itself into a hydrophobic cavity of the protein. SLAM binding widens SAP's second binding site for Fyn, which is the next step in the signal transduction cascade. The higher stabilization and less fluctuation of specific residues of SAP in the Fyn binding site, induced by SAP-SLAM complexation, emerge as the key structural elements to trigger the recognition of SAP by the SH3 domain of Fyn. The thermodynamic quantification of the protein due to complexation not only throws deeper understanding in the established mode of SAP-SLAM interaction but also assists in the recognition of the relevant residues of the protein responsible for alterations in its activity.

Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling

Science.gov (United States)

Honda, Kenya; Yanai, Hideyuki; Mizutani, Tatsuaki; Negishi, Hideo; Shimada, Naoya; Suzuki, Nobutaka; Ohba, Yusuke; Takaoka, Akinori; Yeh, Wen-Chen; Taniguchi, Tadatsugu

2004-01-01

Toll-like receptor (TLR) activation is central to immunity, wherein the activation of the TLR9 subfamily members TLR9 and TLR7 results in the robust induction of type I IFNs (IFN-α/β) by means of the MyD88 adaptor protein. However, it remains unknown how the TLR signal “input” can be processed through MyD88 to “output” the induction of the IFN genes. Here, we demonstrate that the transcription factor IRF-7 interacts with MyD88 to form a complex in the cytoplasm. We provide evidence that this complex also involves IRAK4 and TRAF6 and provides the foundation for the TLR9-dependent activation of the IFN genes. The complex defined in this study represents an example of how the coupling of the signaling adaptor and effector kinase molecules together with the transcription factor regulate the processing of an extracellular signal to evoke its versatile downstream transcriptional events in a cell. Thus, we propose that this molecular complex may function as a cytoplasmic transductional-transcriptional processor. PMID:15492225

Very early onset inflammatory bowel disease: Investigation of the IL-10 signaling pathway in Iranian children

NARCIS (Netherlands)

Nemati, Shahram; Teimourian, Shahram; Tabrizi, Mina; Najafi, Mehri; Dara, Naghi; Imanzadeh, Farid; Ahmadi, Mitra; Aghdam, Maryam Kazemi; Tavassoli, Mohmoud; Rohani, Pejman; Madani, Seyyed Ramin; de Boer, Martin; Kuijpers, T. W.; Roos, Dirk

2017-01-01

Background & aim: Comparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as

Analysis of Maneuvering Targets with Complex Motions by Two-Dimensional Product Modified Lv's Distribution for Quadratic Frequency Modulation Signals.

Science.gov (United States)

Jing, Fulong; Jiao, Shuhong; Hou, Changbo; Si, Weijian; Wang, Yu

2017-06-21

For targets with complex motion, such as ships fluctuating with oceanic waves and high maneuvering airplanes, azimuth echo signals can be modeled as multicomponent quadratic frequency modulation (QFM) signals after migration compensation and phase adjustment. For the QFM signal model, the chirp rate (CR) and the quadratic chirp rate (QCR) are two important physical quantities, which need to be estimated. For multicomponent QFM signals, the cross terms create a challenge for detection, which needs to be addressed. In this paper, by employing a novel multi-scale parametric symmetric self-correlation function (PSSF) and modified scaled Fourier transform (mSFT), an effective parameter estimation algorithm is proposed-referred to as the Two-Dimensional product modified Lv's distribution (2D-PMLVD)-for QFM signals. The 2D-PMLVD is simple and can be easily implemented by using fast Fourier transform (FFT) and complex multiplication. These measures are analyzed in the paper, including the principle, the cross term, anti-noise performance, and computational complexity. Compared to the other three representative methods, the 2D-PMLVD can achieve better anti-noise performance. The 2D-PMLVD, which is free of searching and has no identifiability problems, is more suitable for multicomponent situations. Through several simulations and analyses, the effectiveness of the proposed estimation algorithm is verified.

Extracellular signal-regulated kinase activation is required for consolidation and reconsolidation of memory at an early stage of ontogenesis.

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Languille, Solène; Davis, Sabrina; Richer, Paulette; Alcacer, Cristina; Laroche, Serge; Hars, Bernard

2009-11-01

The ability to form long-term memories exists very early during ontogeny; however, the properties of early memory processes, brain structures involved and underlying cellular mechanisms are poorly defined. Here, we examine the role of extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase/ERK signaling cascade, which is crucial for adult memory, in the consolidation and reconsolidation of an early memory using a conditioned taste aversion paradigm in 3-day-old rat pups. We show that intraperitoneal injection of SL327, the upstream mitogen-activated protein kinase kinase inhibitor, impairs both consolidation and reconsolidation of early memory, leaving short-term memory after acquisition and after reactivation intact. The amnesic effect of SL327 diminishes with increasing delays after acquisition and reactivation. Biochemical analyses revealed ERK hyperphosphorylation in the amygdala but not the hippocampus following acquisition, suggesting functional activation of the amygdala as early as post-natal day 3, although there was no clear evidence for amygdalar ERK activation after reactivation. These results indicate that, despite an immature brain, the basic properties of memory and at least some of the molecular mechanisms and brain structures implicated in aversion memory share a number of similarities with the adult and emerge very early during ontogeny.

Flickering gives early warning signals of a critical transition to a eutrophic lake state : Letter

NARCIS (Netherlands)

Wang, R.; Dearing, J.; Langdon, P.G.; Zhang, E.; Yang, X.; Dakos, V.; Scheffer, M.

2012-01-01

There is a recognized need to anticipate tipping points, or critical transitions, in social–ecological systems1, 2. Studies of mathematical3, 4, 5 and experimental6, 7, 8, 9 systems have shown that systems may ‘wobble’ before a critical transition. Such early warning signals10 may be due to the

Jasmonate signaling is activated in the very early stages of iron deficiency responses in rice roots.

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Kobayashi, Takanori; Itai, Reiko Nakanishi; Senoura, Takeshi; Oikawa, Takaya; Ishimaru, Yasuhiro; Ueda, Minoru; Nakanishi, Hiromi; Nishizawa, Naoko K

2016-07-01

Under low iron availability, plants induce the expression of various genes involved in iron uptake and translocation at the transcriptional level. This iron deficiency response is affected by various plant hormones, but the roles of jasmonates in this response are not well-known. We investigated the involvement of jasmonates in rice iron deficiency responses. High rates of jasmonate-inducible genes were induced during the very early stages of iron deficiency treatment in rice roots. Many jasmonate-inducible genes were also negatively regulated by the ubiquitin ligases OsHRZ1 and OsHRZ2 and positively regulated by the transcription factor IDEF1. Ten out of 35 genes involved in jasmonate biosynthesis and signaling were rapidly induced at 3 h of iron deficiency treatment, and this induction preceded that of known iron deficiency-inducible genes involved in iron uptake and translocation. Twelve genes involved in jasmonate biosynthesis and signaling were also upregulated in HRZ-knockdown roots. Endogenous concentrations of jasmonic acid and jasmonoyl isoleucine tended to be rapidly increased in roots in response to iron deficiency treatment, whereas these concentrations were higher in HRZ-knockdown roots under iron-sufficient conditions. Analysis of the jasmonate-deficient cpm2 mutant revealed that jasmonates repress the expression of many iron deficiency-inducible genes involved in iron uptake and translocation under iron sufficiency, but this repression is partly canceled under an early stage of iron deficiency. These results indicate that jasmonate signaling is activated during the very early stages of iron deficiency, which is partly regulated by IDEF1 and OsHRZs.

Blind identification and separation of complex-valued signals

CERN Document Server

Moreau, Eric

2013-01-01

Blind identification consists of estimating a multi-dimensional system only through the use of its output, and source separation, the blind estimation of the inverse of the system. Estimation is generally carried out using different statistics of the output. The authors of this book consider the blind identification and source separation problem in the complex-domain, where the available statistical properties are richer and include non-circularity of the sources - underlying components. They define identifiability conditions and present state-of-the-art algorithms that are based on algebraic methods as well as iterative algorithms based on maximum likelihood theory. Contents 1. Mathematical Preliminaries. 2. Estimation by Joint Diagonalization. 3. Maximum Likelihood ICA. About the Authors Eric Moreau is Professor of Electrical Engineering at the University of Toulon, France. His research interests concern statistical signal processing, high order statistics and matrix/tensor decompositions with applic...

FGF signaling via MAPK is required early and improves Activin A-induced definitive endoderm formation from human embryonic stem cells

Energy Technology Data Exchange (ETDEWEB)

Sui, Lina, E-mail: linasui@vub.ac.be [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium); Mfopou, Josue K. [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium); Geens, Mieke; Sermon, Karen [Department of Embryology and Genetics, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium); Bouwens, Luc [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium)

2012-09-28

Highlights: Black-Right-Pointing-Pointer Deep study the FGF signaling role during DE specification in the context of hESCs. Black-Right-Pointing-Pointer DE differentiation from hESCs has an early dependence on FGF signaling. Black-Right-Pointing-Pointer A serum-free DE protocol is developed based on the findings. Black-Right-Pointing-Pointer The DE cells showed potential to differentiate into pancreatic progenitor cells. -- Abstract: Considering their unlimited proliferation and pluripotency properties, human embryonic stem cells (hESCs) constitute a promising resource applicable for cell replacement therapy. To facilitate this clinical translation, it is critical to study and understand the early stage of hESCs differentiation wherein germ layers are defined. In this study, we examined the role of FGF signaling in Activin A-induced definitive endoderm (DE) differentiation in the absence of supplemented animal serum. We found that activated FGF/MAPK signaling is required at the early time point of Activin A-induced DE formation. In addition, FGF activation increased the number of DE cells compared to Activin A alone. These DE cells could further differentiate into PDX1 and NKX6.1 positive pancreatic progenitors in vitro. We conclude that Activin A combined with FGF/MAPK signaling efficiently induce DE cells in the absence of serum. These findings improve our understanding of human endoderm formation, and constitute a step forward in the generation of clinical grade hESCs progenies for cell therapy.

The response of early neural genes to FGF signaling or inhibition of BMP indicate the absence of a conserved neural induction module

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Rogers Crystal D

2011-12-01

Full Text Available Abstract Background The molecular mechanism that initiates the formation of the vertebrate central nervous system has long been debated. Studies in Xenopus and mouse demonstrate that inhibition of BMP signaling is sufficient to induce neural tissue in explants or ES cells respectively, whereas studies in chick argue that instructive FGF signaling is also required for the expression of neural genes. Although additional signals may be involved in neural induction and patterning, here we focus on the roles of BMP inhibition and FGF8a. Results To address the question of necessity and sufficiency of BMP inhibition and FGF signaling, we compared the temporal expression of the five earliest genes expressed in the neuroectoderm and determined their requirements for induction at the onset of neural plate formation in Xenopus. Our results demonstrate that the onset and peak of expression of the genes vary and that they have different regulatory requirements and are therefore unlikely to share a conserved neural induction regulatory module. Even though all require inhibition of BMP for expression, some also require FGF signaling; expression of the early-onset pan-neural genes sox2 and foxd5α requires FGF signaling while other early genes, sox3, geminin and zicr1 are induced by BMP inhibition alone. Conclusions We demonstrate that BMP inhibition and FGF signaling induce neural genes independently of each other. Together our data indicate that although the spatiotemporal expression patterns of early neural genes are similar, the mechanisms involved in their expression are distinct and there are different signaling requirements for the expression of each gene.

Identifying deterministic signals in simulated gravitational wave data: algorithmic complexity and the surrogate data method

International Nuclear Information System (INIS)

Zhao Yi; Small, Michael; Coward, David; Howell, Eric; Zhao Chunnong; Ju Li; Blair, David

2006-01-01

We describe the application of complexity estimation and the surrogate data method to identify deterministic dynamics in simulated gravitational wave (GW) data contaminated with white and coloured noises. The surrogate method uses algorithmic complexity as a discriminating statistic to decide if noisy data contain a statistically significant level of deterministic dynamics (the GW signal). The results illustrate that the complexity method is sensitive to a small amplitude simulated GW background (SNR down to 0.08 for white noise and 0.05 for coloured noise) and is also more robust than commonly used linear methods (autocorrelation or Fourier analysis)

Two-Stage Translational Control of Dentate Gyrus LTP Consolidation Is Mediated by Sustained BDNF-TrkB Signaling to MNK

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Debabrata Panja

2014-11-01

Full Text Available BDNF signaling contributes to protein-synthesis-dependent synaptic plasticity, but the dynamics of TrkB signaling and mechanisms of translation have not been defined. Here, we show that long-term potentiation (LTP consolidation in the dentate gyrus of live rodents requires sustained (hours BDNF-TrkB signaling. Surprisingly, this sustained activation maintains an otherwise labile signaling pathway from TrkB to MAP-kinase-interacting kinase (MNK. MNK activity promotes eIF4F translation initiation complex formation and protein synthesis in mechanistically distinct early and late stages. In early-stage translation, MNK triggers release of the CYFIP1/FMRP repressor complex from the 5′-mRNA cap. In late-stage translation, MNK regulates the canonical translational repressor 4E-BP2 in a synapse-compartment-specific manner. This late stage is coupled to MNK-dependent enhanced dendritic mRNA translation. We conclude that LTP consolidation in the dentate gyrus is mediated by sustained BDNF signaling to MNK and MNK-dependent regulation of translation in two functionally and mechanistically distinct stages.

Ihh and Runx2/Runx3 signaling interact to coordinate early chondrogenesis: a mouse model.

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Eun-Jung Kim

Full Text Available Endochondral bone formation begins with the development of a cartilage intermediate that is subsequently replaced by calcified bone. The mechanisms occurring during early chondrogenesis that control both mesenchymal cell differentiation into chondrocytes and cell proliferation are not clearly understood in vertebrates. Indian hedgehog (Ihh, one of the hedgehog signaling molecules, is known to control both the hypertrophy of chondrocytes and bone replacement; these processes are particularly important in postnatal endochondral bone formation rather than in early chondrogenesis. In this study, we utilized the maternal transfer of 5E1 to E12.5 in mouse embryos, a process that leads to an attenuation of Ihh activity. As a result, mouse limb bud chondrogenesis was inhibited, and an exogenous recombinant IHH protein enhanced the proliferation and differentiation of mesenchymal cells. Analysis of the genetic relationships in the limb buds suggested a more extensive role for Ihh and Runx genes in early chondrogenesis. The transfer of 5E1 decreased the expression of Runx2 and Runx3, whereas an exogenous recombinant IHH protein increased Runx2 and Runx3 expression. Moreover, a transcription factor Gli1 in hedgehog pathway enhances the direct induction of both Runx2 and Runx3 transcription. These findings suggested that Ihh signaling plays an important role in chondrocyte proliferation and differentiation via interactions with Runx2 and Runx3.

Ihh and Runx2/Runx3 signaling interact to coordinate early chondrogenesis: a mouse model.

Science.gov (United States)

Kim, Eun-Jung; Cho, Sung-Won; Shin, Jeong-Oh; Lee, Min-Jung; Kim, Kye-Seong; Jung, Han-Sung

2013-01-01

Endochondral bone formation begins with the development of a cartilage intermediate that is subsequently replaced by calcified bone. The mechanisms occurring during early chondrogenesis that control both mesenchymal cell differentiation into chondrocytes and cell proliferation are not clearly understood in vertebrates. Indian hedgehog (Ihh), one of the hedgehog signaling molecules, is known to control both the hypertrophy of chondrocytes and bone replacement; these processes are particularly important in postnatal endochondral bone formation rather than in early chondrogenesis. In this study, we utilized the maternal transfer of 5E1 to E12.5 in mouse embryos, a process that leads to an attenuation of Ihh activity. As a result, mouse limb bud chondrogenesis was inhibited, and an exogenous recombinant IHH protein enhanced the proliferation and differentiation of mesenchymal cells. Analysis of the genetic relationships in the limb buds suggested a more extensive role for Ihh and Runx genes in early chondrogenesis. The transfer of 5E1 decreased the expression of Runx2 and Runx3, whereas an exogenous recombinant IHH protein increased Runx2 and Runx3 expression. Moreover, a transcription factor Gli1 in hedgehog pathway enhances the direct induction of both Runx2 and Runx3 transcription. These findings suggested that Ihh signaling plays an important role in chondrocyte proliferation and differentiation via interactions with Runx2 and Runx3.

TOR Complex 2-Ypk1 Signaling Maintains Sphingolipid Homeostasis by Sensing and Regulating ROS Accumulation

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Brad J. Niles

2014-02-01

Full Text Available Reactive oxygen species (ROS are produced during normal metabolism and can function as signaling molecules. However, ROS at elevated levels can damage cells. Here, we identify the conserved target of rapamycin complex 2 (TORC2/Ypk1 signaling module as an important regulator of ROS in the model eukaryotic organism, S. cerevisiae. We show that TORC2/Ypk1 suppresses ROS produced both by mitochondria as well as by nonmitochondrial sources, including changes in acidification of the vacuole. Furthermore, we link vacuole-related ROS to sphingolipids, essential components of cellular membranes, whose synthesis is also controlled by TORC2/Ypk1 signaling. In total, our data reveal that TORC2/Ypk1 act within a homeostatic feedback loop to maintain sphingolipid levels and that ROS are a critical regulatory signal within this system. Thus, ROS sensing and signaling by TORC2/Ypk1 play a central physiological role in sphingolipid biosynthesis and in the maintenance of cell growth and viability.

Persistent activation of DNA damage signaling in response to complex mixtures of PAHs in air particulate matter

International Nuclear Information System (INIS)

Jarvis, Ian W.H.; Bergvall, Christoffer; Bottai, Matteo; Westerholm, Roger; Stenius, Ulla; Dreij, Kristian

2013-01-01

Complex mixtures of polycyclic aromatic hydrocarbons (PAHs) are present in air particulate matter (PM) and have been associated with many adverse human health effects including cancer and respiratory disease. However, due to their complexity, the risk of exposure to mixtures is difficult to estimate. In the present study the effects of binary mixtures of benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) and complex mixtures of PAHs in urban air PM extracts on DNA damage signaling was investigated. Applying a statistical model to the data we observed a more than additive response for binary mixtures of BP and DBP on activation of DNA damage signaling. Persistent activation of checkpoint kinase 1 (Chk1) was observed at significantly lower BP equivalent concentrations in air PM extracts than BP alone. Activation of DNA damage signaling was also more persistent in air PM fractions containing PAHs with more than four aromatic rings suggesting larger PAHs contribute a greater risk to human health. Altogether our data suggests that human health risk assessment based on additivity such as toxicity equivalency factor scales may significantly underestimate the risk of exposure to complex mixtures of PAHs. The data confirms our previous findings with PAH-contaminated soil (Niziolek-Kierecka et al., 2012) and suggests a possible role for Chk1 Ser317 phosphorylation as a biological marker for future analyses of complex mixtures of PAHs. -- Highlights: ► Benzo[a]pyrene (BP), dibenzo[a,l]pyrene (DBP) and air PM PAH extracts were compared. ► Binary mixture of BP and DBP induced a more than additive DNA damage response. ► Air PM PAH extracts were more potent than toxicity equivalency factor estimates. ► Larger PAHs (> 4 rings) contribute more to the genotoxicity of PAHs in air PM. ► Chk1 is a sensitive marker for persistent activation of DNA damage signaling from PAH mixtures.

Persistent activation of DNA damage signaling in response to complex mixtures of PAHs in air particulate matter

Energy Technology Data Exchange (ETDEWEB)

Jarvis, Ian W.H., E-mail: Ian.Jarvis@ki.se [Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm (Sweden); Bergvall, Christoffer, E-mail: Christoffer.Bergvall@anchem.su.se [Department of Analytical Chemistry, Stockholm University, Svante Arrhenius väg 16, SE-106 91 Stockholm (Sweden); Bottai, Matteo, E-mail: Matteo.Bottai@ki.se [Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm (Sweden); Westerholm, Roger, E-mail: Roger.Westerholm@anchem.su.se [Department of Analytical Chemistry, Stockholm University, Svante Arrhenius väg 16, SE-106 91 Stockholm (Sweden); Stenius, Ulla, E-mail: Ulla.Stenius@ki.se [Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm (Sweden); Dreij, Kristian, E-mail: Kristian.Dreij@ki.se [Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm (Sweden)

2013-02-01

Complex mixtures of polycyclic aromatic hydrocarbons (PAHs) are present in air particulate matter (PM) and have been associated with many adverse human health effects including cancer and respiratory disease. However, due to their complexity, the risk of exposure to mixtures is difficult to estimate. In the present study the effects of binary mixtures of benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP) and complex mixtures of PAHs in urban air PM extracts on DNA damage signaling was investigated. Applying a statistical model to the data we observed a more than additive response for binary mixtures of BP and DBP on activation of DNA damage signaling. Persistent activation of checkpoint kinase 1 (Chk1) was observed at significantly lower BP equivalent concentrations in air PM extracts than BP alone. Activation of DNA damage signaling was also more persistent in air PM fractions containing PAHs with more than four aromatic rings suggesting larger PAHs contribute a greater risk to human health. Altogether our data suggests that human health risk assessment based on additivity such as toxicity equivalency factor scales may significantly underestimate the risk of exposure to complex mixtures of PAHs. The data confirms our previous findings with PAH-contaminated soil (Niziolek-Kierecka et al., 2012) and suggests a possible role for Chk1 Ser317 phosphorylation as a biological marker for future analyses of complex mixtures of PAHs. -- Highlights: ► Benzo[a]pyrene (BP), dibenzo[a,l]pyrene (DBP) and air PM PAH extracts were compared. ► Binary mixture of BP and DBP induced a more than additive DNA damage response. ► Air PM PAH extracts were more potent than toxicity equivalency factor estimates. ► Larger PAHs (> 4 rings) contribute more to the genotoxicity of PAHs in air PM. ► Chk1 is a sensitive marker for persistent activation of DNA damage signaling from PAH mixtures.

Complex signal-based optical coherence tomography angiography enables in vivo visualization of choriocapillaris in human choroid

Science.gov (United States)

Chu, Zhongdi; Chen, Chieh-Li; Zhang, Qinqin; Pepple, Kathryn; Durbin, Mary; Gregori, Giovanni; Wang, Ruikang K.

2017-12-01

The choriocapillaris (CC) plays an essential role in maintaining the normal functions of the human eye. There is increasing interest in the community to develop an imaging technique for visualizing the CC, yet this remains underexplored due to technical limitations. We propose an approach for the visualization of the CC in humans via a complex signal-based optical microangiography (OMAG) algorithm, based on commercially available spectral domain optical coherence tomography (SD-OCT). We show that the complex signal-based OMAG was superior to both the phase and amplitude signal-based approaches in detailing the vascular lobules previously seen with histological analysis. With this improved ability to visualize the lobular vascular networks, it is possible to identify the feeding arterioles and draining venules around the lobules, which is important in understanding the role of the CC in the pathogenesis of ocular diseases. With built-in FastTrac™ and montage scanning capabilities, we also demonstrate wide-field SD-OCT angiograms of the CC with a field of view at 9×11 mm2.

Loss of Intralipid®- but not sevoflurane-mediated cardioprotection in early type-2 diabetic hearts of fructose-fed rats: importance of ROS signaling.

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Phing-How Lou

Full Text Available Insulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether Intralipid® and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury.Early type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. Intralipid® (1% was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-% served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by palmitoylcarnitine were obtained.Intralipid® did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not Intralipid® produced protective ROS during reperfusion, which activated Akt. Intralipid® failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but palmitoylcarnitine could not rescue protection and enhance postischemic functional recovery. Cardiac mitochondria from early diabetic rats exhibited an increased content of subunit IV-2 of respiratory complex IV and of uncoupling protein-3.Early type-2 diabetic hearts lose complex IV-mediated protection by Intralipid® potentially due to a switch in complex IV subunit expression and increased mitochondrial uncoupling, but are amenable to complex I-mediated sevoflurane protection.

Analysis of progression of fatigue conditions in biceps brachii muscles using surface electromyography signals and complexity based features.

Science.gov (United States)

Karthick, P A; Makaram, Navaneethakrishna; Ramakrishnan, S

2014-01-01

Muscle fatigue is a neuromuscular condition where muscle performance decreases due to sustained or intense contraction. It is experienced by both normal and abnormal subjects. In this work, an attempt has been made to analyze the progression of muscle fatigue in biceps brachii muscles using surface electromyography (sEMG) signals. The sEMG signals are recorded from fifty healthy volunteers during dynamic contractions under well defined protocol. The acquired signals are preprocessed and segmented in to six equal parts for further analysis. The features, such as activity, mobility, complexity, sample entropy and spectral entropy are extracted from all six zones. The results are found showing that the extracted features except complexity feature have significant variations in differentiating non-fatigue and fatigue zone respectively. Thus, it appears that, these features are useful in automated analysis of various neuromuscular activities in normal and pathological conditions.

Ethylene signalling is mediating the early cadmium-induced oxidative challenge in Arabidopsis thaliana.

Science.gov (United States)

Schellingen, Kerim; Van Der Straeten, Dominique; Remans, Tony; Vangronsveld, Jaco; Keunen, Els; Cuypers, Ann

2015-10-01

Cadmium (Cd) induces the generation of reactive oxygen species (ROS) and stimulates ethylene biosynthesis. The phytohormone ethylene is a regulator of many developmental and physiological plant processes as well as stress responses. Previous research indicated various links between ethylene signalling and oxidative stress. Our results support a correlation between the Cd-induced oxidative challenge and ethylene signalling in Arabidopsis thaliana leaves. The effects of 24 or 72 h exposure to 5 μM Cd on plant growth and several oxidative stress-related parameters were compared between wild-type (WT) and ethylene insensitive mutants (etr1-1, ein2-1, ein3-1). Cadmium-induced responses observed in WT plants were mainly affected in etr1-1 and ein2-1 mutants, of which the growth was less inhibited by Cd exposure as compared to WT and ein3-1 mutants. Both etr1-1 and ein2-1 showed a delayed response in the glutathione (GSH) metabolism, including GSH levels and transcript levels of GSH synthesising and recycling enzymes. Furthermore, the expression of different oxidative stress marker genes was significantly lower in Cd-exposed ein2-1 mutants, evidencing that ethylene signalling is involved in early responses to Cd stress. A model for the cross-talk between ethylene signalling and oxidative stress is proposed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Multi-signal sedimentation velocity analysis with mass conservation for determining the stoichiometry of protein complexes.

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Chad A Brautigam

Full Text Available Multi-signal sedimentation velocity analytical ultracentrifugation (MSSV is a powerful tool for the determination of the number, stoichiometry, and hydrodynamic shape of reversible protein complexes in two- and three-component systems. In this method, the evolution of sedimentation profiles of macromolecular mixtures is recorded simultaneously using multiple absorbance and refractive index signals and globally transformed into both spectrally and diffusion-deconvoluted component sedimentation coefficient distributions. For reactions with complex lifetimes comparable to the time-scale of sedimentation, MSSV reveals the number and stoichiometry of co-existing complexes. For systems with short complex lifetimes, MSSV reveals the composition of the reaction boundary of the coupled reaction/migration process, which we show here may be used to directly determine an association constant. A prerequisite for MSSV is that the interacting components are spectrally distinguishable, which may be a result, for example, of extrinsic chromophores or of different abundances of aromatic amino acids contributing to the UV absorbance. For interacting components that are spectrally poorly resolved, here we introduce a method for additional regularization of the spectral deconvolution by exploiting approximate knowledge of the total loading concentrations. While this novel mass conservation principle does not discriminate contributions to different species, it can be effectively combined with constraints in the sedimentation coefficient range of uncomplexed species. We show in theory, computer simulations, and experiment, how mass conservation MSSV as implemented in SEDPHAT can enhance or even substitute for the spectral discrimination of components. This should broaden the applicability of MSSV to the analysis of the composition of reversible macromolecular complexes.

Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress

KAUST Repository

Yun, Kil-Young; Park, Myoung Ryoul; Mohanty, Bijayalaxmi; Herath, Venura; Xu, Fuyu; Mauleon, Ramil; Wijaya, Edward; Bajic, Vladimir B.; Bruskiewich, Richard; de los Reyes, Benildo G

2010-01-01

-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress

Processing Complex Sounds Passing through the Rostral Brainstem: The New Early Filter Model

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Marsh, John E.; Campbell, Tom A.

2016-01-01

The rostral brainstem receives both “bottom-up” input from the ascending auditory system and “top-down” descending corticofugal connections. Speech information passing through the inferior colliculus of elderly listeners reflects the periodicity envelope of a speech syllable. This information arguably also reflects a composite of temporal-fine-structure (TFS) information from the higher frequency vowel harmonics of that repeated syllable. The amplitude of those higher frequency harmonics, bearing even higher frequency TFS information, correlates positively with the word recognition ability of elderly listeners under reverberatory conditions. Also relevant is that working memory capacity (WMC), which is subject to age-related decline, constrains the processing of sounds at the level of the brainstem. Turning to the effects of a visually presented sensory or memory load on auditory processes, there is a load-dependent reduction of that processing, as manifest in the auditory brainstem responses (ABR) evoked by to-be-ignored clicks. Wave V decreases in amplitude with increases in the visually presented memory load. A visually presented sensory load also produces a load-dependent reduction of a slightly different sort: The sensory load of visually presented information limits the disruptive effects of background sound upon working memory performance. A new early filter model is thus advanced whereby systems within the frontal lobe (affected by sensory or memory load) cholinergically influence top-down corticofugal connections. Those corticofugal connections constrain the processing of complex sounds such as speech at the level of the brainstem. Selective attention thereby limits the distracting effects of background sound entering the higher auditory system via the inferior colliculus. Processing TFS in the brainstem relates to perception of speech under adverse conditions. Attentional selectivity is crucial when the signal heard is degraded or masked: e

Deciphering complex dynamics of water counteraction around secondary structural elements of allosteric protein complex: Case study of SAP-SLAM system in signal transduction cascade.

Science.gov (United States)

Samanta, Sudipta; Mukherjee, Sanchita

2018-01-28

The first hydration shell of a protein exhibits heterogeneous behavior owing to several attributes, majorly local polarity and structural flexibility as revealed by solvation dynamics of secondary structural elements. We attempt to recognize the change in complex water counteraction generated due to substantial alteration in flexibility during protein complex formation. The investigation is carried out with the signaling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, and interacting with SLAM-associated protein (SAP), composed of one SH2 domain. All atom molecular dynamics simulations are employed to the aqueous solutions of free SAP and SLAM-peptide bound SAP. We observed that water dynamics around different secondary structural elements became highly affected as well as nicely correlated with the SLAM-peptide induced change in structural rigidity obtained by thermodynamic quantification. A few instances of contradictory dynamic features of water to the change in structural flexibility are explained by means of occluded polar residues by the peptide. For βD, EFloop, and BGloop, both structural flexibility and solvent accessibility of the residues confirm the obvious contribution. Most importantly, we have quantified enhanced restriction in water dynamics around the second Fyn-binding site of the SAP due to SAP-SLAM complexation, even prior to the presence of Fyn. This observation leads to a novel argument that SLAM induced more restricted water molecules could offer more water entropic contribution during the subsequent Fyn binding and provide enhanced stability to the SAP-Fyn complex in the signaling cascade. Finally, SLAM induced water counteraction around the second binding site of the SAP sheds light on the allosteric property of the SAP, which becomes an integral part of the underlying signal transduction mechanism.

Deciphering complex dynamics of water counteraction around secondary structural elements of allosteric protein complex: Case study of SAP-SLAM system in signal transduction cascade

Science.gov (United States)

Samanta, Sudipta; Mukherjee, Sanchita

2018-01-01

The first hydration shell of a protein exhibits heterogeneous behavior owing to several attributes, majorly local polarity and structural flexibility as revealed by solvation dynamics of secondary structural elements. We attempt to recognize the change in complex water counteraction generated due to substantial alteration in flexibility during protein complex formation. The investigation is carried out with the signaling lymphocytic activation molecule (SLAM) family of receptors, expressed by an array of immune cells, and interacting with SLAM-associated protein (SAP), composed of one SH2 domain. All atom molecular dynamics simulations are employed to the aqueous solutions of free SAP and SLAM-peptide bound SAP. We observed that water dynamics around different secondary structural elements became highly affected as well as nicely correlated with the SLAM-peptide induced change in structural rigidity obtained by thermodynamic quantification. A few instances of contradictory dynamic features of water to the change in structural flexibility are explained by means of occluded polar residues by the peptide. For βD, EFloop, and BGloop, both structural flexibility and solvent accessibility of the residues confirm the obvious contribution. Most importantly, we have quantified enhanced restriction in water dynamics around the second Fyn-binding site of the SAP due to SAP-SLAM complexation, even prior to the presence of Fyn. This observation leads to a novel argument that SLAM induced more restricted water molecules could offer more water entropic contribution during the subsequent Fyn binding and provide enhanced stability to the SAP-Fyn complex in the signaling cascade. Finally, SLAM induced water counteraction around the second binding site of the SAP sheds light on the allosteric property of the SAP, which becomes an integral part of the underlying signal transduction mechanism.

Pluripotent Stem Cell Studies Elucidate the Underlying Mechanisms of Early Embryonic Development

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Lingyu Li

2011-03-01

Full Text Available Early embryonic development is a multi-step process that is intensively regulated by various signaling pathways. Because of the complexity of the embryo and the interactions between the germ layers, it is very difficult to fully understand how these signals regulate embryo patterning. Recently, pluripotent stem cell lines derived from different developmental stages have provided an in vitro system for investigating molecular mechanisms regulating cell fate decisions. In this review, we summarize the major functions of the BMP, FGF, Nodal and Wnt signaling pathways, which have well-established roles in vertebrate embryogenesis. Then, we highlight recent studies in pluripotent stem cells that have revealed the stage-specific roles of BMP，FGF and Nodal pathways during neural differentiation. These findings enhance our understanding of the stepwise regulation of embryo patterning by particular signaling pathways and provide new insight into the mechanisms underlying early embryonic development.

Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema.

Science.gov (United States)

Ruwanpura, Saleela M; McLeod, Louise; Dousha, Lovisa F; Seow, Huei J; Alhayyani, Sultan; Tate, Michelle D; Deswaerte, Virginie; Brooks, Gavin D; Bozinovski, Steven; MacDonald, Martin; Garbers, Christoph; King, Paul T; Bardin, Philip G; Vlahos, Ross; Rose-John, Stefan; Anderson, Gary P; Jenkins, Brendan J

2016-12-15

The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R. To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema. We used the gp130 F/F genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed. Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes. Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.

Complex on the base of the ISKRA 226.6 personal computer for nuclear quadrupole resonance signal processing

International Nuclear Information System (INIS)

Morgunov, V.G.; Kravchenko, Eh.A.

1988-01-01

Complex, designed to conduct investigations by means of nuclear quadrupole resonance (NQR) method, which includes radiospectrometer, multichannel spectrum analyzer and ISKRA 226.6 personal computer, is developed. Analog-to-digital converter (ADC) with buffer storage device, interface and microcomputer are used to process NQR-signals. ADS conversion time is no more, than 50 ns, linearity - 1%. Programs on Fourier analysis of NQR-signals and calculation of relaxation times are developed

Characterizing scaling properties of complex signals with missed data segments using the multifractal analysis

Science.gov (United States)

Pavlov, A. N.; Pavlova, O. N.; Abdurashitov, A. S.; Sindeeva, O. A.; Semyachkina-Glushkovskaya, O. V.; Kurths, J.

2018-01-01

The scaling properties of complex processes may be highly influenced by the presence of various artifacts in experimental recordings. Their removal produces changes in the singularity spectra and the Hölder exponents as compared with the original artifacts-free data, and these changes are significantly different for positively correlated and anti-correlated signals. While signals with power-law correlations are nearly insensitive to the loss of significant parts of data, the removal of fragments of anti-correlated signals is more crucial for further data analysis. In this work, we study the ability of characterizing scaling features of chaotic and stochastic processes with distinct correlation properties using a wavelet-based multifractal analysis, and discuss differences between the effect of missed data for synchronous and asynchronous oscillatory regimes. We show that even an extreme data loss allows characterizing physiological processes such as the cerebral blood flow dynamics.

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Science.gov (United States)

Zeke, András; Misheva, Mariya

2016-01-01

SUMMARY The c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states. PMID:27466283

9.4 COMPLEX SYSTEM THEORY AND THE TRANSDIAGNOSTIC USE OF EARLY WARNING SIGNALS TO FORESEE THE TYPE OF FUTURE TRANSITIONS IN SYMPTOMS

Science.gov (United States)

Wichers, Marieke; Schreuder, Marieke; Hartman, Catharina; Wigman, Hanneke

2018-01-01

Abstract Background Recently, we showed that assumptions from complex system theory seem applicable in the field of psychiatry. This means that indicators of critical slowing down in the system signal the risk for a critical transition in the near future. In the current study we wanted to explore whether the principle of critical slowing down may also be informative to anticipate on the type of symptoms that individuals are most likely to develop. This is relevant as it may lead to personalized prediction of risk of whether adolescents with mixed complaints are most likely to develop either depression, anxiety, somatic or psychotic symptoms in the near future. For example, we hypothesized that critical slowing down in feeling ‘suspicious’ more strongly indicates risk for a future transition to psychotic symptoms, while critical slowing down in feeling ‘down’ more strongly indicates risk for a transition to depressive symptoms. Methods We examined this in a population of adolescents (most between 15 and 18 years) as adolescents are an at-risk group for the development of psychopathology. At baseline experience sampling was performed for 6 days, 10 measurements a day. Affect items were used to assess autocorrelation as an indicator of ‘critical slowing down’ of the system. At baseline and follow-up SCL-90 questionnaires were administered. In total, 147 adolescents participated both in baseline and follow-up measures and showed increases in at least one of the defined symptom dimensions. We examined whether autocorrelation was positively associated with the size of symptom transition and whether different type of transitions (in depression, anxiety etc.) were differentially predicted by autocorrelations in specific affect states. Results The analyses were done very recently, and findings have not been presented before. We found both shared and specific indicators of risk in the development for transition to various symptom dimensions. First

Phosphoproteomic profiling of in vivo signaling in liver by the mammalian target of rapamycin complex 1 (mTORC1.

Directory of Open Access Journals (Sweden)

Gokhan Demirkan

Full Text Available Our understanding of signal transduction networks in the physiological context of an organism remains limited, partly due to the technical challenge of identifying serine/threonine phosphorylated peptides from complex tissue samples. In the present study, we focused on signaling through the mammalian target of rapamycin (mTOR complex 1 (mTORC1, which is at the center of a nutrient- and growth factor-responsive cell signaling network. Though studied extensively, the mechanisms involved in many mTORC1 biological functions remain poorly understood.We developed a phosphoproteomic strategy to purify, enrich and identify phosphopeptides from rat liver homogenates. Using the anticancer drug rapamycin, the only known target of which is mTORC1, we characterized signaling in liver from rats in which the complex was maximally activated by refeeding following 48 hr of starvation. Using protein and peptide fractionation methods, TiO(2 affinity purification of phosphopeptides and mass spectrometry, we reproducibly identified and quantified over four thousand phosphopeptides. Along with 5 known rapamycin-sensitive phosphorylation events, we identified 62 new rapamycin-responsive candidate phosphorylation sites. Among these were PRAS40, gephyrin, and AMP kinase 2. We observed similar proportions of increased and reduced phosphorylation in response to rapamycin. Gene ontology analysis revealed over-representation of mTOR pathway components among rapamycin-sensitive phosphopeptide candidates.In addition to identifying potential new mTORC1-mediated phosphorylation events, and providing information relevant to the biology of this signaling network, our experimental and analytical approaches indicate the feasibility of large-scale phosphoproteomic profiling of tissue samples to study physiological signaling events in vivo.

A Novel Method of Early Diagnosis of Alzheimer’s Disease Based on EEG Signals

Directory of Open Access Journals (Sweden)

Dhiya Al-Jumeily

2015-01-01

Full Text Available Studies have reported that electroencephalogram signals in Alzheimer’s disease patients usually have less synchronization than those of healthy subjects. Changes in electroencephalogram signals start at early stage but, clinically, these changes are not easily detected. To detect this perturbation, three neural synchrony measurement techniques: phase synchrony, magnitude squared coherence, and cross correlation are applied to three different databases of mild Alzheimer’s disease patients and healthy subjects. We have compared the right and left temporal lobes of the brain with the rest of the brain areas (frontal, central, and occipital as temporal regions are relatively the first ones to be affected by Alzheimer’s disease. Moreover, electroencephalogram signals are further classified into five different frequency bands (delta, theta, alpha beta, and gamma because each frequency band has its own physiological significance in terms of signal evaluation. A new approach using principal component analysis before applying neural synchrony measurement techniques has been presented and compared with Average technique. The simulation results indicated that applying principal component analysis before synchrony measurement techniques shows significantly better results as compared to the lateral one. At the end, all the aforementioned techniques are assessed by a statistical test (Mann-Whitney U test to compare the results.

Analysis of Maneuvering Targets with Complex Motions by Two-Dimensional Product Modified Lv’s Distribution for Quadratic Frequency Modulation Signals

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Fulong Jing

2017-06-01

Full Text Available For targets with complex motion, such as ships fluctuating with oceanic waves and high maneuvering airplanes, azimuth echo signals can be modeled as multicomponent quadratic frequency modulation (QFM signals after migration compensation and phase adjustment. For the QFM signal model, the chirp rate (CR and the quadratic chirp rate (QCR are two important physical quantities, which need to be estimated. For multicomponent QFM signals, the cross terms create a challenge for detection, which needs to be addressed. In this paper, by employing a novel multi-scale parametric symmetric self-correlation function (PSSF and modified scaled Fourier transform (mSFT, an effective parameter estimation algorithm is proposed—referred to as the Two-Dimensional product modified Lv’s distribution (2D-PMLVD—for QFM signals. The 2D-PMLVD is simple and can be easily implemented by using fast Fourier transform (FFT and complex multiplication. These measures are analyzed in the paper, including the principle, the cross term, anti-noise performance, and computational complexity. Compared to the other three representative methods, the 2D-PMLVD can achieve better anti-noise performance. The 2D-PMLVD, which is free of searching and has no identifiability problems, is more suitable for multicomponent situations. Through several simulations and analyses, the effectiveness of the proposed estimation algorithm is verified.

A NuRD Complex from Xenopus laevis Eggs Is Essential for DNA Replication during Early Embryogenesis

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Christo P. Christov

2018-02-01

Full Text Available DNA replication in the embryo of Xenopus laevis changes dramatically at the mid-blastula transition (MBT, with Y RNA-independent random initiation switching to Y RNA-dependent initiation at specific origins. Here, we identify xNuRD, an MTA2-containing assemblage of the nucleosome remodeling and histone deacetylation complex NuRD, as an essential factor in pre-MBT Xenopus embryos that overcomes a functional requirement for Y RNAs during DNA replication. Human NuRD complexes have a different subunit composition than xNuRD and do not support Y RNA-independent initiation of DNA replication. Blocking or immunodepletion of xNuRD inhibits DNA replication initiation in isolated nuclei in vitro and causes inhibition of DNA synthesis, developmental delay, and embryonic lethality in early embryos. xNuRD activity declines after the MBT, coinciding with dissociation of the complex and emergence of Y RNA-dependent initiation. Our data thus reveal an essential role for a NuRD complex as a DNA replication factor during early Xenopus development.

Adenovirus type 5 DNA-protein complexes from formaldehyde cross-linked cells early after infection

International Nuclear Information System (INIS)

Spector, David J.; Johnson, Jeffrey S.; Baird, Nicholas L.; Engel, Daniel A.

2003-01-01

We report here the properties of viral DNA-protein complexes that purify with cellular chromatin following formaldehyde cross-linking of intact cells early after infection. The cross-linked viral DNA fractionated into shear-sensitive (S) and shear- resistant (R) components that were separable by sedimentation, which allowed independent characterization. The R component had the density and sedimentation properties expected for DNA-protein complexes and contained intact viral DNA. It accounted for about 50% of the viral DNA recovered at 1.5 h after infection but less than 20% by 4.5 h. The proportion of R component was independent of multiplicity of infection, even at less than one particle per cell. Viral hexon and protein VII, but not protein VI, were detected in the fractions containing the R component. These properties are consistent with those of partially uncoated virions associated with the nuclear envelope. A substantial proportion of the S component viral DNA had the same density as cellular chromatin. Protein VII was the most abundant viral protein present in gradient fractions that contained the S component. Complexes containing USF transcription factor cross-linked to the adenovirus major late promoter were detected by viral chromatin immunoprecipitation of the fractions containing S component. The S component probably contained uncoated nuclear viral DNA that assembles into early viral transcription complexes

From PII signaling to metabolite sensing: a novel 2-oxoglutarate sensor that details PII-NAGK complex formation.

Directory of Open Access Journals (Sweden)

Jan Lüddecke

Full Text Available The widespread PII signal transduction proteins are known for integrating signals of nitrogen and energy supply and regulating cellular behavior by interacting with a multitude of target proteins. The PII protein of the cyanobacterium Synechococcus elongatus forms complexes with the controlling enzyme of arginine synthesis, N-acetyl-L-glutamate kinase (NAGK in a 2-oxoglutarate- and ATP/ADP-dependent manner. Fusing NAGK and PII proteins to either CFP or YFP yielded a FRET sensor that specifically responded to 2-oxoglutarate. The impact of the fluorescent tags on PII and NAGK was evaluated by enzyme assays, surface plasmon resonance spectroscopy and isothermal calorimetric experiments. The developed FRET sensor provides real-time data on PII - NAGK interaction and its modulation by the effector molecules ATP, ADP and 2-oxoglutarate in vitro. Additionally to its utility to monitor 2-oxoglutarate levels, the FRET assay provided novel insights into PII - NAGK complex formation: (i It revealed the formation of an encounter-complex between PII and NAGK, which holds the proteins in proximity even in the presence of inhibitors of complex formation; (ii It revealed that the PII T-loop residue Ser49 is neither essential for complex formation with NAGK nor for activation of the enzyme but necessary to form a stable complex and efficiently relieve NAGK from arginine inhibition; (iii It showed that arginine stabilizes the NAGK hexamer and stimulates PII - NAGK interaction.

Hsp90α forms a stable complex at the cilium neck for the interaction of signalling molecules in IGF-1 receptor signalling.

Science.gov (United States)

Wang, Hongzhong; Zou, Xinle; Wei, Zhuang; Wu, Yuan; Li, Rongxia; Zeng, Rong; Chen, Zhengjun; Liao, Kan

2015-01-01

The primary cilium is composed of an axoneme that protrudes from the cell surface, a basal body beneath the membrane and a transition neck in between. It is a sensory organelle on the plasma membrane, involved in mediating extracellular signals. In the transition neck region of the cilium, the microtubules change from triplet to doublet microtubules. This region also contains the transition fibres that crosslink the axoneme with the membrane and the necklace proteins that regulate molecules being transported into and out of the cilium. In this protein-enriched, complex area it is important to maintain the correct assembly of all of these proteins. Here, through immunofluorescent staining and protein isolation, we identify the molecular chaperone Hsp90α clustered at the periciliary base. At the transition neck region, phosphorylated Hsp90α forms a stable ring around the axoneme. Heat shock treatment causes Hsp90α to dissipate and induces resorption of cilia. We further identify that Hsp90α at the transition neck region represents a signalling platform on which IRS-1 interacts with intracellular downstream signalling molecules involved in IGF-1 receptor signalling. © 2015. Published by The Company of Biologists Ltd.

Early signaling, referral, and treatment of adolescent chronic pain: a study protocol

Directory of Open Access Journals (Sweden)

Voerman Jessica S

2012-06-01

Full Text Available Abstract Background Chronic pain is prevalent among young people and negatively influences their quality of life. Furthermore, chronic pain in adolescence may persist into adulthood. Therefore, it is important early on to promote the self-management skills of adolescents with chronic pain by improving signaling, referral, and treatment of these youngsters. In this study protocol we describe the designs of two complementary studies: a signaling study and an intervention study. Methods and design The signaling study evaluates the Pain Barometer, a self-assessed signaling instrument for chronic pain in adolescents. To evaluate the feasibility of the Pain Barometer, the experiences of youth-health care nurses will be evaluated in semi-structured interviews. Also, we will explore the frequencies of referral per health-care provider. The intervention study evaluates Move It Now, a guided self-help intervention via the Internet for teenagers with chronic pain. This intervention uses cognitive behavioural techniques, including relaxation exercises and positive thinking. The objective of the intervention is to improve the ability of adolescents to cope with pain. The efficacy of Move It Now will be examined in a randomized controlled trial, in which 60 adolescents will be randomly assigned to an experimental condition or a waiting list control condition. Discussion If the Pain Barometer is proven to be feasible and Move It Now appears to be efficacious, a health care pathway can be created to provide the best tailored treatment promptly to adolescents with chronic pain. Move It Now can be easily implemented throughout the Netherlands, as the intervention is Internet based. Trial registration Dutch Trial Register NTR1926

Cell–cell signaling drives the evolution of complex traits: introduction—lung evo-devo

Science.gov (United States)

Torday, John S.; Rehan, V. K.

2009-01-01

Physiology integrates biology with the environment through cell–cell interactions at multiple levels. The evolution of the respiratory system has been “deconvoluted” (Torday and Rehan in Am J Respir Cell Mol Biol 31:8–12, 2004) through Gene Regulatory Networks (GRNs) applied to cell–cell communication for all aspects of lung biology development, homeostasis, regeneration, and aging. Using this approach, we have predicted the phenotypic consequences of failed signaling for lung development, homeostasis, and regeneration based on evolutionary principles. This cell–cell communication model predicts other aspects of vertebrate physiology as adaptational responses. For example, the oxygen-induced differentiation of alveolar myocytes into alveolar adipocytes was critical for the evolution of the lung in land dwelling animals adapting to fluctuating Phanarezoic oxygen levels over the past 500 million years. Adipocytes prevent lung injury due to oxygen radicals and facilitate the rise of endothermy. In addition, they produce the class I cytokine leptin, which augments pulmonary surfactant activity and alveolar surface area, increasing selection pressure for both respiratory oxygenation and metabolic demand initially constrained by high-systemic vascular pressure, but subsequently compensated by the evolution of the adrenomedullary beta-adrenergic receptor mechanism. Conserted positive selection for the lung and adrenals created further selection pressure for the heart, which becomes progressively more complex phylogenetically in tandem with the lung. Developmentally, increasing heart complexity and size impinges precociously on the gut mesoderm to induce the liver. That evolutionary-developmental interaction is significant because the liver provides regulated sources of glucose and glycogen to the evolving physiologic system, which is necessary for the evolution of the neocortex. Evolution of neocortical control furthers integration of physiologic systems. Such

A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu–Gli protein complexes

OpenAIRE

Tukachinsky, Hanna; Lopez, Lyle V.; Salic, Adrian

2010-01-01

In vertebrates, Hedgehog (Hh) signaling initiated in primary cilia activates the membrane protein Smoothened (Smo) and leads to activation of Gli proteins, the transcriptional effectors of the pathway. In the absence of signaling, Gli proteins are inhibited by the cytoplasmic protein Suppressor of Fused (SuFu). It is unclear how Hh activates Gli and whether it directly regulates SuFu. We find that Hh stimulation quickly recruits endogenous SuFu–Gli complexes to cilia, suggesting a model in wh...

Preprotein import into chloroplasts via the Toc and Tic complexes is regulated by redox signals in Pisum sativum.

Science.gov (United States)

Stengel, Anna; Benz, J Philipp; Buchanan, Bob B; Soll, Jürgen; Bölter, Bettina

2009-11-01

The import of nuclear-encoded preproteins is necessary to maintain chloroplast function. The recognition and transfer of most precursor proteins across the chloroplast envelopes are facilitated by two membrane-inserted protein complexes, the translocons of the chloroplast outer and inner envelope (Toc and Tic complexes, respectively). Several signals have been invoked to regulate the import of preproteins. In our study, we were interested in redox-based import regulation mediated by two signals: regulation based on thiols and on the metabolic NADP+/NADPH ratio. We sought to identify the proteins participating in the regulation of these transport pathways and to characterize the preprotein subgroups whose import is redox-dependent. Our results provide evidence that the formation and reduction of disulfide bridges in the Toc receptors and Toc translocation channel have a strong influence on import yield of all tested preproteins that depend on the Toc complex for translocation. Furthermore, the metabolic NADP+/NADPH ratio influences not only the composition of the Tic complex, but also the import efficiency of most, but not all, preproteins tested. Thus, several Tic subcomplexes appear to participate in the translocation of different preprotein subgroups, and the redox-active components of these complexes likely play a role in regulating transport.

Magnetic resonance signal moment determination using the Earth's magnetic field

KAUST Repository

Fridjonsson, Einar Orn; Creber, Sarah A.; Vrouwenvelder, Johannes S.; Johns, Michael L.

2015-01-01

We demonstrate a method to manipulate magnetic resonance data such that the moments of the signal spatial distribution are readily accessible. Usually, magnetic resonance imaging relies on data acquired in so-called k-space which is subsequently Fourier transformed to render an image. Here, via analysis of the complex signal in the vicinity of the centre of k-space we are able to access the first three moments of the signal spatial distribution, ultimately in multiple directions. This is demonstrated for biofouling of a reverse osmosis (RO) membrane module, rendering unique information and an early warning of the onset of fouling. The analysis is particularly applicable for the use of mobile magnetic resonance spectrometers; here we demonstrate it using an Earth's magnetic field system.

Magnetic resonance signal moment determination using the Earth's magnetic field

KAUST Repository

Fridjonsson, Einar Orn

2015-03-01

We demonstrate a method to manipulate magnetic resonance data such that the moments of the signal spatial distribution are readily accessible. Usually, magnetic resonance imaging relies on data acquired in so-called k-space which is subsequently Fourier transformed to render an image. Here, via analysis of the complex signal in the vicinity of the centre of k-space we are able to access the first three moments of the signal spatial distribution, ultimately in multiple directions. This is demonstrated for biofouling of a reverse osmosis (RO) membrane module, rendering unique information and an early warning of the onset of fouling. The analysis is particularly applicable for the use of mobile magnetic resonance spectrometers; here we demonstrate it using an Earth\\'s magnetic field system.

K-Ar Geochronology and isotopic composition of the late oligocene- early miocene Ancud volcanic complex, Chiloe

International Nuclear Information System (INIS)

Munoz B, Jorge; Duhart O, Paul; Farmer, G. Lang; Stern, Charles R

2001-01-01

The Ancud Volcanic Complex (Gally and Sanchez , 1960) forms a portion of the Mid-Tertiary Coastal Magmatic Belt which outcrops in the area of northern Chiloe island. Main exposures occur at Ancud, Punta Polocue, Punihuil, Pumillahue, Tetas de Teguaco and Bahia Cocotue. The Ancud Volcanic Complex consists of basaltic to basaltic andesites lava flows and volcanic necks and rhyolitic pyroclastic flows and vitric domes. Previous studies indicate a Late Oligocene-Early Miocene age (Garcia et al., 1988; Stern and Vergara, 1992; Munoz et al., 2000). The Ancud Volcanic Complex covers and intrudes Palaeozoic-Triassic metamorphic rocks and is partially covered by an early to middle Miocene marine sedimentary sequence known as Lacui Formation (Valenzuela, 1982) and by Pleistocene glacial deposits (Heusser, 1990). At Punihuil locality, lava flows are interbedded with the lower part of the marine sedimentary sequence, which includes significant amounts of redeposited pyroclastic components. Locally, the presence of hyaloclastic breccias suggests interaction of magma with marine water (au)

Early-onset sleep defects in Drosophila models of Huntington's disease reflect alterations of PKA/CREB signaling

Science.gov (United States)

Gonzales, Erin D.; Tanenhaus, Anne K.; Zhang, Jiabin; Chaffee, Ryan P.; Yin, Jerry C.P.

2016-01-01

Huntington's disease (HD) is a progressive neurological disorder whose non-motor symptoms include sleep disturbances. Whether sleep and activity abnormalities are primary molecular disruptions of mutant Huntingtin (mutHtt) expression or result from neurodegeneration is unclear. Here, we report Drosophila models of HD exhibit sleep and activity disruptions very early in adulthood, as soon as sleep patterns have developed. Pan-neuronal expression of full-length or N-terminally truncated mutHtt recapitulates sleep phenotypes of HD patients: impaired sleep initiation, fragmented and diminished sleep, and nighttime hyperactivity. Sleep deprivation of HD model flies results in exacerbated sleep deficits, indicating that homeostatic regulation of sleep is impaired. Elevated PKA/CREB activity in healthy flies produces patterns of sleep and activity similar to those in our HD models. We were curious whether aberrations in PKA/CREB signaling were responsible for our early-onset sleep/activity phenotypes. Decreasing signaling through the cAMP/PKA pathway suppresses mutHtt-induced developmental lethality. Genetically reducing PKA abolishes sleep/activity deficits in HD model flies, restores the homeostatic response and extends median lifespan. In vivo reporters, however, show dCREB2 activity is unchanged, or decreased when sleep/activity patterns are abnormal, suggesting dissociation of PKA and dCREB2 occurs early in pathogenesis. Collectively, our data suggest that sleep defects may reflect a primary pathological process in HD, and that measurements of sleep and cAMP/PKA could be prodromal indicators of disease, and serve as therapeutic targets for intervention. PMID:26604145

Dynamic complexity: plant receptor complexes at the plasma membrane.

Science.gov (United States)

Burkart, Rebecca C; Stahl, Yvonne

2017-12-01

Plant receptor complexes at the cell surface perceive many different external and internal signalling molecules and relay these signals into the cell to regulate development, growth and immunity. Recent progress in the analyses of receptor complexes using different live cell imaging approaches have shown that receptor complex formation and composition are dynamic and take place at specific microdomains at the plasma membrane. In this review we focus on three prominent examples of Arabidopsis thaliana receptor complexes and how their dynamic spatio-temporal distribution at the PM has been studied recently. We will elaborate on the newly emerging concept of plasma membrane microdomains as potential hubs for specific receptor complex assembly and signalling outputs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Formation and biochemical characterization of tube/pelle death domain complexes: critical regulators of postreceptor signaling by the Drosophila toll receptor.

Science.gov (United States)

Schiffmann, D A; White, J H; Cooper, A; Nutley, M A; Harding, S E; Jumel, K; Solari, R; Ray, K P; Gay, N J

1999-09-07

In Drosophila, the Toll receptor signaling pathway is required for embryonic dorso-ventral patterning and at later developmental stages for innate immune responses. It is thought that dimerization of the receptor by binding of the ligand spätzle causes the formation of a postreceptor activation complex at the cytoplasmic surface of the membrane. Two components of this complex are the adaptor tube and protein kinase pelle. These proteins both have "death domains", protein interaction motifs found in a number of signaling pathways, particularly those involved in apoptotic cell death. It is thought that pelle is bound by tube during formation of the activation complexes, and that this interaction is mediated by the death domains. In this paper, we show using the yeast two-hybrid system that the wild-type tube and pelle death domains bind together. Mutant tube proteins which do not support signaling in the embryo are also unable to bind pelle in the 2-hybrid assay. We have purified proteins corresponding to the death domains of tube and pelle and show that these form corresponding heterodimeric complexes in vitro. Partial proteolysis reveals a smaller core consisting of the minimal death domain sequences. We have studied the tube/pelle interaction with the techniques of surface plasmon resonance, analytical ultracentrifugation and isothermal titration calorimetry. These measurements produce a value of K(d) for the complex of about 0.5 microM.

Low-complexity camera digital signal imaging for video document projection system

Science.gov (United States)

Hsia, Shih-Chang; Tsai, Po-Shien

2011-04-01

We present high-performance and low-complexity algorithms for real-time camera imaging applications. The main functions of the proposed camera digital signal processing (DSP) involve color interpolation, white balance, adaptive binary processing, auto gain control, and edge and color enhancement for video projection systems. A series of simulations demonstrate that the proposed method can achieve good image quality while keeping computation cost and memory requirements low. On the basis of the proposed algorithms, the cost-effective hardware core is developed using Verilog HDL. The prototype chip has been verified with one low-cost programmable device. The real-time camera system can achieve 1270 × 792 resolution with the combination of extra components and can demonstrate each DSP function.

Neural Correlates of Success and Failure Signals During Neurofeedback Learning.

Science.gov (United States)

Radua, Joaquim; Stoica, Teodora; Scheinost, Dustin; Pittenger, Christopher; Hampson, Michelle

2018-05-15

Feedback-driven learning, observed across phylogeny and of clear adaptive value, is frequently operationalized in simple operant conditioning paradigms, but it can be much more complex, driven by abstract representations of success and failure. This study investigates the neural processes involved in processing success and failure during feedback learning, which are not well understood. Data analyzed were acquired during a multisession neurofeedback experiment in which ten participants were presented with, and instructed to modulate, the activity of their orbitofrontal cortex with the aim of decreasing their anxiety. We assessed the regional blood-oxygenation-level-dependent response to the individualized neurofeedback signals of success and failure across twelve functional runs acquired in two different magnetic resonance sessions in each of ten individuals. Neurofeedback signals of failure correlated early during learning with deactivation in the precuneus/posterior cingulate and neurofeedback signals of success correlated later during learning with deactivation in the medial prefrontal/anterior cingulate cortex. The intensity of the latter deactivations predicted the efficacy of the neurofeedback intervention in the reduction of anxiety. These findings indicate a role for regulation of the default mode network during feedback learning, and suggest a higher sensitivity to signals of failure during the early feedback learning and to signals of success subsequently. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Design Implementation and Testing of a VLSI High Performance ASIC for Extracting the Phase of a Complex Signal

National Research Council Canada - National Science Library

Altmeyer, Ronald

2002-01-01

This thesis documents the research, circuit design, and simulation testing of a VLSI ASIC which extracts phase angle information from a complex sampled signal using the arctangent relationship: (phi=tan/-1 (Q/1...

Biogenesis of the mitochondrial TOM complex: Mim1 promotes insertion and assembly of signal-anchored receptors.

Science.gov (United States)

Becker, Thomas; Pfannschmidt, Sylvia; Guiard, Bernard; Stojanovski, Diana; Milenkovic, Dusanka; Kutik, Stephan; Pfanner, Nikolaus; Meisinger, Chris; Wiedemann, Nils

2008-01-04

The translocase of the outer membrane (TOM complex) is the central entry gate for nuclear-encoded mitochondrial precursor proteins. All Tom proteins are also encoded by nuclear genes and synthesized as precursors in the cytosol. The channel-forming beta-barrel protein Tom40 is targeted to mitochondria via Tom receptors and inserted into the outer membrane by the sorting and assembly machinery (SAM complex). A further outer membrane protein, Mim1, plays a less defined role in assembly of Tom40 into the TOM complex. The three receptors Tom20, Tom22, and Tom70 are anchored in the outer membrane by a single transmembrane alpha-helix, located at the N terminus in the case of Tom20 and Tom70 (signal-anchored) or in the C-terminal portion in the case of Tom22 (tail-anchored). Insertion of the precursor of Tom22 into the outer membrane requires pre-existing Tom receptors while the import pathway of the precursors of Tom20 and Tom70 is only poorly understood. We report that Mim1 is required for efficient membrane insertion and assembly of Tom20 and Tom70, but not Tom22. We show that Mim1 associates with SAM(core) components to a large SAM complex, explaining its role in late steps of the assembly pathway of Tom40. We conclude that Mim1 is not only required for biogenesis of the beta-barrel protein Tom40 but also for membrane insertion and assembly of signal-anchored Tom receptors. Thus, Mim1 plays an important role in the efficient assembly of the mitochondrial TOM complex.

Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model

International Nuclear Information System (INIS)

Ichimura, Ryohei; Mizukami, Sayaka; Takahashi, Miwa; Taniai, Eriko; Kemmochi, Sayaka; Mitsumori, Kunitoshi; Shibutani, Makoto

2010-01-01

To clarify the involvement of signaling of transforming growth factor (TGF)-β during the hepatocarcinogenesis, the immunohistochemical distribution of related molecules was analyzed in relation with liver cell lesions expressing glutathione S-transferase placental form (GST-P) during liver tumor promotion by fenbendazole, phenobarbital, piperonyl butoxide, or thioacetamide, using rats. Our study focused on early-stage promotion (6 weeks after starting promotion) and late-stage promotion (57 weeks after starting promotion). With regard to Smad-dependent signaling, cytoplasmic accumulation of phosphorylated Smad (phospho-Smad)-2/3 - identified as Smad3 by later immunoblot analysis - increased in the subpopulation of GST-P + foci, while Smad4, a nuclear transporter of Smad2/3, decreased during early-stage promotion. By late-stage promotion, GST-P + lesions lacking phospho-Smad2/3 had increased in accordance with lesion development from foci to carcinomas, while Smad4 largely disappeared in most proliferative lesions. With regard to Smad-independent mitogen-activated protein kinases, GST-P + foci that co-expressed phospho-p38 mitogen-activated protein kinase increased during early-stage promotion; however, p38-downstream phospho-activating transcriptional factor (ATF)-2, ATF3, and phospho-c-Myc, were inversely downregulated without relation to promotion. By late-stage promotion, proliferative lesions downregulated phospho-ATF2 and phospho-c-Myc along with lesion development, as with downregulation of phospho-p38 in all lesions. These results suggest that from the early stages, carcinogenic processes were facilitated by disruption of tumor suppressor functions of Smad-dependent signaling, while Smad-independent activation of p38 was an early-stage phenomenon. GST-P - foci induced by promotion with agonists of peroxisome proliferator-activated receptor-α did not change Smad expression, suggesting an aberration in the Smad-dependent signaling prerequisites for induction

Effect of harmonicity on the detection of a signal in a complex masker and on spatial release from masking.

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Astrid Klinge

Full Text Available The amount of masking of sounds from one source (signals by sounds from a competing source (maskers heavily depends on the sound characteristics of the masker and the signal and on their relative spatial location. Numerous studies investigated the ability to detect a signal in a speech or a noise masker or the effect of spatial separation of signal and masker on the amount of masking, but there is a lack of studies investigating the combined effects of many cues on the masking as is typical for natural listening situations. The current study using free-field listening systematically evaluates the combined effects of harmonicity and inharmonicity cues in multi-tone maskers and cues resulting from spatial separation of target signal and masker on the detection of a pure tone in a multi-tone or a noise masker. A linear binaural processing model was implemented to predict the masked thresholds in order to estimate whether the observed thresholds can be accounted for by energetic masking in the auditory periphery or whether other effects are involved. Thresholds were determined for combinations of two target frequencies (1 and 8 kHz, two spatial configurations (masker and target either co-located or spatially separated by 90 degrees azimuth, and five different masker types (four complex multi-tone stimuli, one noise masker. A spatial separation of target and masker resulted in a release from masking for all masker types. The amount of masking significantly depended on the masker type and frequency range. The various harmonic and inharmonic relations between target and masker or between components of the masker resulted in a complex pattern of increased or decreased masked thresholds in comparison to the predicted energetic masking. The results indicate that harmonicity cues affect the detectability of a tonal target in a complex masker.

Early bone anchorage to micro- and nano-topographically complex implant surfaces in hyperglycemia.

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Ajami, Elnaz; Bell, Spencer; Liddell, Robert S; Davies, John E

2016-07-15

The aim of this work was to investigate the effect of implant surface design on early bone anchorage in the presence of hyperglycemia. 108 Wistar rats were separated into euglycemic (EG) controls and STZ-treated hyperglycemic (HG) groups, and received bilateral femoral custom rectangular implants of two surface topographies: grit blasted (GB) and grit-blast with a superimposed calcium phosphate nanotopography (GB-DCD). The peri-implant bone was subjected to a tensile disruption test 5, 7, and 9days post-operatively (n=28/time point); the force was measured; and the residual peri-implant bone was observed by scanning electron microscopy (SEM). Disruption forces at 5days were not significantly different from zero for the GB implants (p=0.24) in either metabolic group; but were for GB+DCD implants in both metabolic groups (pmicro-surfaced implants showed significantly different disruption forces at all time points (e.g. >15N and implants, as all values were very low (implant bone showed compromised intra-fibrillar collagen mineralization in hyperglycemia, while inter-fibrillar and cement line mineralization remained unaffected. Enhanced bone anchorage to the implant surfaces was observed on the nanotopographically complex surface independent of metabolic group. The compromised intra-fibrillar mineralization observed provides a mechanism by which early bone mineralization is affected in hyperglycemia. It is generally accepted that the hyperglycemia associated with diabetes mellitus compromises bone quality, although the mechanism by which this occurs is unknown. Uncontrolled hyperglycemia is therefore a contra-indication for bone implant placement. It is also known that nano-topographically complex implant surfaces accelerate early peri-implant healing. In this report we show that, in our experimental model, nano-topographically complex surfaces can mitigate the compromised bone healing seen in hyperglycemia. Importantly, we also provide a mechanistic explanation for

Intact Mre11/Rad50/Nbs1 Complex Predicts Good Response to Radiotherapy in Early Breast Cancer

International Nuclear Information System (INIS)

Soederlund, Karin; Stal, Olle; Skoog, Lambert; Rutqvist, Lars Erik; Nordenskjoeld, Bo; Askmalm, Marie Stenmark

2007-01-01

Purpose: To investigate the expression and predictive role of the Mre11/Rad50/Nbs1 (MRN) complex and the ataxia-telangiectasia mutated protein (ATM) for the outcome of radiotherapy in breast cancer patients. Methods and Materials: The protein expression of ATM and the DNA repair proteins in the MRN complex were investigated using immunohistochemistry in tumors from 224 women with early breast cancer, who were randomized to receive postoperative radiotherapy or adjuvant chemotherapy. Results: Compared with normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1, and ATM was reduced in a majority of the tumors. Weak expression of the MRN complex was correlated with high histologic grade and estrogen receptor negativity (p = 0.01 and p 0.0001, respectively). Radiotherapy significantly reduced the risk of local recurrence as compared with chemotherapy (p = 0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (relative risk = 0.27, 95% confidence interval = 0.098-0.72, p 0.009), whereas patients with negative/weak MRN expression had no benefit of radiotherapy compared with adjuvant chemotherapy. These results suggest that an intact MRN complex is important for the tumor cell eradicating effect of radiotherapy. Conclusions: Reduced expression of the MRN complex predicts a poor effect of radiotherapy in patients with early breast cancer

Detecting early warning signals of tree mortality in boreal North America using multiscale satellite data.

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Rogers, Brendan M; Solvik, Kylen; Hogg, Edward H; Ju, Junchang; Masek, Jeffrey G; Michaelian, Michael; Berner, Logan T; Goetz, Scott J

2018-02-26

Increasing tree mortality from global change drivers such as drought and biotic infestations is a widespread phenomenon, including in the boreal zone where climate changes and feedbacks to the Earth system are relatively large. Despite the importance for science and management communities, our ability to forecast tree mortality at landscape to continental scales is limited. However, two independent information streams have the potential to inform and improve mortality forecasts: repeat forest inventories and satellite remote sensing. Time series of tree-level growth patterns indicate that productivity declines and related temporal dynamics often precede mortality years to decades before death. Plot-level productivity, in turn, has been related to satellite-based indices such as the Normalized difference vegetation index (NDVI). Here we link these two data sources to show that early warning signals of mortality are evident in several NDVI-based metrics up to 24 years before death. We focus on two repeat forest inventories and three NDVI products across western boreal North America where productivity and mortality dynamics are influenced by periodic drought. These data sources capture a range of forest conditions and spatial resolution to highlight the sensitivity and limitations of our approach. Overall, results indicate potential to use satellite NDVI for early warning signals of mortality. Relationships are broadly consistent across inventories, species, and spatial resolutions, although the utility of coarse-scale imagery in the heterogeneous aspen parkland was limited. Longer-term NDVI data and annually remeasured sites with high mortality levels generate the strongest signals, although we still found robust relationships at sites remeasured at a typical 5 year frequency. The approach and relationships developed here can be used as a basis for improving forest mortality models and monitoring systems. © 2018 John Wiley & Sons Ltd.

Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins.

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Chen, Buxin; Siderovski, David P; Neubig, Richard R; Lawson, Mark A; Trejo, Joann

2014-01-17

The G protein-coupled protease-activated receptor 1 (PAR1) is irreversibly proteolytically activated by thrombin. Hence, the precise regulation of PAR1 signaling is important for proper cellular responses. In addition to desensitization, internalization and lysosomal sorting of activated PAR1 are critical for the termination of signaling. Unlike most G protein-coupled receptors, PAR1 internalization is mediated by the clathrin adaptor protein complex 2 (AP-2) and epsin-1, rather than β-arrestins. However, the function of AP-2 and epsin-1 in the regulation of PAR1 signaling is not known. Here, we report that AP-2, and not epsin-1, regulates activated PAR1-stimulated phosphoinositide hydrolysis via two different mechanisms that involve, in part, a subset of R4 subfamily of "regulator of G protein signaling" (RGS) proteins. A significantly greater increase in activated PAR1 signaling was observed in cells depleted of AP-2 using siRNA or in cells expressing a PAR1 (420)AKKAA(424) mutant with defective AP-2 binding. This effect was attributed to AP-2 modulation of PAR1 surface expression and efficiency of G protein coupling. We further found that ectopic expression of R4 subfamily members RGS2, RGS3, RGS4, and RGS5 reduced activated PAR1 wild-type signaling, whereas signaling by the PAR1 AKKAA mutant was minimally affected. Intriguingly, siRNA-mediated depletion analysis revealed a function for RGS5 in the regulation of signaling by the PAR1 wild type but not the AKKAA mutant. Moreover, activation of the PAR1 wild type, and not the AKKAA mutant, induced Gαq association with RGS3 via an AP-2-dependent mechanism. Thus, AP-2 regulates activated PAR1 signaling by altering receptor surface expression and through recruitment of RGS proteins.

Micro-earthquake signal analysis and hypocenter determination around Lokon volcano complex

International Nuclear Information System (INIS)

Firmansyah, Rizky; Nugraha, Andri Dian; Kristianto

2015-01-01

Mount Lokon is one of five active volcanoes which is located in the North Sulawesi region. Since June 26 th , 2011, standby alert set by the Center for Volcanology and Geological Hazard Mitigation (CVGHM) for this mountain. The Mount Lokon volcano erupted on July 4 th , 2011 and still continuously erupted until August 28 th , 2011. Due to its high seismic activity, this study is focused to analysis of micro-earthquake signal and determine the micro-earthquake hypocenter location around the complex area of Lokon-Empung Volcano before eruption phase in 2011 (time periods of January, 2009 up to March, 2010). Determination of the hypocenter location was conducted with Geiger Adaptive Damping (GAD) method. We used initial model from previous study in Volcan de Colima, Mexico. The reason behind the model selection was based on the same characteristics that shared between Mount Lokon and Colima including andesitic stratovolcano and small-plinian explosions volcanian types. In this study, a picking events was limited to the volcano-tectonics of A and B types, hybrid, long-period that has a clear signal onset, and local tectonic with different maximum S – P time are not more than three seconds. As a result, we observed the micro-earthquakes occurred in the area north-west of Mount Lokon region

The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation.

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Sun, X J; Pons, S; Asano, T; Myers, M G; Glasheen, E; White, M F

1996-05-03

Irs-proteins link the receptors for insulin/IGF-1, growth hormones, and several interleukins and interferons to signaling proteins that contain Src homology-2 (SH2). To identify new Irs-1-binding proteins, we screened a mouse embryo expression library with recombinant [32P]Irs-1, which revealed a specific association between p59fyn and Irs-1. The SH2 domain in p59fyn bound to phosphorylated Tyr895 and Tyr1172, which are located in YXX(L/I) motifs. Mutation of p59fyn at the COOH-terminal tyrosine phosphorylation site (Tyr531) enhanced its binding to Irs-1 during insulin stimulation. Binding experiments with various SH2 protein revealed that Grb-2 was largely excluded from Irs-1 complexes containing p59fyn, whereas Grb-2 and p85 occurred in the same Irs-1 complex. By comparison with the insulin receptor, p59fyn kinase phosphorylated a unique cohort of tyrosine residues in Irs-1. These results outline a role for p59fyn or other related Src-kinases during insulin and cytokine signaling.

Orphan receptor GPR179 forms macromolecular complexes with components of metabotropic signaling cascade in retina ON-bipolar neurons.

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Orlandi, Cesare; Cao, Yan; Martemyanov, Kirill A

2013-10-29

In the mammalian retina, synaptic transmission between light-excited rod photoreceptors and downstream ON-bipolar neurons is indispensable for dim vision, and disruption of this process leads to congenital stationary night blindness in human patients. The ON-bipolar neurons use the metabotropic signaling cascade, initiated by the mGluR6 receptor, to generate depolarizing responses to light-induced changes in neurotransmitter glutamate release from the photoreceptor axonal terminals. Evidence for the identity of the components involved in transducing these signals is growing rapidly. Recently, the orphan receptor, GPR179, a member of the G protein-coupled receptor (GPCR) superfamily, has been shown to be indispensable for the synaptic responses of ON-bipolar cells. In our study, we investigated the interaction of GPR179 with principle components of the signal transduction cascade. We used immunoprecipitation and proximity ligation assays in transfected cells and native retinas to characterize the protein-protein interactions involving GPR179. The influence of cascade components on GPR179 localization was examined through immunohistochemical staining of the retinas from genetic mouse models. We demonstrated that, in mouse retinas, GPR179 forms physical complexes with the main components of the metabotropic cascade, recruiting mGluR6, TRPM1, and the RGS proteins. Elimination of mGluR6 or RGS proteins, but not TRPM1, detrimentally affects postsynaptic targeting or GPR179 expression. These observations suggest that the mGluR6 signaling cascade is scaffolded as a macromolecular complex in which the interactions between the components ensure the optimal spatiotemporal characteristics of signal transduction.

Dynamic facial expressions of emotion transmit an evolving hierarchy of signals over time.

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Jack, Rachael E; Garrod, Oliver G B; Schyns, Philippe G

2014-01-20

Designed by biological and social evolutionary pressures, facial expressions of emotion comprise specific facial movements to support a near-optimal system of signaling and decoding. Although highly dynamical, little is known about the form and function of facial expression temporal dynamics. Do facial expressions transmit diagnostic signals simultaneously to optimize categorization of the six classic emotions, or sequentially to support a more complex communication system of successive categorizations over time? Our data support the latter. Using a combination of perceptual expectation modeling, information theory, and Bayesian classifiers, we show that dynamic facial expressions of emotion transmit an evolving hierarchy of "biologically basic to socially specific" information over time. Early in the signaling dynamics, facial expressions systematically transmit few, biologically rooted face signals supporting the categorization of fewer elementary categories (e.g., approach/avoidance). Later transmissions comprise more complex signals that support categorization of a larger number of socially specific categories (i.e., the six classic emotions). Here, we show that dynamic facial expressions of emotion provide a sophisticated signaling system, questioning the widely accepted notion that emotion communication is comprised of six basic (i.e., psychologically irreducible) categories, and instead suggesting four. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ancient Origin of the CARD–Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions

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Jens Staal

2018-05-01

Full Text Available The CARD–coiled coil (CC/Bcl10/MALT1-like paracaspase (CBM signaling complexes composed of a CARD–CC family member (CARD-9, -10, -11, or -14, Bcl10, and the type 1 paracaspase MALT1 (PCASP1 play a pivotal role in immunity, inflammation, and cancer. Targeting MALT1 proteolytic activity is of potential therapeutic interest. However, little is known about the evolutionary origin and the original functions of the CBM complex. Type 1 paracaspases originated before the last common ancestor of planulozoa (bilaterians and cnidarians. Notably in bilaterians, Ecdysozoa (e.g., nematodes and insects lacks Bcl10, whereas other lineages have a Bcl10 homolog. A survey of invertebrate CARD–CC homologs revealed such homologs only in species with Bcl10, indicating an ancient common origin of the entire CBM complex. Furthermore, vertebrate-like Syk/Zap70 tyrosine kinase homologs with the ITAM-binding SH2 domain were only found in invertebrate organisms with CARD–CC/Bcl10, indicating that this pathway might be related to the original function of the CBM complex. Moreover, the type 1 paracaspase sequences from invertebrate organisms that have CARD–CC/Bcl10 are more similar to vertebrate paracaspases. Functional analysis of protein–protein interactions, NF-κB signaling, and CYLD cleavage for selected invertebrate type 1 paracaspase and Bcl10 homologs supports this scenario and indicates an ancient origin of the CARD–CC/Bcl10/paracaspase signaling complex. By contrast, many of the known MALT1-associated activities evolved fairly recently, indicating that unknown functions are at the basis of the protein conservation. As a proof-of-concept, we provide initial evidence for a CBM- and NF-κB-independent neuronal function of the Caenorhabditis elegans type 1 paracaspase malt-1. In conclusion, this study shows how evolutionary insights may point at alternative functions of MALT1.

Complex-enhanced chaotic signals with time-delay signature suppression based on vertical-cavity surface-emitting lasers subject to chaotic optical injection

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Chen, Jianjun; Duan, Yingni; Zhong, Zhuqiang

2018-03-01

A chaotic system is constructed on the basis of vertical-cavity surface-emitting lasers (VCSELs), where a slave VCSEL subject to chaotic optical injection (COI) from a master VCSEL with the external feedback. The complex degree (CD) and time-delay signature (TDS) of chaotic signals generated by this chaotic system are investigated numerically via permutation entropy (PE) and self-correlation function (SF) methods, respectively. The results show that, compared with master VCSEL subject to optical feedback, complex-enhanced chaotic signals with TDS suppression can be achieved for S-VCSEL subject to COI. Meanwhile, the influences of several controllable parameters on the evolution maps of CD of chaotic signals are carefully considered. It is shown that the CD of chaotic signals for S-VCSEL is always higher than that for M-VCSEL due to the CIO effect. The TDS of chaotic signals can be significantly suppressed by choosing the reasonable parameters in this system. Furthermore, TDS suppression and high CD chaos can be obtained simultaneously in the specific parameter ranges. The results confirm that this chaotic system may effectively improve the security of a chaos-based communication scheme.

Early anti-correlated BOLD signal changes of physiologic origin.

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Bright, Molly G; Bianciardi, Marta; de Zwart, Jacco A; Murphy, Kevin; Duyn, Jeff H

2014-02-15

Negative BOLD signals that are synchronous with resting state fluctuations have been observed in large vessels in the cortical sulci and surrounding the ventricles. In this study, we investigated the origin of these negative BOLD signals by applying a Cued Deep Breathing (CDB) task to create transient hypocapnia and a resultant global fMRI signal decrease. We hypothesized that a global stimulus would amplify the effect in large vessels and that using a global negative (vasoconstrictive) stimulus would test whether these voxels exhibit either inherently negative or simply anti-correlated BOLD responses. Significantly anti-correlated, but positive, BOLD signal changes during respiratory challenges were identified in voxels primarily located near edges of brain spaces containing CSF. These positive BOLD responses occurred earlier than the negative CDB response across most of gray matter voxels. These findings confirm earlier suggestions that in some brain regions, local, fractional changes in CSF volume may overwhelm BOLD-related signal changes, leading to signal anti-correlation. We show that regions with CDB anti-correlated signals coincide with most, but not all, of the regions with negative BOLD signal changes observed during a visual and motor stimulus task. Thus, the addition of a physiological challenge to fMRI experiments can help identify which negative BOLD signals are passive physiological anti-correlations and which may have a putative neuronal origin. Published by Elsevier Inc.

Regulation of Early Steps of GPVI Signal Transduction by Phosphatases: A Systems Biology Approach.

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Joanne L Dunster

2015-11-01

Full Text Available We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2, provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in

VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis

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Gareth W. Fearnley

2016-05-01

Full Text Available Vascular endothelial growth factor A (VEGF-A binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A–VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor–ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145 promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes.

VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.

Science.gov (United States)

Fearnley, Gareth W; Smith, Gina A; Abdul-Zani, Izma; Yuldasheva, Nadira; Mughal, Nadeem A; Homer-Vanniasinkam, Shervanthi; Kearney, Mark T; Zachary, Ian C; Tomlinson, Darren C; Harrison, Michael A; Wheatcroft, Stephen B; Ponnambalam, Sreenivasan

2016-05-15

Vascular endothelial growth factor A (VEGF-A) binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A-VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor-ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes. © 2016. Published by The Company of Biologists Ltd.

"I Understood the Complexity within Diversity": Preparation for Partnership with Families in Early Childhood Settings

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Hedges, Helen; Lee, Debora

2010-01-01

"Partnership between parents and teachers" is a taken-for-granted feature of the philosophy and practice of early childhood education. Yet, the literature suggests this rhetoric belies a more complex and problematic reality for teachers. Making connections with the families and communities they will serve may help teacher education…

Conformational coupling between receptor and kinase binding sites through a conserved salt bridge in a signaling complex scaffold protein.

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Davi R Ortega

Full Text Available Bacterial chemotaxis is one of the best studied signal transduction pathways. CheW is a scaffold protein that mediates the association of the chemoreceptors and the CheA kinase in a ternary signaling complex. The effects of replacing conserved Arg62 of CheW with other residues suggested that the scaffold protein plays a more complex role than simply binding its partner proteins. Although R62A CheW had essentially the same affinity for chemoreceptors and CheA, cells expressing the mutant protein are impaired in chemotaxis. Using a combination of molecular dynamics simulations (MD, NMR spectroscopy, and circular dichroism (CD, we addressed the role of Arg62. Here we show that Arg62 forms a salt bridge with another highly conserved residue, Glu38. Although this interaction is unimportant for overall protein stability, it is essential to maintain the correct alignment of the chemoreceptor and kinase binding sites of CheW. Computational and experimental data suggest that the role of the salt bridge in maintaining the alignment of the two partner binding sites is fundamental to the function of the signaling complex but not to its assembly. We conclude that a key feature of CheW is to maintain the specific geometry between the two interaction sites required for its function as a scaffold.

Low-complexity R-peak detection in ECG signals: a preliminary step towards ambulatory fetal monitoring.

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Rooijakkers, Michiel; Rabotti, Chiara; Bennebroek, Martijn; van Meerbergen, Jef; Mischi, Massimo

2011-01-01

Non-invasive fetal health monitoring during pregnancy has become increasingly important. Recent advances in signal processing technology have enabled fetal monitoring during pregnancy, using abdominal ECG recordings. Ubiquitous ambulatory monitoring for continuous fetal health measurement is however still unfeasible due to the computational complexity of noise robust solutions. In this paper an ECG R-peak detection algorithm for ambulatory R-peak detection is proposed, as part of a fetal ECG detection algorithm. The proposed algorithm is optimized to reduce computational complexity, while increasing the R-peak detection quality compared to existing R-peak detection schemes. Validation of the algorithm is performed on two manually annotated datasets, the MIT/BIH Arrhythmia database and an in-house abdominal database. Both R-peak detection quality and computational complexity are compared to state-of-the-art algorithms as described in the literature. With a detection error rate of 0.22% and 0.12% on the MIT/BIH Arrhythmia and in-house databases, respectively, the quality of the proposed algorithm is comparable to the best state-of-the-art algorithms, at a reduced computational complexity.

Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

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Warut Tulalamba

2012-01-01

Full Text Available Nasopharyngeal carcinoma (NPC is an uncommon cancer, which has a distinctive ethnic and geographic distribution. Etiology of NPC is considered to be related with a complex interaction of environmental and genetic factors as well as Epstein-Barr virus infection. Since NPC is located in the silent painless area, the disease is usually therefore diagnosed at the advanced stages; hence early detection of NPC is difficult. Furthermore, understanding in molecular pathogenesis is still lacking, pondering the identification of effective prognostic and diagnostic biomarkers. Dysregulation of signaling molecules in intracellular signal transduction, which regulate cell proliferation, apoptosis, and adhesion, underlines the basis of NPC pathogenesis. In this paper, the molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression. The important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.

Regulation of Drosophila Brain Wiring by Neuropil Interactions via a Slit-Robo-RPTP Signaling Complex.

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Oliva, Carlos; Soldano, Alessia; Mora, Natalia; De Geest, Natalie; Claeys, Annelies; Erfurth, Maria-Luise; Sierralta, Jimena; Ramaekers, Ariane; Dascenco, Dan; Ejsmont, Radoslaw K; Schmucker, Dietmar; Sanchez-Soriano, Natalia; Hassan, Bassem A

2016-10-24

The axonal wiring molecule Slit and its Round-About (Robo) receptors are conserved regulators of nerve cord patterning. Robo receptors also contribute to wiring brain circuits. Whether molecular mechanisms regulating these signals are modified to fit more complex brain wiring processes is unclear. We investigated the role of Slit and Robo receptors in wiring Drosophila higher-order brain circuits and identified differences in the cellular and molecular mechanisms of Robo/Slit function. First, we find that signaling by Robo receptors in the brain is regulated by the Receptor Protein Tyrosine Phosphatase RPTP69d. RPTP69d increases membrane availability of Robo3 without affecting its phosphorylation state. Second, we detect no midline localization of Slit during brain development. Instead, Slit is enriched in the mushroom body, a neuronal structure covering large areas of the brain. Thus, a divergent molecular mechanism regulates neuronal circuit wiring in the Drosophila brain, partly in response to signals from the mushroom body. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Micro-earthquake signal analysis and hypocenter determination around Lokon volcano complex

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Firmansyah, Rizky, E-mail: rizkyfirmansyah@hotmail.com [Geophysical Engineering, Faculty of Mining and Petroleum Engineering, Institut Teknologi Bandung, Bandung, 40132 (Indonesia); Nugraha, Andri Dian, E-mail: nugraha@gf.itb.ac.id [Global Geophysical Group, Faculty of Mining and Petroleum Engineering, Institut Teknologi Bandung, Bandung, 40132 (Indonesia); Kristianto, E-mail: kris@vsi.esdm.go.id [Center for Volcanology and Geological Hazard Mitigation (CVGHM), Geological Agency, Bandung, 40122 (Indonesia)

2015-04-24

Mount Lokon is one of five active volcanoes which is located in the North Sulawesi region. Since June 26{sup th}, 2011, standby alert set by the Center for Volcanology and Geological Hazard Mitigation (CVGHM) for this mountain. The Mount Lokon volcano erupted on July 4{sup th}, 2011 and still continuously erupted until August 28{sup th}, 2011. Due to its high seismic activity, this study is focused to analysis of micro-earthquake signal and determine the micro-earthquake hypocenter location around the complex area of Lokon-Empung Volcano before eruption phase in 2011 (time periods of January, 2009 up to March, 2010). Determination of the hypocenter location was conducted with Geiger Adaptive Damping (GAD) method. We used initial model from previous study in Volcan de Colima, Mexico. The reason behind the model selection was based on the same characteristics that shared between Mount Lokon and Colima including andesitic stratovolcano and small-plinian explosions volcanian types. In this study, a picking events was limited to the volcano-tectonics of A and B types, hybrid, long-period that has a clear signal onset, and local tectonic with different maximum S – P time are not more than three seconds. As a result, we observed the micro-earthquakes occurred in the area north-west of Mount Lokon region.

Canonical TGF-β Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression.

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Nakashima, Hideyuki; Tsujimura, Keita; Irie, Koichiro; Ishizu, Masataka; Pan, Miao; Kameda, Tomonori; Nakashima, Kinichi

2018-05-16

Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-β (TGF-β) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-β family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG-interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF-β family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-β receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-β signaling is involved in the pathogenesis of neurodevelopmental diseases. SIGNIFICANCE STATEMENT Canonical transforming growth factor-β (TGF-β) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG-interacting factor-dependent canonical TGF-β signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF-β signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our

EFFECT OF COMPLEX FERTILIZERS USED IN EARLY CROP POTATO CULTURE ON LOAMY SAND SOIL

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Wanda Wadas

2015-03-01

Full Text Available To obtain a high tuber yield of early crop potato good conditions for plant growth must be ensured. Potato has a relatively shallow root system and requires significant nutrient inputs to maintain tuber productivity and quality. The paper presents the results of the research on the effect of complex fertilizers type NPK MgS with and without microelements from the nitrophoska (HydroComplex, Nitrophoska Blue Special and Viking 13 and the amophoska group (Polimag S, and single-nutrient fertilizers on the plant growth and tuber yield of very early potato cultivars (‘Aster’, ‘Fresco’, ‘Gloria’ on loamy sand soil. The field experiment was carried out in mideastern Poland (52°03'N, 22°33'E. Potatoes were harvested 75 days after planting (the end of June. The type of fertilizer (single-nutrient or complex fertilizer slightly affected the growth of potato plants. With the use of complex fertilizers, the assimilation leaf area and leaf area index (LAI were similar to the application of single-nutrient fertilizers. Of the examined complex fertilizers, Viking 13 (representing the nitrophoska group without microelements resulted in a smaller increase of assimilation leaf area in comparison with the cultivation without mineral fertilization. The type of fertilizer exerted a greater influence on the plant growth of ‘Aster’ (Poland than ‘Fresco’ (The Netherlands and ‘Gloria’ (Germany. The productive effects of complex fertilizers in early crop potato culture on loamy sand soil were comparable with single-nutrient fertilizers. The highest tuber yield was achieved with the application of Nitrophoska Blue Special (from the nitrophoska group with the lowest NNH4+ concentration; the total tuber yield was higher on average by 2.94 t*ha-1 (21.0% and the yield of marketable tuber fraction (diameter above 30 mm by 2.55 t*ha-1 (20.4% in comparison with the cultivation without mineral fertilization. Although the total tuber yield was a little

Bcl-xL acts downstream of caspase-8 activation by the CD95 death-inducing signaling complex

NARCIS (Netherlands)

Medema, J. P.; Scaffidi, C.; Krammer, P. H.; Peter, M. E.

1998-01-01

The Bcl-2 family member Bcl-xL has often been correlated with apoptosis resistance. We have shown recently that in peripheral human T cells resistance to CD95-mediated apoptosis is characterized by a lack of caspase-8 recruitment to the CD95 death-inducing signaling complex (DISC) and by increased

Phase dynamics of complex-valued neural networks and its application to traffic signal control.

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Nishikawa, Ikuko; Iritani, Takeshi; Sakakibara, Kazutoshi; Kuroe, Yasuaki

2005-01-01

Complex-valued Hopfield networks which possess the energy function are analyzed. The dynamics of the network with certain forms of an activation function is de-composable into the dynamics of the amplitude and phase of each neuron. Then the phase dynamics is described as a coupled system of phase oscillators with a pair-wise sinusoidal interaction. Therefore its phase synchronization mechanism is useful for the area-wide offset control of the traffic signals. The computer simulations show the effectiveness under the various traffic conditions.

Distribution and Variability of Satellite-Derived Signals of Isolated Convection Initiation Events Over Central Eastern China

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Huang, Yipeng; Meng, Zhiyong; Li, Jing; Li, Wanbiao; Bai, Lanqiang; Zhang, Murong; Wang, Xi

2017-11-01

This study combined measurements from the Chinese operational geostationary satellite Fengyun-2E (FY-2E) and ground-based weather radars to conduct a statistical survey of isolated convection initiation (CI) over central eastern China (CEC). The convective environment in CEC is modulated by the complex topography and monsoon climate. From May to August 2010, a total of 1,630 isolated CI signals were derived from FY-2E using a semiautomated method. The formation of these satellite-derived CI signals peaks in the early afternoon and occurs with high frequency in areas with remarkable terrain inhomogeneity (e.g., mountain, water, and mountain-water areas). The high signal frequency areas shift from northwest CEC (dry, high altitude) in early summer to southeast CEC (humid, low altitude) in midsummer along with an increasing monthly mean frequency. The satellite-derived CI signals tend to have longer lead times (the time difference between satellite-derived signal formation and radar-based CI) in the late morning and afternoon than in the early morning and night. During the early morning and night, the distinction between cloud top signatures and background terrestrial radiation becomes less apparent, resulting in delayed identification of the signals and thus short and even negative lead times. A decline in the lead time is observed from May to August, likely due to the increasing cloud growth rate and warm-rain processes. Results show increasing lead times with increasing landscape elevation, likely due to more warm-rain processes over the coastal sea and plain, along with a decreasing cloud growth rate from hill and mountain to the plateau.

Reveal or Conceal? An Explorative Study of Signaling Strategies to Build Legitimacy in Cleantech Ventures

DEFF Research Database (Denmark)

Bjørnåli, Ekaterina; Giones, Ferran; Billström, Anders

perceived weaknesses. For cleantech entrepreneurs, having a focus on direct signaling on how the technology performs and its market potential seems to be a more fruitful strategy than signaling the environmental impact of technology in the early stage. While having an experienced board helps to issue...... environmentally friendly handling of waste. They represent an extreme case of technology entrepreneurship: combining a strong focus on capital-intensive technologies with complex industrial markets. Cleantech ventures face greater firm and industry-level legitimacy challenges while accessing external resources...... guide in the spring 2016, and collected secondary data on the firms. Results and Implications Our findings describe the motivations and distinctive characteristics of the signaling actions. Cleantech ventures pursue several parallel signaling strategies, shifting from resources to customers’ acquisition...

Ca2+/nuclear factor of activated T cells signaling is enriched in early-onset rectal tumors devoid of canonical Wnt activation.

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Kumar, Raju; Raman, Ratheesh; Kotapalli, Viswakalyan; Gowrishankar, Swarnalata; Pyne, Saumyadipta; Pollack, Jonathan R; Bashyam, Murali D

2018-02-01

Our previous extensive analysis revealed a significant proportion of early-onset colorectal tumors from India to be localized to the rectum in younger individuals and devoid of deregulated Wnt/β-catenin signaling. In the current study, we performed a comprehensive genome-wide analysis of clinically well-annotated microsatellite stable early-onset sporadic rectal cancer (EOSRC) samples. Results revealed extensive DNA copy number alterations in rectal tumors in the absence of deregulated Wnt/β-catenin signaling. More importantly, transcriptome profiling revealed a (non-Wnt/β-catenin, non-MSI) genetic signature that could efficiently and specifically identify Wnt- rectal cancer. The genetic signature included a significant representation of genes belonging to Ca 2+ /NFAT signaling pathways that were validated in additional samples. The validated NFAT target genes exhibited significantly higher expression levels than canonical Wnt/β-catenin targets in Wnt- samples, an observation confirmed in other CRC expression data sets as well. We confirmed the validated genes to be transcriptionally regulated by NFATc1 by (a) evaluating their respective transcript levels and (b) performing promoter-luciferase and chromatin immunoprecipitation assays following ectopic expression as well as knockdown of NFATc1 in CRC cells. NFATc1 and its targets RUNX2 and GSN could drive increased migration in CRC cells. Finally, the validated genes were associated with poor survival in the cancer genome atlas CRC expression data set. This study is the first comprehensive molecular characterization of EOSRC that appears to be driven by noncanonical tumorigenesis pathways. Early-onset sporadic rectal cancer exhibits DNA gain and loss without Wnt activation. Ca 2+ /NFAT signaling appears to be activated in the absence of Wnt activation. An eight-gene genetic signature distinguishes Wnt+ and Wnt- rectal tumors. NFAT and its target genes regulate tumorigenic properties in CRC cells.

Cadherin complexes recruit mRNAs and RISC to regulate epithelial cell signaling.

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Kourtidis, Antonis; Necela, Brian; Lin, Wan-Hsin; Lu, Ruifeng; Feathers, Ryan W; Asmann, Yan W; Thompson, E Aubrey; Anastasiadis, Panos Z

2017-10-02

Cumulative evidence demonstrates that most RNAs exhibit specific subcellular distribution. However, the mechanisms regulating this phenomenon and its functional consequences are still under investigation. Here, we reveal that cadherin complexes at the apical zonula adherens (ZA) of epithelial adherens junctions recruit the core components of the RNA-induced silencing complex (RISC) Ago2, GW182, and PABPC1, as well as a set of 522 messenger RNAs (mRNAs) and 28 mature microRNAs (miRNAs or miRs), via PLEKHA7. Top canonical pathways represented by these mRNAs include Wnt/β-catenin, TGF-β, and stem cell signaling. We specifically demonstrate the presence and silencing of MYC, JUN, and SOX2 mRNAs by miR-24 and miR-200c at the ZA. PLEKHA7 knockdown dissociates RISC from the ZA, decreases loading of the ZA-associated mRNAs and miRNAs to Ago2, and results in a corresponding increase of MYC, JUN, and SOX2 protein expression. The present work reveals a mechanism that directly links junction integrity to the silencing of a set of mRNAs that critically affect epithelial homeostasis. © 2017 Kourtidis et al.

Early gene Broad complex plays a key role in regulating the immune response triggered by ecdysone in the Malpighian tubules of Drosophila melanogaster.

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Verma, Puja; Tapadia, Madhu G

2015-08-01

In insects, humoral response to injury is accomplished by the production of antimicrobial peptides (AMPs) which are secreted in the hemolymph to eliminate the pathogen. Drosophila Malpighian tubules (MTs), however, are unique immune organs that show constitutive expression of AMPs even in unchallenged conditions and the onset of immune response is developmental stage dependent. Earlier reports have shown ecdysone positively regulates immune response after pathogenic challenge however, a robust response requires prior potentiation by the hormone. Here we provide evidence to show that MTs do not require prior potentiation with ecdysone hormone for expression of AMPs and they respond to ecdysone very fast even without immune challenge, although the different AMPs Diptericin, Cecropin, Attacin, Drosocin show differential expression in response to ecdysone. We show that early gene Broad complex (BR-C) could be regulating the IMD pathway by activating Relish and physically interacting with it to activate AMPs expression. BR-C depletion from Malpighian tubules renders the flies susceptible to infection. We also show that in MTs ecdysone signaling is transduced by EcR-B1 and B2. In the absence of ecdysone signaling the IMD pathway associated genes are down regulated and activation and translocation of transcription factor Relish is also affected. Copyright © 2015 Elsevier Ltd. All rights reserved.

Changes in the Phosphoproteome and Metabolome Link Early Signaling Events to Rearrangement of Photosynthesis and Central Metabolism in Salinity and Oxidative Stress Response in Arabidopsis.

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Chen, Yanmei; Hoehenwarter, Wolfgang

2015-12-01

Salinity and oxidative stress are major factors affecting and limiting the productivity of agricultural crops. The molecular and biochemical processes governing the plant response to abiotic stress have often been researched in a reductionist manner. Here, we report a systemic approach combining metabolic labeling and phosphoproteomics to capture early signaling events with quantitative metabolome analysis and enzyme activity assays to determine the effects of salt and oxidative stress on plant physiology. K(+) and Na(+) transporters showed coordinated changes in their phosphorylation pattern, indicating the importance of dynamic ion homeostasis for adaptation to salt stress. Unique phosphorylation sites were found for Arabidopsis (Arabidopsis thaliana) SNF1 kinase homolog10 and 11, indicating their central roles in the stress-regulated responses. Seven Sucrose Non-fermenting1-Related Protein Kinase2 kinases showed varying levels of phosphorylation at multiple serine/threonine residues in their kinase domain upon stress, showing temporally distinct modulation of the various isoforms. Salinity and oxidative stress also lead to changes in protein phosphorylation of proteins central to photosynthesis, in particular the kinase State Transition Protein7 required for state transition and light-harvesting II complex proteins. Furthermore, stress-induced changes of the phosphorylation of enzymes of central metabolism were observed. The phosphorylation patterns of these proteins were concurrent with changes in enzyme activity. This was reflected by altered levels of metabolites, such as the sugars sucrose and fructose, glycolysis intermediates, and amino acids. Together, our study provides evidence for a link between early signaling in the salt and oxidative stress response that regulates the state transition of photosynthesis and the rearrangement of primary metabolism. © 2015 American Society of Plant Biologists. All Rights Reserved.

Enhancement of MS Signal Processing For Improved Cancer Biomarker Discovery

Science.gov (United States)

Si, Qian

Technological advances in proteomics have shown great potential in detecting cancer at the earliest stages. One way is to use the time of flight mass spectroscopy to identify biomarkers, or early disease indicators related to the cancer. Pattern analysis of time of flight mass spectra data from blood and tissue samples gives great hope for the identification of potential biomarkers among the complex mixture of biological and chemical samples for the early cancer detection. One of the keys issues is the pre-processing of raw mass spectra data. A lot of challenges need to be addressed: unknown noise character associated with the large volume of data, high variability in the mass spectroscopy measurements, and poorly understood signal background and so on. This dissertation focuses on developing statistical algorithms and creating data mining tools for computationally improved signal processing for mass spectrometry data. I have introduced an advanced accurate estimate of the noise model and a half-supervised method of mass spectrum data processing which requires little knowledge about the data.

LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes

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Peter Draber

2015-12-01

Full Text Available Ubiquitination and deubiquitination are crucial for assembly and disassembly of signaling complexes. LUBAC-generated linear (M1 ubiquitin is important for signaling via various immune receptors. We show here that the deubiquitinases CYLD and A20, but not OTULIN, are recruited to the TNFR1- and NOD2-associated signaling complexes (TNF-RSC and NOD2-SC, at which they cooperate to limit gene activation. Whereas CYLD recruitment depends on its interaction with LUBAC, but not on LUBAC’s M1-chain-forming capacity, A20 recruitment requires this activity. Intriguingly, CYLD and A20 exert opposing effects on M1 chain stability in the TNF-RSC and NOD2-SC. While CYLD cleaves M1 chains, and thereby sensitizes cells to TNF-induced death, A20 binding to them prevents their removal and, consequently, inhibits cell death. Thus, CYLD and A20 cooperatively restrict gene activation and regulate cell death via their respective activities on M1 chains. Hence, the interplay between LUBAC, M1-ubiquitin, CYLD, and A20 is central for physiological signaling through innate immune receptors.

The late endosomal HOPS complex anchors active G-protein signaling essential for pathogenesis in magnaporthe oryzae.

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Ravikrishna Ramanujam

Full Text Available In Magnaporthe oryzae, the causal ascomycete of the devastating rice blast disease, the conidial germ tube tip must sense and respond to a wide array of requisite cues from the host in order to switch from polarized to isotropic growth, ultimately forming the dome-shaped infection cell known as the appressorium. Although the role for G-protein mediated Cyclic AMP signaling in appressorium formation was first identified almost two decades ago, little is known about the spatio-temporal dynamics of the cascade and how the signal is transmitted through the intracellular network during cell growth and morphogenesis. In this study, we demonstrate that the late endosomal compartments, comprising of a PI3P-rich (Phosphatidylinositol 3-phosphate highly dynamic tubulo-vesicular network, scaffold active MagA/GαS, Rgs1 (a GAP for MagA, Adenylate cyclase and Pth11 (a non-canonical GPCR in the likely absence of AKAP-like anchors during early pathogenic development in M. oryzae. Loss of HOPS component Vps39 and consequently the late endosomal function caused a disruption of adenylate cyclase localization, cAMP signaling and appressorium formation. Remarkably, exogenous cAMP rescued the appressorium formation defects associated with VPS39 deletion in M. oryzae. We propose that sequestration of key G-protein signaling components on dynamic late endosomes and/or endolysosomes, provides an effective molecular means to compartmentalize and control the spatio-temporal activation and rapid downregulation (likely via vacuolar degradation of cAMP signaling amidst changing cellular geometry during pathogenic development in M. oryzae.

Differences In Early T-Cell Signaling In Cultures Grown In a Rotating Clinostat vs. Static Controls

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Alexamder. M.; Nelman-Gonzales, M.; Penkala, J.; Sams, C.

1999-01-01

Altered gravity has previously been demonstrated to be a stress that can influence components of the immune system. Specifically, T-cell activation has been shown to be affected by changes in gravity, exhibiting a decrease in proliferative response to in vitro stimulation in microgravity. Subsequent ground based studies utilizing a rotating clinostat to model some of the effects of microgravity have been consistent with earlier flight based experiments. These ground and flight experiments have examined T-cell activation by measuring various responses including production of cytokines, DNA synthesis and the production of various cell surface activation markers. These indicators of T-cell activation were measured anywhere from 4 to 72 hours after stimulation. Prior to the work described here, the initial signaling events in T-cell activation had not been directly examined. The goal of this project was to determine how the process of early signal transduction was affected by growth in a rotating clinostat. Here we directly show a defect in signaling from TCR to MAPK in purified peripheral T-cells activated in the clinostat by OKT3/antiCD28 coated microbeads as compared to static controls.

An interplay between 2 signaling pathways: Melatonin-cAMP and IP3–Ca2+ signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum

International Nuclear Information System (INIS)

Furuyama, Wakako; Enomoto, Masahiro; Mossaad, Ehab; Kawai, Satoru; Mikoshiba, Katsuhiko; Kawazu, Shin-ichiro

2014-01-01

Highlights: • A melatonin receptor antagonist blocked Ca 2+ oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca 2+ - and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca 2+ ) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca 2+ imaging showed that LZ treatment completely abolished Ca 2+ oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP 3 –Ca 2+ and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum

Efficient transmission of subthreshold signals in complex networks of spiking neurons.

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Torres, Joaquin J; Elices, Irene; Marro, J

2015-01-01

We investigate the efficient transmission and processing of weak, subthreshold signals in a realistic neural medium in the presence of different levels of the underlying noise. Assuming Hebbian weights for maximal synaptic conductances--that naturally balances the network with excitatory and inhibitory synapses--and considering short-term synaptic plasticity affecting such conductances, we found different dynamic phases in the system. This includes a memory phase where population of neurons remain synchronized, an oscillatory phase where transitions between different synchronized populations of neurons appears and an asynchronous or noisy phase. When a weak stimulus input is applied to each neuron, increasing the level of noise in the medium we found an efficient transmission of such stimuli around the transition and critical points separating different phases for well-defined different levels of stochasticity in the system. We proved that this intriguing phenomenon is quite robust, as it occurs in different situations including several types of synaptic plasticity, different type and number of stored patterns and diverse network topologies, namely, diluted networks and complex topologies such as scale-free and small-world networks. We conclude that the robustness of the phenomenon in different realistic scenarios, including spiking neurons, short-term synaptic plasticity and complex networks topologies, make very likely that it could also occur in actual neural systems as recent psycho-physical experiments suggest.

Efficient transmission of subthreshold signals in complex networks of spiking neurons.

Directory of Open Access Journals (Sweden)

Joaquin J Torres

Full Text Available We investigate the efficient transmission and processing of weak, subthreshold signals in a realistic neural medium in the presence of different levels of the underlying noise. Assuming Hebbian weights for maximal synaptic conductances--that naturally balances the network with excitatory and inhibitory synapses--and considering short-term synaptic plasticity affecting such conductances, we found different dynamic phases in the system. This includes a memory phase where population of neurons remain synchronized, an oscillatory phase where transitions between different synchronized populations of neurons appears and an asynchronous or noisy phase. When a weak stimulus input is applied to each neuron, increasing the level of noise in the medium we found an efficient transmission of such stimuli around the transition and critical points separating different phases for well-defined different levels of stochasticity in the system. We proved that this intriguing phenomenon is quite robust, as it occurs in different situations including several types of synaptic plasticity, different type and number of stored patterns and diverse network topologies, namely, diluted networks and complex topologies such as scale-free and small-world networks. We conclude that the robustness of the phenomenon in different realistic scenarios, including spiking neurons, short-term synaptic plasticity and complex networks topologies, make very likely that it could also occur in actual neural systems as recent psycho-physical experiments suggest.

Applying Statistical and Complex Network Methods to Explore the Key Signaling Molecules of Acupuncture Regulating Neuroendocrine-Immune Network

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Kuo Zhang

2018-01-01

Full Text Available The mechanisms of acupuncture are still unclear. In order to reveal the regulatory effect of manual acupuncture (MA on the neuroendocrine-immune (NEI network and identify the key signaling molecules during MA modulating NEI network, we used a rat complete Freund’s adjuvant (CFA model to observe the analgesic and anti-inflammatory effect of MA, and, what is more, we used statistical and complex network methods to analyze the data about the expression of 55 common signaling molecules of NEI network in ST36 (Zusanli acupoint, and serum and hind foot pad tissue. The results indicate that MA had significant analgesic, anti-inflammatory effects on CFA rats; the key signaling molecules may play a key role during MA regulating NEI network, but further research is needed.

The Complex Trauma Questionnaire (ComplexTQ:Development and preliminary psychometric properties of an instrument for measuring early relational trauma

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Carola eMaggiora Vergano

2015-09-01

Full Text Available Research on the etiology of adult psychopathology and its relationship with childhood trauma has focused primarily on specific forms of maltreatment. This study developed an instrument for the assessment of childhood and adolescence trauma that would aid in identifying the role of co-occurring childhood stressors and chronic adverse conditions. The Complex Trauma Questionnaire (ComplexTQ, in both clinician and self-report versions, is a measure for the assessment of multi-type maltreatment: physical, psychological, and sexual abuse; physical and emotional neglect as well as other traumatic experiences, such rejection, role reversal, witnessing domestic violence, separations, and losses. The four-point Likert scale allows to specifically indicate with which caregiver the traumatic experience has occurred. A total of 229 participants, a sample of 79 nonclinical and that of 150 high-risk and clinical participants, were assessed with the ComplexTQ clinician version applied to Adult Attachment Interview (AAI transcripts. Initial analyses indicate acceptable inter-rater reliability. A good fit to a 6-factor model regarding the experience with the mother and to a 5-factor model with the experience with the father was obtained; the internal consistency of factors derived was good. Convergent validity was provided with the AAI scales. ComplexTQ factors discriminated normative from high-risk and clinical samples. The findings suggest a promising, reliable, and valid measurement of early relational trauma that is reported; furthermore, it is easy to complete and is useful for both research and clinical practice.

Ultrastructural Complexity of Nuclear Components During Early Apoptotic Phases in Breast Cancer Cells

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Christian Castelli

2001-01-01

Full Text Available Fractal morphometry was used to investigate the ultrastructural features of the plasma membrane, perinuclear membrane and nuclear chromatin in SK‐BR‐3 human breast cancer cells undergoing apoptosis. Cells were incubated with 1 μM calcimycin (A23187 for 24 h. Cells in the early stage of apoptosis had fractal dimension (FD values indicating that their plasma membranes were less rough (lower FD than those of control cells, while their perinuclear membranes were unaffected. Changes of the chromatin texture within the entire nucleus and in selected nuclear domains were more pronounced in treated cells. This confirms that the morphological reorganization imputable to a loss of structural complexity (reduced FD occurs in the early stage of apoptosis, is accompanied by the inhibition of distinct enzymatic events and precedes the onset of conventional cellular markers, which can only be detected during the active phases of the apoptotic process.

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

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Borahay, Mostafa A; Al-Hendy, Ayman; Kilic, Gokhan S; Boehning, Darren

2015-01-01

Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics. PMID:25879625

Regulation of neurite morphogenesis by interaction between R7 regulator of G protein signaling complexes and G protein subunit Gα13.

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Scherer, Stephanie L; Cain, Matthew D; Kanai, Stanley M; Kaltenbronn, Kevin M; Blumer, Kendall J

2017-06-16

The R7 regulator of G protein signaling family (R7-RGS) critically regulates nervous system development and function. Mice lacking all R7-RGS subtypes exhibit diverse neurological phenotypes, and humans bearing mutations in the retinal R7-RGS isoform RGS9-1 have vision deficits. Although each R7-RGS subtype forms heterotrimeric complexes with Gβ 5 and R7-RGS-binding protein (R7BP) that regulate G protein-coupled receptor signaling by accelerating deactivation of G i/o α-subunits, several neurological phenotypes of R7-RGS knock-out mice are not readily explained by dysregulated G i/o signaling. Accordingly, we used tandem affinity purification and LC-MS/MS to search for novel proteins that interact with R7-RGS heterotrimers in the mouse brain. Among several proteins detected, we focused on Gα 13 because it had not been linked to R7-RGS complexes before. Split-luciferase complementation assays indicated that Gα 13 in its active or inactive state interacts with R7-RGS heterotrimers containing any R7-RGS isoform. LARG (leukemia-associated Rho guanine nucleotide exchange factor (GEF)), PDZ-RhoGEF, and p115RhoGEF augmented interaction between activated Gα 13 and R7-RGS heterotrimers, indicating that these effector RhoGEFs can engage Gα 13 ·R7-RGS complexes. Because Gα 13 /R7-RGS interaction required R7BP, we analyzed phenotypes of neuronal cell lines expressing RGS7 and Gβ 5 with or without R7BP. We found that neurite retraction evoked by Gα 12/13 -dependent lysophosphatidic acid receptors was augmented in R7BP-expressing cells. R7BP expression blunted neurite formation evoked by serum starvation by signaling mechanisms involving Gα 12/13 but not Gα i/o These findings provide the first evidence that R7-RGS heterotrimers interact with Gα 13 to augment signaling pathways that regulate neurite morphogenesis. This mechanism expands the diversity of functions whereby R7-RGS complexes regulate critical aspects of nervous system development and function. © 2017 by

EDF-1 downregulates the CaM/Cn/NFAT signaling pathway during adipogenesis

International Nuclear Information System (INIS)

López-Victorio, Carlos J.; Velez-delValle, Cristina; Beltrán-Langarica, Alicia; Kuri-Harcuch, Walid

2013-01-01

Highlights: ► EDF-1 participates early adipogenesis in 3T3F442A cells induced with Staurosporine/Dexamethasone. ► EDF-1 associates with CaM and Cn, most likely inactivating Cn. ► EDF-1/CaM complex seems to prevent NFATc1 activation by Cn. ► EDF-1 regulates the Cn/CaM/NFATc1 pathway during adipogenesis. ► EDF-1 may regulate the activation of Cn through a complex formation with CaM. - Abstract: The endothelial differentiation factor-1 (EDF-1) is a calmodulin binding protein that regulates calmodulin-dependent enzymes. In endothelial cells, this factor can form a protein complex with calmodulin. We analyzed the relationship between this factor and the members of calmodulin/calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway during adipogenesis of 3T3-F442A cells. We found that the expression of edf1 is upregulated during early adipogenesis, whereas that of calcineurin gene is lowered, suggesting that this pathway should be downregulated to allow for adipogenesis to occur. We also found that EDF-1 associates with calmodulin and calcineurin, most likely inactivating calcineurin. Our results showed that EDF-1 inactivates the calmodulin/calcineurin/NFAT pathway via sequestration of calmodulin, during early adipogenesis, and we propose a mechanism that negatively regulates the activation of calcineurin through a complex formation between EDF-1 and calmodulin. This finding raises the possibility that modulating this pathway might offer some alternatives to regulate adipose biology

EDF-1 downregulates the CaM/Cn/NFAT signaling pathway during adipogenesis

Energy Technology Data Exchange (ETDEWEB)

López-Victorio, Carlos J.; Velez-delValle, Cristina; Beltrán-Langarica, Alicia [Department of Cell Biology, Center for Research and Advanced Studies-IPN, Apdo. Postal 14-740, México City 07000 (Mexico); Kuri-Harcuch, Walid, E-mail: walidkuri@gmail.com [Department of Cell Biology, Center for Research and Advanced Studies-IPN, Apdo. Postal 14-740, México City 07000 (Mexico)

2013-03-01

Highlights: ► EDF-1 participates early adipogenesis in 3T3F442A cells induced with Staurosporine/Dexamethasone. ► EDF-1 associates with CaM and Cn, most likely inactivating Cn. ► EDF-1/CaM complex seems to prevent NFATc1 activation by Cn. ► EDF-1 regulates the Cn/CaM/NFATc1 pathway during adipogenesis. ► EDF-1 may regulate the activation of Cn through a complex formation with CaM. - Abstract: The endothelial differentiation factor-1 (EDF-1) is a calmodulin binding protein that regulates calmodulin-dependent enzymes. In endothelial cells, this factor can form a protein complex with calmodulin. We analyzed the relationship between this factor and the members of calmodulin/calcineurin/nuclear factor of activated T-cells (NFAT) signaling pathway during adipogenesis of 3T3-F442A cells. We found that the expression of edf1 is upregulated during early adipogenesis, whereas that of calcineurin gene is lowered, suggesting that this pathway should be downregulated to allow for adipogenesis to occur. We also found that EDF-1 associates with calmodulin and calcineurin, most likely inactivating calcineurin. Our results showed that EDF-1 inactivates the calmodulin/calcineurin/NFAT pathway via sequestration of calmodulin, during early adipogenesis, and we propose a mechanism that negatively regulates the activation of calcineurin through a complex formation between EDF-1 and calmodulin. This finding raises the possibility that modulating this pathway might offer some alternatives to regulate adipose biology.

Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis.

Science.gov (United States)

Hu, Fang; Xu, Yong; Liu, Feng

2016-06-01

Mammalian or mechanistic target of rapamycin (mTOR) senses nutrient, energy, and hormone signals to regulate metabolism and energy homeostasis. mTOR activity in the hypothalamus, which is associated with changes in energy status, plays a critical role in the regulation of food intake and body weight. mTOR integrates signals from a variety of "energy balancing" hormones such as leptin, insulin, and ghrelin, although its action varies in response to these distinct hormonal stimuli as well as across different neuronal populations. In this review, we summarize and highlight recent findings regarding the functional roles of mTOR complex 1 (mTORC1) in the hypothalamus specifically in its regulation of body weight, energy expenditure, and glucose/lipid homeostasis. Understanding the role and underlying mechanisms behind mTOR-related signaling in the brain will undoubtedly pave new avenues for future therapeutics and interventions that can combat obesity, insulin resistance, and diabetes. Copyright © 2016 the American Physiological Society.

Reward processing in the value-driven attention network: reward signals tracking cue identity and location.

Science.gov (United States)

Anderson, Brian A

2017-03-01

Through associative reward learning, arbitrary cues acquire the ability to automatically capture visual attention. Previous studies have examined the neural correlates of value-driven attentional orienting, revealing elevated activity within a network of brain regions encompassing the visual corticostriatal loop [caudate tail, lateral occipital complex (LOC) and early visual cortex] and intraparietal sulcus (IPS). Such attentional priority signals raise a broader question concerning how visual signals are combined with reward signals during learning to create a representation that is sensitive to the confluence of the two. This study examines reward signals during the cued reward training phase commonly used to generate value-driven attentional biases. High, compared with low, reward feedback preferentially activated the value-driven attention network, in addition to regions typically implicated in reward processing. Further examination of these reward signals within the visual system revealed information about the identity of the preceding cue in the caudate tail and LOC, and information about the location of the preceding cue in IPS, while early visual cortex represented both location and identity. The results reveal teaching signals within the value-driven attention network during associative reward learning, and further suggest functional specialization within different regions of this network during the acquisition of an integrated representation of stimulus value. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Tuning plant signaling and growth to survive salt

NARCIS (Netherlands)

Julkowska, M.M.; Testerink, C.

2015-01-01

Salinity is one of the major abiotic factors threatening food security worldwide. Recently, our understanding of early processes underlying salinity tolerance has expanded. In this review, early signaling events, such as phospholipid signaling, calcium ion (Ca(2+)) responses, and reactive oxygen

Investigating complex patterns of blocked intestinal artery blood pressure signals by empirical mode decomposition and linguistic analysis

International Nuclear Information System (INIS)

Yeh, J-R; Lin, T-Y; Shieh, J-S; Chen, Y; Huang, N E; Wu, Z; Peng, C-K

2008-01-01

In this investigation, surgical operations of blocked intestinal artery have been conducted on pigs to simulate the condition of acute mesenteric arterial occlusion. The empirical mode decomposition method and the algorithm of linguistic analysis were applied to verify the blood pressure signals in simulated situation. We assumed that there was some information hidden in the high-frequency part of the blood pressure signal when an intestinal artery is blocked. The empirical mode decomposition method (EMD) has been applied to decompose the intrinsic mode functions (IMF) from a complex time series. But, the end effects and phenomenon of intermittence damage the consistence of each IMF. Thus, we proposed the complementary ensemble empirical mode decomposition method (CEEMD) to solve the problems of end effects and the phenomenon of intermittence. The main wave of blood pressure signals can be reconstructed by the main components, identified by Monte Carlo verification, and removed from the original signal to derive a riding wave. Furthermore, the concept of linguistic analysis was applied to design the blocking index to verify the pattern of riding wave of blood pressure using the measurements of dissimilarity. Blocking index works well to identify the situation in which the sampled time series of blood pressure signal was recorded. Here, these two totally different algorithms are successfully integrated and the existence of the existence of information hidden in high-frequency part of blood pressure signal has been proven

Investigating complex patterns of blocked intestinal artery blood pressure signals by empirical mode decomposition and linguistic analysis

Energy Technology Data Exchange (ETDEWEB)

Yeh, J-R; Lin, T-Y; Shieh, J-S [Department of Mechanical Engineering, Yuan Ze University, 135 Far-East Road, Chung-Li, Taoyuan, Taiwan (China); Chen, Y [Far Eastern Memorial Hospital, Taiwan (China); Huang, N E [Research Center for Adaptive Data Analysis, National Central University, Taiwan (China); Wu, Z [Center for Ocean-Land-Atmosphere Studies (United States); Peng, C-K [Beth Israel Deaconess Medical Center, Harvard Medical School (United States)], E-mail: s939205@ mail.yzu.edu.tw

2008-02-15

In this investigation, surgical operations of blocked intestinal artery have been conducted on pigs to simulate the condition of acute mesenteric arterial occlusion. The empirical mode decomposition method and the algorithm of linguistic analysis were applied to verify the blood pressure signals in simulated situation. We assumed that there was some information hidden in the high-frequency part of the blood pressure signal when an intestinal artery is blocked. The empirical mode decomposition method (EMD) has been applied to decompose the intrinsic mode functions (IMF) from a complex time series. But, the end effects and phenomenon of intermittence damage the consistence of each IMF. Thus, we proposed the complementary ensemble empirical mode decomposition method (CEEMD) to solve the problems of end effects and the phenomenon of intermittence. The main wave of blood pressure signals can be reconstructed by the main components, identified by Monte Carlo verification, and removed from the original signal to derive a riding wave. Furthermore, the concept of linguistic analysis was applied to design the blocking index to verify the pattern of riding wave of blood pressure using the measurements of dissimilarity. Blocking index works well to identify the situation in which the sampled time series of blood pressure signal was recorded. Here, these two totally different algorithms are successfully integrated and the existence of the existence of information hidden in high-frequency part of blood pressure signal has been proven.

Rac1 augments Wnt signaling by stimulating β-catenin–lymphoid enhancer factor-1 complex assembly independent of β-catenin nuclear import

Science.gov (United States)

Jamieson, Cara; Lui, Christina; Brocardo, Mariana G.; Martino-Echarri, Estefania; Henderson, Beric R.

2015-01-01

ABSTRACT β-Catenin transduces the Wnt signaling pathway and its nuclear accumulation leads to gene transactivation and cancer. Rac1 GTPase is known to stimulate β-catenin-dependent transcription of Wnt target genes and we confirmed this activity. Here we tested the recent hypothesis that Rac1 augments Wnt signaling by enhancing β-catenin nuclear import; however, we found that silencing/inhibition or up-regulation of Rac1 had no influence on nuclear accumulation of β-catenin. To better define the role of Rac1, we employed proximity ligation assays (PLA) and discovered that a significant pool of Rac1–β-catenin protein complexes redistribute from the plasma membrane to the nucleus upon Wnt or Rac1 activation. More importantly, active Rac1 was shown to stimulate the formation of nuclear β-catenin–lymphoid enhancer factor 1 (LEF-1) complexes. This regulation required Rac1-dependent phosphorylation of β-catenin at specific serines, which when mutated (S191A and S605A) reduced β-catenin binding to LEF-1 by up to 50%, as revealed by PLA and immunoprecipitation experiments. We propose that Rac1-mediated phosphorylation of β-catenin stimulates Wnt-dependent gene transactivation by enhancing β-catenin–LEF-1 complex assembly, providing new insight into the mechanism of cross-talk between Rac1 and canonical Wnt/β-catenin signaling. PMID:26403202

An interplay between 2 signaling pathways: Melatonin-cAMP and IP{sub 3}–Ca{sup 2+} signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium falciparum

Energy Technology Data Exchange (ETDEWEB)

Furuyama, Wakako [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Enomoto, Masahiro [Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, M5G1L7 Toronto, Ontario (Canada); Mossaad, Ehab [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan); Kawai, Satoru [Laboratory of Tropical Medicine and Parasitology, Dokkyo Medical University, Mibu, Tochigi 321-0293 (Japan); Mikoshiba, Katsuhiko [Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama 351-0198 (Japan); Kawazu, Shin-ichiro, E-mail: skawazu@obihiro.ac.jp [National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555 (Japan)

2014-03-28

Highlights: • A melatonin receptor antagonist blocked Ca{sup 2+} oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca{sup 2+}- and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca{sup 2+}) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca{sup 2+} imaging showed that LZ treatment completely abolished Ca{sup 2+} oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP{sub 3}–Ca{sup 2+} and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum.

Improving the arterial input function in dynamic contrast enhanced MRI by fitting the signal in the complex plane.

Science.gov (United States)

Simonis, Frank F J; Sbrizzi, Alessandro; Beld, Ellis; Lagendijk, Jan J W; van den Berg, Cornelis A T

2016-10-01

Dynamic contrast enhanced (DCE) imaging is a widely used technique in oncologic imaging. An essential prerequisite for obtaining quantitative values from DCE-MRI is the determination of the arterial input function (AIF). However, it is very challenging to accurately estimate the AIF using MR. A comprehensive model, which uses complex data instead of either magnitude or phase, was developed to improve AIF estimation. The model was first applied to simulated data. Subsequently, the accuracy of the estimated contrast agent concentration was validated in a phantom. Finally the method was applied to existing DCE scans of 13 prostate cancer patients. The complex signal method combines the complementary strengths of the magnitude and phase method, increasing the precision and accuracy of concentration estimation in simulated and phantom data. The in vivo AIFs show a good agreement between arterial voxels (standard deviation in the peak and tail equal 0.4 mM and 0.12 mM, respectively). Furthermore, the dynamic behavior closely followed the AIF obtained with DCE-CT in the same patients (mean correlation coefficient: 0.92). By using the complex signal, the AIF estimation becomes more accurate and precise. This might enable patient specific AIFs, thereby improving the quantitative values obtained from DCE-MRI. Magn Reson Med 76:1236-1245, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Higher burden of supraventricular ectopic complexes early after catheter ablation for atrial fibrillation is associated with increased risk of recurrent atrial fibrillation

DEFF Research Database (Denmark)

Alhede, Christina; Johannessen, Arne; Dixen, Ulrik

2018-01-01

AIMS: Early identification of patients who could benefit from early re-intervention after catheter ablation is highly warranted. Our aim was to investigate the association between post-procedural burden of supraventricular ectopic complexes (SVEC) and the risk of long-term atrial fibrillation (AF...

Increased Nerve Growth Factor Signaling in Sensory Neurons of Early Diabetic Rats Is Corrected by Electroacupuncture

Directory of Open Access Journals (Sweden)

Stefania Lucia Nori

2013-01-01

Full Text Available Diabetic polyneuropathy (DPN, characterized by early hyperalgesia and increased nerve growth factor (NGF, evolves in late irreversible neuropathic symptoms with reduced NGF support to sensory neurons. Electroacupuncture (EA modulates NGF in the peripheral nervous system, being effective for the treatment of DPN symptoms. We hypothesize that NGF plays an important pathogenic role in DPN development, while EA could be useful in the therapy of DPN by modulating NGF expression/activity. Diabetes was induced in rats by streptozotocin (STZ injection. One week after STZ, EA was started and continued for three weeks. NGF system and hyperalgesia-related mediators were analyzed in the dorsal root ganglia (DRG and in their spinal cord and skin innervation territories. Our results show that four weeks long diabetes increased NGF and NGF receptors and deregulated intracellular signaling mediators of DRG neurons hypersensitization; EA in diabetic rats decreased NGF and NGF receptors, normalized c-Jun N-terminal and p38 kinases activation, decreased transient receptor potential vanilloid-1 ion channel, and possibly activated the nuclear factor kappa-light-chain-enhancer of activated B cells (Nf-κB. In conclusion, NGF signaling deregulation might play an important role in the development of DPN. EA represents a supportive tool to control DPN development by modulating NGF signaling in diabetes-targeted neurons.

Negative regulation of β-catenin/Tcf signaling by naringenin in AGS gastric cancer cell

International Nuclear Information System (INIS)

Lee, Ju Hyung; Park, Chi Hoon; Jung, Kyung Chae; Rhee, Ho Sung; Yang, Chul Hak

2005-01-01

Functional activation of β-catenin/Tcf signaling plays an important role in early events in carcinogenesis. We examined the effect of naringenin against β-catenin/Tcf signaling in gastric cancer cells. Reporter gene assay showed that naringenin inhibited β-catenin/Tcf signaling efficiently. In addition, the inhibition of β-catenin/Tcf signaling by naringenin in HEK293 cells transiently transfected with constitutively mutant β-catenin gene, whose product is not phosphorylated by GSK3β, indicates that its inhibitory mechanism was related to β-catenin itself or downstream components. To investigate the precise inhibitory mechanism, we performed immunofluorescence, Western blot, and EMSA. As a result, our data revealed that the β-catenin distribution and the levels of nuclear β-catenin and Tcf-4 proteins were unchanged after naringenin treatment. Moreover, the binding activities of Tcf complexes to consensus DNA were not affected by naringenin. Taken together, these data suggest that naringenin inhibits β-catenin/Tcf signaling in gastric cancer with unknown mechanisms

ANALYSIS OF FORECASTING METHODS FROM THE POINT OF VIEW OF EARLY WARNING CONCEPT IN PROJECT MANAGEMENT

Directory of Open Access Journals (Sweden)

Florin POPESCU

2017-12-01

Full Text Available Early warning system (EWS based on a reliable forecasting process has become a critical component of the management of large complex industrial projects in the globalized transnational environment. The purpose of this research is to critically analyze the forecasting methods from the point of view of early warning, choosing those useful for the construction of EWS. This research addresses complementary techniques, using Bayesian Networks, which addresses both uncertainties and causality in project planning and execution, with the goal of generating early warning signals for project managers. Even though Bayesian networks have been widely used in a range of decision-support applications, their application as early warning systems for project management is still new.

Deciphering deterioration mechanisms of complex diseases based on the construction of dynamic networks and systems analysis

Science.gov (United States)

Li, Yuanyuan; Jin, Suoqin; Lei, Lei; Pan, Zishu; Zou, Xiufen

2015-03-01

The early diagnosis and investigation of the pathogenic mechanisms of complex diseases are the most challenging problems in the fields of biology and medicine. Network-based systems biology is an important technique for the study of complex diseases. The present study constructed dynamic protein-protein interaction (PPI) networks to identify dynamical network biomarkers (DNBs) and analyze the underlying mechanisms of complex diseases from a systems level. We developed a model-based framework for the construction of a series of time-sequenced networks by integrating high-throughput gene expression data into PPI data. By combining the dynamic networks and molecular modules, we identified significant DNBs for four complex diseases, including influenza caused by either H3N2 or H1N1, acute lung injury and type 2 diabetes mellitus, which can serve as warning signals for disease deterioration. Function and pathway analyses revealed that the identified DNBs were significantly enriched during key events in early disease development. Correlation and information flow analyses revealed that DNBs effectively discriminated between different disease processes and that dysfunctional regulation and disproportional information flow may contribute to the increased disease severity. This study provides a general paradigm for revealing the deterioration mechanisms of complex diseases and offers new insights into their early diagnoses.

Second-hand signals

DEFF Research Database (Denmark)

Bergenholtz, Carsten

2014-01-01

Studies of signaling theory have traditionally focused on the dyadic link between the sender and receiver of the signal. Within a science‐based perspective this framing has led scholars to investigate how patents and publications of firms function as signals. I explore another important type...... used by various agents in their search for and assessment of products and firms. I conclude by arguing how this second‐hand nature of signals goes beyond a simple dyadic focus on senders and receivers of signals, and thus elucidates the more complex interrelations of the various types of agents...

Interdependence of free zinc changes and protein complex assembly - insights into zinc signal regulation.

Science.gov (United States)

Kocyła, Anna; Adamczyk, Justyna; Krężel, Artur

2018-01-24

Cellular zinc (Zn(ii)) is bound with proteins that are part of the proteomes of all domains of life. It is mostly utilized as a catalytic or structural protein cofactor, which results in a vast number of binding architectures. The Zn(ii) ion is also important for the formation of transient protein complexes with a Zn(ii)-dependent quaternary structure that is formed upon cellular zinc signals. The mechanisms by which proteins associate with and dissociate from Zn(ii) and the connection with cellular Zn(ii) changes remain incompletely understood. In this study, we aimed to examine how zinc protein domains with various Zn(ii)-binding architectures are formed under free Zn(ii) concentration changes and how formation of the Zn(ii)-dependent assemblies is related to the protein concentration and reactivity. To accomplish these goals we chose four zinc domains with different Zn(ii)-to-protein binding stoichiometries: classical zinc finger (ZnP), LIM domain (Zn 2 P), zinc hook (ZnP 2 ) and zinc clasp (ZnP 1 P 2 ) folds. Our research demonstrated a lack of changes in the saturation level of intraprotein zinc binding sites, despite various peptide concentrations, while homo- and heterodimers indicated a concentration-dependent tendency. In other words, at a certain free Zn(ii) concentration, the fraction of a formed dimeric complex increases or decreases with subunit concentration changes. Secondly, even small or local changes in free Zn(ii) may significantly affect protein saturation depending on its architecture, function and subcellular concentration. In our paper, we indicate the importance of interdependence of free Zn(ii) availability and protein subunit concentrations for cellular zinc signal regulation.

Selective disruption of the AKAP signaling complexes.

Science.gov (United States)

Kennedy, Eileen J; Scott, John D

2015-01-01

Synthesis of the second messenger cAMP activates a variety of signaling pathways critical for all facets of intracellular regulation. Protein kinase A (PKA) is the major cAMP-responsive effector. Where and when this enzyme is activated has profound implications on the cellular role of PKA. A-Kinase Anchoring Proteins (AKAPs) play a critical role in this process by orchestrating spatial and temporal aspects of PKA action. A popular means of evaluating the impact of these anchored signaling events is to biochemically interfere with the PKA-AKAP interface. Hence, peptide disruptors of PKA anchoring are valuable tools in the investigation of local PKA action. This article outlines the development of PKA isoform-selective disruptor peptides, documents the optimization of cell-soluble peptide derivatives, and introduces alternative cell-based approaches that interrogate other aspects of the PKA-AKAP interface.

Ant Queen Egg-Marking Signals: Matching Deceptive Laboratory Simplicity with Natural Complexity

DEFF Research Database (Denmark)

van Zweden, Jelle Stijn; Heinze, Jürgen; Boomsma, Jacobus Jan

2009-01-01

Background Experiments under controlled laboratory conditions can produce decisive evidence for testing biological hypotheses, provided they are representative of the more complex natural conditions. However, whether this requirement is fulfilled is seldom tested explicitly. Here we provide a lab....../field comparison to investigate the identity of an egg-marking signal of ant queens. Our study was based on ant workers resolving conflict over male production by destroying each other's eggs, but leaving queen eggs unharmed. For this, the workers need a proximate cue to discriminate between the two egg types...... that this compound by itself is not the natural queen egg-marking pheromone. We subsequently investigated the overall differences of entire chemical profiles of eggs, and found that queen-laid eggs in field colonies are more distinct from worker-laid eggs than in lab colonies, have more variation in profiles...

IL-7 Induces an Epitope Masking of γc Protein in IL-7 Receptor Signaling Complex

Directory of Open Access Journals (Sweden)

Tae Sik Goh

2017-01-01

Full Text Available IL-7 signaling via IL-7Rα and common γ-chain (γc is necessary for the development and homeostasis of T cells. Although the delicate mechanism in which IL-7Rα downregulation allows the homeostasis of T cell with limited IL-7 has been well known, the exact mechanism behind the interaction between IL-7Rα and γc in the absence or presence of IL-7 remains unclear. Additionally, we are still uncertain as to how only IL-7Rα is separately downregulated by the binding of IL-7 from the IL-7Rα/γc complex. We demonstrate here that 4G3, TUGm2, and 3E12 epitope masking of γc protein are induced in the presence of IL-7, indicating that the epitope alteration is induced by IL-7 binding to the preassembled receptor core. Moreover, the epitope masking of γc protein is inversely correlated with the expression of IL-7Rα upon IL-7 binding, implying that the structural alteration of γc might be involved in the regulation of IL-7Rα expression. The conformational change in γc upon IL-7 binding may contribute not only to forming the functional IL-7 signaling complex but also to optimally regulating the expression of IL-7Rα.

IL-7 Induces an Epitope Masking of γc Protein in IL-7 Receptor Signaling Complex

Science.gov (United States)

Goh, Tae Sik; Jo, Yuna; Lee, Byunghyuk; Kim, Geona; Hwang, Hyunju; Ko, Eunhee; Kang, Seung Wan; Oh, Sae-Ock; Baek, Sun-Yong; Yoon, Sik; Lee, Jung Sub

2017-01-01

IL-7 signaling via IL-7Rα and common γ-chain (γc) is necessary for the development and homeostasis of T cells. Although the delicate mechanism in which IL-7Rα downregulation allows the homeostasis of T cell with limited IL-7 has been well known, the exact mechanism behind the interaction between IL-7Rα and γc in the absence or presence of IL-7 remains unclear. Additionally, we are still uncertain as to how only IL-7Rα is separately downregulated by the binding of IL-7 from the IL-7Rα/γc complex. We demonstrate here that 4G3, TUGm2, and 3E12 epitope masking of γc protein are induced in the presence of IL-7, indicating that the epitope alteration is induced by IL-7 binding to the preassembled receptor core. Moreover, the epitope masking of γc protein is inversely correlated with the expression of IL-7Rα upon IL-7 binding, implying that the structural alteration of γc might be involved in the regulation of IL-7Rα expression. The conformational change in γc upon IL-7 binding may contribute not only to forming the functional IL-7 signaling complex but also to optimally regulating the expression of IL-7Rα. PMID:28127156

Early motor learning changes in upper-limb dynamics and shoulder complex loading during handrim wheelchair propulsion.

Science.gov (United States)

Vegter, Riemer J K; Hartog, Johanneke; de Groot, Sonja; Lamoth, Claudine J; Bekker, Michel J; van der Scheer, Jan W; van der Woude, Lucas H V; Veeger, Dirkjan H E J

2015-03-10

To propel in an energy-efficient manner, handrim wheelchair users must learn to control the bimanually applied forces onto the rims, preserving both speed and direction of locomotion. Previous studies have found an increase in mechanical efficiency due to motor learning associated with changes in propulsion technique, but it is unclear in what way the propulsion technique impacts the load on the shoulder complex. The purpose of this study was to evaluate mechanical efficiency, propulsion technique and load on the shoulder complex during the initial stage of motor learning. 15 naive able-bodied participants received 12-minutes uninstructed wheelchair practice on a motor driven treadmill, consisting of three 4-minute blocks separated by two minutes rest. Practice was performed at a fixed belt speed (v = 1.1 m/s) and constant low-intensity power output (0.2 W/kg). Energy consumption, kinematics and kinetics of propulsion technique were continuously measured. The Delft Shoulder Model was used to calculate net joint moments, muscle activity and glenohumeral reaction force. With practice mechanical efficiency increased and propulsion technique changed, reflected by a reduced push frequency and increased work per push, performed over a larger contact angle, with more tangentially applied force and reduced power losses before and after each push. Contrary to our expectations, the above mentioned propulsion technique changes were found together with an increased load on the shoulder complex reflected by higher net moments, a higher total muscle power and higher peak and mean glenohumeral reaction forces. It appears that the early stages of motor learning in handrim wheelchair propulsion are indeed associated with improved technique and efficiency due to optimization of the kinematics and dynamics of the upper extremity. This process goes at the cost of an increased muscular effort and mechanical loading of the shoulder complex. This seems to be associated with an

Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants

Directory of Open Access Journals (Sweden)

Subhasis eSamanta

2015-09-01

Full Text Available Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channelling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic and molecular analyses have unravelled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator’s involvement in these processes.

Importance of Mediator complex in the regulation and integration of diverse signaling pathways in plants.

Science.gov (United States)

Samanta, Subhasis; Thakur, Jitendra K

2015-01-01

Basic transcriptional machinery in eukaryotes is assisted by a number of cofactors, which either increase or decrease the rate of transcription. Mediator complex is one such cofactor, and recently has drawn a lot of interest because of its integrative power to converge different signaling pathways before channeling the transcription instructions to the RNA polymerase II machinery. Like yeast and metazoans, plants do possess the Mediator complex across the kingdom, and its isolation and subunit analyses have been reported from the model plant, Arabidopsis. Genetic, and molecular analyses have unraveled important regulatory roles of Mediator subunits at every stage of plant life cycle starting from flowering to embryo and organ development, to even size determination. It also contributes immensely to the survival of plants against different environmental vagaries by the timely activation of its resistance mechanisms. Here, we have provided an overview of plant Mediator complex starting from its discovery to regulation of stoichiometry of its subunits. We have also reviewed involvement of different Mediator subunits in different processes and pathways including defense response pathways evoked by diverse biotic cues. Wherever possible, attempts have been made to provide mechanistic insight of Mediator's involvement in these processes.

Critical nodes in signalling pathways

DEFF Research Database (Denmark)

Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

2006-01-01

Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role...... using insulin signalling as a model system....

Optimal sensor configuration for complex systems with application to signal detection in structures

DEFF Research Database (Denmark)

Sadegh, Payman; Spall, J. C.

2000-01-01

sensor outputs. Secondly, we describe an efficient and practical algorithm to achieve the optimization goals, based on simultaneous perturbation stochastic approximation (SPSA). SPSA avoids the need for detailed modeling of the sensor response by simply relying on observed responses as obtained......The paper considers the problem of sensor configuration for complex systems. The contribution of the paper is twofold. Firstly, we define an appropriate criterion that is based on maximizing overall sensor responses while minimizing redundant information as measured by correlations between multiple...... by limited experimentation with test sensor configurations. We illustrate the application of the approach to optimal placement of acoustic sensors for signal detection in structures. This includes both a computer simulation study for an aluminum plate, and real experimentations on a steel I-beam....

NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer.

Science.gov (United States)

Wallez, Yann; Mace, Peter D; Pasquale, Elena B; Riedl, Stefan J

2012-05-01

The CAS (CRK-associated substrate) family of adaptor proteins comprises 4 members, which share a conserved modular domain structure that enables multiple protein-protein interactions, leading to the assembly of intracellular signaling platforms. Besides their physiological role in signal transduction downstream of a variety of cell surface receptors, CAS proteins are also critical for oncogenic transformation and cancer cell malignancy through associations with a variety of regulatory proteins and downstream effectors. Among the regulatory partners, the 3 recently identified adaptor proteins constituting the NSP (novel SH2-containing protein) family avidly bind to the conserved carboxy-terminal focal adhesion-targeting (FAT) domain of CAS proteins. NSP proteins use an anomalous nucleotide exchange factor domain that lacks catalytic activity to form NSP-CAS signaling modules. Additionally, the NSP SH2 domain can link NSP-CAS signaling assemblies to tyrosine-phosphorylated cell surface receptors. NSP proteins can potentiate CAS function by affecting key CAS attributes such as expression levels, phosphorylation state, and subcellular localization, leading to effects on cell adhesion, migration, and invasion as well as cell growth. The consequences of these activities are well exemplified by the role that members of both families play in promoting breast cancer cell invasiveness and resistance to antiestrogens. In this review, we discuss the intriguing interplay between the NSP and CAS families, with a particular focus on cancer signaling networks.

[Curcumin alleviates early brain injury following subarachnoid hemorrhage in rats by inhibiting JNK/c-Jun signal pathway].

Science.gov (United States)

Li, Xia; Zhu, Ji

2018-03-01

Objective To investigate the inhibitory effect of curcumin on early brain injury following subarachnoid hemorrhage (SAH) by inhibiting JNK/ c-Jun signal pathway. Methods Sixty adult male SD rats were randomly divided into four groups: sham operation group (sham group), SAH group, SAH group treated with 100 mg/(kg.d) curcumin and SAH group treated with 200 mg/(kg.d) curcumin, with 15 rats in each group. Endovascular puncture was used to induce SAH model. Nissl staining was used to test whether neurons were broken. TUNEL staining was used to detect apoptosis. Immunohistochemistry was used to investigate the expression of caspase-3. Western blot analysis was used to detect the expressions of p-JNK, JNK, p-c-Jun, c-Jun, and caspase-3. Results Nissl staining indicated the decrease of Nissl bodies in SAH group, but increase of Nissl bodies in SAH group treated with curcumin. TUNEL staining showed that there were more apoptotic neurons in SAH group compared with sham group, while apoptotic neurons decreased after the treatment with curcumin, more obviously in the group treated with 200 mg/(kg.d) curcumin. The expressions of p-JNK, JNK, p-c-Jun, c-Jun, and caspase-3 were up-regulated in SAH group compared with sham group. However, the expressions of those proteins were down-regulated after the treatment with curcumin, especially by higher-dose curcumin treatment. Conclusion Curcumin might suppress early brain injury after SAH by inhibiting JNK/c-Jun signal pathway and neuron apoptosis.

A Novel NHE1-Centered Signaling Cassette Drives Epidermal Growth Factor Receptor–Dependent Pancreatic Tumor Metastasis and Is a Target for Combination Therapy

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Rosa Angela Cardone

2015-02-01

Full Text Available Pancreatic ductal adenocarcinoma (PDAC is one of the most lethal cancers principally because of early invasion and metastasis. The epidermal growth factor receptor (EGFR is essential for PDAC development even in the presence of Kras, but its inhibition with erlotinib gives only a modest clinical response, making the discovery of novel EGFR targets of critical interest. Here, we revealed by mining a human pancreatic gene expression database that the metastasis promoter Na+/H+ exchanger (NHE1 associates with the EGFR in PDAC. In human PDAC cell lines, we confirmed that NHE1 drives both basal and EGF-stimulated three-dimensional growth and early invasion via invadopodial extracellular matrix digestion. EGF promoted the complexing of EGFR with NHE1 via the scaffolding protein Na+/H+ exchanger regulatory factor 1, engaging EGFR in a negative transregulatory loop that controls the extent and duration of EGFR oncogenic signaling and stimulates NHE1. The specificity of NHE1 for growth or invasion depends on the segregation of the transient EGFR/Na+/H+ exchanger regulatory factor 1/NHE1 signaling complex into dimeric subcomplexes in different lipid raftlike membrane domains. This signaling complex was also found in tumors developed in orthotopic mice. Importantly, the specific NHE1 inhibitor cariporide reduced both three-dimensional growth and invasion independently of PDAC subtype and synergistically sensitized these behaviors to low doses of erlotinib.

Activation of the Aryl Hydrocarbon Receptor Interferes with Early Embryonic Development

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Manolis Gialitakis

2017-11-01

Full Text Available The transcriptional program of early embryonic development is tightly regulated by a set of well-defined transcription factors that suppress premature expression of differentiation genes and sustain the pluripotent identity. It is generally accepted that this program can be perturbed by environmental factors such as chemical pollutants; however, the precise molecular mechanisms remain unknown. The aryl hydrocarbon receptor (AHR is a widely expressed nuclear receptor that senses environmental stimuli and modulates target gene expression. Here, we have investigated the AHR interactome in embryonic stem cells by mass spectrometry and show that ectopic activation of AHR during early differentiation disrupts the differentiation program via the chromatin remodeling complex NuRD (nucleosome remodeling and deacetylation. The activated AHR/NuRD complex altered the expression of differentiation-specific genes that control the first two developmental decisions without affecting the pluripotency program. These findings identify a mechanism that allows environmental stimuli to disrupt embryonic development through AHR signaling.

Sequence distance via parsing complexity: Heartbeat signals

International Nuclear Information System (INIS)

Degli Esposti, M.; Farinelli, C.; Menconi, G.

2009-01-01

We compare and discuss the use of different symbolic codings of electrocardiogram (ECG) signals in order to distinguish healthy patients from hospitalized ones. To this aim, we recall a parsing-based similarity distance and compare the performances of several methods of classification of data.

Sensitive and fast detection of fructose in complex media via symmetry breaking and signal amplification using surface-enhanced Raman spectroscopy.

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Sun, Fang; Bai, Tao; Zhang, Lei; Ella-Menye, Jean-Rene; Liu, Sijun; Nowinski, Ann K; Jiang, Shaoyi; Yu, Qiuming

2014-03-04

A new strategy is proposed to sensitively and rapidly detect analytes with weak Raman signals in complex media using surface-enhanced Raman spectroscopy (SERS) via detecting the SERS signal changes of the immobilized probe molecules on SERS-active substrates upon binding of the analytes. In this work, 4-mercaptophenylboronic acid (4-MPBA) was selected as the probe molecule which was immobilized on the gold surface of a quasi-three-dimensional plasmonic nanostructure array (Q3D-PNA) SERS substrate to detect fructose. The molecule of 4-MPBA possesses three key functions: molecule recognition and reversible binding of the analyte via the boronic acid group, amplification of SERS signals by the phenyl group and thus shielding of the background noise of complex media, and immobilization on the surface of SERS-active substrates via the thiol group. Most importantly, the symmetry breaking of the 4-MPBA molecule upon fructose binding leads to the change of area ratio between totally symmetric 8a ring mode and nontotally symmetric 8b ring mode, which enables the detection. The detection curves were obtained in phosphate-buffered saline (PBS) and in undiluted artificial urine at clinically relevant concentrations, and the limit of detection of 0.05 mM was achieved.

Entamoeba histolytica: a beta 1 integrin-like fibronectin receptor assembles a signaling complex similar to those of mammalian cells.

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Flores-Robles, Donaciano; Rosales, Carlos; Rosales-Encina, José Luis; Talamás-Rohana, Patricia

2003-01-01

During tissue invasion, Entamoeba histolytica trophozoites interact with endothelial cells and extracellular matrix (ECM) proteins such as fibronectin (FN), collagen, and laminin. It has been demonstrated that trophozoites interact with FN through a beta1 integrin-like FN receptor (beta 1EhFNR), activating tyrosine kinases. In order to characterize the signaling process triggered by the amoebic receptor, activation, and association of tyrosine kinases and structural proteins were determined. As a result of FN binding by the beta 1EhFNR, the receptor itself, FAK, and paxillin were phosphorylated in tyrosine. Co-immunoprecipitation experiments showed that a multimolecular signaling complex was formed by the amoebic FN receptor, FAK, paxillin, and vinculin. These results strongly suggest that a signaling pathway, similar to the one used in mammalian cells, is activated when E. histolytica trophozoites adhere to FN.

Edaravone attenuates lipopolysaccharide-induced acute respiratory distress syndrome associated early pulmonary fibrosis via amelioration of oxidative stress and transforming growth factor-β1/Smad3 signaling.

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Wang, Xida; Lai, Rongde; Su, Xiangfen; Chen, Guibin; Liang, Zijing

2018-01-01

Pulmonary fibrosis is responsible for the both short-term and long-term outcomes in patients with acute respiratory distress syndrome (ARDS). There is still no effective cure to improve prognosis. The purpose of this study was to investigate whether edaravone, a free radical scavenger, have anti-fibrosis effects in the rat model of ARDS associated early pulmonary fibrosis by lipopolysaccharide (LPS) administration. Rats were subjected to intravenous injection of LPS, and edaravone was given intraperitoneally after LPS administration daily for 7 consecutive days. LPS treatment rapidly increased lung histopathology abnormalities, coefficient of lung, hydroxyproline and collagen I levels, stimulated myofibroblast differentiation and induced expression of TGF-β1 and activation of TGF-β1/Smad3 signaling as early as day 7 after LPS injection. Moreover, LPS intoxication significantly increased the contents of malondialdehyde (MDA), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), whereas it dramatically decreased superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities from day 1 after LPS treatment. On the contrary, edaravone treatment ameliorated LPS-induced myofibroblast differentiation and pulmonary fibrosis, simultaneously, and attenuated LPS-stimulated oxidative stress and activation of TGF-β1/Smad3 signaling. Collectively, edaravone may attenuate ARDS associated early pulmonary fibrosis through amelioration of oxidative stress and TGF-β1/Smad3 signaling pathway. Edaravone may be a promising drug candidate for the treatment of ARDS-related pulmonary fibrosis in early period. Copyright © 2017 Elsevier Inc. All rights reserved.

Signals and systems laboratory with Matlab

CERN Document Server

Palamides, Alex

2010-01-01

Introduction to MATLAB®Working EnvironmentGetting StartedMemory ManagementVectorsMatricesPlotting with MATLABComplex NumbersM-FilesInput-Output CommandsFile ManagementLogical-Relational OperatorsControl FlowSymbolic VariablesPolynomials(Pseudo)Random NumbersSignalsCategorization by the Variable TypeBasic Continuous-Time SignalsDiscrete-Time SignalsProperties of SignalsTransformations of the Time Variable for Continuous-Time SignalsTransformations of the Time Variable for Discrete-Time SignalsSystemsSystems ClassificationProperties of SystemsTime Domain System AnalysisImpulse ResponseContinuous Time Convolution Convolution PropertiesInterconnections of SystemsStabilityDiscrete-Time ConvolutionSystems Described by Difference EquationsFiltersStability Criterion for Discrete-Time SystemsSystems Described by Differential EquationsStep Response of a SystemFourier SeriesOrthogonality of Complex Exponential SignalsComplex Exponential Fourier SeriesTrigonometric Fourier SeriesFourier Series in the Cosine with Phase F...

HACE1 Negatively Regulates Virus-Triggered Type I IFN Signaling by Impeding the Formation of the MAVS-TRAF3 Complex

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He-Ting Mao

2016-05-01

Full Text Available During virus infection, the cascade signaling pathway that leads to the production of proinflammatory cytokines is controlled at multiple levels to avoid detrimental overreaction. HACE1 has been characterized as an important tumor suppressor. Here, we identified HACE1 as an important negative regulator of virus-triggered type I IFN signaling. Overexpression of HACE1 inhibited Sendai virus- or poly (I:C-induced signaling and resulted in reduced IFNB1 production and enhanced virus replication. Knockdown of HACE1 expression exhibited the opposite effects. Ubiquitin E3 ligase activity of the dead mutant HACE1/C876A had a comparable inhibitory function as WT HACE1, suggesting that the suppressive function of HACE1 on virus-induced signaling is independent of its E3 ligase activity. Further study indicated that HACE1 acted downstream of MAVS and upstream of TBK1. Mechanistic studies showed that HACE1 exerts its inhibitory role on virus-induced signaling by disrupting the MAVS-TRAF3 complex. Therefore, we uncovered a novel function of HACE1 in innate immunity regulation.

Multivariate Analysis for the Processing of Signals

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Beattie J.R.

2014-01-01

Full Text Available Real-world experiments are becoming increasingly more complex, needing techniques capable of tracking this complexity. Signal based measurements are often used to capture this complexity, where a signal is a record of a sample’s response to a parameter (e.g. time, displacement, voltage, wavelength that is varied over a range of values. In signals the responses at each value of the varied parameter are related to each other, depending on the composition or state sample being measured. Since signals contain multiple information points, they have rich information content but are generally complex to comprehend. Multivariate Analysis (MA has profoundly transformed their analysis by allowing gross simplification of the tangled web of variation. In addition MA has also provided the advantage of being much more robust to the influence of noise than univariate methods of analysis. In recent years, there has been a growing awareness that the nature of the multivariate methods allows exploitation of its benefits for purposes other than data analysis, such as pre-processing of signals with the aim of eliminating irrelevant variations prior to analysis of the signal of interest. It has been shown that exploiting multivariate data reduction in an appropriate way can allow high fidelity denoising (removal of irreproducible non-signals, consistent and reproducible noise-insensitive correction of baseline distortions (removal of reproducible non-signals, accurate elimination of interfering signals (removal of reproducible but unwanted signals and the standardisation of signal amplitude fluctuations. At present, the field is relatively small but the possibilities for much wider application are considerable. Where signal properties are suitable for MA (such as the signal being stationary along the x-axis, these signal based corrections have the potential to be highly reproducible, and highly adaptable and are applicable in situations where the data is noisy or

Genetic and proteomic evidence for roles of Drosophila SUMO in cell cycle control, Ras signaling, and early pattern formation.

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Minghua Nie

2009-06-01

Full Text Available SUMO is a protein modifier that is vital for multicellular development. Here we present the first system-wide analysis, combining multiple approaches, to correlate the sumoylated proteome (SUMO-ome in a multicellular organism with the developmental roles of SUMO. Using mass-spectrometry-based protein identification, we found over 140 largely novel SUMO conjugates in the early Drosophila embryo. Enriched functional groups include proteins involved in Ras signaling, cell cycle, and pattern formation. In support of the functional significance of these findings, sumo germline clone embryos exhibited phenotypes indicative of defects in these same three processes. Our cell culture and immunolocalization studies further substantiate roles for SUMO in Ras signaling and cell cycle regulation. For example, we found that SUMO is required for efficient Ras-mediated MAP kinase activation upstream or at the level of Ras activation. We further found that SUMO is dynamically localized during mitosis to the condensed chromosomes, and later also to the midbody. Polo kinase, a SUMO substrate found in our screen, partially colocalizes with SUMO at both sites. These studies show that SUMO coordinates multiple regulatory processes during oogenesis and early embryogenesis. In addition, our database of sumoylated proteins provides a valuable resource for those studying the roles of SUMO in development.

Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

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Wei, Hongen; Malik, Mazhar; Sheikh, Ashfaq M.; Merz, George; Ted Brown, W.; Li, Xiaohong

2011-01-01

Recent studies suggest that one of the major pathways to the pathogenesis of autism is reduced cell migration. Focal adhesion kinase (FAK) has an important role in neural migration, dendritic morphological characteristics, axonal branching, and synapse formation. The FAK-Src complex, activated by upstream reelin and integrin β1, can initiate a cascade of phosphorylation events to trigger multiple intracellular pathways, including mitogen-activated protein kinase–extracellular signal–regulated kinase and phosphatidylinositol 3-kinase–Akt signaling. In this study, by using B lymphoblasts as a model, we tested whether integrin β1 and FAK-Src signaling are abnormally regulated in autism and whether abnormal FAK-Src signaling leads to defects in B-lymphoblast adhesion, migration, proliferation, and IgG production. To our knowledge, for the first time, we show that protein expression levels of both integrin β1 and FAK are significantly decreased in autistic lymphoblasts and that Src protein expression and the phosphorylation of an active site (Y416) are also significantly decreased. We also found that lymphoblasts from autistic subjects exhibit significantly decreased migration, increased adhesion properties, and an impaired capacity for IgG production. The overexpression of FAK in autistic lymphoblasts countered the adhesion and migration defects. In addition, we demonstrate that FAK mediates its effect through the activation of Src, phosphatidylinositol 3-kinase–Akt, and mitogen-activated protein kinase signaling cascades and that paxillin is also likely involved in the regulation of adhesion and migration in autistic lymphoblasts. PMID:21703394

Key Markers of mTORC1-Dependent and mTORC1-Independent Signaling Pathways Regulating Protein Synthesis in Rat Soleus Muscle During Early Stages of Hindlimb Unloading.

Science.gov (United States)

Mirzoev, Timur; Tyganov, Sergey; Vilchinskaya, Natalia; Lomonosova, Yulia; Shenkman, Boris

2016-01-01

The purpose of the study was to assess the amount of rRNA and phosphorylation status of the key markers of mTORC1-dependent (70s6k, 4E-BP1) and mTORC1-independent (GSK-3β, AMPK) signaling pathways controlling protein synthesis in rat soleus during early stages of mechanical unloading (hindlimb suspension (HS) for 1-, 3- and 7 days). The content of the key signaling molecules of various anabolic signaling pathways was determined by Western-blotting. The amount of 28S rRNA was evaluated by RT-PCR. The rate of protein synthesis was assessed using in-vivo SUnSET technique. HS for 3 and 7 days induced a significant (pprotein synthesis in soleus muscle in comparison with control. HS within 24 hours resulted in a significant (pprotein synthesis in rat soleus during early stages of simulated microgravity is associated with impaired ribosome biogenesis as well as reduced activity of mTORC1-independent signaling pathways. © 2016 The Author(s) Published by S. Karger AG, Basel.

Signal one and two blockade are both critical for non-myeloablative murine HSCT across a major histocompatibility complex barrier.

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Kia J Langford-Smith

Full Text Available Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM:blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan. We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.

Signal one and two blockade are both critical for non-myeloablative murine HSCT across a major histocompatibility complex barrier.

Science.gov (United States)

Langford-Smith, Kia J; Sandiford, Zara; Langford-Smith, Alex; Wilkinson, Fiona L; Jones, Simon A; Wraith, J Ed; Wynn, Robert F; Bigger, Brian W

2013-01-01

Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.

Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress

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Wijaya Edward

2010-01-01

Full Text Available Abstract Background The transcriptional regulatory network involved in low temperature response leading to acclimation has been established in Arabidopsis. In japonica rice, which can only withstand transient exposure to milder cold stress (10°C, an oxidative-mediated network has been proposed to play a key role in configuring early responses and short-term defenses. The components, hierarchical organization and physiological consequences of this network were further dissected by a systems-level approach. Results Regulatory clusters responding directly to oxidative signals were prominent during the initial 6 to 12 hours at 10°C. Early events mirrored a typical oxidative response based on striking similarities of the transcriptome to disease, elicitor and wounding induced processes. Targets of oxidative-mediated mechanisms are likely regulated by several classes of bZIP factors acting on as1/ocs/TGA-like element enriched clusters, ERF factors acting on GCC-box/JAre-like element enriched clusters and R2R3-MYB factors acting on MYB2-like element enriched clusters. Temporal induction of several H2O2-induced bZIP, ERF and MYB genes coincided with the transient H2O2 spikes within the initial 6 to 12 hours. Oxidative-independent responses involve DREB/CBF, RAP2 and RAV1 factors acting on DRE/CRT/rav1-like enriched clusters and bZIP factors acting on ABRE-like enriched clusters. Oxidative-mediated clusters were activated earlier than ABA-mediated clusters. Conclusion Genome-wide, physiological and whole-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress and developmental responses leads to modulated growth and vigor maintenance contributing to a delay of plastic injuries.

Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress

KAUST Repository

Yun, Kil-Young

2010-01-25

Background: The transcriptional regulatory network involved in low temperature response leading to acclimation has been established in Arabidopsis. In japonica rice, which can only withstand transient exposure to milder cold stress (10C), an oxidative-mediated network has been proposed to play a key role in configuring early responses and short-term defenses. The components, hierarchical organization and physiological consequences of this network were further dissected by a systems-level approach.Results: Regulatory clusters responding directly to oxidative signals were prominent during the initial 6 to 12 hours at 10C. Early events mirrored a typical oxidative response based on striking similarities of the transcriptome to disease, elicitor and wounding induced processes. Targets of oxidative-mediated mechanisms are likely regulated by several classes of bZIP factors acting on as1/ocs/TGA-like element enriched clusters, ERF factors acting on GCC-box/JAre-like element enriched clusters and R2R3-MYB factors acting on MYB2-like element enriched clusters.Temporal induction of several H2O2-induced bZIP, ERF and MYB genes coincided with the transient H2O2spikes within the initial 6 to 12 hours. Oxidative-independent responses involve DREB/CBF, RAP2 and RAV1 factors acting on DRE/CRT/rav1-like enriched clusters and bZIP factors acting on ABRE-like enriched clusters. Oxidative-mediated clusters were activated earlier than ABA-mediated clusters.Conclusion: Genome-wide, physiological and whole-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress and developmental responses leads to modulated growth and vigor maintenance contributing to a delay of plastic injuries. 2010 Yun et al; licensee BioMed Central Ltd.

Non-Smad signaling pathways.

Science.gov (United States)

Mu, Yabing; Gudey, Shyam Kumar; Landström, Maréne

2012-01-01

Transforming growth factor-beta (TGFβ) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGFβ signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (TβRI and TβRII, respectively). The activated TβR complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGFβ also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGFβ-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGFβ-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGFβ are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGFβ-induced responses by non-Smad signaling pathways.

Supervised Learning with Complex-valued Neural Networks

CERN Document Server

Suresh, Sundaram; Savitha, Ramasamy

2013-01-01

Recent advancements in the field of telecommunications, medical imaging and signal processing deal with signals that are inherently time varying, nonlinear and complex-valued. The time varying, nonlinear characteristics of these signals can be effectively analyzed using artificial neural networks.  Furthermore, to efficiently preserve the physical characteristics of these complex-valued signals, it is important to develop complex-valued neural networks and derive their learning algorithms to represent these signals at every step of the learning process. This monograph comprises a collection of new supervised learning algorithms along with novel architectures for complex-valued neural networks. The concepts of meta-cognition equipped with a self-regulated learning have been known to be the best human learning strategy. In this monograph, the principles of meta-cognition have been introduced for complex-valued neural networks in both the batch and sequential learning modes. For applications where the computati...

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation*

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Ramírez, Valerie T.; Ramos-Fernández, Eva; Henríquez, Juan Pablo; Lorenzo, Alfredo; Inestrosa, Nibaldo C.

2016-01-01

Wnt ligands play crucial roles in the development and regulation of synapse structure and function. Specifically, Wnt-5a acts as a secreted growth factor that regulates dendritic spine formation in rodent hippocampal neurons, resulting in postsynaptic development that promotes the clustering of the PSD-95 (postsynaptic density protein 95). Here, we focused on the early events occurring after the interaction between Wnt-5a and its Frizzled receptor at the neuronal cell surface. Additionally, we studied the role of heterotrimeric G proteins in Wnt-5a-dependent synaptic development. We report that FZD9 (Frizzled9), a Wnt receptor related to Williams syndrome, is localized in the postsynaptic region, where it interacts with Wnt-5a. Functionally, FZD9 is required for the Wnt-5a-mediated increase in dendritic spine density. FZD9 forms a precoupled complex with Gαo under basal conditions that dissociates after Wnt-5a stimulation. Accordingly, we found that G protein inhibition abrogates the Wnt-5a-dependent pathway in hippocampal neurons. In particular, the activation of Gαo appears to be a key factor controlling the Wnt-5a-induced dendritic spine density. In addition, we found that Gβγ is required for the Wnt-5a-mediated increase in cytosolic calcium levels and spinogenesis. Our findings reveal that FZD9 and heterotrimeric G proteins regulate Wnt-5a signaling and dendritic spines in cultured hippocampal neurons. PMID:27402827

TGF-β superfamily signaling in testis formation and early male germline development.

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Young, Julia C; Wakitani, Shoichi; Loveland, Kate L

2015-09-01

The TGF-β ligand superfamily contains at least 40 members, many of which are produced and act within the mammalian testis to facilitate formation of sperm. Their progressive expression at key stages and in specific cell types determines the fertility of adult males, influencing testis development and controlling germline differentiation. BMPs are essential for the interactive instructions between multiple cell types in the early embryo that drive initial specification of gamete precursors. In the nascent foetal testis, several ligands including Nodal, TGF-βs, Activins and BMPs, serve as key masculinizing switches by regulating male germline pluripotency, somatic and germline proliferation, and testicular vascularization and architecture. In postnatal life, local production of these factors determine adult testis size by regulating Sertoli cell multiplication and differentiation, in addition to specifying germline differentiation and multiplication. Because TGF-β superfamily signaling is integral to testis formation, it affects processes that underlie testicular pathologies, including testicular cancer, and its potential to contribute to subfertility is beginning to be understood. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Role of Paracrine and Autocrine Signaling in the Early Phase of Adipogenic Differentiation of Adipose-derived Stem Cells

Science.gov (United States)

Hemmingsen, Mette; Vedel, Søren; Skafte-Pedersen, Peder; Sabourin, David; Collas, Philippe; Bruus, Henrik; Dufva, Martin

2013-01-01

Introduction High cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways. Methods and results Adipogenic differentiation of human adipose-derived stem cells (ASCs) cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium). Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin). The positive effects of conditioned medium were observed early in the differentiation process. Conclusions Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment phase of the differentiation process. PMID:23723991

The role of paracrine and autocrine signaling in the early phase of adipogenic differentiation of adipose-derived stem cells.

Directory of Open Access Journals (Sweden)

Mette Hemmingsen

Full Text Available INTRODUCTION: High cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways. METHODS AND RESULTS: Adipogenic differentiation of human adipose-derived stem cells (ASCs cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium. Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin. The positive effects of conditioned medium were observed early in the differentiation process. CONCLUSIONS: Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s were shown to act in the recruitment phase of the differentiation process.

The Hedgehog Signal Induced Modulation of Bone Morphogenetic Protein Signaling: An Essential Signaling Relay for Urinary Tract Morphogenesis

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Nakagata, Naomi; Miyagawa, Shinichi; Suzuki, Kentaro; Kitazawa, Sohei; Yamada, Gen

2012-01-01

Background Congenital diseases of the urinary tract are frequently observed in infants. Such diseases present a number of developmental anomalies such as hydroureter and hydronephrosis. Although some genetically-modified mouse models of growth factor signaling genes reproduce urinary phenotypes, the pathogenic mechanisms remain obscure. Previous studies suggest that a portion of the cells in the external genitalia and bladder are derived from peri-cloacal mesenchymal cells that receive Hedgehog (Hh) signaling in the early developmental stages. We hypothesized that defects in such progenitor cells, which give rise to urinary tract tissues, may be a cause of such diseases. Methodology/Principal Findings To elucidate the pathogenic mechanisms of upper urinary tract malformations, we analyzed a series of Sonic hedgehog (Shh) deficient mice. Shh−/− displayed hydroureter and hydronephrosis phenotypes and reduced expression of several developmental markers. In addition, we suggested that Shh modulation at an early embryonic stage is responsible for such phenotypes by analyzing the Shh conditional mutants. Tissue contribution assays of Hh-responsive cells revealed that peri-cloacal mesenchymal cells, which received Hh signal secreted from cloacal epithelium, could contribute to the ureteral mesenchyme. Gain- and loss-of-functional mutants for Hh signaling revealed a correlation between Hh signaling and Bone morphogenetic protein (Bmp) signaling. Finally, a conditional ablation of Bmp receptor type IA (BmprIA) gene was examined in Hh-responsive cell lineages. This system thus made it possible to analyze the primary functions of the growth factor signaling relay. The defective Hh-to-Bmp signaling relay resulted in severe urinary tract phenotypes with a decrease in the number of Hh-responsive cells. Conclusions/Significance This study identified the essential embryonic stages for the pathogenesis of urinary tract phenotypes. These results suggested that Hh

Subretinal Fluid Levels of Signal-Transduction Proteins and Apoptosis Molecules in Macula-Off Retinal Detachment Undergoing Scleral Buckle Surgery.

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Carpineto, Paolo; Aharrh-Gnama, Agbeanda; Ciciarelli, Vincenzo; Borrelli, Enrico; Petti, Francesco; Aloia, Raffaella; Lamolinara, Alessia; Di Nicola, Marta; Mastropasqua, Leonardo

2016-12-01

To evaluate signal transduction and early apoptosis protein levels in subretinal fluid collected during scleral buckling surgery for macula-off rhegmatogenous retinal detachment (RRD). Our aim was to assess both their relation with RRD features and their influence on the posttreatment outcome. Thirty-three eyes of 33 RRD patients scheduled for scleral buckle surgery were enrolled in the study. Undiluted subretinal fluid samples were collected during surgery and analyzed via magnetic bead-based immunoassay. All patients underwent a complete ophthalmologic evaluation at baseline and at each follow-up visit (months 1, 3, and 6). Moreover, both at baseline and at the postsurgery month 6 visit, the patients were tested by means of spectral-domain optical coherence tomography (SD-OCT) in order to evaluate the average ganglion cell-inner plexiform complex thickness, as well as the photoreceptor inner segment/outer segment junction status. Patients' clinical features (retinal detachment size, detachment duration, and occurrence of proliferative vitreoretinopathy) were associated with several early apoptotic factors (caspase-8, caspase-9, and B-cell lymphoma 2 [Bcl-2]-associated death promoter [BAD]). Furthermore, both early apoptosis factors (caspase-8, Bcl-2, and p53) and signal-transduction proteins (ERK 1/2) were found to influence the postsurgery month 3 OCT characteristics. Signal-transduction proteins and early apoptosis proteins are associated with different clinical features and postsurgery outcomes.

Early modern human diversity suggests subdivided population structure and a complex out-of-Africa scenario

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Gunz, Philipp; Bookstein, Fred L.; Mitteroecker, Philipp; Stadlmayr, Andrea; Seidler, Horst; Weber, Gerhard W.

2009-01-01

The interpretation of genetic evidence regarding modern human origins depends, among other things, on assessments of the structure and the variation of ancient populations. Because we lack genetic data from the time when the first anatomically modern humans appeared, between 200,000 and 60,000 years ago, instead we exploit the phenotype of neurocranial geometry to compare the variation in early modern human fossils with that in other groups of fossil Homo and recent modern humans. Variation is assessed as the mean-squared Procrustes distance from the group average shape in a representation based on several hundred neurocranial landmarks and semilandmarks. We find that the early modern group has more shape variation than any other group in our sample, which covers 1.8 million years, and that they are morphologically similar to recent modern humans of diverse geographically dispersed populations but not to archaic groups. Of the currently competing models of modern human origins, some are inconsistent with these findings. Rather than a single out-of-Africa dispersal scenario, we suggest that early modern humans were already divided into different populations in Pleistocene Africa, after which there followed a complex migration pattern. Our conclusions bear implications for the inference of ancient human demography from genetic models and emphasize the importance of focusing research on those early modern humans, in particular, in Africa. PMID:19307568

Early Detection of Amyotrophic Lateral Sclerosis (ALS using the Gait Motor Signal Frequency Analysis

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Behzad Abedi

2016-06-01

Full Text Available Abstract Background: ALS is a progressive neuro-muscular disease, which is characterized by motor neuron loss in the Central Nervous System (CNS and Peripheral Nervous System (PNS. Up to now, no accurate clinical method for diagnosis of the disease have been provided. In most cases, ALS patients are unable to walk normally due to abnormalities in the nervous system. For this reason, one of the most appropriate methods in the diagnosis of ALS from other neurological diseases or from healthy volunteers is the gait motor signal analysis. Materials and Methods: In this study, gait signals available in Physionet database have been used. The database consists of 13 patients with ALS (ALS1, ALS2, …, ALS13 and 16 normal subjects (CO1, CO2, …, CO16. The patients participating in this study had no history of any psychiatric disorders and did not use any assistive device for walking, like wheelchair. The power spectrum of stride, swing, and stance of normal subjects and patients was computed for both left and right legs. To provide appropriate inputs for the classifier, the frequency band of the power spectrum of all signals was divided into eight equal parts. The area of all regions was computed. Three frequency band of the lower range of power spectra selected as inputs of the classifier. Results: In this study, power spectra, as frequency attributes, were used to explore probable differences of time series in both patients and healthy subjects. Conclusion: Artificial Neural Network was used to classify normal and ALS groups with the accuracy of 83% for the test data set. It seems that the present algorithm can be used in discriminating patients from normal subjects in the early stages of the disease.

Toward multimodal signal detection of adverse drug reactions.

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Harpaz, Rave; DuMouchel, William; Schuemie, Martijn; Bodenreider, Olivier; Friedman, Carol; Horvitz, Eric; Ripple, Anna; Sorbello, Alfred; White, Ryen W; Winnenburg, Rainer; Shah, Nigam H

2017-12-01

Improving mechanisms to detect adverse drug reactions (ADRs) is key to strengthening post-marketing drug safety surveillance. Signal detection is presently unimodal, relying on a single information source. Multimodal signal detection is based on jointly analyzing multiple information sources. Building on, and expanding the work done in prior studies, the aim of the article is to further research on multimodal signal detection, explore its potential benefits, and propose methods for its construction and evaluation. Four data sources are investigated; FDA's adverse event reporting system, insurance claims, the MEDLINE citation database, and the logs of major Web search engines. Published methods are used to generate and combine signals from each data source. Two distinct reference benchmarks corresponding to well-established and recently labeled ADRs respectively are used to evaluate the performance of multimodal signal detection in terms of area under the ROC curve (AUC) and lead-time-to-detection, with the latter relative to labeling revision dates. Limited to our reference benchmarks, multimodal signal detection provides AUC improvements ranging from 0.04 to 0.09 based on a widely used evaluation benchmark, and a comparative added lead-time of 7-22 months relative to labeling revision dates from a time-indexed benchmark. The results support the notion that utilizing and jointly analyzing multiple data sources may lead to improved signal detection. Given certain data and benchmark limitations, the early stage of development, and the complexity of ADRs, it is currently not possible to make definitive statements about the ultimate utility of the concept. Continued development of multimodal signal detection requires a deeper understanding the data sources used, additional benchmarks, and further research on methods to generate and synthesize signals. Copyright © 2017 Elsevier Inc. All rights reserved.

TGF-β/Smad2/3 signaling directly regulates several miRNAs in mouse ES cells and early embryos.

Directory of Open Access Journals (Sweden)

Nicholas Redshaw

Full Text Available The Transforming Growth Factor-β (TGF-β signaling pathway is one of the major pathways essential for normal embryonic development and tissue homeostasis, with anti-tumor but also pro-metastatic properties in cancer. This pathway directly regulates several target genes that mediate its downstream functions, however very few microRNAs (miRNAs have been identified as targets. miRNAs are modulators of gene expression with essential roles in development and a clear association with diseases including cancer. Little is known about the transcriptional regulation of the primary transcripts (pri-miRNA, pri-miR from which several mature miRNAs are often derived. Here we present the identification of miRNAs regulated by TGF-β signaling in mouse embryonic stem (ES cells and early embryos. We used an inducible ES cell system to maintain high levels of the TGF-β activated/phosphorylated Smad2/3 effectors, which are the transcription factors of the pathway, and a specific inhibitor that blocks their activation. By performing short RNA deep-sequencing after 12 hours Smad2/3 activation and after 16 hours inhibition, we generated a database of responsive miRNAs. Promoter/enhancer analysis of a subset of these miRNAs revealed that the transcription of pri-miR-181c/d and the pri-miR-341∼3072 cluster were found to depend on activated Smad2/3. Several of these miRNAs are expressed in early mouse embryos, when the pathway is known to play an essential role. Treatment of embryos with TGF-β inhibitor caused a reduction of their levels confirming that they are targets of this pathway in vivo. Furthermore, we showed that pri-miR-341∼3072 transcription also depends on FoxH1, a known Smad2/3 transcription partner during early development. Together, our data show that miRNAs are regulated directly by the TGF-β/Smad2/3 pathway in ES cells and early embryos. As somatic abnormalities in functions known to be regulated by the TGF-β/Smad2/3 pathway underlie tumor

Early-Late Heterobimetallic Complexes Linked by Phosphinoamide Ligands. Tuning Redox Potentials and Small Molecule Activation

Energy Technology Data Exchange (ETDEWEB)

Thomas, Christine M. [Brandeis Univ., Waltham, MA (United States)

2015-08-01

Recent attention in the chemical community has been focused on the energy efficient and environmentally benign conversion of abundant small molecules (CO2, H2O, etc.) to useful liquid fuels. This project addresses these goals by examining fundamental aspects of catalyst design to ultimately access small molecule activation processes under mild conditions. Specifically, Thomas and coworkers have targetted heterobimetallic complexes that feature metal centers with vastly different electronic properties, dictated both by their respective positions on the periodic table and their coordination environment. Unlike homobimetallic complexes featuring identical or similar metals, the bonds between metals in early/late heterobimetallics are more polarized, with the more electron-rich late metal center donating electron density to the more electron-deficient early metal center. While metal-metal bonds pose an interesting strategy for storing redox equivalents and stabilizing reactive metal fragments, the polar character of metal-metal bonds in heterobimetallic complexes renders these molecules ideally poised to react with small molecule substrates via cleavage of energy-rich single and double bonds. In addition, metal-metal interactions have been shown to dramatically affect redox potentials and promote multielectron redox activity, suggesting that metal-metal interactions may provide a mechanism to tune redox potentials and access substrate reduction/activation at mild overpotentials. This research project has provided a better fundamental understanding of how interactions between transition metals can be used as a strategy to promote and/or control chemical transformations related to the clean production of fuels. While this project focused on the study of homogeneous systems, it is anticipated that the broad conclusions drawn from these investigations will be applicable to heterogeneous catalysis as well, particularly on heterogeneous processes that occur at interfaces in

A sensitive detection assay based on signal amplification technology for Alzheimer's disease's early biomarker in exosome.

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Zhou, Jie; Meng, Lingchang; Ye, Weiran; Wang, Qiaolei; Geng, Shizhen; Sun, Chong

2018-08-31

Alzheimer's disease (AD) considered as the third health "killer" has seriously threatened the health of the elderly. However, the modern diagnostic strategies of AD present several disadvantages: the low accuracy and specificity resulting in some false-negative diagnoses, and the poor sensitivity leading to a delayed treatment. In view of this situation, a enzyme-free and target-triggered signal amplification strategy, based on graphene oxide (GO) and entropy-driven strand displacement reaction (ESDR) principle, was proposed. In this strategy, when the hairpin structure probes (H)specially binds with beta-amyloid-(1-42) oligomers (Aβ42 oligomers), it's structure will be opened, causing the bases complementary to FAM-labeled replacement probes R (R1 and R2) exposed. At this time, R1 and R2 will hybridize with H, resulting in the bound Aβ42 oligomers released. The released Aβ42 oligomers would participate in the next cycle reaction, making the signal amplified. As a quencher, GO could absorb the free single-stranded DNA R1 and R2 and quench their fluorescence; however, the DNA duplex still exists free and keeps its signal-on. Through the detection of Aβ42 oligomers in exosomes, this ultrasensitive detection method with the advantages of low limit of detection (LOD, 20 pM), great accuracy, excellent precision and convenience provides an excellent prospect for AD's early diagnosis. Copyright © 2018 Elsevier B.V. All rights reserved.

Positive and negative peptide signals control stomatal density.

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Shimada, Tomoo; Sugano, Shigeo S; Hara-Nishimura, Ikuko

2011-06-01

The stoma is a micro valve found on aerial plant organs that promotes gas exchange between the atmosphere and the plant body. Each stoma is formed by a strict cell lineage during the early stages of leaf development. Molecular genetics research using the model plant Arabidopsis has revealed the genes involved in stomatal differentiation. Cysteine-rich secretory peptides of the EPIDERMAL PATTERNING FACTOR-LIKE (EPFL) family play crucial roles as extracellular signaling factors. Stomatal development is orchestrated by the positive factor STOMAGEN/EPFL9 and the negative factors EPF1, EPF2, and CHALLAH/EPFL6 in combination with multiple receptors. EPF1 and EPF2 are produced in the stomatal lineage cells of the epidermis, whereas STOMAGEN and CHALLAH are derived from the inner tissues. These findings highlight the complex cell-to-cell and intertissue communications that regulate stomatal development. To optimize gas exchange, particularly the balance between the uptake of carbon dioxide (CO(2)) and loss of water, plants control stomatal activity in response to environmental conditions. The CO(2) level and light intensity influence stomatal density. Plants sense environmental cues in mature leaves and adjust the stomatal density of newly forming leaves, indicating the involvement of long-distance systemic signaling. This review summarizes recent research progress in the peptide signaling of stomatal development and discusses the evolutionary model of the signaling machinery.

Revitalizing Complex Analysis: A Transition-to-Proof Course Centered on Complex Topics

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Sachs, Robert

2017-01-01

A new transition course centered on complex topics would help in revitalizing complex analysis in two ways: first, provide early exposure to complex functions, sparking greater interest in the complex analysis course; second, create extra time in the complex analysis course by eliminating the "complex precalculus" part of the course. In…

Signaling Role of Fructose Mediated by FINS1/FBP in Arabidopsis thaliana

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Cho, Young-Hee; Yoo, Sang-Dong

2011-01-01

Sugars are evolutionarily conserved signaling molecules that regulate the growth and development of both unicellular and multicellular organisms. As sugar-producing photosynthetic organisms, plants utilize glucose as one of their major signaling molecules. However, the details of other sugar signaling molecules and their regulatory factors have remained elusive, due to the complexity of the metabolite and hormone interactions that control physiological and developmental programs in plants. We combined information from a gain-of-function cell-based screen and a loss-of-function reverse-genetic analysis to demonstrate that fructose acts as a signaling molecule in Arabidopsis thaliana. Fructose signaling induced seedling developmental arrest and interacted with plant stress hormone signaling in a manner similar to that of glucose. For fructose signaling responses, the plant glucose sensor HEXOKINASE1 (HXK1) was dispensable, while FRUCTOSE INSENSITIVE1 (FINS1), a putative FRUCTOSE-1,6-BISPHOSPHATASE, played a crucial role. Interestingly, FINS1 function in fructose signaling appeared to be independent of its catalytic activity in sugar metabolism. Genetic analysis further indicated that FINS1–dependent fructose signaling may act downstream of the abscisic acid pathway, in spite of the fact that HXK1–dependent glucose signaling works upstream of hormone synthesis. Our findings revealed that multiple layers of controls by fructose, glucose, and abscisic acid finely tune the plant autotrophic transition and modulate early seedling establishment after seed germination. PMID:21253566

Multipronged attenuation of macrophage-colony stimulating factor signaling by Epstein-Barr virus BARF1

Energy Technology Data Exchange (ETDEWEB)

Shim, Ann Hye-Ryong; Chang, Rhoda Ahn; Chen, Xiaoyan; Longnecker, Richard; He, Xiaolin [NWU

2014-10-02

The ubiquitous EBV causes infectious mononucleosis and is associated with several types of cancers. The EBV genome encodes an early gene product, BARF1, which contributes to pathogenesis, potentially through growth-altering and immune-modulating activities, but the mechanisms for such activities are poorly understood. We have determined the crystal structure of BARF1 in complex with human macrophage-colony stimulating factor (M-CSF), a hematopoietic cytokine with pleiotropic functions in development and immune response. BARF1 and M-CSF form a high-affinity, stable, ring-like complex in both solution and the crystal, with a BARF1 hexameric ring surrounded by three M-CSF dimers in triangular array. The binding of BARF1 to M-CSF dramatically reduces but does not completely abolish M-CSF binding and signaling through its cognate receptor FMS. A three-pronged down-regulation mechanism is proposed to explain the biological effect of BARF1 on M-CSF:FMS signaling. These prongs entail control of the circulating and effective local M-CSF concentration, perturbation of the receptor-binding surface of M-CSF, and imposition of an unfavorable global orientation of the M-CSF dimer. Each prong may reduce M-CSF:FMS signaling to a limited extent but in combination may alter M-CSF:FMS signaling dramatically. The downregulating mechanism of BARF1 underlines a viral modulation strategy, and provides a basis for understanding EBV pathogenesis.

Branched-chain amino acids in metabolic signalling and insulin resistance

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Lynch, Christopher J.; Adams, Sean H.

2015-01-01

Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM. PMID:25287287

Tsunami Early Warning via a Physics-Based Simulation Pipeline

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Wilson, J. M.; Rundle, J. B.; Donnellan, A.; Ward, S. N.; Komjathy, A.

2017-12-01

Through independent efforts, physics-based simulations of earthquakes, tsunamis, and atmospheric signatures of these phenomenon have been developed. With the goal of producing tsunami forecasts and early warning tools for at-risk regions, we join these three spheres to create a simulation pipeline. The Virtual Quake simulator can produce thousands of years of synthetic seismicity on large, complex fault geometries, as well as the expected surface displacement in tsunamigenic regions. These displacements are used as initial conditions for tsunami simulators, such as Tsunami Squares, to produce catalogs of potential tsunami scenarios with probabilities. Finally, these tsunami scenarios can act as input for simulations of associated ionospheric total electron content, signals which can be detected by GNSS satellites for purposes of early warning in the event of a real tsunami. We present the most recent developments in this project.

Searching for early-warning signals of impending dieback and death in Mediterranean oaks

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Colangelo, Michele; Ripullone, Francesco; Julio Camarero, Jesus; De Micco, Veronica; Gazol, Antonio; Gentilesca, Tiziana; Borghetti, Marco

2017-04-01

In recent decades, forest dieback episodes have been recorded worldwide affecting different tree species. In particular, several cases of widespread dieback and increased mortality rates have been described for Mediterranean oak (Quercus spp.) species. These dieback cases are revealing the high vulnerability of Mediterranean oaks, manifested as a loss in tree vigour (leaf shedding, canopy and shoot dieback), growth decline and sometimes tree death, as a consequence of temperatures rising at unprecedented rates and drying trends. However, in the wake of the so-called 'oak decline phenomenon', the attention on these species has generally been limited, perhaps because they are often regarded as well-adapted to the dry conditions typical of Mediterranean areas. Indeed, according to recent studies, the reduced size, the ability to sprout and the anisohydric behavior of Mediterranean oak species (reduced control of water loss and high stomatal conductance rates) would make them better adapted to withstand heat and drought stress then taller and non-sprouting isohydric species (e.g. conifer, with strict control of water loss by closing stomata). Here, we investigated the vulnerability of Mediterranean oaks by comparing neighboring living and recently dead trees in species with low (Q. pubescens), intermediate (Q. cerris, Q. frainetto) and high (Q. robur) sensitivity to water shortage. We analysed changes in tree vigour using tree-ring width and functional wood anatomical traits as proxies to search for early-warning signals of dieback, in connection with the main proposed dieback mechanisms (hydraulic failure and/or carbon starvation). We also modeled the probability of tree death as a function of tree size (diameter, height) by quantifying recent changes in growth and wood anatomy along tree-ring series. Contrary to the general concept that trees tend to experience increasing cavitation risk with increasing height, our studies show that smaller oaks are more prone to die

Effect of multi-nutrient complex fertilizers on growth and tuber yield of very early potato (Solanum tuberosum L. cultivars

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Wanda Wadas

2013-10-01

Full Text Available The aim of the study was to compare the effect of multi-nutrient complex fertilizers (HydroComplex, Nitrophoska Blue Special and Viking 13 from the nitrophoska group, and Polimag S from the amophoska group and single-nutrient fertilizers on the growth and tuber yield of very early potato cultivars (‘Aster’, ‘Fresco’, ‘Gloria’. The field experiment was carried out on podzolic soil in mid-eastern Poland during 2005–2007. The study showed a greater beneficial effect of HydroComplex and Nitrophoska Blue Special on the growth of very early potato cultivars than that of Viking 13 and Polimag S. The application of HydroComplex and Nitrophoska Blue Special resulted in greater above-ground plant biomass and assimilation leaf area compared with single-nutrient fertilizers; the leaf area index (LAI was higher by 0.28 and 0.32, respectively. The differences were smaller and not statistically confirmed with the use of Polimag S and Viking 13. When the multi-nutrient complex fertilizers were applied, leaf weight ratio (LWR, leaf area ratio (LAR and specific leaf area (SLA were similar to the single-nutrient fertilizers. Of the multi-nutrient complex fertilizers, only Nitrophoska Blue Special resulted in higher tuber yield, on average by 2.40 t × ha-1, compared with the single-nutrient fertilizers. The studied cultivars showed a similar response to applied fertilizers. LAI for ‘Gloria’ was higher than for ‘Aster’ and ‘Fresco’, with smaller LAR found in ‘Gloria’. LWR for ‘Fresco’ was smaller than for ‘Aster’ and ‘Gloria’, with higher SLA found in ‘Fresco’. The tuber yield of ‘Aster” (24.04 t × ha-1 was higher on average by 3 t × ha-1 than for ‘Fresco’ and ‘Gloria’.

Development of earthquake early warning system using real time signal of broadband seismogram

International Nuclear Information System (INIS)

Gunawan, Hendar; Puspito, Nanang T.; Ibrahim, Gunawan; Harjadi, Prih

2012-01-01

Earthquake pose serious threat of live and properties for urban area near subduction zone offshore and active fault on land. Jakarta and Bandung is an example of big city that no system of Earthquake early warning (EEW) event very high urbanization, and has many important infra structure in the area. The capital city is potentially high risk ground shaking. EEW can be usefull tool for reducing earthquake hazard, if spatial relation between cities and earthquake source is favorable for such warning and their citizens are properly trained to response early warning message. An EEW and rapid response system can provide the critical information needed to minimized lost of live and property and direct rescue. Earthquake ground shaking with magnitude M>6.0 from zone of Megathrust, southern of West Java should potentially damage in the area of west java especially Bandung and Jakarta City. This research development of EEW parameter such as amplitude displacement (Pd), rapid magnitude determination (M) and Peak ground Velocity (PGV). We explore the practical approach to EEW with the use of Broadband seismogram signal. Time effective EEW which epicenter from megathrust zone has potential to provide EEW in the area of west java such as Jakarta first ground shaking more or less 60 second later and strong shaking 118 second after EEW Alarm on CISI Station. EEW notification at potentially damage in the area of west java can be predicted from the characteristic of Pd > 0.5 cm, M> 6 and PGV > 10 cm/sec. GIS as a tool for presentation of hazard mapping in the affected area.

Outcomes in diabetic foot ulcer patients with isolated T2 marrow signal abnormality in the underlying bone: should the diagnosis of ''osteitis'' be changed to ''early osteomyelitis''?

International Nuclear Information System (INIS)

Duryea, Dennis; Bernard, Stephanie; Flemming, Donald; Walker, Eric; French, Cristy

2017-01-01

To evaluate the variability of clinical treatment and outcomes based on reporting of diabetic foot ulcer MRI findings of adjacent marrow T2 hyperintensity with normal T1 signal. A retrospective review was conducted of 46 MRI examinations evaluating diabetic foot ulcers that demonstrated normal T1 marrow signal, but T2 marrow hyperintensity deep to the ulcer. The cohort was divided based on MRI report impressions into three groups; ''osteitis without osteomyelitis'' (OW), ''osteitis but cannot exclude early osteomyelitis'' (OCEO) and ''early osteomyelitis'' (EO). Patient demographics (age, gender) and accessory MRI findings of ulcer and sinus tract depth were recorded. Initial clinical assessment and medical treatment (route and duration of antibiotics), healing versus disease progression and histology or microbiology results were recorded. The isolated marrow T2 signal hyperintensity was reported as OW in 12 patients, OCEO in 18, and EO in 16. No statistical difference in clinical assessment was demonstrated between the OW, OCEO, and EO groups. Pathological condition was available in 15 patients within 0-7 days (mean 2.4 days) of the MRI examination, with 14 (93%) of these positive for osteomyelitis by histopathology or positive cultures. Initial diagnosis of or progression to osteomyelitis was shown in 28 patients (61%). Treatment of suspected osteomyelitis is heavily determined by clinical factors. Patients who initially demonstrate only T2 marrow signal abnormality under a diabetic ulcer are eventually diagnosed as osteomyelitis in 61% of cases and deserve aggressive treatment as early osteomyelitis when meeting clinical parameters. (orig.)

Excessive Leucine-mTORC1-Signalling of Cow Milk-Based Infant Formula: The Missing Link to Understand Early Childhood Obesity

OpenAIRE

Melnik, Bodo C.

2012-01-01

Increased protein supply by feeding cow-milk-based infant formula in comparison to lower protein content of human milk is a well-recognized major risk factor of childhood obesity. However, there is yet no conclusive biochemical concept explaining the mechanisms of formula-induced childhood obesity. It is the intention of this article to provide the biochemical link between leucine-mediated signalling of mammalian milk proteins and adipogenesis as well as early adipogenic programming. Leucine ...

Cooperative ethylene receptor signaling

OpenAIRE

Liu, Qian; Wen, Chi-Kuang

2012-01-01

The gaseous plant hormone ethylene is perceived by a family of five ethylene receptor members in the dicotyledonous model plant Arabidopsis. Genetic and biochemical studies suggest that the ethylene response is suppressed by ethylene receptor complexes, but the biochemical nature of the receptor signal is unknown. Without appropriate biochemical measures to trace the ethylene receptor signal and quantify the signal strength, the biological significance of the modulation of ethylene responses ...

Coordinate Activation of Redox-Dependent ASK1/TGF-β Signaling by a Multiprotein Complex (MPK38, ASK1, SMADs, ZPR9, and TRX) Improves Glucose and Lipid Metabolism in Mice.

Science.gov (United States)

Seong, Hyun-A; Manoharan, Ravi; Ha, Hyunjung

2016-03-10

To explore the molecular connections between redox-dependent apoptosis signal-regulating kinase 1 (ASK1) and transforming growth factor-β (TGF-β) signaling pathways and to examine the physiological processes in which coordinated regulation of these two signaling pathways plays a critical role. We provide evidence that the ASK1 and TGF-β signaling pathways are interconnected by a multiprotein complex harboring murine protein serine-threonine kinase 38 (MPK38), ASK1, Sma- and Mad-related proteins (SMADs), zinc-finger-like protein 9 (ZPR9), and thioredoxin (TRX) and demonstrate that the activation of either ASK1 or TGF-β activity is sufficient to activate both the redox-dependent ASK1 and TGF-β signaling pathways. Physiologically, the restoration of the downregulated activation levels of ASK1 and TGF-β signaling in genetically and diet-induced obese mice by adenoviral delivery of SMAD3 or ZPR9 results in the amelioration of adiposity, hyperglycemia, hyperlipidemia, and impaired ketogenesis. Our data suggest that the multiprotein complex linking ASK1 and TGF-β signaling pathways may be a potential target for redox-mediated metabolic complications.

Regulation of early signaling and gene expression in the α-particle and bystander response of IMR-90 human fibroblasts

Directory of Open Access Journals (Sweden)

Hei Tom K

2010-07-01

Full Text Available Abstract Background The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is well established. To understand early signaling and gene regulation in bystander cells, we used a bio-informatics approach, measuring global gene expression at 30 minutes and signaling pathways between 30 minutes and 4 hours after exposure to α-particles in IMR-90 fibroblasts. Methods We used whole human genome microarrays and real time quantitative PCR to measure and validate gene expression. Microarray analysis was done using BRB-Array Tools; pathway and ontology analyses were done using Ingenuity Pathway Analysis and PANTHER, respectively. We studied signaling in irradiated and bystander cells using immunoblotting and semi-quantitative image analysis. Results Gene ontology suggested signal transduction and transcriptional regulation responding 30 minutes after treatment affected cell structure, motility and adhesion, and interleukin synthesis. We measured time-dependent expression of genes controlled by the NF-κB pathway; matrix metalloproteinases 1 and 3; chemokine ligands 2, 3 and 5 and interleukins 1β, 6 and 33. There was an increased response of this set of genes 30 minutes after treatment and another wave of induction at 4 hours. We investigated AKT-GSK3β signaling and found both AKT and GSK3β are hyper-phosphorylated 30 minutes after irradiation and this effect is maintained through 4 hours. In bystander cells, a similar response was seen with a delay of 30 minutes. We proposed a network model where the observed decrease in phosphorylation of β-catenin protein after GSK3β dependent inactivation can trigger target gene expression at later times after radiation exposure Conclusions These results are the first to show that the radiation induced bystander signal induces a widespread gene expression response at 30 minutes after treatment and these changes are accompanied by modification of

Toward a Theoretical Model of Text Complexity for the Early Grades: Learning from the Past, Anticipating the Future

Science.gov (United States)

Mesmer, Heidi Anne; Cunningham, James W.; Hiebert, Elfrieda H.

2012-01-01

In this conceptual essay, we offer rationales and evidence for critical components of a working model of text complexity for the early grades. In the first three sections of the article, we examine word-level, syntax-level, and discourse-level features of text, posing questions for future research. In the fourth section, we address elements of…

Emergence of complex chemistry on an organic monolayer.

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Prins, Leonard J

2015-07-21

In many origin-of-life scenarios, inorganic materials, such as FeS or mineral clays, play an important role owing to their ability to concentrate and select small organic molecules on their surface and facilitate their chemical transformations into new molecules. However, considering that life is made up of organic matter, at a certain stage during the evolution the role of the inorganic material must have been taken over by organic molecules. How this exactly happened is unclear, and, indeed, a big gap separates the rudimentary level of organization involving inorganic materials and the complex organization of cells, which are the building blocks of life. Over the past years, we have extensively studied the interaction of small molecules with monolayer-protected gold nanoparticles (Au NPs) for the purpose of developing innovative sensing and catalytic systems. During the course of these studies, we realized that the functional role of this system is very similar to that typically attributed to inorganic surfaces in the early stages of life, with the important being difference that the functional properties (molecular recognition, catalysis, signaling, adaptation) originate entirely from the organic monolayer rather than the inorganic support. This led us to the proposition that this system may serve as a model that illustrates how the important role of inorganic surfaces in dictating chemical processes in the early stages of life may have been taken over by organic matter. Here, we reframe our previously obtained results in the context of the origin-of-life question. The following functional roles of Au NPs will be discussed: the ability to concentrate small molecules and create different local populations, the ability to catalyze the chemical transformation of bound molecules, and, finally, the ability to install rudimentary signaling pathways and display primitive adaptive behavior. In particular, we will show that many of the functional properties of the system

Astrocyte Ca2+ signalling: an unexpected complexity

OpenAIRE

Volterra, Andrea; Liaudet, Nicolas; Savtchouk, Iaroslav

2014-01-01

Astrocyte Ca(2+) signalling has been proposed to link neuronal information in different spatial-temporal dimensions to achieve a higher level of brain integration. However, some discrepancies in the results of recent studies challenge this view and highlight key insufficiencies in our current understanding. In parallel, new experimental approaches that enable the study of astrocyte physiology at higher spatial-temporal resolution in intact brain preparations are beginning to reveal an unexpec...

IgD, cyclooxygenase-2 and ribosomal protein S6-PS240 immune response in a case of early psoriasis

Directory of Open Access Journals (Sweden)

Ana Maria Abreu Velez

2018-02-01

Full Text Available Psoriasis is an inflammatory skin disease. Five classic types of psoriasis have been defined: plaque, inverse, pustular, guttate, and erythrodermic. The early psoriasis immunologic skin immune response is not well understood. Here we aim to show an immune and cell signaling response in a case of early psoriasis. A 56 year old female presented with a desquamative lesion on her right leg. A skin biopsy for hematoxylin and eosin (H&E and immunohistochemistry (IHC staining was taken. The diagnosis indicated early psoriasis, and IHC showed positive IgD staining in the epidermal corneal layer, as well as positive staining with ribosomal protein S6-pS240 (RIBO in the hyperproliferative epidermis. Cyclooxygenase-2 (COX-2 was also very positive in the granular layer in spots, at the basement membrane zone of the skin and in the inflammatory infiltrate in the dermis subjacent to hyperproliferative psoriatic areas. In an early case of psoriasis, we confirmed the presence of IgD, RIBO and COX-2. Each molecule seems to be playing a role in inflammation and intracellular signaling pathways in early psoriasis. The role of IgD is unknown, and this case brings to light the complexity of the pathologic changes occurring in early psoriatic lesions.

The ShcA SH2 domain engages a 14-3-3/PI3'K signaling complex and promotes breast cancer cell survival.

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Ursini-Siegel, J; Hardy, W R; Zheng, Y; Ling, C; Zuo, D; Zhang, C; Podmore, L; Pawson, T; Muller, W J

2012-11-29

The ShcA adapter protein transmits activating signals downstream of receptor and cytoplasmic tyrosine kinases through the establishment of phosphotyrosine-dependent complexes. In this regard, ShcA possesses both a phosphotyrosine-binding domain (PTB) and Src homology 2 domain (SH2), which bind phosphotyrosine residues in a sequence-specific manner. Although the majority of receptor tyrosine kinases expressed in breast cancer cells bind the PTB domain, very little is known regarding the biological importance of SH2-driven ShcA signaling during mammary tumorigenesis. To address this, we employed transgenic mice expressing a mutant ShcA allele harboring a non-functional SH2 domain (ShcR397K) under the transcriptional control of the endogenous ShcA promoter. Using transplantation approaches, we demonstrate that SH2-dependent ShcA signaling within the mammary epithelial compartment is essential for breast tumor outgrowth, survival and the development of lung metastases. We further show that the ShcA SH2 domain activates the AKT pathway, potentially through a novel SH2-mediated complex between ShcA, 14-3-3ζ and the p85 regulatory subunit of phosphatidylinositol 3 (PI3') kinase. This study is the first to demonstrate that the SH2 domain of ShcA is critical for tumor survival during mammary tumorigenesis.

[Effects of Biejiajian Pills on Wnt signal pathway signal molecules β-catenin/TCF4 complex activities and downstream proteins cyclin D1 and MMP-2 in hepatocellular carcinoma cells].

Science.gov (United States)

Wen, Bin; Sun, Haitao; He, Songqi; Cheng, Yang; Jia, Wenyan; Fan, Eryan; Pang, Jie

2014-12-01

To study the effect of Biejiajian Pills on Wnt signal pathway and the mechanisms underlying its action to suppress the invasiveness of hepatocellular carcinoma. HepG2 cells cultured in the serum of rats fed with Biejiajian Pills for 48 h were examined for β-catenin expression using immunofluorescence, β-catenin/TCF4 complex activity with luciferase, and expressions of the downstream proteins cyclin D1 and MMP-2 using qRT-PCR. Biejiajian Pills-treated sera significantly reduced the expressions of cytoplasmic and nuclear β-catenin protein, cyclin D1 and MMP-2 proteins and lowered the activities of β-catenin/TCF4 complex. Biejiajian Pills may serve as a potential anti-tumor agent, whose effect might be mediated by inhibiting the Wnt/β-catenin pathway.

Detection of signals in noise

CERN Document Server

Whalen, Anthony D; Declaris, Nicholas

1971-01-01

Detection of Signals in Noise serves as an introduction to the principles and applications of the statistical theory of signal detection. The book discusses probability and random processes; narrowband signals, their complex representation, and their properties described with the aid of the Hilbert transform; and Gaussian-derived processes. The text also describes the application of hypothesis testing for the detection of signals and the fundamentals required for statistical detection of signals in noise. Problem exercises, references, and a supplementary bibliography are included after each c

Signaling aggression.

Science.gov (United States)

van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

2011-01-01

From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds. Copyright © 2011 Elsevier Inc. All rights reserved.

A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling

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Beautrait, Alexandre; Paradis, Justine S.; Zimmerman, Brandon; Giubilaro, Jenna; Nikolajev, Ljiljana; Armando, Sylvain; Kobayashi, Hiroyuki; Yamani, Lama; Namkung, Yoon; Heydenreich, Franziska M.; Khoury, Etienne; Audet, Martin; Roux, Philippe P.; Veprintsev, Dmitry B.; Laporte, Stéphane A.; Bouvier, Michel

2017-04-01

In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

[Classification and MR imaging of triangular fibrocartilage complex lesions].

Science.gov (United States)

Zhan, H L; Liu, Y; Bai, R J; Qian, Z H; Ye, W; Li, Y X; Wu, B D

2016-06-07

To explore the MRI characteristics of injuries of triangular fibrocartilage complex (TFCC), and provide imaging basis for the early diagnosis and treatment of the injuries. A total of 10 healthy volunteers without wrist injuries and 200 patients from Beijing Jishuitan Hospital who complained ulnar-sided wrist pain and were highly suspected as the injury of TFCC underwent the wrist magnetic resonance examination. All subjects were in a prone position and underwent examination on coronal T1WI scan and PD-FS on 3 planes respectively. Then the MRI characteristics of 3 healthy volunteers and 67 patients with TFCC injuries that confirmed by operation were analyzed. According to the comparative analysis of normal anatomy and Palmer classification, the injuries were classified and MRI features of different types of injuries were analyzed. At last, imaging findings were compared with surgical results. Three healthy volunteers without injuries showed mainly in low signal intensity on T1WI and PD-FS images. According to Palmer classification, there were 52 traumatic injuries (ⅠA 9, ⅠB 25, ⅠC 3, ⅠD 13, In addition, 1 has central perforation and ulnar avulsion and 1 has ulnar and radial injuries simultaneously) and 15 degenerative injuries (ⅡA 5, ⅡB 1, ⅡC 2 , ⅡD 1 , ⅡE 6) among 67 patients. The central perforation mainly demonstrated as linear high signal perpendicular to the disk, and run in a sagittal line. The ulnar, distal, and radial avulsion mainly showed the injuries were irregular, the structures were ambiguous, and there was high signal intensity in the injured structures on PD-FS. Degenerative injuries demonstrated the irregularity of TFC and heterogeneous signals on PD-FS. There were mixed intermediate-high signals and changes in the articular cartilage of lunate and ulna, high signal in the lunotriquetral ligament and ulnocarpal or radioulnar arthritis. MRI can demonstrate the anatomy of TFCC accurately, evaluate and make the general classification

PI3K-AKT-mTOR-Signaling and beyond: the Complex Network in Gastroenteropancreatic Neuroendocrine Neoplasms

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Briest, Franziska; Grabowski, Patricia

2014-01-01

Gastroenteropancreatic neuroendocrine neoplasms are heterogeneous in their clinical behavior and require therapies specially tailored according to staging, grading, origin and expression of peptide receptors. Despite extensive scientific efforts, the therapy options are still not satisfactory. The main reasons are due to the lack of a broad mechanistic knowledge, an insufficient classification of specific diagnostic sub-groups, and predictive markers. GEP-NEN tumors evade early diagnosis because of slow asymptomatic growth behavior and are frequently not detected until metastasized. How signaling networks contribute to tumor progression and how these networks interact remains unclear in large parts. In this review we summarize the knowledge on the growth factor responsive non-angiogenetic pathways in sporadic GEP-NENs, highlight promising mechanistic research approaches, and describe important therapy targets. PMID:24578720

Regulator of G-protein signaling - 5 (RGS5 is a novel repressor of hedgehog signaling.

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William M Mahoney

Full Text Available Hedgehog (Hh signaling plays fundamental roles in morphogenesis, tissue repair, and human disease. Initiation of Hh signaling is controlled by the interaction of two multipass membrane proteins, patched (Ptc and smoothened (Smo. Recent studies identify Smo as a G-protein coupled receptor (GPCR-like protein that signals through large G-protein complexes which contain the Gαi subunit. We hypothesize Regulator of G-Protein Signaling (RGS proteins, and specifically RGS5, are endogenous repressors of Hh signaling via their ability to act as GTPase activating proteins (GAPs for GTP-bound Gαi, downstream of Smo. In support of this hypothesis, we demonstrate that RGS5 over-expression inhibits sonic hedgehog (Shh-mediated signaling and osteogenesis in C3H10T1/2 cells. Conversely, signaling is potentiated by siRNA-mediated knock-down of RGS5 expression, but not RGS4 expression. Furthermore, using immuohistochemical analysis and co-immunoprecipitation (Co-IP, we demonstrate that RGS5 is present with Smo in primary cilia. This organelle is required for canonical Hh signaling in mammalian cells, and RGS5 is found in a physical complex with Smo in these cells. We therefore conclude that RGS5 is an endogenous regulator of Hh-mediated signaling and that RGS proteins are potential targets for novel therapeutics in Hh-mediated diseases.

Nuclear pore complex-mediated modulation of TCR signaling is required for naïve CD4+ T cell homeostasis.

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Borlido, Joana; Sakuma, Stephen; Raices, Marcela; Carrette, Florent; Tinoco, Roberto; Bradley, Linda M; D'Angelo, Maximiliano A

2018-05-07

Nuclear pore complexes (NPCs) are channels connecting the nucleus with the cytoplasm. We report that loss of the tissue-specific NPC component Nup210 causes a severe deficit of naïve CD4 + T cells. Nup210-deficient CD4 + T lymphocytes develop normally but fail to survive in the periphery. The decreased survival results from both an impaired ability to transmit tonic T cell receptor (TCR) signals and increased levels of Fas, which sensitize Nup210 -/- naïve CD4 + T cells to Fas-mediated cell death. Mechanistically, Nup210 regulates these processes by modulating the expression of Cav2 (encoding Caveolin-2) and Jun at the nuclear periphery. Whereas the TCR-dependent and CD4 + T cell-specific upregulation of Cav2 is critical for proximal TCR signaling, cJun expression is required for STAT3-dependent repression of Fas. Our results uncover an unexpected role for Nup210 as a cell-intrinsic regulator of TCR signaling and T cell homeostasis and expose NPCs as key players in the adaptive immune system.

Early Flood Detection for Rapid Humanitarian Response: Harnessing Near Real-Time Satellite and Twitter Signals

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Brenden Jongman

2015-10-01

Full Text Available Humanitarian organizations have a crucial role in response and relief efforts after floods. The effectiveness of disaster response is contingent on accurate and timely information regarding the location, timing and impacts of the event. Here we show how two near-real-time data sources, satellite observations of water coverage and flood-related social media activity from Twitter, can be used to support rapid disaster response, using case-studies in the Philippines and Pakistan. For these countries we analyze information from disaster response organizations, the Global Flood Detection System (GFDS satellite flood signal, and flood-related Twitter activity analysis. The results demonstrate that these sources of near-real-time information can be used to gain a quicker understanding of the location, the timing, as well as the causes and impacts of floods. In terms of location, we produce daily impact maps based on both satellite information and social media, which can dynamically and rapidly outline the affected area during a disaster. In terms of timing, the results show that GFDS and/or Twitter signals flagging ongoing or upcoming flooding are regularly available one to several days before the event was reported to humanitarian organizations. In terms of event understanding, we show that both GFDS and social media can be used to detect and understand unexpected or controversial flood events, for example due to the sudden opening of hydropower dams or the breaching of flood protection. The performance of the GFDS and Twitter data for early detection and location mapping is mixed, depending on specific hydrological circumstances (GFDS and social media penetration (Twitter. Further research is needed to improve the interpretation of the GFDS signal in different situations, and to improve the pre-processing of social media data for operational use.

Opening up of plasmalemma type-1 VDAC to form apoptotic "find me signal" pathways is essential in early apoptosis - evidence from the pathogenesis of cystic fibrosis resulting from failure of apoptotic cell clearance followed by sterile inflammation.

Science.gov (United States)

Thinnes, Friedrich P

2014-04-01

Cell membrane-standing type-1 VDAC is involved in cell volume regulation and thus apoptosis. The channel has been shown to figure as a pathway for osmolytes of varying classes, ATP included. An early event in apoptotic cell death is the release of "find me signals" by cells that enter the apoptotic process. ATP is one of those signals. Apoptotic cells this way attract phagocytes for an immunologically silent cell clearance. Thus, whenever apoptosis fails by a blockade of plasmalemma type-1 VDAC processes of sterile inflammation must be assumed for cell elimination. This is evident from a close look on the pathogenetic process of cystic fibrosis (CF). However, in normal airway epithelia two different anion channels cooperate to guarantee an appropriate volume of airway surface liquid (ASL) necessary for surface clearing: the cystic fibrosis conductance regulator (CFTR) and the outwardly rectifying chloride channel (ORCC) complex also called "alternate chloride channel" and under the control of the CFTR. There are arguments, that type-1 VDAC forms the channel part of the ORCC complex, and it has been shown that CFTR and type-1 VDAC co-localize in the apical membranes of human surface respiratory epithelium. In cystic fibrosis, the central cAMP-dependent regulation of ion and water transport via functional CFTR is lost. Here, CFTR molecules do not reach the apical membranes of airway epithelia anymore or work in an insufficient way, respectively. In addition, type-1 VDAC is no longer available to work as a "find me signal" pathway. In consequence, clearing away of apoptotic cells is blocked. There are experimental data on the channel characteristics of type-1 VDAC under the anion channel blocker DIDS (4,4-diisothiocyanato-stilbenedisulphonic acid) that argue in favor of this hypothesis. Together, type-1 VDAC should be kept as a "find me signal" pathway, which may give way to several classes of such signals. Copyright © 2014 Elsevier Inc. All rights reserved.

How the nucleus and mitochondria communicate in energy production during stress: nuclear MtATP6, an early-stress responsive gene, regulates the mitochondrial F₁F₀-ATP synthase complex.

Science.gov (United States)

Moghadam, Ali Asghar; Ebrahimie, Eemaeil; Taghavi, Seyed Mohsen; Niazi, Ali; Babgohari, Mahbobeh Zamani; Deihimi, Tahereh; Djavaheri, Mohammad; Ramezani, Amin

2013-07-01

A small number of stress-responsive genes, such as those of the mitochondrial F1F0-ATP synthase complex, are encoded by both the nucleus and mitochondria. The regulatory mechanism of these joint products is mysterious. The expression of 6-kDa subunit (MtATP6), a relatively uncharacterized nucleus-encoded subunit of F0 part, was measured during salinity stress in salt-tolerant and salt-sensitive cultivated wheat genotypes, as well as in the wild wheat genotypes, Triticum and Aegilops using qRT-PCR. The MtATP6 expression was suddenly induced 3 h after NaCl treatment in all genotypes, indicating an early inducible stress-responsive behavior. Promoter analysis showed that the MtATP6 promoter includes cis-acting elements such as ABRE, MYC, MYB, GTLs, and W-boxes, suggesting a role for this gene in abscisic acid-mediated signaling, energy metabolism, and stress response. It seems that 6-kDa subunit, as an early response gene and nuclear regulatory factor, translocates to mitochondria and completes the F1F0-ATP synthase complex to enhance ATP production and maintain ion homeostasis under stress conditions. These communications between nucleus and mitochondria are required for inducing mitochondrial responses to stress pathways. Dual targeting of 6-kDa subunit may comprise as a mean of inter-organelle communication and save energy for the cell. Interestingly, MtATP6 showed higher and longer expression in the salt-tolerant wheat and the wild genotypes compared to the salt-sensitive genotype. Apparently, salt-sensitive genotypes have lower ATP production efficiency and weaker energy management than wild genotypes; a stress tolerance mechanism that has not been transferred to cultivated genotypes.

Synergistic effect of signaling from receptors of soluble platelet agonists and outside-in signaling in formation of a stable fibrinogen-integrin αIIbβ3-actin cytoskeleton complex.

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Budnik, Ivan; Shenkman, Boris; Savion, Naphtali

2015-01-01

Thrombus formation in the injured vessel wall is a highly complex process involving various blood-born components that go through specific temporal and spatial changes as observed by intravital videomicroscopy. Platelets bind transiently to the developing thrombus and may either become stably incorporated into or disengage from the thrombus. The aim of the present study was to reveal the processes involved in the formation of a stable thrombus. Platelet-rich plasma and washed platelets were studied by the aggregometer. The aggregate stability was challenged by eptifibatide. Platelet Triton-insoluble fraction was prepared and the actin and αIIb content in the cytoskeleton was analyzed by western blot. Maximal actin polymerization is achieved 1min after platelet activation while maximal αIIbβ3-actin cytoskeleton association requires 5 to 10min of activation and fibrinogen-mediated platelet-to-platelet bridging. Thus, actin polymerization is dependent on platelet activation and requires neither αIIbβ3 integrin occupation nor platelet aggregation. Formation of a stable aggregate requires platelet activation for more than 1min, complete increase in actin cytoskeleton fraction and partial association of αIIbβ3 with the actin cytoskeleton. However, direct αIIbβ3 activation is not sufficient for cytoskeleton complex formation. Thus, stable αIIbβ3-fibrinogen interaction, representing stable aggregate, is achieved after more than 1min agonist activation, involving inside-out and outside-in signaling but not after direct integrin activation, involving only outside-in signaling. Formation of a stable fibrinogen-αIIbβ3-actin cytoskeleton complex is the result of the combined effect of platelet stimulation by soluble agonists, activation of αIIbβ3, fibrinogen binding and platelet-to-platelet bridging. Copyright © 2014 Elsevier Ltd. All rights reserved.

Signals and systems for dummies

CERN Document Server

Wickert, Mark

2013-01-01

Getting mixed signals in your signals and systems course? The concepts covered in a typical signals and systems course are often considered by engineering students to be some of the most difficult to master. Thankfully, Signals & Systems For Dummies is your intuitive guide to this tricky course, walking you step-by-step through some of the more complex theories and mathematical formulas in a way that is easy to understand. From Laplace Transforms to Fourier Analyses, Signals & Systems For Dummies explains in plain English the difficult concepts that can trip you up

Numerical Signal Analysis of Thermo-Cyclically Operated MOG Gas Sensor Arrays for Early Identification of Emissions from Overloaded Electric Cables

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Rolf Seifert

2015-10-01

Full Text Available A thermo-cyclically operated multi metal oxide gas sensor (MOG array is introduced together with a novel signal analysis approach (SimSens for identifying the emissions from overheated isolation cable materials thereby detecting the fires originated in electrical cabinets at early stages. The MOG array can yield specific conductance signatures appropriate to specifically identify gases. The obtained results bear good capability for detection and identification of pyrolysis gas emissions at relatively low sample heating temperatures even before a visible color-change of the polyvinyl chloride (PVC-isolation material. The dynamic conductance signals were evaluated using SimSens, a numerical analysis tool designed for simultaneous evaluation of conductance profiles. The results show promising pyrolysis gas identification and concentration determination capabilities in relation to the conductance profile shapes of model gases like carbon monoxide (CO and propene.

R7-binding protein targets the G protein β5/R7-regulator of G protein signaling complex to lipid rafts in neuronal cells and brain

Directory of Open Access Journals (Sweden)

Zhang Jian-Hua

2007-09-01

Full Text Available Abstract Background Heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins, composed of Gα, Gβ, and Gγ subunits, are positioned at the inner face of the plasma membrane and relay signals from activated G protein-coupled cell surface receptors to various signaling pathways. Gβ5 is the most structurally divergent Gβ isoform and forms tight heterodimers with regulator of G protein signalling (RGS proteins of the R7 subfamily (R7-RGS. The subcellular localization of Gβ 5/R7-RGS protein complexes is regulated by the palmitoylation status of the associated R7-binding protein (R7BP, a recently discovered SNARE-like protein. We investigate here whether R7BP controls the targeting of Gβ5/R7-RGS complexes to lipid rafts, cholesterol-rich membrane microdomains where conventional heterotrimeric G proteins and some effector proteins are concentrated in neurons and brain. Results We show that endogenous Gβ5/R7-RGS/R7BP protein complexes are present in native neuron-like PC12 cells and that a fraction is targeted to low-density, detergent-resistant membrane lipid rafts. The buoyant density of endogenous raft-associated Gβ5/R7-RGS protein complexes in PC12 cells was similar to that of lipid rafts containing the palmitoylated marker proteins PSD-95 and LAT, but distinct from that of the membrane microdomain where flotillin was localized. Overexpression of wild-type R7BP, but not its palmitoylation-deficient mutant, greatly enriched the fraction of endogenous Gβ5/R7-RGS protein complexes in the lipid rafts. In HEK-293 cells the palmitoylation status of R7BP also regulated the lipid raft targeting of co-expressed Gβ5/R7-RGS/R7BP proteins. A fraction of endogenous Gβ5/R7-RGS/R7BP complexes was also present in lipid rafts in mouse brain. Conclusion A fraction of Gβ5/R7-RGS/R7BP protein complexes is targeted to low-density, detergent-resistant membrane lipid rafts in PC12 cells and brain. In cultured cells, the palmitoylation status of

Proliferative signaling initiated in ACTH receptors

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C.F.P. Lotfi

2000-10-01

Full Text Available This article reviews recent results of studies aiming to elucidate modes of integrating signals initiated in ACTH receptors and FGF2 receptors, within the network system of signal transduction found in Y1 adrenocortical cells. These modes of signal integration should be central to the mechanisms underlying the regulation of the G0->G1->S transition in the adrenal cell cycle. FGF2 elicits a strong mitogenic response in G0/G1-arrested Y1 adrenocortical cells, that includes a rapid and transient activation of extracellular signal-regulated kinases-mitogen-activated protein kinases (ERK-MAPK (2 to 10 min, b transcription activation of c-fos, c-jun and c-myc genes (10 to 30 min, c induction of c-Fos and c-Myc proteins by 1 h and cyclin D1 protein by 5 h, and d onset of DNA synthesis stimulation within 8 h. ACTH, itself a weak mitogen, interacts with FGF2 in a complex manner, blocking the FGF2 mitogenic response during the early and middle G1 phase, keeping ERK-MAPK activation and c-Fos and cyclin D1 induction at maximal levels, but post-transcriptionally inhibiting c-Myc expression. c-Fos and c-Jun proteins are mediators in both the strong and the weak mitogenic responses respectively triggered by FGF2 and ACTH. Induction of c-Fos and stimulation of DNA synthesis by ACTH are independent of PKA and are inhibited by the PKC inhibitor GF109203X. In addition, ACTH is a poor activator of ERK-MAPK, but c-Fos induction and DNA synthesis stimulation by ACTH are strongly inhibited by the inhibitor of MEK1 PD98059.

HiJAK’d Signaling; the STAT3 Paradox in Senescence and Cancer Progression

International Nuclear Information System (INIS)

Junk, Damian J.; Bryson, Benjamin L.; Jackson, Mark W.

2014-01-01

Clinical and epidemiological data have associated chronic inflammation with cancer progression. Most tumors show evidence of infiltrating immune and inflammatory cells, and chronic inflammatory disorders are known to increase the overall risk of cancer development. While immune cells are often observed in early hyperplastic lesions in vivo, there remains debate over whether these immune cells and the cytokines they produce in the developing hyperplastic microenvironment act to inhibit or facilitate tumor development. The interleukin-6 (IL-6) family of cytokines, which includes IL-6 and oncostatin M (OSM), among others (LIF, CT-1, CNTF, and CLC), are secreted by immune cells, stromal cells, and epithelial cells, and regulate diverse biological processes. Each of the IL-6 family cytokines signals through a distinct receptor complex, yet each receptor complex uses a shared gp130 subunit, which is critical for signal transduction following cytokine binding. Activation of gp130 results in the activation of Signal Transducer and Activator of Transcription 3 (STAT3), and the Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3K) signaling cascades. Tumor suppressive signaling can often be observed in normal cells following prolonged STAT3 activation. However, there is mounting evidence that the IL-6 family cytokines can contribute to later stages of tumor progression in many ways. Here we will review how the microenvironmental IL-6 family cytokine OSM influences each stage of the transformation process. We discuss the intrinsic adaptations a developing cancer cell must make in order to tolerate and circumvent OSM-mediated growth suppression, as well as the OSM effectors that are hijacked during tumor expansion and metastasis. We propose that combining current therapies with new ones that suppress the signals generated from the tumor microenvironment will significantly impact an oncologist’s ability to treat cancer

Simplifying and Complicating Early Social Complexity: An Introduction

OpenAIRE

Kaulicke, Peter

2012-01-01

This contribution treats some of the basic problems related to the origins of social complexity in ancient Perú and to such crucial definitions as domestication and sedentism. The necessity of including the concept of simplicity in discussions of complexity is stressed, as well as that of discerning the relevance and interrelation between simple and complex institutions. Further, the corresponding chronology of Perú also is in need of standardization and more precise definitions. Lastly, the ...

A Framework of Working Across Disciplines in Early Design and R&D of Large Complex Engineered Systems

Science.gov (United States)

McGowan, Anna-Maria Rivas; Papalambros, Panos Y.; Baker, Wayne E.

2015-01-01

This paper examines four primary methods of working across disciplines during R&D and early design of large-scale complex engineered systems such as aerospace systems. A conceptualized framework, called the Combining System Elements framework, is presented to delineate several aspects of cross-discipline and system integration practice. The framework is derived from a theoretical and empirical analysis of current work practices in actual operational settings and is informed by theories from organization science and engineering. The explanatory framework may be used by teams to clarify assumptions and associated work practices, which may reduce ambiguity in understanding diverse approaches to early systems research, development and design. The framework also highlights that very different engineering results may be obtained depending on work practices, even when the goals for the engineered system are the same.

The bias and signal attenuation present in conventional pollen-based climate reconstructions as assessed by early climate data from Minnesota, USA.

Science.gov (United States)

St Jacques, Jeannine-Marie; Cumming, Brian F; Sauchyn, David J; Smol, John P

2015-01-01

The inference of past temperatures from a sedimentary pollen record depends upon the stationarity of the pollen-climate relationship. However, humans have altered vegetation independent of changes to climate, and consequently modern pollen deposition is a product of landscape disturbance and climate, which is different from the dominance of climate-derived processes in the past. This problem could cause serious signal distortion in pollen-based reconstructions. In the north-central United States, direct human impacts have strongly altered the modern vegetation and hence the pollen rain since Euro-American settlement in the mid-19th century. Using instrumental temperature data from the early 1800 s from Fort Snelling (Minnesota), we assessed the signal distortion and bias introduced by using the conventional method of inferring temperature from pollen assemblages in comparison to a calibration set from pre-settlement pollen assemblages and the earliest instrumental climate data. The early post-settlement calibration set provides more accurate reconstructions of the 19th century instrumental record, with less bias, than the modern set does. When both modern and pre-industrial calibration sets are used to reconstruct past temperatures since AD 1116 from pollen counts from a varve-dated record from Lake Mina, Minnesota, the conventional inference method produces significant low-frequency (centennial-scale) signal attenuation and positive bias of 0.8-1.7 °C, resulting in an overestimation of Little Ice Age temperature and likely an underestimation of the extent and rate of anthropogenic warming in this region. However, high-frequency (annual-scale) signal attenuation exists with both methods. Hence, we conclude that any past pollen spectra from before Euro-American settlement in this region should be interpreted using a pre-Euro-American settlement pollen set, paired to the earliest instrumental climate records. It remains to be explored how widespread this problem is

The bias and signal attenuation present in conventional pollen-based climate reconstructions as assessed by early climate data from Minnesota, USA.

Directory of Open Access Journals (Sweden)

Jeannine-Marie St Jacques

Full Text Available The inference of past temperatures from a sedimentary pollen record depends upon the stationarity of the pollen-climate relationship. However, humans have altered vegetation independent of changes to climate, and consequently modern pollen deposition is a product of landscape disturbance and climate, which is different from the dominance of climate-derived processes in the past. This problem could cause serious signal distortion in pollen-based reconstructions. In the north-central United States, direct human impacts have strongly altered the modern vegetation and hence the pollen rain since Euro-American settlement in the mid-19th century. Using instrumental temperature data from the early 1800 s from Fort Snelling (Minnesota, we assessed the signal distortion and bias introduced by using the conventional method of inferring temperature from pollen assemblages in comparison to a calibration set from pre-settlement pollen assemblages and the earliest instrumental climate data. The early post-settlement calibration set provides more accurate reconstructions of the 19th century instrumental record, with less bias, than the modern set does. When both modern and pre-industrial calibration sets are used to reconstruct past temperatures since AD 1116 from pollen counts from a varve-dated record from Lake Mina, Minnesota, the conventional inference method produces significant low-frequency (centennial-scale signal attenuation and positive bias of 0.8-1.7 °C, resulting in an overestimation of Little Ice Age temperature and likely an underestimation of the extent and rate of anthropogenic warming in this region. However, high-frequency (annual-scale signal attenuation exists with both methods. Hence, we conclude that any past pollen spectra from before Euro-American settlement in this region should be interpreted using a pre-Euro-American settlement pollen set, paired to the earliest instrumental climate records. It remains to be explored how widespread

Employing the Hilbert-Huang Transform to analyze observed natural complex signals: Calm wind meandering cases

Science.gov (United States)

Martins, Luis Gustavo Nogueira; Stefanello, Michel Baptistella; Degrazia, Gervásio Annes; Acevedo, Otávio Costa; Puhales, Franciano Scremin; Demarco, Giuliano; Mortarini, Luca; Anfossi, Domenico; Roberti, Débora Regina; Costa, Felipe Denardin; Maldaner, Silvana

2016-11-01

In this study we analyze natural complex signals employing the Hilbert-Huang spectral analysis. Specifically, low wind meandering meteorological data are decomposed into turbulent and non turbulent components. These non turbulent movements, responsible for the absence of a preferential direction of the horizontal wind, provoke negative lobes in the meandering autocorrelation functions. The meandering characteristic time scales (meandering periods) are determined from the spectral peak provided by the Hilbert-Huang marginal spectrum. The magnitudes of the temperature and horizontal wind meandering period obtained agree with the results found from the best fit of the heuristic meandering autocorrelation functions. Therefore, the new method represents a new procedure to evaluate meandering periods that does not employ mathematical expressions to represent observed meandering autocorrelation functions.

Early AIDS dementia complex

International Nuclear Information System (INIS)

Mountz, J.M.; Speed, N.M.; Adams, K.; Schwartz, J.A.; Gross, M.D.; Ostrow, D.G.

1988-01-01

A frequent complication of the acquired immunodeficiency syndrome (AIDS) is AIDS dementia complex (ADC). The authors evaluated seven patients with AIDS (aged 28-55 years, all male) for ADC by psychiatric evaluation, neuropsychological testing, CT scanning, and IMP-SPECT. Six of seven patients exhibited cognitive or behavioral abnormalities. Neuropsychological testing showed general deficits but no cases of explicit dementia. SPECT showed marked abnormalities in two cases: posterior temporal-parietal diminution of tracer uptake in one case (posterior/anterior=0.81) and marked right/left subcortical asymmetry (1.17) in the other. In three additional cases there was asymmetric tracer uptake in the subcortical and parietal regions. CT findings were normal in all seven cases. The authors conclude that functional imaging with the use of IMP-SPECT may be a useful method to follow ADC progression and response to therapy

The biology of skin wetness perception and its implications in manual function and for reproducing complex somatosensory signals in neuroprosthetics

Science.gov (United States)

Ackerley, Rochelle

2017-01-01

Our perception of skin wetness is generated readily, yet humans have no known receptor (hygroreceptor) to signal this directly. It is easy to imagine the sensation of water running over our hands or the feel of rain on our skin. The synthetic sensation of wetness is thought to be produced from a combination of specific skin thermal and tactile inputs, registered through thermoreceptors and mechanoreceptors, respectively. The present review explores how thermal and tactile afference from the periphery can generate the percept of wetness centrally. We propose that the main signals include information about skin cooling, signaled primarily by thinly myelinated thermoreceptors, and rapid changes in touch, through fast-conducting, myelinated mechanoreceptors. Potential central sites for integration of these signals, and thus the perception of skin wetness, include the primary and secondary somatosensory cortices and the insula cortex. The interactions underlying these processes can also be modeled to aid in understanding and engineering the mechanisms. Furthermore, we discuss the role that sensing wetness could play in precision grip and the dexterous manipulation of objects. We expand on these lines of inquiry to the application of the knowledge in designing and creating skin sensory feedback in prosthetics. The addition of real-time, complex sensory signals would mark a significant advance in the use and incorporation of prosthetic body parts for amputees in everyday life. PMID:28123008

EGS in sedimentary basins: sensitivity of early-flowback tracer signals to induced-fracture parameters

Science.gov (United States)

Karmakar, Shyamal; Ghergut, Julia; Sauter, Martin

2015-04-01

-effective aperture, in a water fracture (WF), or - fracture thickness and porosity, for a gel-proppant fracture (GPF). We find that parameter determination from SW early signals can significantly be improved by concomitantly using a number of solute tracers with different transport and retardation behaviour. We considered tracers of different sorptivity to proppant coatings, and to matrix rock surfaces, for GPF, as well as contrasting-diffusivity or -sorptivity tracers, for WF. An advantage of this SW approach is that it requires only small chaser volumes (few times the fracture volume), not relying on advective penetration into the rock matrix. Thus, selected tracer species are to be injected during the very last stage of the fracturing process, when fracture sizes and thus target parameters are supposed to attain more or less stable values. We illustrate the application of these tracer test design principles using hydro- and lithostratigraphy data from the Geothermal Research Platform at Groß Schönebeck [4], targeting a multi-layer reservoir (sedimentary and crystalline formations in 4-5 km depth) in the NE-German Sedimentary Basin. Acknowledgments: This work benefited from long-term support from Baker Hughes (Celle) and from the Lower-Saxonian Science and Culture Ministry (MWK Niedersachsen) within the applied research project gebo (Geothermal Energy and High-Performance Drilling, 2009-2014). The first author gratefully acknowledges continued financial support from the DAAD (German Academic Exchange Service) to pursuing Ph. D. work. References: [1] http://www.sciencedirect.com/science/article/pii/S1876610214017391 [2] http://www.geothermal-energy.org/cpdb/record_detail.php?id=7215 [3] http://www.geothermal-energy.org/cpdb/record_detail.php?id=19034 [4] http://www.gfz-potsdam.de/en/scientific-services/laboratories/gross-schoenebeck/

Fetal QRS extraction from abdominal recordings via model-based signal processing and intelligent signal merging

International Nuclear Information System (INIS)

Haghpanahi, Masoumeh; Borkholder, David A

2014-01-01

Noninvasive fetal ECG (fECG) monitoring has potential applications in diagnosing congenital heart diseases in a timely manner and assisting clinicians to make more appropriate decisions during labor. However, despite advances in signal processing and machine learning techniques, the analysis of fECG signals has still remained in its preliminary stages. In this work, we describe an algorithm to automatically locate QRS complexes in noninvasive fECG signals obtained from a set of four electrodes placed on the mother’s abdomen. The algorithm is based on an iterative decomposition of the maternal and fetal subspaces and filtering of the maternal ECG (mECG) components from the fECG recordings. Once the maternal components are removed, a novel merging technique is applied to merge the signals and detect the fetal QRS (fQRS) complexes. The algorithm was trained and tested on the fECG datasets provided by the PhysioNet/CinC challenge 2013. The final results indicate that the algorithm is able to detect fetal peaks for a variety of signals with different morphologies and strength levels encountered in clinical practice. (paper)

Dietary tomato and lycopene impact androgen signaling- and carcinogenesis-related gene expression during early TRAMP prostate carcinogenesis

Science.gov (United States)

Wan, Lei; Tan, Hsueh-Li; Thomas-Ahner, Jennifer M.; Pearl, Dennis K.; Erdman, John W.; Moran, Nancy E.; Clinton, Steven K.

2014-01-01

Consumption of tomato products containing the carotenoid lycopene is associated with a reduced risk of prostate cancer. To identify gene expression patterns associated with early testosterone-driven prostate carcinogenesis, which are impacted by dietary tomato and lycopene, wild type (WT) and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were fed control or tomato- or lycopene-containing diets from 4-10 wk-of-age. Eight-week-old mice underwent sham surgery, castration, or castration followed by testosterone-repletion (2.5 mg/kg/d initiated 1 wk after castration). Ten-wk-old intact TRAMP mice exhibit early multifocal prostatic intraepithelial neoplasia (PIN). Of the 200 prostate cancer-related genes measured by quantitative NanoString®, 189 are detectable, 164 significantly differ by genotype, 179 by testosterone status, and 30 by diet type (Plycopene feeding (Srd5a1) and by tomato-feeding (Srd5a2, Pxn, and Srebf1). Additionally, tomato-feeding significantly reduced expression of genes associated with stem cell features, Aldh1a and Ly6a, while lycopene-feeding significantly reduced expression of neuroendocrine differentiation-related genes, Ngfr and Syp. Collectively, these studies demonstrate a profile of testosterone-regulated genes associated with early stages of prostate carcinogenesis that are potential mechanistic targets of dietary tomato components. Future studies on androgen signaling/metabolism, stem cell features, and neuroendocrine differentiation pathways may elucidate the mechanisms by which dietary tomato and lycopene impact prostate cancer risk. PMID:25315431

Spectral Correlation of Multicarrier Modulated Signals and Its Application for Signal Detection

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Zhang Haijian

2010-01-01

Full Text Available Spectral correlation theory for cyclostationary time-series signals has been studied for decades. Explicit formulas of spectral correlation function for various types of analog-modulated and digital-modulated signals are already derived. In this paper, we investigate and exploit the cyclostationarity characteristics for two kinds of multicarrier modulated (MCM signals: conventional OFDM and filter bank based multicarrier (FBMC signals. The spectral correlation characterization of MCM signal can be described by a special linear periodic time-variant (LPTV system. Using this LPTV description, we have derived the explicit theoretical formulas of nonconjugate and conjugate cyclic autocorrelation function (CAF and spectral correlation function (SCF for OFDM and FBMC signals. According to theoretical spectral analysis, Cyclostationary Signatures (CS are artificially embedded into MCM signal and a low-complexity signature detector is, therefore, presented for detecting MCM signal. Theoretical analysis and simulation results demonstrate the efficiency and robustness of this CS detector compared to traditionary energy detector.

E3 ligase Hei10: a multifaceted structure-based signaling molecule with roles within and beyond meiosis

Science.gov (United States)

De Muyt, Arnaud; Zhang, Liangran; Piolot, Tristan; Kleckner, Nancy; Espagne, Eric; Zickler, Denise

2014-01-01

Human enhancer of invasion-10 (Hei10) mediates meiotic recombination and also plays roles in cell proliferation. Here we explore Hei10’s roles throughout the sexual cycle of the fungus Sordaria with respect to localization and effects of null, RING-binding, and putative cyclin-binding (RXL) domain mutations. Hei10 makes three successive types of foci. Early foci form along synaptonemal complex (SC) central regions. At some of these positions, depending on its RING and RXL domains, Hei10 mediates development and turnover of two sequential types of recombination complexes, each demarked by characteristic amplified Hei10 foci. Integration with ultrastructural data for recombination nodules further reveals that recombination complexes differentiate into three types, one of which corresponds to crossover recombination events during or prior to SC formation. Finally, Hei10 positively and negatively modulates SUMO localization along SCs by its RING and RXL domains, respectively. The presented findings suggest that Hei10 integrates signals from the SC, associated recombination complexes, and the cell cycle to mediate both the development and programmed turnover/evolution of recombination complexes via SUMOylation/ubiquitination. Analogous cell cycle-linked assembly/disassembly switching could underlie localization and roles for Hei10 in centrosome/spindle pole body dynamics and associated nuclear trafficking. We suggest that Hei10 is a unique type of structure-based signal transduction protein. PMID:24831702

Liquid Argon TPC Signal Formation, Signal Processing and Hit Reconstruction

Energy Technology Data Exchange (ETDEWEB)

Baller, Bruce [Fermilab

2017-03-11

This document describes the early stage of the reconstruction chain that was developed for the ArgoNeuT and MicroBooNE experiments at Fermilab. These experiments study accelerator neutrino interactions that occur in a Liquid Argon Time Projection Chamber. Reconstructing the properties of particles produced in these interactions requires knowledge of the micro-physics processes that affect the creation and transport of ionization electrons to the readout system. A wire signal deconvolution technique was developed to convert wire signals to a standard form for hit reconstruction, to remove artifacts in the electronics chain and to remove coherent noise.

Disruption of the Cdc42/Par6/aPKC or Dlg/Scrib/Lgl Polarity Complex Promotes Epithelial Proliferation via Overlapping Mechanisms.

Science.gov (United States)

Schimizzi, Gregory V; Maher, Meghan T; Loza, Andrew J; Longmore, Gregory D

2016-01-01

The establishment and maintenance of apical-basal polarity is a defining characteristic and essential feature of functioning epithelia. Apical-basal polarity (ABP) proteins are also tumor suppressors that are targeted for disruption by oncogenic viruses and are commonly mutated in human carcinomas. Disruption of these ABP proteins is an early event in cancer development that results in increased proliferation and epithelial disorganization through means not fully characterized. Using the proliferating Drosophila melanogaster wing disc epithelium, we demonstrate that disruption of the junctional vs. basal polarity complexes results in increased epithelial proliferation via distinct downstream signaling pathways. Disruption of the basal polarity complex results in JNK-dependent proliferation, while disruption of the junctional complex primarily results in p38-dependent proliferation. Surprisingly, the Rho-Rok-Myosin contractility apparatus appears to play opposite roles in the regulation of the proliferative phenotype based on which polarity complex is disrupted. In contrast, non-autonomous Tumor Necrosis Factor (TNF) signaling appears to suppress the proliferation that results from apical-basal polarity disruption, regardless of which complex is disrupted. Finally we demonstrate that disruption of the junctional polarity complex activates JNK via the Rho-Rok-Myosin contractility apparatus independent of the cortical actin regulator, Moesin.

Time-resolved dissection of early phosphoproteome and ensuing proteome changes in response to TGF-β

DEFF Research Database (Denmark)

J D'Souza, Rochelle C; Knittle, Anna M; Nagaraj, Nagarjuna

2014-01-01

and phosphorylation and knowledge of protein interactions and transcriptional regulation provided a comprehensive representation of the dynamic signaling events underlying TGF-β-induced changes in cell behavior. Our data suggest that in epithelial cells stimulated with TGF-β, early signaling is a mixture of both pro...... changes of cultured human keratinocytes undergoing EMT and cell cycle arrest in response to stimulation with TGF-β. We quantified significant changes in 2079 proteins and 2892 phosphorylation sites regulated by TGF-β. We identified several proteins known to be involved in TGF-β-induced cellular processes...... by phosphorylation of the transcriptional regulators of the SMAD family by the TGF-β receptor complex, we observed rapid kinetics of changes in protein phosphorylation, indicating that many responses were mediated through SMAD-independent TGF-β signaling. Combined analysis of changes in protein abundance...

Temporal Patterns in Sheep Fetal Heart Rate Variability Correlate to Systemic Cytokine Inflammatory Response: A Methodological Exploration of Monitoring Potential Using Complex Signals Bioinformatics.

Directory of Open Access Journals (Sweden)

Christophe L Herry

Full Text Available Fetal inflammation is associated with increased risk for postnatal organ injuries. No means of early detection exist. We hypothesized that systemic fetal inflammation leads to distinct alterations of fetal heart rate variability (fHRV. We tested this hypothesis deploying a novel series of approaches from complex signals bioinformatics. In chronically instrumented near-term fetal sheep, we induced an inflammatory response with lipopolysaccharide (LPS injected intravenously (n = 10 observing it over 54 hours; seven additional fetuses served as controls. Fifty-one fHRV measures were determined continuously every 5 minutes using Continuous Individualized Multi-organ Variability Analysis (CIMVA. CIMVA creates an fHRV measures matrix across five signal-analytical domains, thus describing complementary properties of fHRV. We implemented, validated and tested methodology to obtain a subset of CIMVA fHRV measures that matched best the temporal profile of the inflammatory cytokine IL-6. In the LPS group, IL-6 peaked at 3 hours. For the LPS, but not control group, a sharp increase in standardized difference in variability with respect to baseline levels was observed between 3 h and 6 h abating to baseline levels, thus tracking closely the IL-6 inflammatory profile. We derived fHRV inflammatory index (FII consisting of 15 fHRV measures reflecting the fetal inflammatory response with prediction accuracy of 90%. Hierarchical clustering validated the selection of 14 out of 15 fHRV measures comprising FII. We developed methodology to identify a distinctive subset of fHRV measures that tracks inflammation over time. The broader potential of this bioinformatics approach is discussed to detect physiological responses encoded in HRV measures.

CDIP1-BAP31 Complex Transduces Apoptotic Signals from Endoplasmic Reticulum to Mitochondria under Endoplasmic Reticulum Stress

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Takushi Namba

2013-10-01

Full Text Available Resolved endoplasmic reticulum (ER stress response is essential for intracellular homeostatic balance, but unsettled ER stress can lead to apoptosis. Here, we show that a proapoptotic p53 target, CDIP1, acts as a key signal transducer of ER-stress-mediated apoptosis. We identify B-cell-receptor-associated protein 31 (BAP31 as an interacting partner of CDIP1. Upon ER stress, CDIP1 is induced and enhances an association with BAP31 at the ER membrane. We also show that CDIP1 binding to BAP31 is required for BAP31 cleavage upon ER stress and for BAP31-Bcl-2 association. The recruitment of Bcl-2 to the BAP31-CDIP1 complex, as well as CDIP1-dependent truncated Bid (tBid and caspase-8 activation, contributes to BAX oligomerization. Genetic knockout of CDIP1 in mice leads to impaired response to ER-stress-mediated apoptosis. Altogether, our data demonstrate that the CDIP1/BAP31-mediated regulation of mitochondrial apoptosis pathway represents a mechanism for establishing an ER-mitochondrial crosstalk for ER-stress-mediated apoptosis signaling.

Green tea polyphenols alleviate early BBB damage during experimental focal cerebral ischemia through regulating tight junctions and PKCalpha signaling.

Science.gov (United States)

Liu, Xiaobai; Wang, Zhenhua; Wang, Ping; Yu, Bo; Liu, Yunhui; Xue, Yixue

2013-07-21

It has been supposed that green tea polyphenols (GTPs) have neuroprotective effects on brain damage after brain ischemia in animal experiments. Little is known regarding GTPs' protective effects against the blood-brain barrier (BBB) disruption after ischemic stroke. We investigated the effects of GTPs on the expression of claudin-5, occludin, and ZO-1, and the corresponding cellular mechanisms involved in the early stage of cerebral ischemia. Male Wistar rats were subjected to a middle cerebral artery occlusion (MCAO) for 0, 30, 60, and 120 min. GTPs (400 mg/kg/day) or vehicle was administered by intragastric gavage twice a day for 30 days prior to MCAO. At different time points, the expression of claudin-5, occludin, ZO-1, and PKCα signaling pathway in microvessel fragments of cerebral ischemic tissue were evaluated. GTPs reduced BBB permeability at 60 min and 120 min after ischemia as compared with the vehicle group. Transmission electron microscopy also revealed that GTPs could reverse the opening of tight junction (TJ) barrier at 60 min and 120 min after MACO. The decreased mRNA and protein expression levels of claudin-5, occludin, and ZO-1 in microvessel fragments of cerebral ischemic tissue were significantly prevented by treatment with GTPs at the same time points after ischemia in rats. Furthermore, GTPs could attenuate the increase in the expression levels of PKCα mRNA and protein caused by cerebral ischemia. These results demonstrate that GTPs may act as a potential neuroprotective agent against BBB damage at the early stage of focal cerebral ischemia through the regulation of TJ and PKCα signaling.

Signal transduction by the major histocompatibility complex class I molecule

DEFF Research Database (Denmark)

Pedersen, A E; Skov, Svend; Bregenholt, S

1999-01-01

Ligation of cell surface major histocompatibility class I (MHC-I) proteins by antibodies, or by their native counter receptor, the CD8 molecule, mediates transduction of signals into the cells. MHC-I-mediated signaling can lead to both increased and decreased activity of the MHC-I-expressing cell...... and functioning, MHC-I molecules might be of importance for the maintenance of cellular homeostasis not only within the immune system, but also in the interplay between the immune system and other organ systems....

Decreased Complexity in Alzheimer's Disease: Resting-State fMRI Evidence of Brain Entropy Mapping

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Bin Wang

2017-11-01

Full Text Available Alzheimer's disease (AD is a frequently observed, irreversible brain function disorder among elderly individuals. Resting-state functional magnetic resonance imaging (rs-fMRI has been introduced as an alternative approach to assessing brain functional abnormalities in AD patients. However, alterations in the brain rs-fMRI signal complexities in mild cognitive impairment (MCI and AD patients remain unclear. Here, we described the novel application of permutation entropy (PE to investigate the abnormal complexity of rs-fMRI signals in MCI and AD patients. The rs-fMRI signals of 30 normal controls (NCs, 33 early MCI (EMCI, 32 late MCI (LMCI, and 29 AD patients were obtained from the Alzheimer's disease Neuroimaging Initiative (ADNI database. After preprocessing, whole-brain entropy maps of the four groups were extracted and subjected to Gaussian smoothing. We performed a one-way analysis of variance (ANOVA on the brain entropy maps of the four groups. The results after adjusting for age and sex differences together revealed that the patients with AD exhibited lower complexity than did the MCI and NC controls. We found five clusters that exhibited significant differences and were distributed primarily in the occipital, frontal, and temporal lobes. The average PE of the five clusters exhibited a decreasing trend from MCI to AD. The AD group exhibited the least complexity. Additionally, the average PE of the five clusters was significantly positively correlated with the Mini-Mental State Examination (MMSE scores and significantly negatively correlated with Functional Assessment Questionnaire (FAQ scores and global Clinical Dementia Rating (CDR scores in the patient groups. Significant correlations were also found between the PE and regional homogeneity (ReHo in the patient groups. These results indicated that declines in PE might be related to changes in regional functional homogeneity in AD. These findings suggested that complexity analyses using PE

A deep learning approach for fetal QRS complex detection.

Science.gov (United States)

Zhong, Wei; Liao, Lijuan; Guo, Xuemei; Wang, Guoli

2018-04-20

Non-invasive foetal electrocardiography (NI-FECG) has the potential to provide more additional clinical information for detecting and diagnosing fetal diseases. We propose and demonstrate a deep learning approach for fetal QRS complex detection from raw NI-FECG signals by using a convolutional neural network (CNN) model. The main objective is to investigate whether reliable fetal QRS complex detection performance can still be obtained from features of single-channel NI-FECG signals, without canceling maternal ECG (MECG) signals. A deep learning method is proposed for recognizing fetal QRS complexes. Firstly, we collect data from set-a of the PhysioNet/computing in Cardiology Challenge database. The sample entropy method is used for signal quality assessment. Part of the bad quality signals is excluded in the further analysis. Secondly, in the proposed method, the features of raw NI-FECG signals are normalized before they are fed to a CNN classifier to perform fetal QRS complex detection. We use precision, recall, F-measure and accuracy as the evaluation metrics to assess the performance of fetal QRS complex detection. The proposed deep learning method can achieve relatively high precision (75.33%), recall (80.54%), and F-measure scores (77.85%) compared with three other well-known pattern classification methods, namely KNN, naive Bayes and SVM. the proposed deep learning method can attain reliable fetal QRS complex detection performance from the raw NI-FECG signals without canceling MECG signals. In addition, the influence of different activation functions and signal quality assessment on classification performance are evaluated, and results show that Relu outperforms the Sigmoid and Tanh on this particular task, and better classification performance is obtained with the signal quality assessment step in this study.

Signal Processing Methods for Flood Early Warning Systems

NARCIS (Netherlands)

Pyayt, A.L.; Mokhov, I.I.; Kozionov, A.P.; Kusherbaeva, V.T.; Krzhizhanovskaya, V.V.; Broekhuijsen, B.J.; Meijer, R.J.; Hinkelmann, R.; Nasermoaddeli, M.H.; Liong, S.Y.; Savic, D.; Fröhle, P.; Daemrich, K.F.

2012-01-01

We present in a data-driven approach for detection of anomalies in earthen dam (dike) behaviour that can indicate the onset of flood defence structure failure. This approach is implemented in the UrbanFlood early warning system's Artificial Intelligence component that processes dike measurements in

Bmp signaling mediates endoderm pouch morphogenesis by regulating Fgf signaling in zebrafish

Science.gov (United States)

Swartz, Mary E.; McCarthy, Neil; Norrie, Jacqueline L.; Eberhart, Johann K.

2016-01-01

The endodermal pouches are a series of reiterated structures that segment the pharyngeal arches and help pattern the vertebrate face. Multiple pathways regulate the complex process of endodermal development, including the Bone morphogenetic protein (Bmp) pathway. However, the role of Bmp signaling in pouch morphogenesis is poorly understood. Using genetic and chemical inhibitor approaches, we show that pouch morphogenesis requires Bmp signaling from 10-18 h post-fertilization, immediately following gastrulation. Blocking Bmp signaling during this window results in morphological defects to the pouches and craniofacial skeleton. Using genetic chimeras we show that Bmp signals directly to the endoderm for proper morphogenesis. Time-lapse imaging and analysis of reporter transgenics show that Bmp signaling is necessary for pouch outpocketing via the Fibroblast growth factor (Fgf) pathway. Double loss-of-function analyses demonstrate that Bmp and Fgf signaling interact synergistically in craniofacial development. Collectively, our analyses shed light on the tissue and signaling interactions that regulate development of the vertebrate face. PMID:27122171

Rheb may complex with RASSF1A to coordinate Hippo and TOR signaling.

Science.gov (United States)

Nelson, Nicholas; Clark, Geoffrey J

2016-06-07

The TOR pathway is a vital component of cellular homeostasis that controls the synthesis of proteins, nucleic acids and lipids. Its core is the TOR kinase. Activation of the TOR pathway suppresses autophagy, which plays a vital but complex role in tumorigenesis. The TOR pathway is regulated by activation of the Ras-related protein Rheb, which can bind mTOR. The Hippo pathway is a major growth control module that regulates cell growth, differentiation and apoptosis. Its core consists of an MST/LATS kinase cascade that can be activated by the RASSF1A tumor suppressor. The TOR and Hippo pathways may be coordinately regulated to promote cellular homeostasis. However, the links between the pathways remain only partially understood. We now demonstrate that in addition to mTOR regulation, Rheb also impacts the Hippo pathway by forming a complex with RASSF1A. Using stable clones of two human lung tumor cell lines (NCI-H1792 and NCI-H1299) with shRNA-mediated silencing or ectopic overexpression of RASSF1A, we show that activated Rheb stimulates the Hippo pathway, but is suppressed in its ability to stimulate the TOR pathway. Moreover, by selectively labeling autophagic vacuoles we show that RASSF1A inhibits the ability of Rheb to suppress autophagy and enhance cell growth. Thus, we identify a new connection that impacts coordination of Hippo and TOR signaling. As RASSF1A expression is frequently lost in human tumors, the RASSF1A status of a tumor may impact not just its Hippo pathway status, but also its TOR pathway status.

Cannabis use in early adolescence: Evidence of amygdala hypersensitivity to signals of threat

Directory of Open Access Journals (Sweden)

Philip A. Spechler

2015-12-01

Full Text Available Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n = 70 of 14-year olds with a history of cannabis use to a group (n = 70 of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood.

Cannabis use in early adolescence: Evidence of amygdala hypersensitivity to signals of threat.

Science.gov (United States)

Spechler, Philip A; Orr, Catherine A; Chaarani, Bader; Kan, Kees-Jan; Mackey, Scott; Morton, Aaron; Snowe, Mitchell P; Hudson, Kelsey E; Althoff, Robert R; Higgins, Stephen T; Cattrell, Anna; Flor, Herta; Nees, Frauke; Banaschewski, Tobias; Bokde, Arun L W; Whelan, Robert; Büchel, Christian; Bromberg, Uli; Conrod, Patricia; Frouin, Vincent; Papadopoulos, Dimitri; Gallinat, Jurgen; Heinz, Andreas; Walter, Henrik; Ittermann, Bernd; Gowland, Penny; Paus, Tomáš; Poustka, Luise; Martinot, Jean-Luc; Artiges, Eric; Smolka, Michael N; Schumann, Gunter; Garavan, Hugh

2015-12-01

Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n=70) of 14-year olds with a history of cannabis use to a group (n=70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood. Copyright © 2015. Published by Elsevier Ltd.

Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function.

Science.gov (United States)

Clemente, M G; De Virgiliis, S; Kang, J S; Macatagney, R; Musu, M P; Di Pierro, M R; Drago, S; Congia, M; Fasano, A

2003-02-01

Despite the progress made in understanding the immunological aspects of the pathogenesis of coeliac disease (CD), the early steps that allow gliadin to cross the intestinal barrier are still largely unknown. The aim of this study was to establish whether gliadin activates a zonulin dependent enterocyte intracellular signalling pathway(s) leading to increased intestinal permeability. The effect of gliadin on the enterocyte actin cytoskeleton was studied on rat intestinal epithelial (IEC-6) cell cultures by fluorescence microscopy and spectrofluorimetry. Zonulin concentration was measured on cell culture supernatants by enzyme linked immunosorbent assay. Transepithelial intestinal resistance (Rt) was measured on ex vivo intestinal tissues mounted in Ussing chambers. Incubation of cells with gliadin led to a reversible protein kinase C (PKC) mediated actin polymerisation temporarily coincident with zonulin release. A significant reduction in Rt was observed after gliadin addition on rabbit intestinal mucosa mounted in Ussing chambers. Pretreatment with the zonulin inhibitor FZI/0 abolished the gliadin induced actin polymerisation and Rt reduction but not zonulin release. Gliadin induces zonulin release in intestinal epithelial cells in vitro. Activation of the zonulin pathway by PKC mediated cytoskeleton reorganisation and tight junction opening leads to a rapid increase in intestinal permeability.

Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.

Science.gov (United States)

Kleiman, Laura B; Maiwald, Thomas; Conzelmann, Holger; Lauffenburger, Douglas A; Sorger, Peter K

2011-09-02

Epidermal growth factor receptors (ErbB1-4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100-1000 times in the course of a typical immediate-early response to ligand. Rapid phospho-turnover is also observed for EGF-activated ErbB2 and ErbB3, unrelated RTKs, and multiple intracellular adaptor proteins and signaling kinases. Thus, the complexes formed on the cytoplasmic tail of active receptors and the downstream signaling kinases they control are highly dynamic and antagonized by potent phosphatases. We develop a kinetic scheme for binding of anti-ErbB1 drugs to receptors and show that rapid phospho-turnover significantly impacts their mechanisms of action. Copyright © 2011 Elsevier Inc. All rights reserved.

Multiscale Signal Analysis and Modeling

CERN Document Server

Zayed, Ahmed

2013-01-01

Multiscale Signal Analysis and Modeling presents recent advances in multiscale analysis and modeling using wavelets and other systems. This book also presents applications in digital signal processing using sampling theory and techniques from various function spaces, filter design, feature extraction and classification, signal and image representation/transmission, coding, nonparametric statistical signal processing, and statistical learning theory. This book also: Discusses recently developed signal modeling techniques, such as the multiscale method for complex time series modeling, multiscale positive density estimations, Bayesian Shrinkage Strategies, and algorithms for data adaptive statistics Introduces new sampling algorithms for multidimensional signal processing Provides comprehensive coverage of wavelets with presentations on waveform design and modeling, wavelet analysis of ECG signals and wavelet filters Reviews features extraction and classification algorithms for multiscale signal and image proce...

TOR complex 2-Ypk1 signaling is an essential positive regulator of the general amino acid control response and autophagy.

Science.gov (United States)

Vlahakis, Ariadne; Graef, Martin; Nunnari, Jodi; Powers, Ted

2014-07-22

The highly conserved Target of Rapamycin (TOR) kinase is a central regulator of cell growth and metabolism in response to nutrient availability. TOR functions in two structurally and functionally distinct complexes, TOR Complex 1 (TORC1) and TOR Complex 2 (TORC2). Through TORC1, TOR negatively regulates autophagy, a conserved process that functions in quality control and cellular homeostasis and, in this capacity, is part of an adaptive nutrient deprivation response. Here we demonstrate that during amino acid starvation TOR also operates independently as a positive regulator of autophagy through the conserved TORC2 and its downstream target protein kinase, Ypk1. Under these conditions, TORC2-Ypk1 signaling negatively regulates the Ca(2+)/calmodulin-dependent phosphatase, calcineurin, to enable the activation of the amino acid-sensing eIF2α kinase, Gcn2, and to promote autophagy. Our work reveals that the TORC2 pathway regulates autophagy in an opposing manner to TORC1 to provide a tunable response to cellular metabolic status.

NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I*

Science.gov (United States)

Rhein, Virginie F.; Carroll, Joe; Ding, Shujing; Fearnley, Ian M.; Walker, John E.

2016-01-01

Complex I (NADH ubiquinone oxidoreductase) in mammalian mitochondria is an L-shaped assembly of 45 proteins. One arm lies in the inner membrane, and the other extends about 100 Å into the matrix of the organelle. The extrinsic arm contains binding sites for NADH, the primary electron acceptor FMN, and seven iron-sulfur clusters that form a pathway for electrons linking FMN to the terminal electron acceptor, ubiquinone, which is bound in a tunnel in the region of the junction between the arms. The membrane arm contains four antiporter-like domains, energetically coupled to the quinone site and involved in pumping protons from the matrix into the intermembrane space contributing to the proton motive force. Seven of the subunits, forming the core of the membrane arm, are translated from mitochondrial genes, and the remaining subunits, the products of nuclear genes, are imported from the cytosol. Their assembly is coordinated by at least thirteen extrinsic assembly factor proteins that are not part of the fully assembled complex. They assist in insertion of co-factors and in building up the complex from smaller sub-assemblies. One such factor, NDUFAF5, belongs to the family of seven-β-strand S-adenosylmethionine-dependent methyltransferases. However, similar to another family member, RdmB, it catalyzes the introduction of a hydroxyl group, in the case of NDUFAF5, into Arg-73 in the NDUFS7 subunit of human complex I. This modification occurs early in the pathway of assembly of complex I, before the formation of the juncture between peripheral and membrane arms. PMID:27226634

The influence of spectral and spatial characteristics of early reflections on speech intelligibility

DEFF Research Database (Denmark)

Arweiler, Iris; Buchholz, Jörg; Dau, Torsten

The auditory system employs different strategies to facilitate speech intelligibility in complex listening conditions. One of them is the integration of early reflections (ER’s) with the direct sound (DS) to increase the effective speech level. So far the underlying mechanisms of ER processing have...... of listeners that speech intelligibility improved with added ER energy, but less than with added DS energy. An efficiency factor was introduced to quantify this effect. The difference in speech intelligibility could be mainly ascribed to the differences in the spectrum between the speech signals....... binaural). The direction-dependency could be explained by the spectral changes introduced by the pinna, head, and torso. The results will be important with regard to the influence of signal processing strategies in modern hearing aids on speech intelligibility, because they might alter the spectral...

miRNA targeted signaling pathway in the early stage of denervated fast and slow muscle atrophy

Directory of Open Access Journals (Sweden)

Gang Li

2016-01-01

Full Text Available Denervation often results in skeletal muscle atrophy. Different mechanisms seem to be involved in the determination between denervated slow and fast skeletal muscle atrophy. At the epigenetic level, miRNAs are thought to be highly involved in the pathophysiological progress of denervated muscles. We used miRNA microarrays to determine miRNA expression profiles from a typical slow muscle (soleus muscle and a typical fast muscle (tibialis anterior muscle at an early denervation stage in a rat model. Results showed that miR-206, miR-195, miR-23a, and miR-30e might be key factors in the transformation process from slow to fast muscle in denervated slow muscles. Additionally, certain miRNA molecules (miR-214, miR-221, miR-222, miR-152, miR-320, and Let-7e could be key regulatory factors in the denervated atrophy process involved in fast muscle. Analysis of signaling pathway networks revealed the miRNA molecules that were responsible for regulating certain signaling pathways, which were the final targets (e.g., p38 MAPK pathway; Pax3/Pax7 regulates Utrophin and follistatin by HDAC4; IGF1/PI3K/Akt/mTOR pathway regulates atrogin-1 and MuRF1 expression via FoxO phosphorylation. Our results provide a better understanding of the mechanisms of denervated skeletal muscle pathophysiology.

Architecture and evolution of an Early Permian carbonate complex on a tectonically active island in east-central California

Science.gov (United States)

Stevens, Calvin H.; Magginetti, Robert T.; Stone, Paul

2015-01-01

The newly named Upland Valley Limestone represents a carbonate complex that developed on and adjacent to a tectonically active island in east-central California during a brief interval of Early Permian (late Artinskian) time. This lithologically unique, relatively thin limestone unit lies within a thick sequence of predominantly siliciclastic rocks and is characterized by its high concentration of crinoidal debris, pronounced lateral changes in thickness and lithofacies, and a largely endemic fusulinid fauna. Most outcrops represent a carbonate platform and debris derived from it and shed downslope, but another group of outcrops represents one or possibly more isolated carbonate buildups that developed offshore from the platform. Tectonic activity in the area occurred before, probably during, and after deposition of this short-lived carbonate complex.

Oversampling ad converters with improved signal transfer functions

CERN Document Server

Pandita, Bupesh

2011-01-01

This book describes techniques for designing complex, discrete-time I""IGBP ADCs with signal-transfer functions that significantly filter interfering signals. The book provides an understanding of theory, issues, and implementation of discrete complex I""IGBP ADCs. The concepts developed in each chapter are further explained by applying them to a target application of I""IGBP ADCs in DTV receivers.

Purinergic Signalling: Therapeutic Developments

Directory of Open Access Journals (Sweden)

Geoffrey Burnstock

2017-09-01

Full Text Available Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

Early presentation of primary glioblastoma.

Science.gov (United States)

Faguer, R; Tanguy, J-Y; Rousseau, A; Clavreul, A; Menei, P

2014-08-01

Clinical and neuroimaging findings of glioblastomas (GBM) at an early stage have rarely been described and those tumors are most probably under-diagnosed. Furthermore, their genetic alterations, to our knowledge, have never been previously reported. We report the clinical as well as neuroimaging findings of four early cases of patients with GBM. In our series, early stage GBM occurred at a mean age of 57 years. All patients had seizures as their first symptom. In all early stages, MRI showed a hyperintense signal on T2-weighted sequences and an enhancement on GdE-T1WI sequences. A hyperintense signal on diffusion sequences with a low ADC value was also found. These early observed occurrences of GBM developed rapidly and presented the MRI characteristics of classic GBM within a few weeks. The GBM size was multiplied by 32 in one month. Immunohistochemical analysis indicated the de novo nature of these tumors, i.e. absence of mutant IDH1 R132H protein expression, which is a diagnostic marker of low-grade diffuse glioma and secondary GBM. A better knowledge of early GBM presentation would allow a more suitable management of the patients and may improve their prognosis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Decreased SAP expression in T cells from patients with SLE contributes to early signaling abnormalities and reduced IL-2 production

Science.gov (United States)

Karampetsou, Maria P.; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C.; Tsokos, George C.

2016-01-01

T cells from patients with systemic lupus erythematosus (SLE) display a number of functions including increased early signaling events following engagement of the T cell receptor (TCR). Signaling lymphocytic activation molecule family (SLAMF) cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating immune response. Here we present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and 3 men with SLE independently of disease activity. In SLE T cells the SAP protein is also subject to increased degradation by a caspase-3. Forced expression of SAP in SLE T cells simultaneously heightened IL-2 production, calcium (Ca2+) responses and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR antibodies, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype. PMID:27183584

Reactive Oxygen Species-Mediated Loss of Synaptic Akt1 Signaling Leads to Deficient Activity-Dependent Protein Translation Early in Alzheimer's Disease.

Science.gov (United States)

Ahmad, Faraz; Singh, Kunal; Das, Debajyoti; Gowaikar, Ruturaj; Shaw, Eisha; Ramachandran, Arathy; Rupanagudi, Khader Valli; Kommaddi, Reddy Peera; Bennett, David A; Ravindranath, Vijayalakshmi

2017-12-01

Synaptic deficits are known to underlie the cognitive dysfunction seen in Alzheimer's disease (AD). Generation of reactive oxygen species (ROS) by β-amyloid has also been implicated in AD pathogenesis. However, it is unclear whether ROS contributes to synaptic dysfunction seen in AD pathogenesis and, therefore, we examined whether altered redox signaling could contribute to synaptic deficits in AD. Activity dependent but not basal translation was impaired in synaptoneurosomes from 1-month old presymptomatic APP Swe /PS1ΔE9 (APP/PS1) mice, and this deficit was sustained till middle age (MA, 9-10 months). ROS generation leads to oxidative modification of Akt1 in the synapse and consequent reduction in Akt1-mechanistic target of rapamycin (mTOR) signaling, leading to deficiency in activity-dependent protein translation. Moreover, we found a similar loss of activity-dependent protein translation in synaptoneurosomes from postmortem AD brains. Loss of activity-dependent protein translation occurs presymptomatically early in the pathogenesis of AD. This is caused by ROS-mediated loss of pAkt1, leading to reduced synaptic Akt1-mTOR signaling and is rescued by overexpression of Akt1. ROS-mediated damage is restricted to the synaptosomes, indicating selectivity. We demonstrate that ROS-mediated oxidative modification of Akt1 contributes to synaptic dysfunction in AD, seen as loss of activity-dependent protein translation that is essential for synaptic plasticity and maintenance. Therapeutic strategies promoting Akt1-mTOR signaling at synapses may provide novel target(s) for disease-modifying therapy in AD. Antioxid. Redox Signal. 27, 1269-1280.

Early warning signals of simulated Amazon dieback

OpenAIRE

Boulton, Chris; Good, Peter; Lenton, Tim

2013-01-01

Dieback of the Amazon rainforest has been considered a potential tipping point in the Earth system due to the belief that there is more than one stable attractor in its dynamics and for future projections within global climate models (GCMs), in some cases a huge amount of forest is lost abruptly. The rainforest is a huge carbon sink, playing a critical role in the global carbon cycle and so if dieback is going to happen over a short period of time, it is important to have some early warning t...

Multimodal signalling in estrildid finches

DEFF Research Database (Denmark)

Gomes, A. C. R.; Funghi, C.; Soma, M.

2017-01-01

Sexual traits (e.g. visual ornaments, acoustic signals, courtship behaviour) are often displayed together as multimodal signals. Some hypotheses predict joint evolution of different sexual signals (e.g. to increase the efficiency of communication) or that different signals trade off with each other...... (e.g. due to limited resources). Alternatively, multiple signals may evolve independently for different functions, or to communicate different information (multiple message hypothesis). We evaluated these hypotheses with a comparative study in the family Estrildidae, one of the largest songbird...... compromise, but generally courtship dance also evolved independently from other signals. Instead of correlated evolution, we found that song, dance and colour are each related to different socio-ecological traits. Song complexity evolved together with ecological generalism, song performance with investment...

Distinctive EPR signals provide an understanding of the affinity of bis-(3-hydroxy-4-pyridinonato) copper(II) complexes for hydrophobic environments.

Science.gov (United States)

Rangel, Maria; Leite, Andreia; Silva, André M N; Moniz, Tânia; Nunes, Ana; Amorim, M João; Queirós, Carla; Cunha-Silva, Luís; Gameiro, Paula; Burgess, John

2014-07-07

In this work we report the synthesis and characterization of a set of 3-hydroxy-4-pyridinone copper(ii) complexes with variable lipophilicity. EPR spectroscopy was used to characterize the structure of copper(ii) complexes in solution, and as a tool to gain insight into solvent interactions. EPR spectra of solutions of the [CuL2] complexes recorded in different solvents reveal the presence of two copper species whose ratio depends on the nature of the solvent. Investigation of EPR spectra in the pure solvents methanol, dimethylsulfoxide, dichloromethane and their 50% (v/v) mixtures with toluene allowed the characterization of two types of copper signals (gzz = 2.30 and gzz = 2.26) whose spin-Hamiltonian parameters are consistent with solvated and non-solvated square-planar copper(ii) complexes. Regarding the potential biological application of ligands and complexes and to get insight into the partition properties in water-membrane interfaces, EPR spectra were also obtained in water-saturated octanol, an aqueous solution buffered at pH = 7.4 and liposome suspensions, for three compounds representative of different hydro-lipophilic balances. Analysis of the EPR spectra obtained in liposomes allowed establishment of the location of the complexes in the water and lipid phases. In view of the results of this work we put forward the use of EPR spectroscopy to assess the affinity of copper(ii) complexes for a hydrophobic environment and also to obtain indirect information about the lipophilicity of the ligands and similar EPR silent complexes.

Identification of the QRS Complex in the ECG

Directory of Open Access Journals (Sweden)

Martin Paralič

2016-12-01

Full Text Available The cardiovascular heart diseases are one of the most common causes of leading to death of man. Unfortunately, the symptoms vary and the most common reason for critical delays in medical treatment is lack of early warning and patient unawareness. In this paper, we present a development of the mobile application for Electrocardiogram measurements based on communication with a smart clothing using Bluetooth. The objectives of the application are a wireless data collection and analysis of ECG signal. The analysis is aimed for precise detection of QRS complex parameters plus detection of P-wave and T-wave. Measurement and evaluation of multiple PQRST parameters in a series allows detection of anomalies which leads to different heart diseases. Early warning system can help to make preventive actions to avoid severe heart disease. The recorded data are exported to format of the MIT/BIH arrhythmia database to be compatible with the professional medical software. This program will be devoted to the purposes of research and home healthcare instead of clinical diagnosis.

Nonlinear signal processing for ultrasonic imaging of material complexity

Czech Academy of Sciences Publication Activity Database

Dos Santos, S.; Vejvodová, Šárka; Převorovský, Zdeněk

2010-01-01

Roč. 59, č. 2 (2010), s. 108-117 ISSN 1736-6046 Institutional research plan: CEZ:AV0Z20760514 Keywords : nonlinear signal processing * TR-NEWS * symmetry analysis * DORT Subject RIV: BI - Acoustics Impact factor: 0.464, year: 2010 www.eap.ee/proceedings

RF measurements I: signal receiving techniques

CERN Document Server

Caspers, F

2011-01-01

For the characterization of components, systems and signals in the RF and microwave range, several dedicated instruments are in use. In this paper the fundamentals of the RF-signal sampling technique, which has found widespread applications in 'digital' oscilloscopes and sampling scopes, are discussed. The key element in these front-ends is the Schottky diode which can be used either as an RF mixer or as a single sampler. The spectrum analyser has become an absolutely indispensable tool for RF signal analysis. Here the front-end is the RF mixer as the RF section of modern spectrum analysers has a rather complex architecture. The reasons for this complexity and certain working principles as well as limitations are discussed. In addition, an overview of the development of scalar and vector signal analysers is given. For the determination of the noise temperature of a one-port and the noise figure of a two-port, basic concepts and relations are shown. A brief discussion of commonly used noise measurement techniq...

NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I.

Science.gov (United States)

Rhein, Virginie F; Carroll, Joe; Ding, Shujing; Fearnley, Ian M; Walker, John E

2016-07-08

Complex I (NADH ubiquinone oxidoreductase) in mammalian mitochondria is an L-shaped assembly of 45 proteins. One arm lies in the inner membrane, and the other extends about 100 Å into the matrix of the organelle. The extrinsic arm contains binding sites for NADH, the primary electron acceptor FMN, and seven iron-sulfur clusters that form a pathway for electrons linking FMN to the terminal electron acceptor, ubiquinone, which is bound in a tunnel in the region of the junction between the arms. The membrane arm contains four antiporter-like domains, energetically coupled to the quinone site and involved in pumping protons from the matrix into the intermembrane space contributing to the proton motive force. Seven of the subunits, forming the core of the membrane arm, are translated from mitochondrial genes, and the remaining subunits, the products of nuclear genes, are imported from the cytosol. Their assembly is coordinated by at least thirteen extrinsic assembly factor proteins that are not part of the fully assembled complex. They assist in insertion of co-factors and in building up the complex from smaller sub-assemblies. One such factor, NDUFAF5, belongs to the family of seven-β-strand S-adenosylmethionine-dependent methyltransferases. However, similar to another family member, RdmB, it catalyzes the introduction of a hydroxyl group, in the case of NDUFAF5, into Arg-73 in the NDUFS7 subunit of human complex I. This modification occurs early in the pathway of assembly of complex I, before the formation of the juncture between peripheral and membrane arms. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Linear stability theory as an early warning sign for transitions in high dimensional complex systems

International Nuclear Information System (INIS)

Piovani, Duccio; Grujić, Jelena; Jensen, Henrik Jeldtoft

2016-01-01

We analyse in detail a new approach to the monitoring and forecasting of the onset of transitions in high dimensional complex systems by application to the Tangled Nature model of evolutionary ecology and high dimensional replicator systems with a stochastic element. A high dimensional stability matrix is derived in the mean field approximation to the stochastic dynamics. This allows us to determine the stability spectrum about the observed quasi-stable configurations. From overlap of the instantaneous configuration vector of the full stochastic system with the eigenvectors of the unstable directions of the deterministic mean field approximation, we are able to construct a good early-warning indicator of the transitions occurring intermittently. (paper)

Hsp27 regulates Akt activation and polymorphonuclear leukocyte apoptosis by scaffolding MK2 to Akt signal complex.

Science.gov (United States)

Wu, Rui; Kausar, Hina; Johnson, Paul; Montoya-Durango, Diego E; Merchant, Michael; Rane, Madhavi J

2007-07-27

We have shown previously that Akt exists in a signal complex with p38 MAPK, MAPK-activated protein kinase-2 (MK2), and heat shock protein 27 (Hsp27) and MK2 phosphorylates Akt on Ser-473. Additionally, dissociation of Hsp27 from Akt, prior to Akt activation, induced polymorphonuclear leukocyte (PMN) apoptosis. However, the role of Hsp27 in regulating Akt activation was not examined. This study tested the hypothesis that Hsp27 regulates Akt activation and promotes cell survival by scaffolding MK2 to the Akt signal complex. Here we show that loss of Akt/Hsp27 interaction by anti-Hsp27 antibody treatment resulted in loss of Akt/MK2 interaction, loss of Akt-Ser-473 phosphorylation, and induced PMN apoptosis. Transfection of myristoylated Akt (AktCA) in HK-11 cells induced Akt-Ser-473 phosphorylation, activation, and Hsp27-Ser-82 phosphorylation. Cotransfection of AktCA with Hsp27 short interfering RNA, but not scrambled short interfering RNA, silenced Hsp27 expression, without altering Akt expression in HK-11 cells. Silencing Hsp27 expression inhibited Akt/MK2 interaction, inhibited Akt phosphorylation and Akt activation, and induced HK-11 cell death. Deletion mutagenesis studies identified acidic linker region (amino acids 117-128) on Akt as an Hsp27 binding region. Deletion of amino acids 117-128 on Akt resulted in loss of its interaction with Hsp27 and MK2 but not with Hsp90 as demonstrated by immunoprecipitation and glutathione S-transferase pulldown studies. Co-transfection studies demonstrated that constitutively active MK2 (MK2EE) phosphorylated Aktwt (wild type) on Ser-473 but failed to phosphorylate Akt(Delta117-128) mutant in transfixed cells. These studies collectively define a novel role of Hsp27 in regulating Akt activation and cellular apoptosis by mediating interaction between Akt and its upstream activator MK2.

ZAP-70 and p72syk are signaling response elements through MHC class II molecules

DEFF Research Database (Denmark)

Kanner, S B; Grosmaire, L S; Blake, J

1995-01-01

Ligation of major histocompatibility complex (MHC) class II antigens expressed on antigen-activated human CD4+ T-lymphocytes induces early signal transduction events including the activation of tyrosine kinases, the tyrosine phosphorylation of phospholipase-C gamma 1 and the mobilization...... of intracellular calcium. Similar responses have been observed in B-cells following stimulation of MHC class II molecules, including the increased production of intracellular cAMP. In this report, we demonstrate that the ZAP-70 tyrosine kinase is a responsive signaling element following cross-linking of HLA...... by herbimycin A. MHC class II ligation on B-lymphocytes resulted in cell death, which was both qualitatively distinct from Fas-induced apoptosis and partially protected by herbimycin A pretreatment. Thus, ligation of MHC class II molecules expressed on human lymphocytes stimulates the ZAP-70/p72syk family...

The mantle source of island arc magmatism during early subduction: Evidence from Hf isotopes in rutile from the Jijal Complex (Kohistan arc, Pakistan)

Science.gov (United States)

Ewing, Tanya A.; Müntener, Othmar

2018-05-01

The Cretaceous-Paleogene Kohistan arc complex, northern Pakistan, is renowned as one of the most complete sections through a preserved paleo-island arc. The Jijal Complex represents a fragment of the plutonic roots of the Kohistan arc, formed during its early intraoceanic history. We present the first Hf isotope determinations for the Jijal Complex, made on rutile from garnet gabbros. These lithologies are zircon-free, but contain rutile that formed as an early phase. Recent developments in analytical capabilities coupled with a careful analytical and data reduction protocol allow the accurate determination of Hf isotope composition for rutile with <30 ppm Hf for the first time. Rutile from the analysed samples contains 5-35 ppm Hf, with sample averages of 13-17 ppm. Rutile from five samples from the Jijal Complex mafic section, sampling 2 km of former crustal thickness, gave indistinguishable Hf isotope compositions with εHf(i) ranging from 11.4 ± 3.2 to 20.1 ± 5.7. These values are within error of or only slightly more enriched than modern depleted mantle. The analysed samples record variable degrees of interaction with late-stage melt segregations, which produced symplectitic overprints on the main mineral assemblage as well as pegmatitic segregations of hydrous minerals. The indistinguishable εHf(i) across this range of lithologies demonstrates the robust preservation of the Hf isotope composition of rutile. The Hf isotope data, combined with previously published Nd isotope data for the Jijal Complex garnet gabbros, favour derivation from an inherently enriched, Indian Ocean type mantle. This implies a smaller contribution from subducted sediments than if the source was a normal (Pacific-type) depleted mantle. The Jijal Complex thus had only a limited recycled continental crustal component in its source, and represents a largely juvenile addition of new continental crust during the early phases of intraoceanic magmatism. The ability to determine the Hf

A multi-step method with signal quality assessment and fine-tuning procedure to locate maternal and fetal QRS complexes from abdominal ECG recordings

International Nuclear Information System (INIS)

Liu, Chengyu; Li, Peng; Zhao, Lina; Di Maria, Costanzo; Zhang, Henggui; Chen, Zhiqing

2014-01-01

Non-invasive monitoring of fetal electrocardiogram (fECG) plays an important role in detecting and diagnosing fetal diseases. This study aimed to develop a multi-step method for locating both maternal and fetal QRS complexes from abdominal ECG (aECG) recordings. The proposed method included four major steps: abdominal ECG pre-processing, maternal QRS complex locating, maternal ECG cancellation and fetal QRS complex locating. Signal quality assessment (SQA) and fine-tuning for maternal ECG (FTM) were implemented in the first and third steps, respectively. The method was then evaluated using 75 non-invasive 4-channel aECG recordings provided by the PhysioNet/Computing in Cardiology Challenge 2013. The F 1 measure, which is a new index introduced by Behar et al (2013 Proc. Comput. Cardiol. 40 297–300), was used to assess the locating accuracy. The other two indices, mean squared error of heart rate (MSE H R) between the fetal HR signals estimated from the reference and our method (MSE H R in bpm 2 ) and root mean squared difference between the corresponding fetal RR intervals (MSE R R in ms) were also used to assess the locating accuracy. Overall, for the maternal QRS complex, the F 1 measure was 98.4% from the method without the implementation of SQA, and it was improved to 99.8% with SQA. For the fetal QRS complex, the F 1 measure, MSE H R and MSE R R were 84.9%, 185.6 bpm 2 and 19.4 ms for the method without both SQA and FTM procedures. They were improved to 93.9%, 47.5 bpm 2 and 7.6 ms with both SQA and FTM procedures. These improvements were observed from each individual subject. It can be concluded that implementing both SQA and FTM procedures could achieve better performance for locating both maternal and fetal QRS complexes. (paper)

Epoch-based Entropy for Early Screening of Alzheimer's Disease.

Science.gov (United States)

Houmani, N; Dreyfus, G; Vialatte, F B

2015-12-01

In this paper, we introduce a novel entropy measure, termed epoch-based entropy. This measure quantifies disorder of EEG signals both at the time level and spatial level, using local density estimation by a Hidden Markov Model on inter-channel stationary epochs. The investigation is led on a multi-centric EEG database recorded from patients at an early stage of Alzheimer's disease (AD) and age-matched healthy subjects. We investigate the classification performances of this method, its robustness to noise, and its sensitivity to sampling frequency and to variations of hyperparameters. The measure is compared to two alternative complexity measures, Shannon's entropy and correlation dimension. The classification accuracies for the discrimination of AD patients from healthy subjects were estimated using a linear classifier designed on a development dataset, and subsequently tested on an independent test set. Epoch-based entropy reached a classification accuracy of 83% on the test dataset (specificity = 83.3%, sensitivity = 82.3%), outperforming the two other complexity measures. Furthermore, it was shown to be more stable to hyperparameter variations, and less sensitive to noise and sampling frequency disturbances than the other two complexity measures.

Extracellular matrix component signaling in cancer

DEFF Research Database (Denmark)

Multhaupt, Hinke A. B.; Leitinger, Birgit; Gullberg, Donald

2016-01-01

Cell responses to the extracellular matrix depend on specific signaling events. These are important from early development, through differentiation and tissue homeostasis, immune surveillance, and disease pathogenesis. Signaling not only regulates cell adhesion cytoskeletal organization and motil...... as well as matrix constitution and protein crosslinking. Here we summarize roles of the three major matrix receptor types, with emphasis on how they function in tumor progression. [on SciFinder(R)]...

Post-transcriptional regulation of ethylene perception and signaling in Arabidopsis

Energy Technology Data Exchange (ETDEWEB)

Schaller, George Eric [Dartmouth College, Hanover, NH (United States)

2014-03-19

The simple gas ethylene functions as an endogenous regulator of plant growth and development, and modulates such energy relevant processes as photosynthesis and biomass accumulation. Ethylene is perceived in the plant Arabidopsis by a five-member family of receptors related to bacterial histidine kinases. Our data support a general model in which the receptors exist as parts of larger protein complexes. Our goals have been to (1) characterize physical interactions among members of the signaling complex; (2) the role of histidine-kinase transphosphorylation in signaling by the complex; and (3) the role of a novel family of proteins that regulate signal output by the receptors.

Peroxiredoxin-controlled G-CSF signalling at the endoplasmic reticulum-early endosome interface

NARCIS (Netherlands)

K.K. Palande (Karishma); O. Roovers (Onno); J. Gits (Judith); C. Verwijmeren (Carola); Y. Iuchi (Yoshihito); J. Fujii (Junichi); B. Neel; R. Karisch (Robert); J. Tavernier; I.P. Touw (Ivo)

2011-01-01

textabstractReactive oxygen species (ROS) regulate growth factor receptor signalling at least in part by inhibiting oxidation-sensitive phosphatases. An emerging concept is that ROS act locally to affect signal transduction in different subcellular compartments and that ROS levels are regulated by

The role of an early-life variant of the oedipus complex in motivating religious endeavors.

Science.gov (United States)

Osman, Marvin P

2004-01-01

A close reading of sources Freud used in writing Totem and Taboo supports the thesis that a predecessor archaic oedipus complex is instrumental in motivating religious worship. This early-life complex manifests a psychodynamic in which birth, growth, and self-realization, to varying degree in each individual, tend to be psychically correlated with diminution and harm vis-à-vis one's procreators. As a result, the psychodynamic is likely to induce unease over youth exercising its powers. The story of Adam and Eve, which depicts a growing self-determination being stymied and coming to grief, is a mythic epitome of this psychodynamic. Religious practices serve to expiate the sense of unease, partly by replenishing and even recasting seemingly diminished procreators, through myth and ritual, into omnipotent, immortal entities, and partly by reversing individuation's challenge to authority by exhorting submission to, and even union, with the divine parent. The sources used in demonstrating the various means whereby religious practices serve to ameliorate the burden of "original sin" include W. R. Smith (1894), the Old Testament, and studies of archaic religious rites, including those of the Aztecs.

No evidence for activated autophagy in left ventricular myocardium at early reperfusion with protection by remote ischemic preconditioning in patients undergoing coronary artery bypass grafting.

Directory of Open Access Journals (Sweden)

Nilgün Gedik

Full Text Available Remote ischemic preconditioning (RIPC by repeated brief limb ischemia/reperfusion reduces myocardial injury in patients undergoing coronary artery bypass grafting (CABG. Activation of signal transducer and activator of transcription 5 (STAT5 in left ventricular (LV myocardium at early reperfusion is associated with such protection. Autophagy, i.e., removal of dysfunctional cellular components through lysosomes, has been proposed as one mechanism of cardioprotection. Therefore, we analyzed whether or not the protection by RIPC is associated with activated autophagy.CABG patients were randomized to undergo RIPC (3×5 min blood pressure cuff inflation/5 min deflation or placebo (cuff deflated before skin incision (n = 10/10. Transmural myocardial biopsies were taken from the LV before cardioplegia (baseline and at early (5-10 min reperfusion. RIPC-induced protection was reflected by decreased serum troponin I concentration area under the curve (194±17 versus 709±129 ng/ml × 72 h, p = 0.002. Western blotting for beclin-1-phosphorylation and protein expression of autophagy-related gene 5-12 (ATG5-12 complex, light chain 3 (LC3, parkin, and p62 was performed. STAT3-, STAT5- and extracellular signal-regulated protein kinase 1/2 (ERK1/2-phosphorylation was used as positive control to confirm signal activation by ischemia/reperfusion.Signals of all analyzed autophagy proteins did not differ between baseline and early reperfusion and not between RIPC and placebo. STAT5-phosphorylation was greater at early reperfusion only with RIPC (2.2-fold, p = 0.02. STAT3- and ERK1/2-phosphorylation were greater at early reperfusion with placebo and RIPC (≥2.7-fold versus baseline, p≤0.05.Protection through RIPC in patients undergoing CABG surgery does not appear to be associated with enhanced autophagy in LV myocardium at early reperfusion.

Morphological and ecological complexity in early eukaryotic ecosystems.

Science.gov (United States)

Javaux, E J; Knoll, A H; Walter, M R

2001-07-05

Molecular phylogeny and biogeochemistry indicate that eukaryotes differentiated early in Earth history. Sequence comparisons of small-subunit ribosomal RNA genes suggest a deep evolutionary divergence of Eukarya and Archaea; C27-C29 steranes (derived from sterols synthesized by eukaryotes) and strong depletion of 13C (a biogeochemical signature of methanogenic Archaea) in 2,700 Myr old kerogens independently place a minimum age on this split. Steranes, large spheroidal microfossils, and rare macrofossils of possible eukaryotic origin occur in Palaeoproterozoic rocks. Until now, however, evidence for morphological and taxonomic diversification within the domain has generally been restricted to very late Mesoproterozoic and Neoproterozoic successions. Here we show that the cytoskeletal and ecological prerequisites for eukaryotic diversification were already established in eukaryotic microorganisms fossilized nearly 1,500 Myr ago in shales of the early Mesoproterozoic Roper Group in northern Australia.

The E3 ubiquitin ligase protein associated with Myc (Pam) regulates mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling in vivo through N- and C-terminal domains.

Science.gov (United States)

Han, Sangyeul; Kim, Sun; Bahl, Samira; Li, Lin; Burande, Clara F; Smith, Nicole; James, Marianne; Beauchamp, Roberta L; Bhide, Pradeep; DiAntonio, Aaron; Ramesh, Vijaya

2012-08-31

Pam and its homologs (the PHR protein family) are large E3 ubiquitin ligases that function to regulate synapse formation and growth in mammals, zebrafish, Drosophila, and Caenorhabditis elegans. Phr1-deficient mouse models (Phr1(Δ8,9) and Phr1(Magellan), with deletions in the N-terminal putative guanine exchange factor region and the C-terminal ubiquitin ligase region, respectively) exhibit axon guidance/outgrowth defects and striking defects of major axon tracts in the CNS. Our earlier studies identified Pam to be associated with tuberous sclerosis complex (TSC) proteins, ubiquitinating TSC2 and regulating mammalian/mechanistic target of rapamycin (mTOR) signaling. Here, we examine the potential involvement of the TSC/mTOR complex 1(mTORC1) signaling pathway in Phr1-deficient mouse models. We observed attenuation of mTORC1 signaling in the brains of both Phr1(Δ8,9) and Phr1(Magellan) mouse models. Our results establish that Pam regulates TSC/mTOR signaling in vitro and in vivo through two distinct domains. To further address whether Pam regulates mTORC1 through two functionally independent domains, we undertook heterozygous mutant crossing between Phr1(Δ8,9) and Phr1(Magellan) mice to generate a compound heterozygous model to determine whether these two domains can complement each other. mTORC1 signaling was not attenuated in the brains of double mutants (Phr1(Δ8,9/Mag)), confirming that Pam displays dual regulation of the mTORC1 pathway through two functional domains. Our results also suggest that although dysregulation of mTORC1 signaling may be responsible for the corpus callosum defects, other neurodevelopmental defects observed with Phr1 deficiency are independent of mTORC1 signaling. The ubiquitin ligase complex containing Pam-Fbxo45 likely targets additional synaptic and axonal proteins, which may explain the overlapping neurodevelopmental defects observed in Phr1 and Fbxo45 deficiency.

Wnt signaling: Ig-norrin the dogma.

Science.gov (United States)

Clevers, Hans

2004-06-08

Secreted Wnt proteins trigger the intracellular Wnt signaling cascade upon engagement of dedicated Frizzled-Lrp receptor complexes. Unexpectedly, a non-Wnt ligand for this receptor complex has now been discovered. This novel ligand, Norrin, is mutated in the hereditary ocular Norrie syndrome. Copyright 2004 Elsevier Ltd.

High-speed optical signal processing using time lenses

DEFF Research Database (Denmark)

Galili, Michael; Hu, Hao; Guan, Pengyu

2015-01-01

This paper will discuss time lenses and their broad range of applications. A number of recent demonstrations of complex high-speed optical signal processing using time lenses will be outlined with focus on the operating principle.......This paper will discuss time lenses and their broad range of applications. A number of recent demonstrations of complex high-speed optical signal processing using time lenses will be outlined with focus on the operating principle....

Neural Correlates of Temporal Complexity and Synchrony during Audiovisual Correspondence Detection.

Science.gov (United States)

Baumann, Oliver; Vromen, Joyce M G; Cheung, Allen; McFadyen, Jessica; Ren, Yudan; Guo, Christine C

2018-01-01

We often perceive real-life objects as multisensory cues through space and time. A key challenge for audiovisual integration is to match neural signals that not only originate from different sensory modalities but also that typically reach the observer at slightly different times. In humans, complex, unpredictable audiovisual streams lead to higher levels of perceptual coherence than predictable, rhythmic streams. In addition, perceptual coherence for complex signals seems less affected by increased asynchrony between visual and auditory modalities than for simple signals. Here, we used functional magnetic resonance imaging to determine the human neural correlates of audiovisual signals with different levels of temporal complexity and synchrony. Our study demonstrated that greater perceptual asynchrony and lower signal complexity impaired performance in an audiovisual coherence-matching task. Differences in asynchrony and complexity were also underpinned by a partially different set of brain regions. In particular, our results suggest that, while regions in the dorsolateral prefrontal cortex (DLPFC) were modulated by differences in memory load due to stimulus asynchrony, areas traditionally thought to be involved in speech production and recognition, such as the inferior frontal and superior temporal cortex, were modulated by the temporal complexity of the audiovisual signals. Our results, therefore, indicate specific processing roles for different subregions of the fronto-temporal cortex during audiovisual coherence detection.

The Human Nuclear Exosome Targeting Complex Is Loaded onto Newly Synthesized RNA to Direct Early Ribonucleolysis

Directory of Open Access Journals (Sweden)

Michal Lubas

2015-01-01

Full Text Available The RNA exosome complex constitutes the major nuclear eukaryotic 3′-5′ exonuclease. Outside of nucleoli, the human nucleoplasmic exosome is directed to some of its substrates by the nuclear exosome targeting (NEXT complex. How NEXT targets RNA has remained elusive. Using an in vivo crosslinking approach, we report global RNA binding sites of RBM7, a key component of NEXT. RBM7 associates broadly with RNA polymerase II-derived RNA, including pre-mRNA and short-lived exosome substrates such as promoter upstream transcripts (PROMPTs, enhancer RNAs (eRNAs, and 3′-extended products from snRNA and replication-dependent histone genes. Within pre-mRNA, RBM7 accumulates at the 3′ ends of introns, and pulse-labeling experiments demonstrate that RBM7/NEXT defines an early exosome-targeting pathway for 3′-extended snoRNAs derived from such introns. We propose that RBM7 is generally loaded onto newly synthesized RNA to accommodate exosome action in case of available unprotected RNA 3′ ends.

Suppressed neural complexity during ketamine- and propofol-induced unconsciousness.

Science.gov (United States)

Wang, Jisung; Noh, Gyu-Jeong; Choi, Byung-Moon; Ku, Seung-Woo; Joo, Pangyu; Jung, Woo-Sung; Kim, Seunghwan; Lee, Heonsoo

2017-07-13

Ketamine and propofol have distinctively different molecular mechanisms of action and neurophysiological features, although both induce loss of consciousness. Therefore, identifying a common feature of ketamine- and propofol-induced unconsciousness would provide insight into the underlying mechanism of losing consciousness. In this study we search for a common feature by applying the concept of type-II complexity, and argue that neural complexity is essential for a brain to maintain consciousness. To test this hypothesis, we show that complexity is suppressed during loss of consciousness induced by ketamine or propofol. We analyzed the randomness (type-I complexity) and complexity (type-II complexity) of electroencephalogram (EEG) signals before and after bolus injection of ketamine or propofol. For the analysis, we use Mean Information Gain (MIG) and Fluctuation Complexity (FC), which are information-theory-based measures that quantify disorder and complexity of dynamics respectively. Both ketamine and propofol reduced the complexity of the EEG signal, but ketamine increased the randomness of the signal and propofol decreased it. The finding supports our claim and suggests EEG complexity as a candidate for a consciousness indicator. Copyright © 2017 Elsevier B.V. All rights reserved.

ECR-MAPK regulation in liver early development.

Science.gov (United States)

Zhao, Xiu-Ju; Zhuo, Hexian

2014-01-01

Early growth is connected to a key link between embryonic development and aging. In this paper, liver gene expression profiles were assayed at postnatal day 22 and week 16 of age. Meanwhile another independent animal experiment and cell culture were carried out for validation. Significance analysis of microarrays, qPCR verification, drug induction/inhibition assays, and metabonomics indicated that alpha-2u globulin (extracellular region)-socs2 (-SH2-containing signals/receptor tyrosine kinases)-ppp2r2a/pik3c3 (MAPK signaling)-hsd3b5/cav2 (metabolism/organization) plays a vital role in early development. Taken together, early development of male rats is ECR and MAPK-mediated coordination of cancer-like growth and negative regulations. Our data represent the first comprehensive description of early individual development, which could be a valuable basis for understanding the functioning of the gene interaction network of infant development.

Spatial Navigation in Complex and Radial Mazes in APP23 Animals and Neurotrophin Signaling as a Biological Marker of Early Impairment

Science.gov (United States)

Hellweg, Rainer; Huber, Roman; Kuhl, Alexander; Riepe, Matthias W.; Lohmann, Peter

2006-01-01

Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease(AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse…

Measuring Early Communication in Spanish Speaking Children: The Communication Complexity Scale in Peru.

Science.gov (United States)

Atwood, Erin; Brady, Nancy C; Esplund, Amy

There is a great need in the United States to develop presymbolic evaluation tools that are widely available and accurate for individuals that come from a bilingual and/or multicultural setting. The Communication Complexity Scale (CCS) is a measure that evaluates expressive presymbolic communication including gestures, vocalizations and eye gaze. Studying the effectiveness of this tool in a Spanish speaking environment was undertaken to determine the applicability of the CCS with Spanish speaking children. Methods & Procedures: In 2011-2012, researchers from the University of Kansas and Centro Ann Sullivan del Perú (CASP) investigated communication in a cohort of 71 young Spanish speaking children with developmental disabilities and a documented history of self-injurious, stereotyped and aggressive behaviors. Communication was assessed first by parental report with translated versions of the Communication and Symbolic Behavior Scales (CSBS), a well-known assessment of early communication, and then eleven months later with the CCS. We hypothesized that the CCS and the CSBS measures would be significantly correlated in this population of Spanish speaking children. The CSBS scores from time 1 with a mean participant age of 41 months were determined to have a strong positive relationship to the CCS scores obtained at time 2 with a mean participant age of 52 months. The CCS is strongly correlated to a widely accepted measure of early communication. These findings support the validity of the Spanish version of the CCS and demonstrate its usefulness for children from another culture and for children in a Spanish speaking environment.

Earthquake early warning system using real-time signal processing

Energy Technology Data Exchange (ETDEWEB)

Leach, R.R. Jr.; Dowla, F.U.

1996-02-01

An earthquake warning system has been developed to provide a time series profile from which vital parameters such as the time until strong shaking begins, the intensity of the shaking, and the duration of the shaking, can be derived. Interaction of different types of ground motion and changes in the elastic properties of geological media throughout the propagation path result in a highly nonlinear function. We use neural networks to model these nonlinearities and develop learning techniques for the analysis of temporal precursors occurring in the emerging earthquake seismic signal. The warning system is designed to analyze the first-arrival from the three components of an earthquake signal and instantaneously provide a profile of impending ground motion, in as little as 0.3 sec after first ground motion is felt at the sensors. For each new data sample, at a rate of 25 samples per second, the complete profile of the earthquake is updated. The profile consists of a magnitude-related estimate as well as an estimate of the envelope of the complete earthquake signal. The envelope provides estimates of damage parameters, such as time until peak ground acceleration (PGA) and duration. The neural network based system is trained using seismogram data from more than 400 earthquakes recorded in southern California. The system has been implemented in hardware using silicon accelerometers and a standard microprocessor. The proposed warning units can be used for site-specific applications, distributed networks, or to enhance existing distributed networks. By producing accurate, and informative warnings, the system has the potential to significantly minimize the hazards of catastrophic ground motion. Detailed system design and performance issues, including error measurement in a simple warning scenario are discussed in detail.

Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.

Science.gov (United States)

Braun, Daniela A; Rao, Jia; Mollet, Geraldine; Schapiro, David; Daugeron, Marie-Claire; Tan, Weizhen; Gribouval, Olivier; Boyer, Olivia; Revy, Patrick; Jobst-Schwan, Tilman; Schmidt, Johanna Magdalena; Lawson, Jennifer A; Schanze, Denny; Ashraf, Shazia; Ullmann, Jeremy F P; Hoogstraten, Charlotte A; Boddaert, Nathalie; Collinet, Bruno; Martin, Gaëlle; Liger, Dominique; Lovric, Svjetlana; Furlano, Monica; Guerrera, I Chiara; Sanchez-Ferras, Oraly; Hu, Jennifer F; Boschat, Anne-Claire; Sanquer, Sylvia; Menten, Björn; Vergult, Sarah; De Rocker, Nina; Airik, Merlin; Hermle, Tobias; Shril, Shirlee; Widmeier, Eugen; Gee, Heon Yung; Choi, Won-Il; Sadowski, Carolin E; Pabst, Werner L; Warejko, Jillian K; Daga, Ankana; Basta, Tamara; Matejas, Verena; Scharmann, Karin; Kienast, Sandra D; Behnam, Babak; Beeson, Brendan; Begtrup, Amber; Bruce, Malcolm; Ch'ng, Gaik-Siew; Lin, Shuan-Pei; Chang, Jui-Hsing; Chen, Chao-Huei; Cho, Megan T; Gaffney, Patrick M; Gipson, Patrick E; Hsu, Chyong-Hsin; Kari, Jameela A; Ke, Yu-Yuan; Kiraly-Borri, Cathy; Lai, Wai-Ming; Lemyre, Emmanuelle; Littlejohn, Rebecca Okashah; Masri, Amira; Moghtaderi, Mastaneh; Nakamura, Kazuyuki; Ozaltin, Fatih; Praet, Marleen; Prasad, Chitra; Prytula, Agnieszka; Roeder, Elizabeth R; Rump, Patrick; Schnur, Rhonda E; Shiihara, Takashi; Sinha, Manish D; Soliman, Neveen A; Soulami, Kenza; Sweetser, David A; Tsai, Wen-Hui; Tsai, Jeng-Daw; Topaloglu, Rezan; Vester, Udo; Viskochil, David H; Vatanavicharn, Nithiwat; Waxler, Jessica L; Wierenga, Klaas J; Wolf, Matthias T F; Wong, Sik-Nin; Leidel, Sebastian A; Truglio, Gessica; Dedon, Peter C; Poduri, Annapurna; Mane, Shrikant; Lifton, Richard P; Bouchard, Maxime; Kannu, Peter; Chitayat, David; Magen, Daniella; Callewaert, Bert; van Tilbeurgh, Herman; Zenker, Martin; Antignac, Corinne; Hildebrandt, Friedhelm

2017-10-01

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

Can complexity decrease in congestive heart failure?

Science.gov (United States)

Mukherjee, Sayan; Palit, Sanjay Kumar; Banerjee, Santo; Ariffin, M. R. K.; Rondoni, Lamberto; Bhattacharya, D. K.

2015-12-01

The complexity of a signal can be measured by the Recurrence period density entropy (RPDE) from the reconstructed phase space. We have chosen a window based RPDE method for the classification of signals, as RPDE is an average entropic measure of the whole phase space. We have observed the changes in the complexity in cardiac signals of normal healthy person (NHP) and congestive heart failure patients (CHFP). The results show that the cardiac dynamics of a healthy subject is more complex and random compare to the same for a heart failure patient, whose dynamics is more deterministic. We have constructed a general threshold to distinguish the border line between a healthy and a congestive heart failure dynamics. The results may be useful for wide range for physiological and biomedical analysis.

Rictor positively regulates B cell receptor signaling by modulating actin reorganization via ezrin.

Directory of Open Access Journals (Sweden)

Lu Huang

2017-08-01

Full Text Available As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2 has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO mice to investigate how Rictor regulates BCR signaling. We found that the key positive and negative BCR signaling molecules, phosphorylated Brutons tyrosine kinase (pBtk and phosphorylated SH2-containing inositol phosphatase (pSHIP, are reduced and enhanced, respectively, in Rictor KO B cells. This suggests that Rictor positively regulates the early events of BCR signaling. We found that the cellular filamentous actin (F-actin is drastically increased in Rictor KO B cells after BCR stimulation through dysregulating the dephosphorylation of ezrin. The high actin-ezrin intensity area restricts the lateral movement of BCRs upon stimulation, consequently reducing BCR clustering and BCR signaling. The reduction in the initiation of BCR signaling caused by actin alteration is associated with a decreased humoral immune response in Rictor KO mice. The inhibition of actin polymerization with latrunculin in Rictor KO B cells rescues the defects of BCR signaling and B cell differentiation. Overall, our study provides a new pathway linking cell metablism to BCR activation, in which Rictor regulates BCR signaling via actin reorganization.

Photoacoustic signal amplification through plasmonic nanoparticle aggregation

OpenAIRE

Bayer, Carolyn L.; Nam, Seung Yun; Chen, Yun-Sheng; Emelianov, Stanislav Y.

2013-01-01

Photoacoustic imaging, using targeted plasmonic metallic nanoparticles, is a promising noninvasive molecular imaging method. Analysis of the photoacoustic signal generated by plasmonic metallic nanoparticles is complex because of the dependence upon physical properties of both the nanoparticle and the surrounding environment. We studied the effect of the aggregation of gold nanoparticles on the photoacoustic signal amplitude. We found that the photoacoustic signal from aggregated silica-coate...

Rare genomic variants link bipolar disorder to CREB regulated intracellular signaling pathways

Directory of Open Access Journals (Sweden)

Berit eKerner

2013-11-01

Full Text Available Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood stabilizing drugs, such as tricyclic antidepressants, lithium and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.

The Pseudo signal peptide of the corticotropin-releasing factor receptor type 2A prevents receptor oligomerization.

Science.gov (United States)

Teichmann, Anke; Rutz, Claudia; Kreuchwig, Annika; Krause, Gerd; Wiesner, Burkhard; Schülein, Ralf

2012-08-03

N-terminal signal peptides mediate the interaction of native proteins with the translocon complex of the endoplasmic reticulum membrane and are cleaved off during early protein biogenesis. The corticotropin-releasing factor receptor type 2a (CRF(2(a))R) possesses an N-terminal pseudo signal peptide, which represents a so far unique domain within the large protein family of G protein-coupled receptors (GPCRs). In contrast to a conventional signal peptide, the pseudo signal peptide remains uncleaved and consequently forms a hydrophobic extension at the N terminus of the receptor. The functional consequence of the presence of the pseudo signal peptide is not understood. Here, we have analyzed the significance of this domain for receptor dimerization/oligomerization in detail. To this end, we took the CRF(2(a))R and the homologous corticotropin-releasing factor receptor type 1 (CRF(1)R) possessing a conventional cleaved signal peptide and conducted signal peptide exchange experiments. Using single cell and single molecule imaging methods (fluorescence resonance energy transfer and fluorescence cross-correlation spectroscopy, respectively) as well as biochemical experiments, we obtained two novel findings; we could show that (i) the CRF(2(a))R is expressed exclusively as a monomer, and (ii) the presence of the pseudo signal peptide prevents its oligomerization. Thus, we have identified a novel functional domain within the GPCR protein family, which plays a role in receptor oligomerization and which may be useful to study the functional significance of this process in general.

Investigation of new vehicle detectors for high-speed signalized intersections.

Science.gov (United States)

2015-09-01

Early indications from the use of the newest vehicle detectors for high-speed signalized intersections : suggested that they perform well as replacements for the Texas Department of Transportations : (TxDOTs) legacy systems, but this early conc...

Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer

Energy Technology Data Exchange (ETDEWEB)

Khin, Sann Sanda [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Pathology Research Unit, Department of Medical Research (Central Myanmar), Naypyitaw, Union of (Myanmar); Kitazawa, Riko [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Ehime University Graduate School of Medicine, Toon 791-0295, Ehime (Japan); Kondo, Takeshi; Idei, Yuka; Fujimoto, Masayo [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Haraguchi, Ryuma [Ehime University Graduate School of Medicine, Toon 791-0295, Ehime (Japan); Mori, Kiyoshi [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Kitazawa, Sohei, E-mail: kitazawa@m.ehime-u.ac.jp [Kobe University Graduate School of Medicine, Division of Diagnostic Molecular Pathology, Kobe 650-0017 (Japan); Ehime University Graduate School of Medicine, Toon 791-0295, Ehime (Japan)

2011-03-03

Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression.

Epigenetic Alteration by DNA Promoter Hypermethylation of Genes Related to Transforming Growth Factor-β (TGF-β) Signaling in Cancer

International Nuclear Information System (INIS)

Khin, Sann Sanda; Kitazawa, Riko; Kondo, Takeshi; Idei, Yuka; Fujimoto, Masayo; Haraguchi, Ryuma; Mori, Kiyoshi; Kitazawa, Sohei

2011-01-01

Epigenetic alterations in cancer, especially DNA methylation and histone modification, exert a significant effect on the deregulated expression of cancer-related genes and lay an epigenetic pathway to carcinogenesis and tumor progression. Global hypomethylation and local hypermethylation of CpG islands in the promoter region, which result in silencing tumor suppressor genes, constitute general and major epigenetic modification, the hallmark of the neoplastic epigenome. Additionally, methylation-induced gene silencing commonly affects a number of genes and increases with cancer progression. Indeed, cancers with a high degree of methylation (CpG island methylator phenotype/CIMP) do exist and represent a distinct subset of certain cancers including colorectal, bladder and kidney. On the other hand, signals from the microenvironment, especially those from transforming growth factor-β (TGF-β), induce targeted de novo epigenetic alterations of cancer-related genes. While TGF-β signaling has been implicated in two opposite roles in cancer, namely tumor suppression and tumor promotion, its deregulation is also partly induced by epigenetic alteration itself. Although the epigenetic pathway to carcinogenesis and cancer progression has such reciprocal complexity, the important issue is to identify genes or signaling pathways that are commonly silenced in various cancers in order to find early diagnostic and therapeutic targets. In this review, we focus on the epigenetic alteration by DNA methylation and its role in molecular modulations of the TGF-β signaling pathway that cause or underlie altered cancer-related gene expression in both phases of early carcinogenesis and late cancer progression

Multiclausal Utterances Aren't Just for Big Kids: A Framework for Analysis of Complex Syntax Production in Spoken Language of Preschool- and Early School-Age Children

Science.gov (United States)

Arndt, Karen Barako; Schuele, C. Melanie

2013-01-01

Complex syntax production emerges shortly after the emergence of two-word combinations in oral language and continues to develop through the school-age years. This article defines a framework for the analysis of complex syntax in the spontaneous language of preschool- and early school-age children. The purpose of this article is to provide…

Direct modulation and detection link using polybinary signaling

DEFF Research Database (Denmark)

Suhr, L.F.; Vegas Olmos, Juan José; Peucheret, Christophe

2014-01-01

This paper presents experimental results on a spectral efficient optical fiber link by using a novel seven-level polybinary signaling at 14.32 Gbps achieving a potential 7.95 b/s/Hz with very little complexity and processing footprint.......This paper presents experimental results on a spectral efficient optical fiber link by using a novel seven-level polybinary signaling at 14.32 Gbps achieving a potential 7.95 b/s/Hz with very little complexity and processing footprint....

Clustering of transcriptional profiles identifies changes to insulin signaling as an early event in a mouse model of Alzheimer's disease.

Science.gov (United States)

Jackson, Harriet M; Soto, Ileana; Graham, Leah C; Carter, Gregory W; Howell, Gareth R

2013-11-25

Alzheimer's disease affects more than 35 million people worldwide but there is no known cure. Age is the strongest risk factor for Alzheimer's disease but it is not clear how age-related changes impact the disease. Here, we used a mouse model of Alzheimer's disease to identify age-specific changes that occur prior to and at the onset of traditional Alzheimer-related phenotypes including amyloid plaque formation. To identify these early events we used transcriptional profiling of mouse brains combined with computational approaches including singular value decomposition and hierarchical clustering. Our study identifies three key events in early stages of Alzheimer's disease. First, the most important drivers of Alzheimer's disease onset in these mice are age-specific changes. These include perturbations of the ribosome and oxidative phosphorylation pathways. Second, the earliest detectable disease-specific changes occur to genes commonly associated with the hypothalamic-adrenal-pituitary (HPA) axis. These include the down-regulation of genes relating to metabolism, depression and appetite. Finally, insulin signaling, in particular the down-regulation of the insulin receptor substrate 4 (Irs4) gene, may be an important event in the transition from age-related changes to Alzheimer's disease specific-changes. A combination of transcriptional profiling combined with computational analyses has uncovered novel features relevant to Alzheimer's disease in a widely used mouse model and offers avenues for further exploration into early stages of AD.

Association of CD147 and Calcium Exporter PMCA4 Uncouples IL-2 Expression from Early TCR Signaling.

Science.gov (United States)

Supper, Verena; Schiller, Herbert B; Paster, Wolfgang; Forster, Florian; Boulègue, Cyril; Mitulovic, Goran; Leksa, Vladimir; Ohradanova-Repic, Anna; Machacek, Christian; Schatzlmaier, Philipp; Zlabinger, Gerhard J; Stockinger, Hannes

2016-02-01

The Ig superfamily member CD147 is upregulated following T cell activation and was shown to serve as a negative regulator of T cell proliferation. Thus, Abs targeting CD147 are being tested as new treatment strategies for cancer and autoimmune diseases. How CD147 mediates immunosuppression and whether association with other coreceptor complexes is needed have remained unknown. In the current study, we show that silencing of CD147 in human T cells increases IL-2 production without affecting the TCR proximal signaling components. We mapped the immunosuppressive moieties of CD147 to its transmembrane domain and Ig-like domain II. Using affinity purification combined with mass spectrometry, we determined the domain specificity of CD147 interaction partners and identified the calcium exporter plasma membrane calcium ATPase isoform 4 (PMCA4) as the interaction partner of the immunosuppressive moieties of CD147. CD147 does not control the proper membrane localization of PMCA4, but PMCA4 is essential for the CD147-dependent inhibition of IL-2 expression via a calcium-independent mechanism. In summary, our data show that CD147 interacts via its immunomodulatory domains with PMCA4 to bypass TCR proximal signaling and inhibit IL-2 expression. Copyright © 2016 by The American Association of Immunologists, Inc.

Resveratrol upregulates Egr-1 expression and activity involving extracellular signal-regulated protein kinase and ternary complex factors

Energy Technology Data Exchange (ETDEWEB)

Rössler, Oliver G.; Glatzel, Daniel; Thiel, Gerald, E-mail: gerald.thiel@uks.eu

2015-03-01

Many intracellular functions have been attributed to resveratrol, a polyphenolic phytoalexin found in grapes and in other plants. Here, we show that resveratrol induces the expression of the transcription factor Egr-1 in human embryonic kidney cells. Using a chromosomally embedded Egr-1-responsive reporter gene, we show that the Egr-1 activity was significantly elevated in resveratrol-treated cells, indicating that the newly synthesized Egr-1 protein was biologically active. Stimulus-transcription coupling leading to the resveratrol-induced upregulation of Egr-1 expression and activity requires the protein kinases Raf and extracellular signal-regulated protein kinase ERK, while MAP kinase phosphatase-1 functions as a nuclear shut-off device that interrupts the signaling cascade connecting resveratrol stimulation with enhanced Egr-1 expression. On the transcriptional level, Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, connects the intracellular signaling cascade elicited by resveratrol with transcription of the Egr-1 gene. These data were corroborated by the observation that stimulation of the cells with resveratrol increased the transcriptional activation potential of Elk-1. The SRE as well as the GC-rich DNA binding site of Egr-1 function as resveratrol-responsive elements. Thus, resveratrol regulates gene transcription via activation of the stimulus-regulated protein kinases Raf and ERK and the stimulus-responsive transcription factors TCF and Egr-1. - Highlights: • The plant polyphenol resveratrol upregulates Egr-1 expression and activity. • The stimulation of Egr-1 requires the protein kinases ERK and Raf. • Resveratrol treatment upregulates the transcriptional activation potential of Elk-1. • Resveratrol-induced stimulation of Egr-1 requires ternary complex factors. • Two distinct resveratrol-responsive elements were identified.

Resveratrol upregulates Egr-1 expression and activity involving extracellular signal-regulated protein kinase and ternary complex factors

International Nuclear Information System (INIS)

Rössler, Oliver G.; Glatzel, Daniel; Thiel, Gerald

2015-01-01

Many intracellular functions have been attributed to resveratrol, a polyphenolic phytoalexin found in grapes and in other plants. Here, we show that resveratrol induces the expression of the transcription factor Egr-1 in human embryonic kidney cells. Using a chromosomally embedded Egr-1-responsive reporter gene, we show that the Egr-1 activity was significantly elevated in resveratrol-treated cells, indicating that the newly synthesized Egr-1 protein was biologically active. Stimulus-transcription coupling leading to the resveratrol-induced upregulation of Egr-1 expression and activity requires the protein kinases Raf and extracellular signal-regulated protein kinase ERK, while MAP kinase phosphatase-1 functions as a nuclear shut-off device that interrupts the signaling cascade connecting resveratrol stimulation with enhanced Egr-1 expression. On the transcriptional level, Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, connects the intracellular signaling cascade elicited by resveratrol with transcription of the Egr-1 gene. These data were corroborated by the observation that stimulation of the cells with resveratrol increased the transcriptional activation potential of Elk-1. The SRE as well as the GC-rich DNA binding site of Egr-1 function as resveratrol-responsive elements. Thus, resveratrol regulates gene transcription via activation of the stimulus-regulated protein kinases Raf and ERK and the stimulus-responsive transcription factors TCF and Egr-1. - Highlights: • The plant polyphenol resveratrol upregulates Egr-1 expression and activity. • The stimulation of Egr-1 requires the protein kinases ERK and Raf. • Resveratrol treatment upregulates the transcriptional activation potential of Elk-1. • Resveratrol-induced stimulation of Egr-1 requires ternary complex factors. • Two distinct resveratrol-responsive elements were identified

The interaction between early life epilepsy and autistic-like behavioral consequences: a role for the mammalian target of rapamycin (mTOR pathway.

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Delia M Talos

Full Text Available Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1 signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46, phospho-p70S6K (Thr389 and phospho-S6 (Ser235/236, as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308 and phospho-ERK (Thr202/Tyr204. Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures.